Mapping Our Genes—Genome Projects:

How Big? How Fast?

April 1988

NTIS order #PB88-212402
Recommended Citation:

U.S. Congress, Office of Technology Assessment, Mapping Our Genes-The Genmne Projects.’

How Big, How Fast? OTA-BA-373 (Washington, DC: U.S. Government Printing Office, April

1988).

Library of Congress Catalog Card Number 87-619898

For sale by the Superintendent of Documents

U.S. Government Printing Office, Washington, DC 20402-9325

(order form can be found in the back of this report)
Foreword

For the past 2 years, scientific and technical journals in biology and medicine have

extensively covered a debate about whether and how to determine the function and

order of human genes on human chromosomes and when to determine the sequence

of molecular building blocks that comprise DNA in those chromosomes. In 1987, these

issues rose to become part of the public agenda. The debate involves science, technology, and politics. Congress is responsible for ‘(writing the rules” of what various Federal

agencies do and for funding their work. This report surveys the points made so far

in the debate, focusing on those that most directly influence the policy options facing

the U.S. Congress,

The House Committee on Energy and Commerce requested that OTA undertake

the project. The House Committee on Science, Space, and Technology, the Senate Committee on Labor and Human Resources, and the Senate Committee on Energy and Natural Resources also asked OTA to address specific points of concern to them. Congressional interest focused on several issues:

● how to assess the rationales for conducting human genome projects,

● how to fund human genome projects (at what level and through which mechanisms),

● how to coordinate the scientific and technical programs of the several Federal

agencies and private interests already supporting various genome projects, and

● how to strike a balance regarding the impact of genome projects on international

scientific cooperation and international economic competition in biotechnology.

OTA prepared this report with the assistance of several hundred experts throughout the world. Their help included interviews with OTA staff, comments on drafts of

the report, and sending information to OTA. We want to thank those reviewers and

many others who have contributed to making the report more accurate, balanced, and

useful.

This report is one of many OTA reports related to biotechnology and genetics. Recent reports on related topics are Technologies for Detecting Heritable Mutations in

Human Beings, New Developments in Biotechnology: 1) Ownership of Human Tissues

and Cells, Z) Public Perceptions of Biotechnology, 4) U.S. Investment in Biotechnology,

and Human Gene Therapy.

u JOHN H. GIBBONS

Director

.,, Ill
OTA Advisory Panel on Mapping the Human Genome

Kennedy

George F. Cahill, M.D.

LeRoy Walters, Ph.D., Chairman

Director, Center for Bioethics

Institute of Ethics, Georgetown University

Vice President for Scientific Training

and Development

Howard Hughes Medical Institute

Susan E. Cozzens, Ph.D.

Assistant Professor

Department of Science and Technology

Studies

Rensselaer Polytechnic Institute of Technology

Tamara J. Erickson, Ph.D.

Vice President

Health Industries

Arthur D. Little, Inc.

Joseph G. Gall, Ph.D.

Department of Embryology

Carnegie Institution of Washington

Walter B. Goad, Ph.D.

Theoretical Biology Group

Los Alamos National Laboratory

Leroy Hood, Ph.D., M.D.

Chairman

Division of Biology

California Institute of Technology

Horace Freeland Judson

Henry R. Luce Professor

The Writing Seminars

The Johns Hopkins University

William W. Lowrance, Ph.D.

Director, Life Sciences and Public Policy

Program

The Rockefeller University

Norman R. Pace, Ph.D.

Professor of Biology

Department of Biology

Inhiana University

Mark L. Pearson, Ph.D.

Director of Molecular Biology

E.I. du Pent de Nemours & Co.

George Rose, Ph.D.

Professor

Department of Biological Chemistry

Hershey Medical Center

Pennsylvania State University

Margery W. Shaw, M.D., J.D.

Professor of Health Law

University of Texas Health Science Center

Dieter Soil, Ph.D.

Professor

Department of Molecular Biophysics and

Biochemistry

Yale University

Nancy S. Wexler, Ph.D.

president

Hereditary Disease Foundation and

Associate Professor of Clinical

Neuropsychology

Departments of Neurology and Psychiatry

Columbia University

Raymond L. White, Ph.D.

Investigator

Howard Hughes Medical Institute, and

Professor

Department of Human Genetics

University of Utah School of Medicine

NOTE: OTA appreciates and is grateful for the valuable assistance and thoughtful critiques provided by the advisory panel

members. The panel does not, however, necessarily approve, disapprove, or endorse this report. OTA assumes full

responsibility for the report and the accuracy of its contents.
OTA Human Genome

Roger Herdman, Assistant

Project Staff

Director, OTA

Health and Life Sciences Division

Gretchen Kolsrud, Biological Applications Program Manager

Robert Mullan Cook-Deegan, Project Director

Patricia Hoben, Analyst

Jacqueline Courteau, Research Assistant

Gladys White, Analyst

David Guston, OTA Summer Intern

OTA Support Staff

Sharon K. Oatman, Admimistrative Assistant

Linda S. Rayford, Secretary/Word Processing Specialist

Barbara V. Ketchum, Clerical Assistant

Editor

Blair Burns Potter

Graphics

MedSciArtCo, Washington, DC

Contractors

(for list of topics and availability of reports See app. A)

Computer Horizons, Inc.

Theodore Friedmann, University of California, San Diego

Jonathan Glover, New College, Oxford University

Allen Hammond, Consultant, Washington, DC

John Heilbron, University of California, Berkeley, and

Daniel Kevles, California Institute of Technology

Horace Freeland Judson, The Johns Hopkins University

Marc Lappe, University of Illinois at Chicago

Steve Mount, Yale University

Teresa Myers, Consultant, Washington, DC

Richard Myers, University of California, San Francisco

Peter Newmark, London

Susan Rosenfeld, Science and the Law Committee, Association of the Bar of the City of New York

David Weatherall, Oxford University

Akihiro Yoshikawa, Berkeley Roundtable on the International Economy, University of California, Berkeley

OTA Staff Reviewem

L. Val Giddings Kathi Hanna Lisa Heinz

Kevin O’Connor Gary Ellis Mark Schaefer

v
Contents

Page

Chapter 1: Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Chapter 2: Technologies for Mapping DNA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Chapter 3: Applications to Research in Biology and Medicine. . . . . . . . . . . . . . . . . . . . . . , . . . . . .

Chapter 4: Social and Ethical Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Chapter 5: Agencies and Organizations in the United States . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3

21

55

79

93

Chapter 6: Organization of Projects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...115

Chapter 7: International Efforts. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .............133

Chapter 8: Technology Transfer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ., . . . . . . . . . . .165

Appendix A: Topics of OTA Contract Reports. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . , ....179

Appendix B: Participants in OTA Workshops . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..180

Appendix C: Estimated Costs of Human Genome Projects . . . . . . . . . . . . . . . . . . . . . ...........187

Appendix D: Databases, Repositories, and Informatics . . . . . . . . . . . . . . . . . . . . . . . ............189

Appendix E: Bibliometric Analysis of Human Genome Research . . . . . . . . . . . . . . . . . . . . . ......195

Appendix F: Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .............196

Appendix G: Glossary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..201

Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .............207
chapter 1

Summary
CONTENTS

Debates About Mapping the Human Genome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

The Focus of Genome Projects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Misplaced Controversy About “The Human Genome Project” . . . . . . . . . . . . . . . .

The Core Issue: Resource Allocation for Research Infrastructure . . . . . . . . . . . . .

Organization of This Report . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

The Role of Congress. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Options for Action by Congress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Appropriations to Federal Agencies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Access to Information and Materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Organization of Genome Projects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Technology Transfer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Questions for Congressional Oversight . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4

7

9

10

11

11

11

11

12

12

15

17

Figure

1-1. Comparative Scale of Mapping .

Table

1-1. Principal Organizations Involved

Page

. . . . . . . . . . . . . . ‘. . . . . . . . . . , . . . . . . . . . . , 5

Table

Page

in Genome Proiects . . . . . . . . . . . . . . . . . . . 7 L u ,
Chapter 1

Summary

“We want the maximum good per person; but what is good? To one person it is wilderness, to another it is ski lodges for thousands. To one it is estuaries to nourish ducks

for hunters to shoot at; to another it is factory land. Comparing one good with another

is, we usually say, impossible because goods are incommensurable. Incommensurable

cannot be compared.

Theoretically this may be true; but in real life, inconnnensurables are commensurable. All that is needed is a criterion of judgment and a system of weighing.”

Garret Hardin, “The Tragedy of the Commons, ”

Science 162:1243-1248, 1968.

“Congress is the place where we make impossible choices between apples and oranges.

We do it every year in preparing the largest budget on the planet.”

Congressional staff member, 1988.

“All legislative powers granted shall be vested in a Congress of the United States . . . .

No money shall be drawn from the Treasury, but in consequence of appropriations

made by law. . . .“

Article 1, U.S. Constitution.

The mysteries of inheritance are surrendering

to modern biology. Over a century ago, Austrian

monk Gregor Mendel demonstrated that the inheritance of traits could be most simply explained

if it were controlled by factors passed from one

generation to the next. These units of inheritance

came to be called genes. The complete set of genes

from an organism is called its genome. Some traits

are best explained by inheritance of single genes

(e.g., many genetic diseases, colorblindness), but

most, including many nongenetic diseases, involve

combinations of multiple genes with environmental factors.

Scientists discovered in the 1940s that genes consisted of DNA (deoxyribonucleic acid), and in the

1950s they further elucidated the mechanisms of

inheritance. In 1953, Watson and Crick described

the structure of DNA—the double helix—which

provides at once an explanation of how genetic

material is inherited and how genes direct cellular function. DNA encodes the blueprint for every

living thing; it is packed into chromosomes which

can be seen under a light microscope. The genome

of an organism can thus be defined as the DNA

comprising its chromosomes. Each human cell has

46 chromosomes in 23 pairs. One chromosome

of each pair is inherited from each parent. DNA

consists of long chains of chemicals called nucleo -

tide bases. There are four such bases, represented

most simply as A, C, T, and G. The order of bases

making up DNA is called its sequence. The DNA

sequence contains the instructions that specify

the production of molecules, usually proteins, that

provide cellular structure and perform biochemical functions in the cell.

Our understanding of genetics has advanced

remarkably in the last three decades as new methods of manipulating and analyzing DNA have been

developed. Recombinant DNA technology enables

scientists to insert DNA from one organism

directly into that of another, thereby allowing

them to study how genes function in relatively

controlled conditions. New methods to detect and

purify small amounts of DNA, new techniques to

handle and analyze DNA that is millions of bases

long, and novel scientific instruments have augmented the tools scientists use to understand

heredity. These powerful and rapidly evolving

technologies have provoked debate in recent years

about whether and how to mount a concerted

research program to map the human genome and

to determine its DNA sequence.

To date, the combined efforts of government

agencies, university researchers, and private sup3
4

porters of biomedical research have produced

rough but extremely useful maps of DNA markers covering most regions of the human chromosomes. Chromosomal locations of over 1,215

human genes are now known (of the 50,000 to

150,000 estimated to exist), including those causing all 20 of the most common genetic diseases.

Sequencing of DNA from human beings has increased sharply in recent years, yet far fewer than

I percent of the more than 3 billion bases comprising the human genome have been sequenced

(see figure l-l). The function of only a few hundred human genes is known. Some genetic disorders are understood at the molecular level (e.g.,

sickle cell disease and Tay-Sachs disease), but the

mechanisms underlying most genetic diseases remain unknown. Genetic factors underlying other

diseases are known only in barest outline.

The growing power and speed of research in

molecular biology have led to proposals to apply

novel molecular biological methods to the genetics

of entire organisms. Research and technology

efforts aimed at mapping and sequencing large

portions or entire genomes are called genome

projects. These proposals would build on experience already gained from mapping lower organisms (e.g., yeast, nematodes, and bacteria) and sequencing some virus genomes and regions of other

organisms, yet they would be more ambitious in

scale and complexity. More specifically, a public

debate began in 1985 about the feasibility of mapping, and perhaps sequencing, the human genome

and that of certain other organisms. The debate

has often been cast as an on-off decision about

whether there should be a concerted Federal effort, yet this is an oversimplification. There are

many component projects at different stages of

completion: Systematically making maps of human chromosomes is a continuation of ongoing

efforts, for example. Databases for genetic information and repositories for research materials are

essential whether or not there are other special

efforts. Developing new technologies is widely

agreed to be important and will require focused

research programs. The most contentious issue

is whether the DNA sequence of all human chromosomes should be determined. There is little

doubt that large regions of human chromosomes

will be sequenced eventually, but there is vigorous debate about whether a massive, concerted

sequencing effort is warranted. This remains an

open question that is likely to be resolved only

after pilot projects to determine the sequence of

other organisms, small human chromosomes, or

chromosomal regions of special interest have been

performed. Pilot projects can demonstrate the

technologies and should also determine whether

dedicated sequencing efforts are efficient and

scientifically sensible.

Two scientific advisory groups-one reporting

to the Department of Energy (DOE) and the other

convened by the National Research Council (NRC)

of the National Academy of Sciences—recommended augmented funding of $200 million per

year for genome projects. An Office of Technology Assessment (OTA) workshop attempted to estimate the costs of major component projects. Projections fell into the range of $45 to $50 million

per year initially, increasing to $200 to $250 million per year over 5 years. Funding recommendations made by the scientific advisory committees would cover most but not all costs estimated

by OTA.

DEBATES ABOUT MAPPING THE HUMAN GENOME

The debate about mapping the human genome genes, based on direct observation of chromocan be traced through several phases. Until the somes. In successful cases, the location of a gene

1960s, techniques for locating human genes were could be specified within several million bases of

rudimentary, and human genetics was based pri - DNA.

marily on analysis of inheritance patterns of diseases and other observable traits through family In the late 1970s and early 1980s, scientists took

trees. In the late 1960s and through the 1970s, the first steps toward maps of human chromoscientists developed the first maps of human somes based on direct biochemical analysis of
—

5

Figure 1-1 .—Comparative Scale of Mapping

UNTRY

OUNTY

CfiFIOMOSO

NUCLEOTIDE BASE PAIRS

The number of base pairs of DNA in human cells is roughly comparable to the number of people on Earth.

The scale of genetic mapping efforts can be compared to population maps, with chromosomes (50 to 250 million base pairs) analogous to nations, and genes (thousands to millions of base pairs) to towns.
...

6

DNA. DNA fragments of unknown function but

known location were used to study inheritance

of traits far more precisely than before. Calculations suggested that DNA markers, which signify

the presence or absence of particular stretches

of DNA, could be identified for regions of all the

human chromosomes.

Markers can be used to trace which pieces of

DNA, and therefore which parts of chromosomes,

are inherited from which parent. When a genetic

trait is caused by a single gene and that gene is

close to a marker, the marker can be used to ascertain roughly where the gene is located because

the two are inherited together.

The U.S. Government and research agencies

abroad fund most research that uses DNA markers to study diseases and physiological functions

and most university groups searching for new

markers in chromosomal regions of particular interest. In the United States, the National Institutes

of Health (NIH) are the largest funding sources

for biomedical research on genetics.

Construction of maps of DNA markers was

undertaken in the early 1980s, The two largest

collections of markers were developed by the

Howard Hughes Medical Institute (HHMI), a private philanthropy, and Collaborative Research,

Inc., a private corporation. Dozens of university

researchers and other private firms also contributed to this kind of genetic map.

In 1985, DOE began planning the Human Genome Initiative to develop research tools for

molecular genetics. Events leading up to the initiative included a workshop convened by the

University of California at Santa Cruz and internal planning by DOE administrators. DOE considered the initiative an extension of its ongoing

work in molecular biology-largely focused on detecting mutations and other biological effects of

radiation and energy production-that would take

advantage of research staff and instruments located at the national laboratories, which are

funded by DOE, DOE held several public meetings to discuss the technical possibilities. The first

of these was a workshop held in March 1986 in

Santa Fe, New Mexico.

Discussion at that workshop of whether to establish a reference sequence for the entire human

genome touched off a controversy that has persisted ever since. Arguments about the usefulness

of extensive sequence information reached a high

pitch at a conference at Cold Spring Harbor Laboratories in June 1986. Many scientists perceived

a major sequencing effort as a threat to the conduct of basic research in molecular biology because of its projected cost and potential drain on

research talent. Estimates of the cost of sequencing alone (without accounting for mapping or

preparation of DNA to be sequenced) ran to billions of dollars. Calls for central management of

such a prodigious undertaking further heightened

tension because of the strong tradition of decentralized, small-group research in molecular biology. Debate over the appropriate strategy for

deciding which regions to sequence first added

to the din and spilled over into the scientific press.

Major newspapers and magazines have covered

the debate since, giving the Human Genome Initiative a high public profile,

The Cold Spring Harbor discussion was followed

by a series of meetings held by HHMI, NIH, DOE,

NRC, OTA, and others, Plans for special research

initiatives by NIH, DOE, and HHMI have resulted

from these and other discussions. A few private

corporations have also been established (or are

being established) to perform DNA sequencing and

to develop research resources.

This report deals with various projects that have

been proposed by Federal agencies to construct

maps of human and other chromosomes, to improve relevant databases and repositories, and to

improve research methods and instruments.

There is no single human genome project, but

instead many projects. For 1988, there are specific line items in appropriations for DOE and NIH,

and the bulk of the discussion in this report refers

to these new research programs. For purposes

of this report, genome projects refers to the research programs of NIH, DOE, and HHMI, as

well as parallel programs in the private sector or other nations.
7

THE FOCUS OF GENOME PROJECTS

Genome projects have several objectives:

●

●

●

●

●

●

●

to establish, maintain, and enhance databases

containing information about DNA sequences,

location of DNA markers and genes, function

of identified genes, and other related information;

to create maps of human chromosomes consisting of DNA markers that would permit scientists to locate genes quickly;

to create repositories of research materials,

including ordered sets of DNA fragments that

fully represent DNA in the human chromosomes;

to develop new instruments for analyzing

DNA;

to develop new ways to analyze DNA, including biochemical and physical techniques and

computational methods;

to develop similar resources for other organisms that would facilitate biomedical research;

and possibly

to determine the DNA sequence of a large

fraction of the human genome and that of

other organisms.

Genome projects underway or planned by DOE,

NIH, the National Science Foundation (NSF), HHMI,

and other organizations are different but overlapping. They share two features: They would put

new methods and instruments into the tool kit

of molecular biology, and they would build a research infrastructure for geneticists (see table 1-1).

DOE’s Human Genome Initiative began in late

1986 and consists of several projects. One is to

create an ordered set of DNA segments from

known chromosomal locations; this set, if widely

available, could save the tedious steps involved

in isolating DNA for study once a gene’s approximate location is known. It should also reduce needless duplication of effort by different groups studying genes in the same chromosomal region. A

second project is to develop new computational

methods to enhance analysis of genetic map and

DNA sequence data. Another project is to develop

new techniques and instruments for detecting and

analyzing DNA, including automation and robotics. For these projects, DOE expended $4.2 million in 1987 and plans $12 million for 1988. It also

planned to support an additional $7 million in 1987

Table 1-1.—Principal Organizations Involved in Genome Projects

Organization Mission Funding ($OOO,OOOs)a

National Institutes of Health Biomedical research Life sciences: 6,170

(Department of Health Related research: 313

and Human Services) Genome projects: 17.2

NLM biotechnology databases: 3.83

Department of Energy Biological effects of Life sciences: 230

(Office of Health and energy production and Related research: 7

Environmental Research, radiation; use of national Genome projects: 12

Office of Energy Research) laboratory resources

National Science Foundation Basic scientific research Life sciences: 206

(Directorate of Biological, Related research: 32.7

Behavioral, and Social Sciences Genome projects: 0.2

Howard Hughes Medical Institute Biomedical research Life sciences: 240

Genetics: 40

Genetic marker maps: 2 to 4

Databases: 2

atlLife sciences” figureg are estimates for fiscal year 19w; these are total budgets for NIH and HHMI and estimates of relevant Pro9rams fOr NSF and DOE. Figures

for “related research” include basic research projects that Involve maPPin9 or sewencin9, and research infrastructure such as databases and repositories. “Related

research” figures are estimates for fiscal year 1987. “Genome Projects” figures are estimates for fiscal Year 1988, based on appropriations under the December 1987

continuing resolution.

SOURCES: NIH: Rachel Levinson, personal communications, October, November, December 1887, January 1888; DOE: David Smith, personal communications, June,

October 1987, January 1988; NSF: David Kingsbury, personal communications, June and November 1987; HHMI: George Cahill, personal communication,

January 1988.
8

for related research and infrastructure. DOE has

requested $18.5 million for direct support of its

Human Genome Initiative in fiscal year 1989.

NIH has supported special genome projects since

1987, with two objectives: to improve methods

for analyzing the genome of human beings and

other complex organisms and to enhance computational methods. NIH also supports most of the

relevant databases and repositories. It spent an

estimated $313 million on projects that involved

mapping and sequencing in 1987, and several million more on infrastructure. NIH plans somewhat

higher spending for related research in 1988 and

will have two items in its budget—an additional

$17.2 million for genome projects and $3.83 million for increased database support at the National

Library of Medicine. The fiscal year 1989 budget

request for the National Institute of General Medical Sciences of NIH includes $28 million for genome projects.

HHMI has two genome initiatives: one to support key databases containing information about

the genetics of human and other organisms, and

the other to support biomedical research on basic

genetic mechanisms and genetic disease. HHMI’s

budget estimates from 1987 included $40 million

for genetics (including $2 to $4 million for genetic

mapping) and $2 million to support genome

databases.

The NSF plans to increase the number of biology centers it supports, in order to develop new

scientific instrumentation and encourage sharing

of expensive equipment. These and other NSF programs are not genome projects per se, but they

are likely to be integrated with programs of other

agencies in some locations. Instrumentation developed through the biology centers will probably

be directly relevant to genome projects. NSF budget estimates for 1987 were $206 million for life

sciences, of which $32.7 million went to research

related to genome projects and $200,000 went

directly to genome projects.

Mechanisms for interagency coordination of genome projects have evolved over the past 2 years.

Initially, there was informal communication

among DOE, NIH, NSF, and HHMI. The Federal

agencies then formed a working group under the

Domestic Policy Council (DPC), a cabinet-level

group in the White House. A committee to replace

the DPC group is now being organized by the

White House Office of Science and Technology

Policy (OSTP), but its exact composition and function have not yet been determined.

International efforts are concentrated in developed nations with strong research traditions, Mapping genes, both human and nonhuman, has been

an international effort since its inception. International agreements for databases (particularly

those containing DNA sequence data) and collaborations on gene mapping (notably, the Center for

the Study of Human Polymorphism in Paris) have

been in operation for several years. No foreign

government has made a commitment yet to

mapping and sequencing the human genome,

although several governments support related

projects through their usual mechanisms of research funding. The United Kingdom has supported one of the pioneering efforts to map the

genome of a nonhuman organism and additional

work to develop new mapping and sequencing

technologies. Italy has the most specific commitment to the human genome: It funded several pilot projects (up to $1 million per year for 2 years)

to map and perhaps sequence at least one small

human chromosome, with the intent of increasing that budget five- to ten-fold if the projects are

promising. France, the Federal Republic of Germany, and other Western European nations have

substantial commitments to genetics research and

are also discussing international cooperation.

Canada’s medical research planning board is considering special efforts for genome projects. The

European Molecular Biology Laboratory and European Molecular Biology Organization have expressed interest in an international collaboration

to map and sequence the genomes of human and

nonhuman organisms.

Eastern European and Asian nations have expressed interest in using the resulting data, but

they have relatively limited programs for genetics

research. Australia is one possible exception; it

has consistently increased its share of publications

related to genetics over the last decade, and it

would logically be included in any international

planning. Japan is another exception. Its Science

and Technology Agency has expended $3.8 mil-
9

lion to support automation of DNA sequencing several million dollars to study the feasibility of

technologies, the Ministry of Education supports an expanded international effort called the Hua grants program in genetics, and the Ministry man Frontiers Science Program, which could inof International Trade and Industry has devoted elude genome research projects.

MISPLACED CONTROVERSY ABOUT

“THE HUMAN GENOME PROJECT”

Over the past several years, the debate about

genome projects has been vigorous–sometimes

acrimonious. Many articles have appeared in the

scientific press and the general press about “the

genome controversy.” The most conspicuous disagreements, however, have concentrated on issues that are not central to the conduct of genome

projects, Disputes among the executive agencies

have been played up, belying the generally close

cooperation among DOE, NIH, HHMI, private

firms, and other groups in conducting their

respective projects. International cooperation

among gene mappers and database managers has

been successful but has attracted little attention.

Private corporations are already involved in many

of the projects that are furthest along. One firm

has developed an extensive map of human genetic

markers, and others have developed instrumentation useful in research relevant to the mapping

and sequencing of DNA. These companies have

offered few complaints about barriers to technology transfer. Dissent has focused on the impor

tance of and strategy for sequencing DNA of

the entire genome, yet no agency has made a

commitment to massive sequencing. The current commitment is to develop technologies that

would make it faster and less costly and to improve databases to collect and disseminate the resulting information. DOE has expressed interest

in a concerted sequencing program, but only

when technological development reduces its cost

to tens of millions of dollars, in several years at

the earliest.

Some of the debate can be attributed to the title that has often been applied to genome projects

—the Human Genome Project. The term is a useful way to link research initiatives and to distinguish them from ongoing programs for budget

planning. It highlights the ultimate objective–

understanding human biology by developing a

new set of research resources—and captures political support and broad public interest. It has

had the effect, however, of generating rancorous

debate which has inhibited the development of

consensus on how to improve the research infrastructure. The importance of maps, databases, and

repositories has been obscured by the controversy

over massive DNA sequencing.

The title has had several other untoward effects.

The Human Genome Project centers attention exclusively on human genetics, but understanding

human genes will necessarily involve the

study of other organisms. Many of the resources—particularly maps of human chromosomes—will be focused on human beings; but to

interpret human genetic information, similar resources must be developed for other organisms.

New instruments and methods will be applicable

to all DNA.

The Human Genome Project invites confusion

by implying that the human genome will be understood when the project is over. The immediate goal of genome projects is not complete understanding, but creating tools to bring about such

understanding in the 21st century. Understanding encompasses all biomedical research; it does

not distinguish genome projects from others. The

most ambitious possible goal of genome projects

would be to complete the most detailed map: a

reference sequence of the entire human genome.

Even if this were agreed to and developed, it would

not yield immediate understanding of how that

DNA sequence is translated to make a human being. It would not explain how nerve cells become

connected in the immensely complex anatomy of

the brain. It would not even provide complete answers to how individuals differ or how they have

evolved. Sequence data, like other genetic information, is meaningful only when compared among

individuals and correlated with biological function.
10

There is no single, monolithic Human Genome

Project. In fact, there are several distinct components at various stages of development. Some instruments and many databases already exist; some

genetic maps are more than half complete; repositories for DNA used in research have only been

organized in the past few years; and other projects

are planned but not yet begun. Whether there

will ever be large and expensive research facilities for component specific genome projects is

an open question that can be answered only as

the technologies evolve.

The Human Genome Project conjures up images of largescale projects such as the Man=

hattan Project to build the first atomic bomb,

the Apollo Project for a manned Moon landing, the space station, or the superconducting

supercollider. Genome projects do not belong

in this category. Component genome projects

will not require budgets as large as such megaprojects, nor are the technical ends as focused.

Genome projects must be distinguished from the

sequencing of the entire human genome, which

is but a component still in the planning phase,

There will be no single event such as the Moon

landing or the space shuttle launching, nor is there

likely to be construction of a new multi-billiondollar facility such as the superconducting supercollider. Genome projects do not now require such

facilities. Some projects may require facilities to

perform services for mapping or sequencing in

the future, yet such facilities would not be larger

than the molecular biology centers already established at a few major research universities, Mapping or sequencing facilities would differ only by

being devoted to production work rather than

pure science. The results of genome projects are

not contingent on completion of large capitalintensive dedicated units, and the data and instruments will be integrated into biology and medicine as the projects progress. Genome projects are,

in this respect, analogous to navigational charts

or road maps, which are useful even as they are

being updated. Some persons believe a shortage

of trained scientific and technical personnel in the

United States could prove troublesome for molecular biology, but the genome projects proposed thus

far are not so large in scale, even in comparison

to other areas of biology, as to cause shortages

in other areas. Genome projects are relatively modest compared to other large science projects now

under consideration by the Federal Government,

THE CORE ISSUE: RESOURCE ALLOCATION FOR

RESEARCH INFRASTRUCTURE

Most issues that need to be addressed regarding genome projects are variations on the problem of the commons: how to create and maintain

resources of use to all. It can be difficult to develop goods useful to all if each individual has no

direct incentive to pay for them and only a few

are adversely affected.

The core issue concerning genome projects is

resource allocation. What priority should be given

to funding databases, materials repositories,

genetic map projects, and development of new

technologies? Should genome projects have precedence over other projects important to biological

and biomedical research? These projects will benefit the entire biomedical research community,

and ultimately the Nation and the world, but their

funding must be drawn from the same agencies

that support basic research. Funding for genome

projects will thus be taken from agencies that support research on neuroscience, cancer, immunology, and many other promising and rapidly moving fields.

The flow of information from molecular biology is overwhelming the resources devoted to handling it. Federal agencies, HHMI, and other interested groups are acting to manage the deluge.

Research dedicated to improving databases,

maps, repositories, and research methods

premises to increase efficiency overall by de

ing once systematically what would otherwise

be duplicated by many groups using more

primitive technologies. Whether massive, concerted DNA sequencing is similarly efficient can

only be demonstrated by trying it on a smaller

scale.
11

ORGANIZATION

The following sections describe options for congressional action, Subsequent chapters address

the issues raised here in greater detail. Chapter

2 provides technical background and explains how

genome projects might be conducted. Chapter 3

reviews how results might be used in biology and

medicine. Chapter 4 outlines some long-term social and ethical issues surrounding human genome

projects. Chapter 5 surveys agencies and organiOF THIS REPORT

zations in the United States actively supporting

human genome projects. Chapter 6 discusses how

genome projects might be organized among these

agencies and organizations. Chapter 7 briefly surveys activities in foreign countries, and chapter

8 presents issues involved in technology transfer,

Appendixes contain background on material used

to produce this report, databases, costs of projects,

and mapping and sequencing publications.

THE ROLE OF CONGRESS

Genome projects have come to the attention of

Congress for three reasons. First, they have become highly visible because of the extensive debate surrounding them. Second, they involve agencies in different executive departments; therefore,

mechanisms for coordinating them are less clear

than if they were all in a single department. Third,

results of genome projects will lead to new scientific and medical instruments for analysis of DNA,

development of new genetic tests for use in clinical diagnosis, and other products and services,

Techniques developed to analyze DNA will expedite biological research and will provide data and

technologies crucial to the development of many

new products. In this sense, genome projects

promise economic returns, although the form and

magnitude of them are not predictable. Genome

projects have thus been linked to international

competitiveness in biotechnology and its economic

implications for American commerce in coming

decades.

Congress has three roles regarding genome

projects:

1. annual appropriations to Federal agencies

funding the projects;

2. authorization of actions by executive agencies to setup formal coordinating structures

or of specific mandates of agencies; and

3. oversight of agencies’ conduct of their

projects.

OPTIONS FOR ACTION BY CONGRESS

Options for congressional action discussed here will set an upper limit on the size and number

build on the discussions above and those in chap- of projects that are federally supported; committees 4 through 6. Background material and de- merit by executive agencies, and their grantees

tails can be found in those chapters. and contractors, will determine the speed and

scope of projects within those limits.

Appropriations to Federal Agencies The critical judgment in appropriations is the

The pace of federally funded genome projects importance of the work to be supported relative

will be determined principally by the annual ap- to other research and activities supported by the

propriations set by Congress and by the execu- Federal Government. The two national scientific

tive agencies’ commitment to the projects, Al- groups that have written reports on genome

though agencies retain some authority to projects, a DOE advisory subcommittee and an

“reprogram” funds for activities that fall within NRC committee, have both recommended substantheir mandates, large efforts cannot be sustained tial additional funding for genome projects, evenwithout specific appropriations. Appropriations tually equaling $200 million per year. OTA inde-
12

pendently projected costs of genome projects at

a workshop and through subsequent interviews

and letters. Appendix B summarizes cost estimates,

including the history of those made by other

groups, and reviews the process OTA used to

make its estimates. The cost of funding all component projects was estimated as increasing from

$47 million the first year to $228 million the fifth

year. This would permit strengthening of databases and repositories, construction of several varieties of chromosomal maps, development of

many new technologies, and initiation of pilot

projects for DNA sequencing.

Access to Information and Materials

The information produced by genetics research

has swamped existing management systems. Materials to facilitate molecular genetic research have

also proliferated, straining the resources devoted

to making them widely available. These management problems will intensify as new technologies

further accelerate research. Several of the genome

projects are intended to systematically archive information, collect and store research materials,

and make information and materials widely available to the research community. Improving data=

base and repository services is imperative

whether or not other genome projects pm

ceed. If genetic mapping and sequencing initiatives are pursued, then databases and repositories

will be needed even more. Bills have been introduced to improve coordination of and access to

molecular biology databases through the National

Library of Medicine. Each major repository and

database has its own advisory panel of outside

scientists. NIH has appointed an internal committee to report on NIH-supported repositories. Two

international meetings were held in 1987 to discuss management of databases that contain DNA

sequence data. NIH and DOE cosponsored a meeting on databases and repositories in August 1987,

and appropriations to DOE and NIH have been

increased to support databases and repositories.

Congress has the options of maintaining current

funding levels or increasing funds for database

and repository services through the current system of agency planning and congressional oversight. Seeking recommendations from an advisory

committee on how to integrate the development

of databases and repositories with genome projects is an additional option.

Organization of Genome Projects

Congress could pass legislation to organize human genome projects—in fact, bills on organization have dominated discussion in Congress. There

are four principal choices: 1) to designate a single

agency to coordinate the projects, 2) to establish

an interagency task force, 3) to establish a national

consortium, or 4) to rely on congressional oversight of interagency agreement and consultation.

Establishing an interagency task force through

legislation or encouraging agencies to do so by

oversight are the least problematic choices. Designating a lead agency would be politically troublesome and would risk interruption of ongoing research programs atone or more agencies. Devising

a single national consortium to manage the many

diverse genome projects is likely.to prove impractical. See chapter 6 for a more detailed discussion

of these options.

Designate a Lead Agency

Congress could choose to designate a lead

agency to coordinate and provide principal funding for genome projects. The chief advantage of

a lead agency is accountability through clear authority. The purpose of focusing authority would

be to reduce duplication of effort, to enhance coordination, and to give Congress a single agency

on which to concentrate oversight. The chief disadvantage is that the difficult political process of

selecting a lead agency would delay progress and

diminish overall funding. If line item funding for

genome projects at the nonlead agency–NIH or

DOE—were eliminated, then agreement would

have to be reached to add funds for the lead

agency. This is a difficult process because it involves a completely different set of congressional

committees and subcommittees for each agency.

The choice of a lead agency would likely precipitate a protracted battle among agencies and congressional committees, which could only serve to

delay projects. Furthermore, activities of NIH,

DOE, NSF, HHMI, and other organizations are complementary rather than competitive and duplicative. Appointing a Iead agency could complicate
13

planning for the other agencies. As an alternative, each agency could take the lead in projects

best suited to its mandate and expertise. This

would result in a task force or consultative arrangement, discussed below, rather than a single

lead agency. Designating a lead agency would attempt to centralize authority, but it is not clear

that this would improve efficiency, communication, or coordination.

Designation of a lead agency for genome projects

could, paradoxically, diminish rather than enhance

accountability to Congress. This follows from the

organizational structure of congressional committees. Genome projects supported by NIH, DOE,

and NSF are authorized by several committees and

subcommittees in both the House of Representatives and the Senate. Currently, each committee

or subcommittee has independent authority to

oversee programs in agencies under its jurisdiction, and interest in human genome projects has

been high. Designating a lead agency would limit

most oversight responsibility to a single committee. Further, a lead agency could not fully centralize authority, because HHMI is a nongovernment organization. Picking a lead agency would

be politically difficult and is unlikely to occur unless there is strong evidence of the advantages

of centralized authority for Federal efforts. The

evidence to date is quite to the contrary: Agencies are communicating, sharing personnel, using

compatible peer review procedures, and jointly

funding projects in overlapping areas.

Designating a lead agency might eliminate pluralism in Federal funding of genome projects. An

investigator wishing to pursue a genome project

can now apply to NIH and DOE, or NIH and NSF

for funding (depending on the nature of the

project), If there were a single lead agency controlling genome projects, the choices would be

limited, diminishing the pluralistic funding that

has been a mainstay of American biology. If the

lead agency had only an administrative role and

did not provide the greatest amount of funds, then

there would be little point in calling it a lead

agency.

Congress sets independent budgets for NSF, NIH,

and DOE through different subcommittees in the

House and Senate appropriations committees.

With several subcommittees involved, projects

have alternative sources of support in Congress.

Designating a lead agency would reduce this flexibility. The danger of pluralism is that different

agencies will duplicate each other’s work, will fail

to cooperate, will fail to identify gaps in research,

or will receive uncoordinated or inappropriate

appropriations due to the absence of a clear authority structure. To date, such funding disarray

has failed to materialize. There are checks and

balances in the congressional budget process,

through the Office of Management and Budget

(OMB), and through the interagency consultation

group in OSTP.

Arguments for a centralized and highly organized effort would be stronger if genome projects

addressed a national health emergency, such as

AIDS or polio, or if they were aimed at a single

technical or scientific objective. But genome

projects are many and diverse. Focused responsibility may nonetheless become necessary for

some of them. Mapping, for example, might be

more efficiently done at production centers as

methods mature, and DNA sequencing might require dedicated facilities if the technology

demands high capital investment or central management, If dedicated service centers are established, administration by a single agency or formal interagency agreement would be necessary

to ensure standardization and efficiency. Such

services would only be components of overall ge -

nome projects, however; integration of the various projects would still be needed.

If genome projects were neglected or inconspicuous elements in agencies’ programs, then the advantages of central oversight through a single

agency would carry more weight. This has not

been the case. Genome projects have been given

high priority–first by DOE and more recently by

NIH—and there has been extensive media attention to agencies’ management of them. There is

thus little danger in the foreseeable future that

genome projects will receive insufficient attention

or that mismanagement will escape congressional

scrutiny.

The agency most affected by genome projects

will be the NIH. If Congress finds that the advantages of a lead agency outweigh the disadvantages,
14

then NIH is the natural choice for lead agency.

This is because biomedical research is NIH’s central mandate, whereas NSF’s and DOE’s research

programs include physical as well as life sciences.

NIH funds over 10 times more genetics research

than any other government or nongovernment

organization, and researchers funded by NIH are

the most numerous of the intended beneficiaries

of genome projects. Researchers supported by

DOE, NSF, and other organizations have important contributions to make, however, and some

projects fall outside the mainstream of research

supported by NIH. Genome projects that involve

expertise in physical science, engineering, and

other fields outside biomedical research would

benefit from participation in or leadership by NSF

or DOE. DOE in particular has vigorously promoted a Federal program to develop new technologies and to create sets of ordered DNA fragments. Some DOE-supported projects are logical

extensions of work at the national laboratories,

and DOE is the natural agency to conduct these.

If NIH were designated the lead agency, it would

be important to recognize and plan for the ongoing efforts of DOE.

Establish an Interagency Task Force

The chief advantage of an interagency task force

is that it builds on existing research programs and

planning efforts in different agencies and does

not require a single lead agency. A task force could

monitor all genome projects, government and nongovernment, obtain scientific advice, foster communication, and make recommendations to Congress and the appropriate agencies. Discussion at

an OTA workshop in August 1987 stressed that

agencies should have outside scientific advice and

that advice given to one agency should take into

account activities supported by other agencies.

No advisory body exists to carry out this task. The

chief disadvantage of a task force is that no one

agency is accountable for the conduct of genome

projects.

Creating a task force entails decisions about who

should be represented, how appointments are to

be made, and where the task force would be located administratively. Legislation could specify

that it represent government, academic, industrial, and other relevant expertise and could stipu -

late the terms of membership and the appointment process. The task force could be made part

of a government agency (making it in effect the

lead agency), administratively autonomous, or attached to an existing quasi-governmental institution such as the National Academy of Sciences.

Several bills to establish such coordination and

advisory groups have been introduced in the looth

Congress and are likely to be acted upon in 1988.

Create a National Consortium

A consortium would involve one or more agencies in concert with private partners to support

genome projects. The chief advantages of a consortium are administrative flexibility, possible

funding by private firms to reduce government

funding, and direct involvement of industrial

partners—which would presumably hasten technology transfer. Some potential disadvantages are

unclear lines of authority (caused by competing

needs of government and private partners) and

statements by the private sector that genome

projects should be funded exclusively by the Federal Government (e.g., a poll taken by the Industrial Biotechnology Association). Accountability

would be complicated in two respects. First, there

are many genome projects, and it is difficult to

imagine a single consortium that could oversee

them all. Second, the possible commingling of government and nongovernment funds could prove

troublesome. Consortia might nonetheless be

formed for specific tasks. Some genome projects

in technology development will undoubtedly be

of great interest to industry and might attract private funding. Such projects (e.g., developing automated DNA mapping instruments or DNA detection methods) are likely to be highly focused,

however, and organized at the local rather than

the national level. Accountability would not be

as diffuse for local consortia focused on specific

technical objectives as for a single national consortium with multiple objectives and dozens of

projects to manage.

The Technology Transfer Act of 1986 (Public

Law 99-502) grants government agencies authority to form consortia with private corporations

and provides guidelines for doing so. President

Reagan’s Executive Order 12591 (April 1987) further extends this authority and encourages fed-
15

erally owned laboratories to form consortia. Agencies thus have the requisite authority already. If

Congress finds terms of the 1986 bill inappropriate in some details—for example, regarding patent policies or royalty arrangements—then the

statute could be amended or special measures relating to genome projects could be added as

amendments to other bills.

One bill introduced early in the 100th Congress

would have established a national consortium specifically to manage genome projects, but the bill

has since been replaced by one that establishes

a new advisory body (covered above as a task

force). A national consortium is not the only, and

perhaps not the most effective, way to obtain industrial input for genome projects and to facilitate technology transfer. Alternatives are to encourage agencies to participate in the formation

of local consortia; to facilitate exchange of industrial and academic expertise through training exchange programs, symposiums, and other mechanisms; and to include industrial representation

on any national advisory groups.

Rely on Congressional Oversight

If Congress takes no explicit action, several outcomes are possible. Federal agencies could continue planning processes similar to those followed

in 1986 and 1987, consisting of informal communication and coordination through an interagency

group with members from NIH, DOE, NSF, OSTP,

OMB, and other agencies. To date, NIH, DOE, and

NSF have sought outside advice from various

standing advisory committees, a practice that has

resulted in conflicting recommendations. This

problem could be remedied without legislation:

The agencies could establish a single interagency

advisory committee of outside experts appointed

by the agencies or by a third party, such as the

National Academy of Sciences or a private philanthropy. The advisory committee could report to

the agencies directly.

A Committee on Life Sciences is forming in

OSTP. The interagency nature and conspicuousness of genome projects make them a natural topic

for this committee. OSTP is considering the creation of a special subcommittee on genome projects.

Whether OSTP’S efforts meet the objectives

desired by Congress will depend on effective coordination and an appropriate balance among government, university, industrial, philanthropic, legal, bioethical, and other representatives on the

subcommittee. If OSTP’S subcommittee is composed exclusively of government representatives,

then its primary function will be interagency communication. The main stumbling block to interagency planning to date has been conflicting advice from outside advisory bodies, not lack of

interagency communication. Pluralism in funding is usually a virtue, but making conflicting recommendations to different agencies is not. Any

national coordinating group should take a global

view of activities in all agencies and harmonize

the advice given them.

The chief advantage of relying solely on congressional oversight is that it requires no new legislation. One disadvantage is that interagency

agreement on appointments and operating

budgets for a coordinating body might prove difficult without a congressional mandate and might

not initially include an appropriate range of nongovernment experts. Another potential disadvantage is that initiatives undertaken by an administration in the absence of legislation could crumble

under the weight of later interagency disagreements or neglect by a subsequent administration.

Flexibility is beneficial if projects are short-lived,

but genome projects are not. Long-term stability

is essential to the efficient conduct of genome

projects because they will require sustained support over many years. Oversight of agency action

could nonetheless be all that is required. Deficiencies of a task force set up by agencies could later

be modified indirectly through congressional oversight or threat of legislation.

Technology Transfer

Congress appropriates funds to support scientific research for several reasons, the principal

one for biomedical research being to improve

health. Increasingly, however, biomedical research

is being regarded as a national investment, and

policies to facilitate economically fruitful applications of new knowledge are receiving attention

in Congress. The process of exploiting new knowl -
16

edge for practical purposes is called technolo~

transfer. Some persons favor increased funding

for genome projects because they believe the

projects will lead to marketable products (instruments, research materials) or will accelerate research in areas that will later yield marketable

products. Technology transfer can be improved

through patent policies, exchange of industrial and

academic personnel, symposiums for industrial

and academic scientists, formation of consortia

to develop specific technologies or services, and

engaging industry in planning genome projects.

Programs for exchanging personnel and sponsoring symposiums will fall to agencies through

normal policy paths and can be monitored by Congress. Consortium formation and industry representation on planning bodies have been discussed above. The remaining policy area is patent

and copyright law.

Patent policies of Federal agencies have changed

dramatically during the past decade. The Patent

and Trademark Amendments of 1980 (Public Law

96-517), as amended in 1984 (Public Law 98-620),

were devised to facilitate commercialization of federally sponsored research. President Reagan issued directives to Federal agencies in February

1983 and April 1987 to this same end. And Congress passed the Technology Transfer Act of 1986

(Public Law 99-502), which contains patent licensing and joint venture provisions with authority

to form consortia with private interests. These

patent policies, following outlines of policies pioneered by NIH and NSF in the late 1970s, encourage institutions receiving Federal grants or

contracts to patent products and processes resulting from federally funded work. A 1987 General

Accounting Office report judged that the policies

have increased patenting of research results.

Aside from a possible change regarding DOE

policies (see ch. 8), genome projects raise no new

questions of patent or copyright law. Genome

projects would be subject to the same statutes and

executive orders as other scientific efforts. There

is a clear role for congressional oversight, however, in ensuring that data are shared promptly

and fully.

In mid-1987, proposals to form private corporations to map and sequence the human genome

stirred a controversy. Scientists expressed concern that scientific exchange would be impeded

by such efforts and that information would be

sequestered through copyrights and patents. If

private corporations do form to develop map and

sequence data and research materials, they will

operate at private expense. If they are successful, scientists will have new information, services,

and materials available for a price. If they fail, scientists should be no worse off, unless the government fails to support work it would otherwise

have funded. To date, government agencies have

not dropped plans for genome projects because

of corporate efforts.

Corporate efforts need not entail restricted access to information, Corporations can provide

services not appropriately performed by laboratories conducting basic scientific research (e.g.,

mapping, sequencing, or database management).

Universities and large corporations can manage

research facilities, such as the national laboratories, under contract. Corporations could also

participate in consortia focused on specific technical objectives. Private firms could be given grants

to develop new methods under the Small Business Innovation Research program; they would

retain title to inventions, but they would have the

same obligation to share data and materials as

universities or other grantees. The essential point

is not whether a grantee or a contractor is a

university or corporation, but whether the research results will be widely shared.

It is essential to ensure timely exchange of data

and materials from federally sponsored projects.

Maps, databases, and repositories will be useful

only if they are accurate and complete; they will

be complete only if all participants make prompt

contributions. Inmost cases, patent requirements

should not substantially delay disclosure of data.

Many data will not be relevant to a patentable invention. When research results do include a patentable invention, advance planning for filing pat -

ent applications should minimize delays. The main

option for Congress in this area is to oversee the

conduct of genome projects. Changes in agency

policies for data exchange could be made if problems emerge.
17

Congress could also direct agencies to make it

easier for persons receiving Federal grants or contracts to understand patent policies in the United

States and abroad. At present, many of the published guidelines and regulations for NIH, DOE,

and NSF are out of date. Investigators contemplating genome projects will probably contact more

than one Federal agency for research support;

it would be helpful to have a document summarizing the practices of the different agencies. Such

a document could also explain the benefits of filing patents early and outline procedures for

patenting abroad.

Questions for Congressional

oversigh t

Congressional oversight will most often involve

an informal exchange among congressional staff,

executive agency personnel, and other interested

parties, Oversight can be a potent incentive for

cooperation among agencies and for good conduct of executive actions. Congress may wish to

hold hearings from time to time to address such

questions as: Are genome projects being efficient}

administered? Are agencies duplicating efforts on

genome projects? Are agencies communicating effectively? Are agencies ensuring that access to

shared data is relatively easy and fair? Are databases receiving the information they need to be

most useful (e.g., map and sequence data)? Are

commercial opportunities being exploited? Are

shared research resources being neglected? Are

issues of special interest to Congress, such as social and ethical implications of genome projects,

being adequately addressed? Do genome projects

supported by Federal agencies reflect national

needs and social priorities? Are foreign go/ern -

ments funding a proportionate share of genetics

research and the research infrastructure? Are foreign governments sharing data and materials to

the same degree as LT.S. agencies?
Chapter 2

Technologies for

Mapping DNA
CONTENTS

Page

Organization and Function of Genetic

Information . . . . . . . . . . . . . . . . . . . . . . . 21

What Is a Genome? . . . . . . . . . . . . . . . . . . 21

How Are Genomes Organized? . . . . . . . . . 21

What Is the Genetic Code? . . . . . . . . . . . . 21

How Big Is the Human Genome? . . . . . . . 24

How Does the Human Genome Compare

to Other Genomes?. . . . . . . . . . . . . . . . . 24

Why Does Hereditary Information

Change? . . . . . . . . . . . . . . . . . . . . . . . . . . 25

Genetic Linkage Maps . . . . . . . . . . . . . . . . . . 26

Linkage Maps of Restriction Fragment

Length Polymorphisms . . . . . . . . . . . . . 28

RFLP Mapping . . . . . . . . . . . . . . . . . . . . . . 28

When Is a Map of RFLP Markers

Complete? . . . . . . . . . . . . . . . . . . . . . . . . 29

Low-Resolution Physical Mapping

Technologies . . . . . . . . . . . . . . . . . . . . . . 30

Somatic Cell Hybridization . . . . . . . . . . . . 30

Chromosome Sorting . . . . . . . . . . . . . . . . . 31

Karyotyping . . . . . . . . . . . . . . . . . . . . . . . . 32

Chromosome Banding . . . . . . . . . . . . . . . . 33

In Situ Hybridization . . . . . . . . . . . . . . . . . 33

Other Methods for Mapping Genes . . . . . 34

High-Resolution Physical Mapping

Technologies . . . . . . . . . . . . . . . . . . . . . . 3S

Cloning Vectors as Mapping Tools . . . . . . 35

Physical Mapping of Restriction Enzyme

Sites . . . . . . . ... . . . . ....4.... 37

Physical Mapping of Nonhuman

Genomes . . . . . . . . . . . . . . . . . . . . . . . . . 41

Strategies for Physical Mapping of the

Human Genome . . . . . . . . . . . . . . . . . . . 43

DNA Sequencing Technologies . . . . . . . . . 44

Automation and Robotics in Mapping and

Sequencing . . . . . . . . . . . . . . . . . . . . . . . 46

Chapter 2 References . . . . . . . . . . . . . . . . . . 48

Figures u

Figure Page

2-1.

2-2.

2-3.

2-4.

2-5.

2-6.

2-7.

2-8.

The Structure of DNA . . . . . . . . . . . . . 22

Replication of DNA . . . . . . . . . . . . . . . . 22

Gene Expression . . . . . . . . . . . . . . . . . . 23

Number of Human Gene Loci

Identified From 1958 to 1987 . . . . . . . 24

Separation of Linked Genes by

Crossing Over of Chromosomes

During Meiosis . . . . . . . . . . . . . . . . . . . 26

Detection of Restriction Fragment

Length Polymorphisms Using

Radioactively Labeled DNA Probes. ., 29

Somatic Cell Hybridization . . . . . . . . . 31

Chromosome Purification by the

Flow Sorter . . . . . . . . . . . . . . . . . . . . . . 32

2-9. DNA Cloning in Plasmids. . . . . . . . . . . 36

2-10. Separation of Intact Yeast

Chromosomes by Pulsed Field

Gel Electrophoresis. . . . . . . . . . . . . . . . 38

2-11. Constructing a Library of Clones

Containing Overlapping

Chromosomal Fragments . . . . . . . . . . . 38

2-12. Making a Contig Map . . . . . . . . . . . . . . 39

2-13. DNA Sequencing by the Sanger

Method . . . . . . . . . . . . . . . . . . . . . . . . . 45

2-14. DNA Sequencing by the Maxam and

Gilbert Method . . . . . . . . . . . . . . . . . . . 46

2-15. Automated DNA Sequencing Using

Table

2-1.

2-2.

2-3.

Fluorescently Labeled DNA. ........................ 48

Tables

Page

The Genetic Code . . . . . . . . . . . . . . . . . 23

Haploid Amounts of DNA in Various

Organisms . . . . . . . . . . . . . . . . . . . . . . . 25

Amount of Genome Sequenced in

Several Well-Studied Organisms . . . . . 47
Chapter 2

Technologies for Mapping DNA

ORGANIZATION AND FUNCTION OF GENETIC INFORMATION

what Is a Genome?

The fundamental physical and functional unit

of heredity is the gene. Genetics is the study of

the patterns of inheritance of specific traits. The

chemical bearer of genetic information is deoxyribonucleic acid (DNA). The DNA of multicellular

organisms such as insects, animals, and human

beings is associated with protein in highly condensed microscopic bodies called chromosomes.

A single set, or haploid number, of chromosomes

is present in the egg and sperm cells of animals

and in the pollen cells of plants. All body cells,

or somatic cells, carry a double set, or diploid number, of chromosomes, one originating from each

parental set, The entire complement of genetic

material in the set of chromosomes of a particular organism is defined as its genome.

How Are Genomes organized?

Long before genetic material was identified as

DNA, maps of genes on chromosomes were constructed, and many of the details of transmission

of genes from generation to generation were elucidated [Judson, see app, A]. The gene for colorblindness, for example, was assigned to the human X chromosome in 1911 (80), about 40 years

before the discovery of the structure of DNA. In

fact, it has been known for nearly a century that

the genetic material:

● has a structure that is maintained in stable

form,

● is able to serve as a model for replicas of itself,

● has an information code that can be expressed, and

● is capable of change or variation.

Each of these features can be described in molecular terms based on the structure and function of

DNA.

To know how DNA controls cell function, and

ultimately the structure and function of an entire organism, it is necessary to understand its

structure. In multicellular organisms, DNA is generally found as two linear strands wrapped around

each other in the form of a double helix. A DNA

strand is a polymeric chain made of nucleotides,

each consisting of a nitrogenous base, a deoxyribose sugar, and a phosphate molecule (figure Z1). The arrangement of nucleotides along the DNA

backbone is called the DNA sequence. There are

four nucleotides used in DNA sequences: adenosine (A), guanosine (G), cytidine (C), and thymidine (T). The two strands of DNA in the helix are

held together by weak bonds between base pairs

of nucleotides. In nature, base pairs form only

between A’s and T’s and between G’s and C’s. The

size of a genome is generally given as its total

number of base pairs.

A full genome of DNA is regenerated each time

a cell undergoes division to yield two daughter

cells. During cell division, the DNA double helix

unwinds, the weak bonds between base pairs

break, and the DNA strands separate. Free nucleo -

tides are then matched up with their complementary bases on each of the separated chains, and

two new complementary chains are made (figure

2-2). In human and other higher organisms, DNA

replication occurs in the nucleus of the cell. This

DNA replication process was first proposed in

1953 by Francis H.C. Crick and James D. Watson

(19,73,74).

What Is the Genetic Code?

Most genes carry an information code that specifies how to build proteins. Proteins are an essential class of large molecules that function in the

formation and repair of an organism’s cells and

tissues. Proteins can be components of essential

structures within cells, or they can carry out more

active roles in the overall function of a particular

cell type. Included in this important class of

molecules are hormones such as insulin, antibodies to fight cellular infections, and receptors on

the cell’s surface for modulating interactions be21
tween a particular tissue and its surroundings (68).

Enzymes are a specialized group of proteins that

Figure 2-1 .—The Structure of DNA

Phosphate Molecule

/ Deoxyribose

/ /

Sugar Molecule

Nitrogenous

0

,

increase the rate of the biochemical processes that

take place in metabolism.

Proteins are long chains of smaller molecules,

called amino acids, that fold into the unique structures necessary for protein function. The information for generating proteins of specific amino

When DNA replicates, the original strands unwind and sewe

as templates for the building of new, complementary strands.

The daughter molecules are exact copies of the parent, each

daughter having one of the parent strands.

SOURCE: Office of Technology Assessment, 1988.
23

acid sequences is found in the genetic code-a code ribonucleic acid (mRNA). The structure of

based on sequences of nucleotides that are “read” ribonucleic acid (RNA) is very similar to that of

in groups of three (table 2-I). Genetic informa- DNA. Figure 2-3 illustrates the major steps in gene

tion is transmitted from DNA sequences to pro- expressi’on, namely:

tein via another large molecule called messenger

Table 2.1.—The Genetic Code

Codon Amino Acid I Codon Amino Acid

Uuu Phenylalanine Ucu Serine

Uuc Phenylalanme Ucc Serine

UUA Leucine UCA Serine

UUG Leucme UCG Serine

Cuu Leucme Ccu Proline

Cuc Leucine ccc Proline

CUA Leucine CCA Proline

CUG Leucme CCG Proline

AUU Isoleucine ACU Threonine

AUC Isoleucine ACC Threonine

AUA Isoleucine ACA Threonme

AUG Methionine ACG Threonine

(start)

GUU Valine GCU Valine

GUC Valine GCC Alanine

GUA Valine GCA Alanine

GUG Valine GCG Alanine

Codon Amino Acid

UAU Tyrosine

UAC Tyrosine

UAA stop

UAG stop

CAU Histidine

CAC Histidine

CM Glutamine

CAG Glutamine

MU Asparagine MC Asparagine

AAA Lysine

AAG Lysine

GAU Aspartic acid

GAC Aspartic acid

GAA Glutamic acid

GAG Glutamic acid

Codon Amino Acid

UGU Cysteine

UGC Cysteine

UGA stop

UGG Tryptophan

CGU Arginine

CGC Arginine

CGA Arginine

CGG Ar~inine

AGU Serine

AGC Serine

AGA Arginine

AGG Arginine

GGU Glycine

GGC Glycine

GGA Glycine

GGG Glycine

SOURCES: Office of Technology Assessment and National Institute of General Medical Sciences, 198S.

Figure 2“3.—Gene Expression

Each codon, or triplet of nucleotides in

RNA, codes for an amino acid. Twenty

different amino acids are produced from

a total of 64 different RNA codons, but

some amino acids are specified by more

than one codon (e.g., phenylalanine is

specified by UUU and by UUC). In addition,

one codon (AUG) specifies the start of a

protein, and three codons (UAA, UAG, and

UGA) specify the termination of a protein.

Mutations in the nucleotide sequence can

change the resulting protein structure if

the mutation alters the amino acid specified by a codon or if it alters the reading

frame by deleting or adding a nucleotide.

U=uracil (thymine) A =adenine

C=cytosine G =guanine

I CYTOPLASM

In the first step of gene expression, messenger RNA (mRNA) is synthesized, or transcribed, from genes by a process somewhat

similar to DNA replication. In higher organisms, this process takes place in the nucleus of a cell. In response to certain signals

(e.g., association with a particular protein), sequences of DNA adjacent to, or sometimes within, genes control the synthesis

of mRNA. Protein synthesis, or translation, is the second major step in gene expression. Messenger RNA molecules are known

as such because t hey carry messages specif ic to each of t he 20 different amino acids that make UP proteins. Once synthesized,

mRNAs leave the nucleus of the cell and go to another cellular compartment, the cytoplasm, where their messages are t ranslated into the chains of amino acids that make up proteins. A single amino acid is coded by a sequence of three nucleotides

in the mRNA, called a codon. The main component of the translation machinery is the ribosome—a structure composed of

proteins and another class of RNAs, ribosomal RNAs. The ribosome reads the genetic code of the mRNA, while a third kind

of RNA molecule, transfer RNA (tRNA), mediates protein synthesis by bringing amino acids to the ribosome for attachment

to the growing amino acid chain. Transfer RNAs have three nucleotide bases that are complementary to the codons in the

mRNA (see table 2-l).

SOURCE: Office of Technology Assessment, 1988.
— —

24

● transcription of DNA into mRNA, and

● translation of mRNA into protein.

By these processes, the genetic code directs amino

acids to be joined together in the order specified

by the sequence of nucleotides in the messenger

RNA, which was in turn determined by the sequence of nucleotides in the DNA.

In molecular terms, a gene is a region of a

chromosome whose DNA sequence can be

transcribed to produce a biologically active

RNA molecule. Messenger RNAs constitute the

major class of biologically active RNAs. Other RNAs

may act as lattices to stabilize certain cell structures or may participate directly in important cellular processes such as protein synthesis.

How Big Is the Human Genome?

The diploid human genome consists of 46 chromosomes—22 pairs of autosomes and 1 pair of

sex chromosomes (two X chromosomes for females and an X and a Y chromosome for males).

A single egg cell has 22 different autosomes and

a single X chromosome, whereas sperm cells carry

22 different autosomes and either an X or a Y chromosome.

Scientists estimate the total number of human

genes per haploid genome at 50,000 to 100,000.

The characterization of the structure of human

genes on chromosomes was made possible recently through recombinant DNA technology (the

use of molecular biology tools to combine DNA

from one organism with that of another). It is now

known that human genes can vary in size from

fewer than 10)000 base pairs to more than 2 million. The entire haploid genome is approximately

3 billion base pairs, So far, researchers are far

from having determined where each human gene

is located on the 24 chromosomes. Victor McKusick of The Johns Hopkins University maintains

Mendelian Inheritance in Man, an encyclopedia

of expressed genes [see app. D]. According to the

October 1, 1987, count, 4,257 genes were represented in the encyclopedia; of those, at least 1)200

had been mapped to specific chromosomes or regions of chromosomes (51). Figure 2-4 illustrates

the years of effort invested thus far in identifying even this small fraction of the total number

of human genes.

How Does the Human Genome

Compare to Other Genomes?

Before much was known about the DNA sequences that make up genomes, it was thought

that the amount of DNA per haploid genome

would increase in proportion to the biological complexity of the organism. Since chromosomes can

vary in size, the total amount of DNA in a haploid

cell is a better indicator of actual genome size than

the number of chromosomes. Table 2-2 shows that

higher plants and animals do have much more

DNA than lower organisms, There are some notable exceptions, however, to the correlation between overall genome size and complexity of the

organism, A good example is the salamander,

which has a haploid DNA content more than 30

times greater than that of humans, even though

it is obviously a smaller, less complex organism.

Similarly, the cells of some species of plants have

a greater DNA content than human cells (72).

This inconsistency between DNA content and

the apparent complexity of an organism is known

to geneticists as the C-va.lueparadox (C-value refers

to the haploid genome size). A great deal of research has been devoted to determining the scientific basis for the C-value paradox. Variations

Figure 2-4.–Number of Human Gene Loci Identified

1958

1966

1968

1971

1975

1978

1983

1986

1987

From 1958 to 1987

I I 1 1 1

0 1000 2000 3000 4000 5000

SOURCE: Victor McKusick, The Johns Hopkins University Medical School, Baltimore, MD.
25

Table 2-2.—Haploid Amounts of DNA in

Various Organisms

Organism Number of base pairs

(millions)

Bacterium. . . . . . . . . . . . . . . . . . . . . .

Yeast. ... , . . . . . . . . . . . . . . . . . . . . .

Nematode . . . . . . . . . . . . . . . . . . . . . .

Fruit fly. . . . . . . . . . . . . . . . . . . . . . . .

Chicken . . . . . . . . . . . . . . . . . . . . . . .

Human . . . . . . . . . . . . . . . . . . . . . . . .

Mouse . . . . . . . . . . . . . . . . . . . . . . . . .

Corn . . . . . . . . . . . . . . . . . . . . . . . . . .

Salamander . . . . . . . . . . . . . . . . . . . .

Lilv . . . . . . . . . . . . . . . . . . . . . . . . . . .

4.7

15

80

155

1,000

2,800

3,000

15,000

90,000

90,000

SOURCES:

B. Alberts, D.Bray, J. Lewis, et al., Mo/ecu/arBio/ogy of fhe Ce//(NewYork, NY:

Garland Publishing, 1983)

C. Burks,GenBank”, LosAlamosNational Laboratory, Los Alamos, NM,personal

communication, March 1988.

T. Cavalier-Smith (cd), The Evo/utionof Genorne Size (New York, NY: Wiley&

Sons, 1985)

J. Darnell, H. Lodish, and D. Baltimore, Molecular Cc// Biology (New York, NY:

Scientific American, 1988),

in genome size usually arise from increases in the

amount of DNA per chromosome, not from increases in numbers of chromosomes. The genomes of all higher organisms contain sequences

of DNA that occur as large numbers of repeated

units, either clustered in one chromosomal region

or in regions dispersed throughout the entire genome. These repeated sequences contribute to

wide variations in total DNA content among what

are often closely related species.

In large genomes such as the human genome,

intron sequences also contribute to size. Introns

are DNA sequences occurring within the coding

region of a gene. They are transcribed into mRNA,

but are cut (spliced) out of the message before

it is translated into protein. Introns can increase

the number of base pairs in a gene by more than

tenfold. Many genes also have long regions at their

ends that are transcribed into mRNA but are not

translated into protein. In addition, some proteincoding genes have given rise to gene families that

make several closely related protein products.

Other gene families consist of hundreds or thousands of closely related genes (72).

The untranslated sequences within or at the

ends of genes, gene families, and moderately or

frequently repeated DNA sequences between

genes still do not account for all of the DNA in

the genomes of higher organisms, nor for the variations in genome size among these organisms.

Many scientists interpret these facts to mean that

some fraction of DNA in the human genome is

expendable; although there is little agreement on

the size of this fraction, some believe it to be more

than 90 percent of the genome (27,54). The implication of the C-value paradox, that much of human DNA is expendable, is one reason that some

esteemed scientists do not favor a major effort

to obtain a complete nucleotide sequence of the

human genome. They believe time would be better spent identifying and understanding the function of gene products that contribute to the cellular processes leading to the development of an

organism as complex as man (l). On the other

hand, some scientists consider the C-value paradox to be one of the many mysteries that might

be unraveled once entire genomes have been analyzed in greater detail.

Why Does Hereditary Information

Change?

Hereditary variation is the result of changes

occurring by mutation —a change in the sequence

or number of nucleotides—which occurs during

DNA replication. Mutations formed in sex cells

are inherited by offspring, whereas those that oc -

cur in somatic cells remain only in the affected

organism. Some diseases, such as certain human

cancers, arise from factors in both of these categories. Mutations are also acquired by artificial

means, such as exposure to chemicals or certain

forms of radiation.1 Such factors can cause a

change in a single DNA base pair that may modify or inactivate a protein, if one is encoded in

that region of the chromosome.

More extreme mutations, involving changes in

the structure of a single chromosome or changes

in chromosome number, can occur; for example:

● deletion of a chromosome,

● duplication of a chromosome or a piece of

a chromosome,

1A 1986 OTA report, Technologies for Detecting Heritable Mutations in Human Beings, addresses the kinds and effects of mutations in human beings and new technologies for detecting mutations and measuring mutation rates.
26

Figure 2-5.—Separation of Linked Genes by Crossing

Over of Chromosomes During Meiosis

● translocation, or insertion of a chromosome

fragment from one chromosome pair into an

unmatched member of a different pair, and

. inversion, or the breakage of a chromosome

fragment followed by its rejoining in the opposite orientation.

In diploid cells, there is a tendency for each DNA

molecule to undergo some form of modification

or rearrangement with each cell division. The progenitors of sex cells area special class of diploid

cells that undergo two rounds of cell duplication

in a process called meiosis. Meiosis results in four

instead of two daughter cells, each with a haploid

set of chromosomes. Before the first meiotic cell

division, each member of a chromosome pair is

replicated, forming two sets of chromosome pairs.

At this stage, the cell has two identical copies of

chromosomes of maternal origin and two identical copies of chromosomes of paternal origin. Also

at this time, the chromosome pair of maternal origin is in close association with that of paternal

origin, and an event called crossing over can occur; that is, one maternal and one paternal chromosome can break, exchange corresponding sections of DNA, and then rejoin (figure 2-5). (This

process is also referred to as recombination.) In

this way, two of the four resulting sex cells have

chromosomes with new combinations of genes,

while the other two cells carry the parental (original) combinations of genes. Since chromosomes

originating maternally or paternally can carry

different forms of any given gene, new combinations of traits are created by such crossovers.

GENETIC LINKAGE

Because of recombination during meiosis, cer- others,

tain groups of traits originating on one chromo- can be

some are not always inherited together (figure

MAPS

so only genes on the same chromosome

linked.

2-5). The closer, or more linked, genes are on a Gene mapping, broadly defined, is the asparticular chromosome, the smaller the probabil- signment of genes to chromosomes. A genetic

ity that they will be separated during meiosis. Each linkage map permits investigators to ascertain

chromosome is inherited independently of all one genetic locus relative to another on the ba-
. —

27

sis of how often they are inherited together.

Strictly speaking, a genetic locus is an identifiable region, or marker, on a chromosome. The

marker can bean expressed region of DNA (a gene)

or some segment of DNA that has no known coding function but whose pattern of inheritance can

be determined, Variation at genetic loci is essential to genetic linkage mapping, The markers that

serve to identify chromosome locations must

vary in order to be useful for linkage studies

in families, because only when the parents

have different forms at the marker locus can

linkage to a gene be followed in their children.

Alleles are the alternative forms of a particular

genetic locus. For example, at the locus for eye

color, there are blue and brown alleles. During

meiosis, all of the genetic loci on a chromosome

remain together unless they are separated by

crossing over between chromosome pairs.

Distance on genetic maps is measured by how

often a particular genetic locus is inherited

separately from some marker. This measure of

genetic distance is called recombination frequency. The amount of recombination is expressed in units called centimorgans. One centimorgan is equal to a 1 percent chance of a genetic

locus being separated from a marker due to recombination in a single generation.

During the generation of sex cells in human beings, if a gene and a DNA marker are separated

by recombination in 1 percent of the cases studied, then they are, on average, separated by 1 million base pairs. The relationship between genetic

map distance (recombination frequencies) and

physical map distance (measured in DNA base

pairs) can vary, however, by five-or even tenfold.

Recombination can vary from near zero, if genetic

loci are very close, to 50 percent, between genetic

loci that are far apart on the chromosome or on

different chromosomes. Some chromosome regions are highly prone to recombination and exhibit high recombination frequencies, while other

chromosome regions appear to be resistant to

recombination. Interestingly, the rate of recombination in the same region of a particular chromosome typically varies among males and females,

and it is often greater in females. The reasons for

this have not been established. Double or multiple crossover events can also occur between two

loci that are widely separated. Each of these variations in recombination frequencies complicates

the relationship between genetic and physical

maps. Nevertheless, if a genetic linkage map were

constructed with a set of markers separated by

an average of 1 centimorgan, then most genes

could be located within a range of 100)000 to 10

million base pairs.

Genetic linkage between two or more observable traits can be established with greater certainty

in large populations. For this reason, large families are preferred for mapping studies. If two

genetic loci are closely linked, then their separation by recombination during meiosis is unlikely

and a large family must be studied to determine

how close they are on the genetic map. As more

loci are placed on the genetic map, it becomes possible to determine the location of a new trait on

the basis of its inheritance pattern compared to

two or three others already on the map. The frequency with which multiple traits are inherited

together generally must be calculated for many

individuals over many generations before genetic

mapping results are statistically significant.

The X chromosome is particularly amenable to

linkage analysis because male traits directly reflect the genes on the single X chromosome

present. For this reason, the genetic linkage map

of the X chromosome is the most nearly complete

of all chromosome maps.

Mapping of genetic loci on autosomes, on the

other hand, is not as easy, unless the gene is found

to be linked to a marker that has already been

mapped through the study of family inheritance

patterns. The first assignment of a gene to a specific autosomal chromosome came in 1968, when

researchers showed that the Duffy blood group,

which can be identified in families by biochemical methods, is linked to a variation in chromosome 1 (23). About the same time, the feasibility

of correlating specific genes with particular chromosomes or chromosome regions by a technology called somatic cell hybridization was demonstrated (75). This and other experimental methods

developed in the 1970s radically advanced the

study of human genetics, allowing investigators

to locate autosomal genes on human genetic and

physical maps [Judson, see app. Al (50,58).
28

LINKAGE MAPS OF RESTRICTION FRAGMENT

LENGTH POLYMORPHISMS

The advent of recombinant DNA technology in

the 1970s brought about a tremendously useful

new way to create genetic linkage maps. Examination of DNA from any two individuals reveals

that variations in DNA sequence occur at random

about once in every 300 to 500 base pairs (37).

These variations occur both within and outside

of genes, and most do not lead to functional

changes in the protein products of genes. Kan and

DOZY (40) were the first to demonstrate this phenomenon experimentally, by showing that one particular DNA sequence, recognized by the restriction enzyme HpaI, was lost in certain individuals.

(Restriction enzymes are proteins that recognize

specific, short nucleotide sequences and cut the

DNA at those sites.) This alteration in the DNA

correlated with the inheritance of sickle cell

disease.

This important discovery led researchers to propose that natural differences in DNA sequence

(pol’orphisms) might replace other chemical and

morphological markers as a way to track chromosomes through a family (5,64). In addition to

polymorphisms in restriction enzyme cutting sites,

it is possible to detect differences among individuals in the number of copies of short DNA sequences repeated in tandem. Polymorphic sequences can occur within a restriction enzyme

cutting site or between sites. In either case, the

lengths of DNA fragments generated upon cutting the DNA with restriction enzymes will vary

among individuals having different alleles at such

locations. These polymorphic sequences are thus

commonly referred to as restriction fragment

length polymorphism (RFLP) markers.

In 1983, genetic linkage between a RFLP marker

on chromosome 4 and Huntington’s disease (a neurological disease that usually strikes its victims by

the age of 35) was discovered (31), paving the way

for the general use of RFLPs as markers for genes

responsible for inherited disorders. The more frequently a RFLP marker is inherited with the gene,

the more likely it is to be physically close to the

gene, and hence the more useful it is as a gene

marker. The major limitations to the usefulness

of RFLP markers are how polymorphic they are

(hOW much they vary among individuals), how

many other markers exist in the same region, and

the extent to which DNA samples of large families are available for analysis (43,44).

RFLP Mapping

A RFLP map is a type of genetic linkage map,

consisting of markers distributed throughout the

genome. Construction of the map involves determining the linkages between RFLP markers, their

arrangement along the chromosomes, and the

genetic distances between them. RFLP markers

are identified and mapped by comparing the sizes

and numbers of restriction enzyme fragments

generated from different individuals. Just as

genetic loci representing expressed DNA segments

have alternate, or allelic, forms, so may RFLPs.

The value of any marker depends mostly on how

many variants it displays. The more often the

marker varies in a population, the more likely it

is that an individual will inherit two different

alleles at the marker location (one on each member of a matched pair of chromosomes), making

it possible to detect recombination between markers in that individual’s offspring (76).

In RFLP mapping, DNA obtained from white

blood cells (lymphocytes) or other tissues of several different individuals are first cut into fragments using restriction enzymes (figure 2-6). The

fragments are then separated by size. This is accomplished by a procedure called electrophoresis, in which a mixture of DNA fragments of various sizes is placed in a polymeric gel (e.g., agarose)

and then exposed to an electric field. Because the

chemical makeup of DNA gives it a net negative

charge, the DNA fragments will travel in an electric field toward a positive electrode. Large DNA

fragments will move more slowly than small ones,

thus the mixture is separated, or resolved, according to size. With very large pieces of DNA, the

use of restriction enzymes yields numerous fragments along the entire length of the gel, making

it necessary to identify RFLPs using radioactively

labeled, single-strand segments of DNA called DNA

probes (65). RFLP markers are identified by vir-
29

tue of their ability to form base pairs (hybridize)

with DNA probes that have complementary sequences of nucleotides. Some useful probes for

Figure 2-6.—Detection of Restriction Fragment Length

Polymorphisms Using Radioactively Labeled

DNA Probes

Genomic DNA From Three Blood Samples

A B c

+

Expose on X-Ray Film

For Autoradiography

Film

Variations in DNA sequences at particular marker sites are

observed as differences in numbers and sizes of DNA fragments among samples taken from different individuals (shown

here as samples A, B, and C).

SOURCE: Off Ice of Technology Assessment, 1988,

RFLP mapping are fragments of genes; others are

randomly isolated DNA segments that identify

polymorphisms; still others are complementary

to sequences with variable numbers of tandemly

repeated, shorter sequences that occur frequently

within the genome. A technique called autoradiography is used to show the image of a band on

an X-ray film wherever the agarose gel held a restriction enzyme fragment that hybridized to the

DNA probe. Where polymorphisms occur, different patterns will be observed among samples taken

from different individuals [Myers, see app. A] (figure 2-6).

When Is a Map of RFLP Markers

Complete?

Botstein and co-workers (5) predicted in 1980

that only 150 different markers would be needed

to link all human genes to chromosomal regions

containing RFLPs. In practice, however, it has been

estimated that many more markers may have to

be studied and evaluated in order to find the minimum number which would be randomly distributed over the genome (45). It now appears that

hundreds of DNA probes for highly polymorphic

sequences, scattered widely over the genome, will

be required for a complete human linkage map

(77).

With a l0-centimorgan map, for example, there

is a greater than 90 percent chance of being able

to determine the rough chromosomal location of

any gene associated with an inherited disease. Raymond White and colleagues at the Howard Hughes

Medical Institute at the University of Utah have

taken advantage of one such tandemly repeated

sequence, known as VNTR, to create a set of

probes useful for making a complete RFLP map

of the human genome (76). White’s RFLP map, with

continuously linked landmarks separated on average by 10 centimorgans (about 10 to 20 million

base pairs), is nearly complete. At the ninth international Human Gene Mapping Workshop, held

in September 1987, he reported 475 markers covering 17 human chromosomes, based on the DNA

from 59 different three-generation families.

White’s group and other geneticists believe that

a l-centimorgan RFLP marker map, determined

from normal families and consisting of thousands

of markers spaced an average of 1 million base
30

pairs apart, would be the ideal research tool (see

ch. 3 for further discussion) (17,52).

Another group, led by Helen Donis-Keller at Collaborative Research, Inc. (Waltham, MA), reported

its own RFLP linkage map, consisting of 403 markers an average of 9 centimorgans apart. A new

gene or marker on their map can be located relative to the existing markers 95 percent of the time

(24).

As physical markers that can be followed ge

netically, RFLPs are the key to linking the

genetic and physical maps of the human ge

nome. RFLP linkage maps, as well as linkage maps

of expressed genes, can be correlated with banding patterns and other identifiable regions of chromosomes by somatic cell hybridization and in situ

hybridization. These and other relatively low resolution physical mapping technologies are described in the following sections.

LOW-RESOLUTION PHYSICAL MAPPING TECHNOLOGIES

A physical map is a representation of the locations of identifiable landmarks on DNA. For the

human genome, the physical map of lowest resolution is found in the banding patterns on the 22

autosomes and the X and Y chromosomes observable under the light microscope. This map has at

most 1,000 landmarks (i.e., visible bands) (57).

Another type of relatively low resolution physical map illustrates the positions of expressed segments of DNA relative to certain regions of the

chromosome or to specific chromosome bands.

Expressed genes include those that are transcribed

into mRNA and then translated into protein, and

another class of essential genes that are transcribed into RNA but not translated into proteins.

Included in the latter class are transfer and ribo -

somal RNAs involved in protein synthesis, RNAs

involved in the removal of intron sequences from

mRNAs, and an RNA associated with the cellular

protein secretion machinery. Procedures are available to make DNA copies, or complementary DNAs

(cDAVIS), of RNA transcripts. These cDNAs can in

turn be mapped to genomic DNA sequences by

somatic cell hybridization, in situ hybridization,

and other low-resolution physical mapping methods. A physical map illustrating the location of

expressed genes is often referred to as a cDNA

map. As noted earlier, only 1,200 of the 50,000

to 100,000 human genes have been physically

mapped to chromosomes.

A high-resolution physical map can be made by

cutting up the entire human genome with restriction enzymes and ordering the resultant DNA segments as they were originally oriented on the chromosomes. This third type of physical map, a contig

map, can be related to the maps of chromosome

bands and expressed genes. The physical map

of highest possible resolution or greatest

molecular detail, is the complete nucleotide se

quence of the human genome. Thus there is a

continuum of mapping techniques that ranges

from low to high resolution (see table 2-2). These

techniques are discussed in this section, on lowresolution physical mapping, and in the following one, on high-resolution physical mapping

methods.

Somatic Cell Hybridization

The somatic cell hybridization technique for

gene mapping typically employs human fibroblast

and rodent tumor cells grown in culture. The hu -
31

man and mouse cells are fused (hybridized) together using certain chemicals, Sendai virus, or

an electric field, as illustrated in figure 2-7 (58).

The chromosomes of each of the fused cells become mixed, and many of the chromosomes are

lost from the hybrid cell. Human chromosomes

are preferentially lost over rodent chromosomes,

but there is generally no preference for which

human chromosomes are lost. The individual hybrid cells are then propagated in culture and maintained as cell lines. In practice, the hybrid cell lines

resulting from cell fusions contain different subsets of between 8 to 12 human chromosomes in

addition to rodent chromosomes (58).

Using a large set (panel) of somatic cell hybrids

containing different chromosome combinations,

it is possible to correlate the presence or absence

of a particular chromosome with a particular gene.

Assignment of a gene to a chromosome is made

by detecting a protein produced by a hybrid cell

line and associating it with the chromosome

unique to that cell line. Alternatively, if the gene

to be mapped has already been isolated by DNA

cloning procedures, then the gene can be used

directly to identify complementary nucleotide sequences in the DNA extracted from somatic cell

hybrids.

Modifications of the somatic cell hybridization

method have been devised to generate single chromosome hybrids; to date, hybrid cells containing

single copies of human chromosomes 7, 16, 17,

19, X, and Y are available (58). Somatic cell hybrid

lines carrying chromosomes with deletion or

translocation mutations are also useful low-resolution mapping tools because they make it possible to infer the location of a particular gene.’

Chromosome Sorting

Chromosome sorting offers an alternative to the

screening of somatic cell hybrid panels for lowresolution gene mapping. In this approach, DNA

hybridization is used to map genes to chromosomes that have been differentiated by flow

The Institute for Medical Research, in Camden, New Jersey, estab

Iished a repository for SCHS with chromosome rearrangements called

the Human Mutant Cell Library. The availability of this centralized

storage facility has accelerated the rate of mapping human genes

to specific chromosomal locations.

Figure 2-7.—Somatic Cell Hybridization

Human Sendai Mouse

fibroblast virus tumor cel l

Somatic cell hybrids are generated by the process of cell fusion, an event that can be enhanced by adding Sendai virus.

Initially, the hybrid cell contains complete sets of chromosomes from both parental cells, but hybrids of human and

mouse celIs are unstable and chromosomes from the human

cells are preferentially lost. After a few generations in culture, a line of hybrid cells is established that contains both

mouse and human chromosomes.

SOURCE: Office of Technology Assessment, 1988.
32

Photo credit: Larry Oaaven, Los A/amos National Laboratory, Los Alamos, NM

Flow cytometry facility for chromosome sorting at

Los Alamos National Laboratow.

cytometry and purified by flow sorting. Fluorescent markers that bind to chromosomes are used

in flow cytometry as the basis of separating chromosomes from one another in a flow sorter (figure 2-8) (21,29,30,46). Because human chromosomes differ in the degree to which they bind the

fluorescent markers, it is possible to use this approach to physically separate some chromosomes

from others. The dual-laser chromosome sorter

has been used successfully to separate all the human chromosomes except chromosomes 10 and

11. In addition, chromosomes from cell lines with

translocations and deletions can be used to narrow the location of the gene to a certain chromosomal region (46).

To determine on which chromosome a gene lies,

chromosomes are sorted onto different paper

filters made of nitrocellulose. There the DNA is

denatured and hybridized with a radioactively labeled DNA probe complementary to the gene to

be mapped. (In general, the cDNA is available for

use as a probe for the gene.) On whichever chromosome the gene appears, the two sequences will

hybridize, and the hybridization can be observed

using autoradiography.

Karyotyping

At a stage of cell division when chromosomes

have duplicated but not yet separated from one

Figure 2-8.—Chromosome Purification by

the Flow Sorter

Fluorescence / / /

for Analysis

.

Chromosomes stained with a fluorescent dye are passed

through a laser beam. Each time, the amount of fluorescence

is measured and the chromosome deflected accordingly. The

chromosomes are then collected as droplets.

SOURCE: Courtesy of Los Alamos National Laboratory, Los Alamos, NM

another, they condense to form structures with

features that can be observed under a light microscope. The structure of human chromosomes can

be studied by chemically fixing white blood cells

at the appropriate stage of cell division and then

photographing the chromosome spreads as they

appear on slides under the microscope. Individual chromosomes are identified in the photograph,

cut out, and, in the case of autosomes, matched

with their morphologically identical chromosome

partner to generate a karyotype. Karyotyping has

been most useful for correlating gross chromosomal abnormalities with the characteristics of

specific diseases (e.g., Down’s syndrome and

Turner’s syndrome).
33

Photo credit: Roger Lebo, the University of California, San Francisco Medical

Center. Reprinted with permission from Alan R. Liss, Inc.

Assignment of a gene and genes with related sequences to specific human chromosomes. Samples of

the 21 different human chromosomes were sorted onto

11 circular filters and then hybridized to a radioactively

labeled DNA probe from the aldolase gene (aldolase

is an enzyme involved in the metabolism of sugars).

Most of the radioactive signal in the autoradiograph

appears on the filter with chromosome 9, indicating

that the complementary DNA sequence is in that chromosome. The autoradiograph also shows some hybridization to chromosomes 17 and 10, indicating that aldolase genes with different, but similar, sequences are

found on these chromosomes.

Chromosome Banding

Using fluorescent dyes as chromosome-specific

stains, Caspersson and others (10-I2) developed

optical methods for observing the banding patterns on human chromosomes. These methods

reveal more details of chromosome morphology

than does simple karyotyping. The bands are chromosomal regions that appear as stripes on chromosome spreads when viewed under the light

microscope. Each of the 24 different human chromosomes has a unique banding pattern, thus the

bands can be used to identify individual chromosomes. Genes can be mapped to specific bands

by identifying differences between the banding

patterns on chromosomes from normal individuals and those on the chromosomes from an individual with a significant chromosomal alteration.

Nearly 1,000 distinct bands have been detected

on the 24 human chromosomes by staining and

light microscopy, and an average of 100 genes is

represented in a single band (50). Chromosome

banding is a useful procedure for finding the general location of a gene, but it does not offer sufficient resolution to identify the exact position of

a gene relative to other genes mapped in the same

region (58).

In Situ Hybridization

Family linkage and somatic cell hybridization

are not direct mapping methods; they are based

on the correlation between traits and the frequency of transmission of those traits in families.

Karyotyping and analysis of chromosome banding allow a specific trait to be correlated with a

particular chromosome or a large region of a chromosome. Advances in molecular biology have

overcome the limitations of those techniques by

providing means for more precise mapping of

genetic markers. One such method is in situ

hybridization of isolated genes or gene fragments

to chromosomal DNA.

The in situ hybridization technique was originally developed by Mary Lou Pardue and Joseph

Gall for detection of genes encoding ribosomal

RNAs in chromosomes from Drosophila salivary

glands (56). In the typical in situ hybridization experiment, the DNA corresponding to a particular

gene or gene fragment is used to probe for complementary sequences in chromosomes (28). The

chromosomes to be analyzed are fixed on a microscope slide, where the DNA strands are chemically treated and separated. Next, the radioactively

labeled DNA probe is mixed with the chromosomes on the slide. Under proper conditions, the

DNA probe hybridizes with the gene sequence

wherever it is located on the prepared chromosomes.

Results of in situ hybridization can be seen by

exposing the slides to a photographic emulsion

for a long period, then analyzing the photographs

under a microscope. Wherever the radioactively

labeled DNA strands have paired with complementary chromosomal regions, tiny silver grains appear. The location of a specific gene can be found

by counting the number of grains in each region

and using computer methods to analyze the data

(58). Although in situ hybridization has been a

principal method for the mapping of human genes

to autosomes, higher-resolution methods are nec -
34

1 2 3

13 14 15 16 17 18

essary. The procedure is limited to a resolution

of about 10 million base pairs, a substantial portion of the total length of most chromosomes. Since

many genes could fit into such a region, the exact

location of the gene of interest must still be determined precisely (58).

Other Methods for Mapping Genes

Several other techniques for mapping human

genes are available, including gene dosage mapping and comparative mapping of species. In gene

dosage mapping, a correlation is made between

the amount of gene product and the presence of

extra genes or the absence of a gene or chromosome fragment, Biochemical analysis of cellular

contents isolated from an individual with a particular genetic disease, or from somatic cell hybrid lines derived from that individual’s cells, is

performed to measure amounts of gene products.

The structure of the altered chromosome (or chromosomes) is then characterized by one or more

of the methods already described.

Comparative mapping of species can provide

useful human gene mapping information. This is

particularly true among mammals, where it has

been demonstrated that different species have similar patterns of gene organization on certain chromosomes [Computer Horizons, Inc., see app. A].

For example, tabulations show that all of the human autosomes except chromosome 13 have at

least two linked genes which are also linked in

the mouse (35).

Comparison of the banding patterns of chromosomes from different species have also proved

useful in matching chromosomes between species, even though differences in total numbers of

chromosomes exist. There is, for example, a striking resemblance between chimpanzee and human
35

6 7 8 9 10 11 12

A female with the extra chromosome 21 associated with Down’s syndrome.

●

chromosomes (81). In recent years, DNA sequence have been used to isolate or confirm the identity

comparisons between widely differing organisms of specific human genes (see ch. 3).

HIGH-RESOLUTION PHYSICAL MAPPING TECHNOLOGIES

Construction of high-resolution physical

maps of whole genomes involves cutting the

component DNA with restriction enzymes,

analyzing the chemical characteristics of each

fragment, and then reconstructing the original order of the fragments in the genome. Generally, the DNA fragments to be ordered are isolated from chromosomes; united with carrier, or

vector, DNA molecules originating from viruses,

bacteria, or the cells of higher organisms; and introduced into suitable host cells, where the isolated DNA can be reproduced in large quantities,

A fragment of DNA is said to be cloned when it

is stably maintained as part of a DNA vector in

a single line of cells. A set of clones representing

overlapping segments of DNA encompassing an

entire genome is called a genomic library. In order to make a physical map, the clones in the

genomic library must be ordered in relation to

one another’s position on the chromosome. The

following sections describe in more detail the

methods currently available for creating highresolution physical maps and their application to

the genomes of specific organisms.

Cloning Vectors as Mapping Tools

Any genome mapping project first requires the

isolation, usually by cloning technologies, of fragments of chromosomal DNA. Several different
36

Photo credit: Stephen O’Brien, The National Cancer institute, Frederick, MD.

Reprinted with permission from Nature 317:14G144, 1985.

A comparative alignment of chromosomes from the giant panda (AME) and the brown bear (UAR). The putative matches between the whole chromosomes, or chromosome segments, of each animal were based on the

thickness of stained bands on the chromosomes and

on the spacing and intensity of the bands. This type

of molecular information has been used to establish

the phylogeny of these bears and to demonstrate some

of the problems in using the appearance of animals,

instead of their chromosome structure,

in studies of evolution.

types of cloning vectors have been developed using

recombinant DNA technology:

●

●

●

Plasmid vectors are circular DNA molecules

of 1,000 to 10,000 base pairs that can carry

additional DNA sequences in fragment inserts

up to 12,000 base pairs (2,4). Plasmids exist

as minichromosomes in bacterial cells (usually between 10 to 100 copies per cell) and

are separate from the main bacterial chromosome.

Phage lambda chromosomes are about 50,000

base pairs and can accept foreign DNA inserts

up to about 23,000 base pairs (33,79). Just as

viruses infect human cells, phage infect bacterial cells and generate hundreds of descendants.

Cosmid vectors are plasmids that also contain specific sequences from the bacterial

phage lambda. Cosmids are about 5,000 base

●

pairs, but because they contain phage lambda

sequences, they can carry DNA inserts up to

about 45)000 base pairs (figure 2-9) (25,34,36).

Yeast artificial chromosomes are dasrnids

containing portions of yeast chrohosomal

DNA that function in replication. These artificial chromosomes can accommodate foreign

DNA fragment inserts nearly 1 million base

pairs long (6).

Figure 2-9.—DNA Cloning in Plasmids

Chromosomal DNA

to be Cloned
37

Most of the physical mapping work carried out

to date has employed bacteriophage and cosmid

cloning vectors because the yeast artificial chromosome vectors have only recently been developed [Myers, see app. A].

physical Mapping of Restriction

Enzyme Sites

With the exception of DNA sequencing, restriction enzyme mapping is the method that gives the

highest-resolution picture of DNA as it is organized

in a chromosome. Several basic steps are involved

in the construction of this type of physical map

for part or all of a genome:

• purifying chromosomal DNA,

• fragmenting DNA by restriction enzymes,

. inserting all the resulting DNA fragments into

DNA vectors to establish a collection (library)

of cloned fragments, and

● ordering the clones to reflect the original

order of the DNA fragments on the chromosome.

Variations in any of these steps can affect the resolution of the physical map.

Purification of Chromosomal DNA

Whole chromosomes are the best source of DNA

for genomic libraries. Mixtures of chromosomes

can be extracted directly from cells, but for organisms with complex genomes, such as human beings, it might be desirable to first separate the

different chromosomes and then create sets of

clones from the individually purified chromosomes.

Mixtures of whole chromosomes extracted from

human cells can be sorted by flow cytometry. Somatic cell hybrid lines carrying one or a few human chromosomes can also be used as a highly

enriched source of particular chromosomes. The

refinement of existing methods and the development of new technologies for obtaining

large amounts of purified human chromosomes will be crucial in the early stages of human genome mapping projects.

Fragmentation of DNA

The availability of chromosome fragments of

decreasing size allows mapping at higher resolution. A technology called pulsed field gel electrophoresis (PFGE) allows separation of DNA

molecules ranging in size from 20,000 to 10 million or more base pairs (8,9)13)61) [Myers, see app.

A].

During PFGE, large DNA fragments are subjected to an electric field that is switched back

and forth across opposite directions for short

pulses of time. This alteration in the direction of

the electric field allows very large DNA molecules

(up to tens of millions of base pairs) to migrate

into the agarose gel and separate from one

another, even though the normal size limit for elec -

trophoretic separation of DNA molecules during

conventional agarose gel electrophoresis is about

50,000 base pairs. This method is so powerful that

it has been used successfully to separate all 14

of the yeast chromosomes from each other (figure 2-10) [Myers, see app. A]. Since intact human

chromosomes have an average size of approximately 100 million base pairs, the PFGE technique

is only useful for separating large fragments made

from individual, purified human chromosomes.

The level of detail possible on a physical map

depends on the restriction enzyme or enzymes

used. There are a few restriction enzymes that

cut DNA very infrequently, generating small numbers of large fragments (ranging from several

thousand to a million base pairs). Most restriction

enzymes cut DNA more frequently, generating

large numbers of small fragments (ranging from

fewer than a hundred to greater than a thousand

base pairs). The relative order of a small set of

large fragments is easier to determine than the

order of a large set of short fragments, but it gives

a lower-resolution physical map. The choice of

enzyme thus depends on the purpose of the physical map. If the aim is to have fragments of a size

amenable to DNA sequencing, then a mapped restriction site at least every 500 base pairs would

be ideal, but a mapped site every 2,000 to 3,000

base pairs would also be practical. Given the

technology currently available, sequencing

the DNA of the 3-billion-basepair haploid human genome might require the prior mapping
38

of as many as 6 million restriction enzyme cutting sites (69) [Myers, see app. Al.

Figure 2.11.—Constructing a Librarv of Clones

Containing Overlapping Ch;omosomal Fragments

Construction of Libraries

of DNA Fragments

For physical mapping projects, it is important

to have as much DNA as needed. The use of cloned

DNA fragments offers this advantage. Fragments

of DNA from whole chromosomes are generally

cloned into vectors such as plasmids, cosmids, DNA

Figure 2-10.—Separation of Intact Yeast Chromosomes

by Pulsed Field Gel Electrophoresis

CHROMOSOME BAND SIZE (Thousands

of Base Pairs)

3

AA

5

10

2

13

15 1125

1600

2500

well

SOURCES: Chris Traver and Ronald Davis, California Institute of Technology,

Pasadena, CA. SOURCE: Office of Technology Assessment, 1988.
39

phage chromosomes, and artificial yeast chromosomes. These vectors can be stably maintained

in host cells (bacteria or yeast) that multiply rapidly to provide the amounts of DNA necessary for

restriction enzyme mapping and DNA sequencing. DNA fragments are usually cloned by cutting

the vector of choice with a restriction enzyme and

then connecting the newly generated ends of the

vector to the ends of the DNA fragments with the

enzyme DNA ligase. The resuhing collection of

clones is called a library. There is no obvious order to the library, and the relationship between

the components can only be established by physical mapping.

In order to establish that any two clones represent chromosomal segments that normally occur

next to one another in the genome, it is necessary to have collections of clones representing partially overlapping regions of chromosomal DNA

(figure 2-11). To create libraries of overlapping

clones, the chromosomal DNA is treated with a

frequent-cutting restriction enzyme, one that cuts

every 500 base pairs or so, but conditions are controlled so that the enzyme is not allowed to cut

the DNA at all the possible restriction enzyme sites.

Instead, by lowering the amount of restriction enzyme used, only partial cutting is allowed. The

experimental conditions for partial cutting are adjusted so that DNA fragments are generated with

an average size equal to the vector’s capacity (usually 20,000 to 50,000 base pairs). In theory, no one

of the cutting sites will be recognized by the restriction enzyme more frequently than another,

so a population of overlapping segments representing all possible cutting sites in the original DNA

sample should be generated. These fragments are

then cloned in the appropriate vector.

Determination of the Order of Clones

The clones in a library are ordered by subdividing the chromosomal DNA inserts into even

smaller fragments and identifying which clones

have some common subfragments. Figure 2-12 illustrates how this is done. A particular DNA clone

(vector plus the chromosomal DNA insert) is

cleaved with one or more restriction enzymes

(other than that used to make the clones) under

conditions in which all sites are recognized and

cut. The resulting fragments are then run on a

Figure 2-12.—Making a Contig Map

Clone A Clone B Clone C Clone D

Clone A Clone B Clone C Clone D

Larger

Fragments

Analyze Data for Restriction

Enzyme Fragment Overlaps

Establish Order of

Genomic Clones

Clone A

Clone B

Clone D

SOURCE: Office of Technology Assessment, 1988.

gel made of agarose. After electrophoresis, a pattern of fragments is observed along the length

of the gel. If the DNA fragments are present in

sufficient amounts, they can be seen under ultraviolet light after staining the gel with the dye
40

ethidium bromide; otherwise, the phosphates at

the ends of the DNA fragments are labeled with

a radioactive isotope and viewed after autoradiography. A unique pattern of bands appears (corresponding to DNA fragments) for any given clone

because of the unique arrangement of restriction

enzyme sites in the region of the chromosome

from which that clone was derived. If two clones

contain overlapping segments of DNA, then a portion of the banding pattern for each will be identical. For example, if the clone order is A-B-C-D,

then the restriction enzyme fragments from clone

A will partially overlap with those from clone B,

clone B fragments with clone C, and so on (figure

2-12).

Groupings of clones representing overlapping,

or contiguous, regions of the genome are known

as contigs (18)66). on an incomplete physical map,

contigs are separated by gaps where not enough

clones have been mapped to allow the connection of neighboring contigs. Of all the steps in physical mapping, the connection of all the contigs is

the one that faces the greatest number of technical problems. Therefore, the time required to

achieve a complete physical map of any geGENOMIC MAP OF BACTERIOPHAGE T4

ATRme, DNA

Genomic map of bacteriophage T4. The genome of bacteriophage T4 contains about 166,000 base pairs. Shown are maps

illustrating the names of mapped genes (outer circle), genetic map distances (second largest circle), which are measured

in mimdes in bacteria and their phage, and posit ions of DNA cutting sites for a variety of restriction enzymes (inner circles).
41

nome is a function of the time required to connect neighboring contigs.

Physical Mapping of Nonhuman

Genomes

So far, high-resolution mapping of entire genomes has focused on nonhuman organisms. Most

of the technologies applicable to human genetic

and physical mapping, therefore, have been developed from work on other organisms. Mapping

of complete genomes is well underway for several species of bacteria and yeast, for the nematode, and is beginning for the fruit fly. These

organisms have long served as excellent model

systems for what are sometimes found to be

universal genetic and biochemical mechanisms

governing cell physiology. The technologies employed in these high-resolution genome mapping

projects range from making contig maps to fine

mapping by DNA sequencing.

The Bacterial Genome

For many years, bacteria (mainly Escherichia

coli) and phage (viruses that infect bacteria) have

been principal research subjects of molecular biologists, molecular geneticists, and biochemists.

Because of the relative ease of studying gene function in E. coli, it is the organism whose genetics

and biochemistry are closest to being completely

understood. The DNA of this bacterium is contained in a single circular chromosome of 4.7 million base pairs (63). The genetic map of E. coli is

quite extensive, with about 1)200 of the 5,000 or

so known genes already cloned (3). In addition,

the nucleotide sequence of over 20 percent of this

bacterial genome is known (26).

Progress on the physical map of the E. coli genome is good. Cassandra Smith and co-workers

at Columbia University made a complete physical map of this genome using a restriction enzyme

called Not I, which cuts DNA only infrequently

(63). Not I recognizes a sequence eight nucleotides

long that is expected to occur by chance once

every 34,000 base pairs. Only 22 Not I sites were

found in the E. coli genome (63).

A higher-resolution physical map of E. coli was

generated by Kohara and colleagues (42) at Nagoya

University in Japan. These researchers devised

an innovative, rapid mass-analysis mapping approach involving eight different restriction enzymes. In a period of time equivalent to only onehalf of a person-year, this group generated a highresolution physical map covering 99 percent of

the E. coli genome, leaving only seven gaps. An

independent effort to generate a high-resolution

map of the cutting sites for three different,

frequent-cutting restriction enzymes is also near

completion at the University of Wisconsin, Madison (20).

The work of the researchers in Wisconsin and

Japan is important because it generates an ordered

set of clones. A map indicating the order of a library of genomic clones is immediately useful to

anyone wishing to examine DNA corresponding

to a gene whose position on the map is known.

The physical map is correlated with the genetic

map at many sites in E. coli, primarily as a result

of including in the analysis clones containing

known genes. Kohara and co-workers demonstrated that the use of large fragments for connecting groups of clones is not necessary for E.

coli. Because of the computational limitations on

connecting great numbers of small fragments,

however, large-fragment maps, analogous to the

Not I map of E. coli, will no doubt play a significant role in mapping large genomes, such as the

human genome.

The Yeast Genome

An ongoing project to map the 15 million base

pairs in the Saccharomyces cerevisiae (baker’s

yeast) genome has been described by olson and

colleagues (55) at Washington University. These

researchers initiated the mapping project to facilitate the organization of the vast amount of information already available on this organism. As

Olson writes:

Just as conventional cartography provides

an indispensable framework for organizing

data in fields as diverse as demography and

geophysics, it is reasonable to suppose that

“DNA cartography” will prove equally useful

in organizing the vast quantities of molecular genetic data that may be expected to accumulate in the coming decades (55).
42

A large fraction of the S. cerevisiae genome

(about 95 percent) is available in clones that have

been joined together in over 400 contiguously

mapped stretches. These contigs are being correlated with a complete large-fragment restriction map for the yeast genome. These combined

maps make it possible to construct or identify a

mapped region 30,000 to 100,000 base pairs in

length around virtually any starting point, typically a cloned gene [Mount, see app. A].

The Nematode Genome

The nematode Caenorhabditis elegans is a popular organism among developmental biologists because the origin and function of all 958 cells in

the adult animal are known, offering researchers the opportunity to study the basis of organis -

mal development. With its 3-day generation time,

C. elegans is also suited to genetic studies, Molecular biologists, interested in the molecular basis of

development, would find an ordered set of clones

from the nematode genome particularly useful

for their work [Mount, see app. A].

Coulson and Sulston at the Medical Research

Council in England initiated a C. elegans mapping

project to provide such tools and to establish communications among the laboratories working on

this organism, Like the S. cerevisiae genome mapping project, this resulted in a set of clones that

covers most of the genome (18). One difference

is that the C. elegans clones are put into order

by the fingerprinting method: Distances from each

cleavage site for one enzyme to the nearest site

for a second enzyme were measured, and clones

sharing a number of such distances (measured

as lengths of restriction fragments observed on

polyacrylamide gels) were considered to overlap.

This process makes identification of overlapping

regions somewhat easier (because the information is denser), at the expense of more precise

physical map information. A second difference

is that cosmid clones were used in the nematode

project, while phage clones were used in the yeast

project. Cosmid clones can accommodate larger

DNA inserts than phage clones, but they can also

be less stable, with portions of the inserts becoming deleted more often (17). At present, over 700

contigs, ranging from 35)

000 to 350,000 base pairs

in length and representing 90 percent of the C.

elegans genome, have been characterized (71).

The Fruit Fly Genome

The genetics of the common fruit fly, Drosophila

melanogaster, are the best characterized of any

multicellular organism. One reason for studying

fruit flies is that it is possible to carry out a saturating screen to detect mutations of a particular type.

In a saturating screen, every gene that could mutate to produce the defect being studied is identified. (This accomplishment is crucial to a complete

understanding of many cellular processes.) The

saturating screen technique allows for a comprehensive genetic analysis because the entire genome can be examined for the presence of genes

that are involved in a particular process. The most

celebrated example is an exhaustive study of mutations that are lethal to the fly in its larval stage

(39,53,78) [Mount, see app. A].

Until recently, the physical mapping of the 165

million base pairs in the D. melanogaster genome

had not been undertaken by any one laboratory.

Roughly 500 to 1)000 genomic clones have been

obtained in various laboratories in various vectors; all of these clones have been localized to a

chromosomal map position by in situ hybridization to polytene chromosomes (a multicopy set

of D. melanogaster chromosomes unique to its salivary gland). A listing of these clones is maintained

by John Merriam and colleagues at the University of California, Los Angeles, and the clones are

made available to all researchers [Mount, see app.

A].

Work by Michael Ashburner and co-investigators at Cambridge University on a comprehensive

map of overlapping cosmid clones of the D.

melanogaster genome was approved for funding

by the European Economic Community in late

1987. This project is expected to follow the fingerprinting strategy of the nematode project, with

the important difference that cytological maps

(maps of banding patterns derived from microscopic analysis of stained chromosomes) of D.

melanogaster chromosomes will be exploited.

First, the technique of microdissection cloning

(whereby DNA is excised from precise regions of

the salivary gland polytene chromosomes and

cloned) will be used to generate region-specific

genomic clones. These microdissection clones are

not of sufficient quality to be used directly, but

they can be used to correlate cosmids in a stand-
43

ard genomic library with specific chromosomal

regions. This step makes it easier to assemble the

contiguous clones into groups. Finally, the position of all contigs with respect to the cytological

map will be confirmed by in situ hybridization,

whereby cosmid clones from the various contigs

would be hybridized to salivary gland chromosomes [Mount, see app. A].

Strategies for Physical Mapping of

the Human Genome

It is likely that making contig maps of large genomes, such as the human genome, will require

a combination of bottom-up mapping and topdown mapping (55). Bottom-up mapping starts by

making genomic clones, then fragmenting these

clones further to decipher the overlaps necessary

for connecting clones into contigs. Top-down mapping (e.g., Smith’s E. coli map) is of lower resolution because it is derived from minimal fragmentation of source DNA. The critical distinction

between the two methods is the size of the

genomic DNA fragments used. Bottom-up mapping starts with relatively small genomic clones,

while top down mapping starts with large genomic

clones. The advantage of top-down mapping is that

it offers more continuity (fewer gaps), while the

bottom-up method has higher resolution (more

detail). In formulating strategies for mapping the

human genome, it will be necessary to decide what

level of molecular detail is necessary to begin a

human genome mapping project. Will informationrich strategies like those used to develop highresolution E. coli restriction enzyme maps (20,42)

or the DNA signposts offered by a RFLP map be

the best first-generation human genome maps?

Contig Mapping

Scientists in the fields of molecular biology and

human genetics who reviewed an OTA contract

report on possible strategies for making contig

maps of the human genome [Myers, see app. A]

favored the following strategy: to map the genome

one chromosome at a time, dividing and subdividing each chromosome into smaller and smaller

segments before beginning restriction enzyme

mapping and ordering of clones. After subdivision, restriction maps of these smaller segments

would be determined and the information linked

together to form continuous maps of whole chromosomes. In principle, this strategy could be broken

1.

2.

3.

4

5.

down into five consecutive steps:

isolation of each human chromosome,

division of each chromosome into a collection of overlapping DNA fragments 0,5 to 5

million base pairs in length,

subdivision and isolation of each of these chromosomal fragments into overlapping DNA

fragments about 40,000 base pairs in length,

determination of the order of the 40,000-basepair DNA fragments as they appear in the

chromosomes and determination of the positions of cutting sites for a restriction enzyme

within each of these fragments, and

use of the mapping information gained in step

4 to link together each of the overlapping o.5

to 5-million-base-pair fragments isolated in

step 2 [Myers, see app. A].

The substantial progress made so far on contig

maps of nonhuman genomes implies that technologies already exist to begin construction of a

global physical map of the human genome. The

haploid human genome (approximately 3 billion

base pairs) is at least 30 times larger than that

of the nematode, the largest genome for which

comprehensive physical mapping has been attempted. Sulston predicted that the mapping work

he and his co-workers have done over the past

4 years could be repeated within 2 person-years,

because much of their time was spent devising

computer methods for data analysis (17). If the

size of a genome were linearly related to the time

required to physically map it, then the human ge -

nome could be mapped to the same degree of completion as the nematode genome (90percent) in

about 60 person-years. Such calculations are simplistic, however, because features of the human

genome other than its size make it potentially more

difficult to map. For example, some DNA sequences are repeated frequently throughout the

human genome, in contrast to the nematode genome, and these are likely to interfere with the

physical mapping process.

Techniques for isolating large chromosomal

fragments should offer solutions to some of

the physical mapping problems expected to

arise from the occurrence of repetitive sequences in the human genome. The two most
44

promising methods developed to date are the PFGE

technology (8)9)13,61) and the yeast artificial chromosome cloning technology (6).

A National Research Council advisory panel on

mapping and sequencing the human genome recommended improvements in technologies for the

following to facilitate the construction of physical

●

●

●

●

●

●

●

maps of large genomes:

separating intact human chromosomes;

separating and immortalizing identified fragments of human chromosomes;

cloning the cDNAs representing expressed

genes, especially those that represent rare

cell-, tissue-, and development-specific

mRNAs;

cloning very large DNA fragments;

purifying very large DNA fragments, including higher-resolution methods for separating

such fragments;

ordering the adjacent DNA fragments in a

DNA clone collection; and

automating the various steps in DNA mapping, including DNA purification and hybridization analysis, and developing novel methods that allow simultaneous handling of many

DNA samples (52).

DNA Sequencing

Strategies for sequencing the entire human

genome are much more controversial than

those for generating contig maps. Some scientists favor sequencing only expressed genes, identified with a cDNA map (17). Others propose that

sequencing should continue to be targeted at specific regions of interest, as is currently done. Still

others hold the view that the whole genome

should be sequenced because it could reveal sequences with important functions that would

otherwise go unidentified (see ch. 3). The National

Research Council panel proposed first that pilot

programs be conducted with a goal of sequencing approximately 1 millon continuous nucleotides (which is about five times as large as the

largest continuous stretch of DNA sequenced to

date) (52). Second, improvements in existing DNA

sequencing technologies would be vigorously encouraged. Finally, extensive sequencing of other

genomes, including the mouse, fruit fly, nematode,

yeast, and bacterial genomes, was recommended

for purposes of comparison (52).

The potential uses of human genome maps and

sequences will likely dominate strategic decisions

on which of the possible methods should be used

to construct them (ch. 3). The strategy currently

favored–preparing physical maps of individual

chromosomes—requires that decisions be made

on which chromosomes should be mapped first.

Mapping smaller chromosomes first in pilot

projects (e.g., chromosomes 21 and 22) would be

the logical strategy from a technical perspective.

Alternatively, selecting chromosomes linked to the

largest numbers of markers for human genetic

diseases (e.g., chromosome 7 and the X chromosome) might make the impact of genome mapping

on clinical medicine more immediate. Efforts are

already underway in a number of U.S. and foreign laboratories (ch. 8) to physically map (at various levels of resolution) human chromosomes

known to be of general clinical significance or to

carry genes of specific interest to the researchers involved. Scientists at Los Alamos and Livermore National Laboratories have begun mapping

chromosomes 16 and 19, respectively. These chromosomes were chosen for their relatively small

sizes and number of clinically relevant genetic

markers. Researchers at Columbia University have

begun work on a physical map of chromosome

21 for similar reasons.

DNA Sequencing Technologies

Two methods for sequencing DNA are standard

in laboratories today. One technique, developed

by Fred Sanger and Alan Coulson at the Medical

Research Council in England (60), uses enzymes

(figure 2-13), while the other, developed by Alan

Maxam and Walter Gilbert at Harvard University,

involves chemicals that degrade DNA (figure 2-

14) (48,49). The two methods differ in the means

by which the DNA fragments are produced; they

are similar in that sets of radioactively labeled DNA

fragments, all with a common origin but terminating in a different nucleotide, are produced in the

DNA sequencing reactions.

George Church at Harvard Biological Laboratories has adapted the Maxam and Gilbert DNA

sequencing method in an innovative technology,
45

Figure 2.1 3.— DNA Sequencing by the Sanger Method

DNA Polymerase I

dATP

dGTP

dCTP

dTTP

Reaction Mixtures

Gel Electrophoresis

Autoradiography to

Detect Radioactive

Bands

Larger

Fragment s

Smaller

Fragments

called multiplex sequencing, that enables a

researcher to analyze a large set of cloned DNA

fragments as a mixture throughout most of the

DNA sequencing steps. Mixtures of clones are

operated on in the same way as a single sample

in traditional sequencing. This is accomplished by

tagging each DNA clone in the mixture with short,

unique sequences of DNA in the first step and then

deciphering the nucleotide sequence of each

In the Sanger method, a cloned DNA fragment is mixed with

a short piece of synthetic DNA complementary to only one

end (the origin) of the cloned fragment. An enzyme called DNA

polymerase is then used to catalyze the synthesis of a complementary strand. During the polymerization reaction, a modified nucleotide, a dideoxynucleotide, is included with a mixture of the four naturally occurring nucleotides (A, G, T, and

C), one of which is labeled with a radioactive phosphorous

or sulfur atom, causing growth of the DNA chain to stop whenever the modified nucieotide is inserted. Four separate reactions, each containing all four normal nucleotides but a

different dideoxynucleotide, can be carried out. A series of

radioactively labeled DNA strands will be made, the lengths

of which depend on the distance from the origin to the nucleotide position where the chain was terminated. For example,

if a short DNA template has four G’s, conditions are set up

such that some molecules will be made with no G dideoxynucleotide analogs, some will terminate at the fourth G position, some at the third G position, and so on. Similarly, the

other three dideoxynucleotides will insert infrequently and

randomly at the appropriate positions in the other three

nucleotide-specific reactions. The series of labeled DNA

strands is subsequently analyzed by polyacrylamide gel electrophoresis. Radioactively labeled DNA is electrophoresed

through a vertical slab of polyacrylamide gel (polyacrylamide

is a polymeric resin in which DNA molecules from 1 to 400

bases long can be separated from one another), an X-ray fiIm

is then placed over the gel and exposed, and the resulting

autoradiograph shows a Iadderlike pattern of bands. The sequencing reactions corresponding to each of the four different bases are run as four adjacent lanes on the polyacrylamide gel, and the resulting ladders of bands are read

alternately to give the sequence of the DNA.

SOURCE: Office of Technology Assessment, 1988.

cloned fragment in the final step. Multiplex sequencing allows the simultaneous analysis of about

40 clones on a single DNA sequencing gel, increasing the efficiency of the standard procedure by

more than a factor of 10 (14). Church and coworkers have been applying the multiplex sequencing strategy to determine the complete

nucleotide sequences of two species of bacteria,

E. coli and Salmonella typhimurium (14).

The major problem with current DNA sequencing technology is the large number of DNA sequences that remains to be determined. Multiplex

is only one of several new sequencing protocols

that could be of great value to large genome sequencing projects. Church and Gilbert devised a

method related to multiplex sequencing that aI10WS sequencing directly from genomic DNA (15).

Another method, developed by researchers at Cetus (Emeryville, CA), involves the selective amplification of specific DNA sequences without prior
46

Figure 2-14.–DNA Sequencing by the Maxam and Gilbert Method

32P of DNA

I T

AUTOMATION AND ROBOTICS

The longest single stretch of DNA sequence determined to date, the genome of the Epstein-Barr

virus, contains fewer than 200,000 base pairs. The

total number of nucleotides sequenced to date

using both chemical and enzymatic sequencing

technologies is about 16 million base pairs [Computer Horizons, Inc., see app. A]. This is the current size of GenBank@

, the U.S. repository of DNA

sequence data [app. D]. Since GenBank” includes

onlv reDorted data, 16 million base Dairs repreIn the Maxam and Gilbert procedure, chemical reactions specific to each of the four bases are used to modify DNA fragments at carefully controlled frequencies. One end of one

strand in a double-stranded DNA fragment is radioactively

labeled, and the labeled DNA is used in each of four separate

react ions and treated with a chemical that specifically nicks

one or two of the four bases in the DNA. When these DNA

molecules are treated with another chemical, the DNA fragments are broken where the base was nicked and are destroyed. Just as in the Sanger sequencing method, the products of the Maxam and Gilbert sequencing procedure are

fragments of varying lengths, each ending at the G, C, T, or

A where the chemical reaction took place. By limiting the

amount of chemicals used in each of the base-specific reactions so they will react only a few times per molecule, it

is possible to obtain all possible double-stranded DNA fragments equal in length to the distance from the radioactively

labeled origin to each of the bases. For any given DNA fragment sequenced, each of the four reactions is eiectrophoresed

separately, as described in figure 2-13, and the sequencing

patterns determined from the autoradiograph.

SOURCE: Office of Technology Assessment, 1988.

cloning (59). Each of these methods could potentially eliminate the steps of cloning and DNA preparation in sequence analysis (41).

Finally, DNA sequencing methods that do not

involve either gel electrophoresis or chemical or

enzymatic reactions have also been proposed. At

the Los Alamos National Laboratory, researchers

are investigating ways to use enhanced fluorescence detection methods in flow cytometry as an

alternative to gel techniques for DNA sequencing. others have suggested scanning tunneling

electron microscopes to read bases directly on a

strand of DNA (57,62).

IN MAPPING AND SEQUENCING

sents a low estimate of the total number of base

pairs sequenced. Reported DNA sequences range

from those of small viruses to those of animals

and plants (table 2-3). So far, less than one-tenth

of 1 percent (1.9 million base pairs) of the nearly

3 billion base pairs in the haploid human genome

has been sequenced and reported (7). The current DNA sequencing rate is estimated to generate only about 2 million base pairs per year of

sequence information (7), a powerful incentive for
47

Table 2-3.—Amount of Genome Sequenced in

Several Well-Studied Organisms

Genome size Percent

Organism (base pairs) sequenced

Escherichia co/i (bacterium) . . 4.7 million 16

Saccharomyces cerevisiae

(yeast) . . . . . . . . . . . . . . . . . . . 15 million 4

Caenorhabditis elegan

(nematode) . . . . . . . . . . . . . . . 80 million .06

Drosophila melanogaster

(fruit fly) . . . . . . . . . . . . . . . . . 155 million .26

A4us musculs (mouse) . . . . . . 3 billion .04

Homo sapiens (human) . . . . . . 2.8 billion .08

SOURCES:

C. Burks, GenBank@, Los Alamos National Laboratory, Los Alamos, NM, personal

communication, March 1988.

GenBank” Release No. 54, December 1987.

devising methods of automating the procedures

involved in preparing for and carrying out DNA

sequencing. Some recent reviews (16,38,41,47,57)

provide detailed accounts of the robotic and automated systems currently available and describe

the kinds of systems being developed or planned

for genome mapping and sequencing.

Any degree of automation will help lower the

overall costs of genome projects, both in time and

in dollars. The primary objective in the use of automation is standardization, driven by the need for

repetitive, highly accurate determinations (41).

Some of the existing automated devices are designed for repetitive DNA cloning steps, such as

the preparation and restriction enzyme cutting

of cloned DNA samples. Similarly, efforts are being made to automate the pouring, loading, and

running of gels for separating DNA and for sequencing DNA. Many of the steps in physical mapping could be adapted to automation. Cloning procedures, DNA probe synthesis, and DNA

hybridizations are only a few of those being explored for application to genome projects. A system that automates some steps in growing DNA

clones, to be used, for example, as gene probes

or for DNA sequencing, was recently introduced

by Perkin-Elmer Cetus Instruments (Norwalk, CT)

(67).

The area of automation that has received the

most attention is DNA sequencing. An international workshop on automation of DNA sequencing technologies was held in 1987 in okayama,

Japan, and the proceedings give an extensive account of the state of the art from an international

perspective (32). There are five steps in the task

of DNA sequence analysis:

1. cloning or otherwise isolating the DNA,

2. preparing the DNA for sequence analysis,

3. performing the chemical (Maxam and Gilbert)

or enzymatic (Sanger) sequencing reactions,

4. running the sequencing gels, and

5. reading the DNA sequence from the gel.

Steps 3 through 5 are the functions most often

performed by the instruments developed as of

early 1988 (16,57, 70); however, none of the companies involved has yet commercialized an integrated system that performs all of the functions.

In 1986, Applied Biosystems, Inc. (Foster City,

CA) introduced the first commercial, automated

DNA sequencer (16). This instrument was made

using technology developed by Leroy Hood and

co-workers at the California Institute of Technology. This and similar machines perform steps 4

and 5. The Applied Biosystems, Inc. system is based

on the Sanger sequencing reaction, with modifications to use different fluorescent dyes instead

of radioactive chemicals to label the primers. Because the sequencing reaction primers are individually labeled with different dyes, each of the

four enzymatic reactions can be run together in

a single lane on the polyacrylamide gel. A laser

activates the dyes, and fluorescence detectors read

the DNA sequence at the bottom of the gel as each

fragment appears. The sequence is determined

directly by a computer (figure 2-15). E.I. du Pent

de Nemours & Co. (Wilmington, DE) introduced

in 1987 an automated system that slightly modifies the technology used by Hood and Applied Biosystems, Inc.; this system can potentially reduce

the number of artifacts read by the fluorescence

detectors. Hitachi, Ltd. (Tokyo, Japan) is also expected to market an instrument that automates

steps 4 and 5, but it too is based on the fluorescence technology developed by Hood and colleagues. In early 1988, another U.S. company,

EE&G Bimolecular (Wellesley, MA), began marketing a machine that automates the same DNA

sequencing and gel-reading methods used manually in most laboratories. Bio-Rad Laboratories

(Richmond, CA) marketed an instrument that
48

Figure 2“15.—Automated DNA Sequencing

Using Fluorescently Labeled DNA

1 ‘

-

I I

Light

Scanning

Laser Excites

Fluorescent Dye

(

‘ 1

SOURCE: Leroy Hood, California Institute of Technology, Pasadena, CA.

scans autoradiographs of DNA sequencing gels

and analyzes the data.

Most of these DNA sequencing systems are

based on manual enzymatic sequencing reactions,

while the gel running and reading are automated.

Only one commercial enterprise, Seiko of Japan,

has reported automating the chemical or enzymatic steps (step 3) in the DNA sequencing protocol (7o). In addition, the University of Manchester Institute of Science (Manchester, England)

has built an automatic reagent manipulating system to carry out the Sanger sequencing reactions

(47).

Robotics are used to give automation flexibility,

to extend its capabilities to complex operations

typically performed by highly skilled laboratory

workers. Conceivably, laboratory robots would

allow programmable devices to do physical work

as well as to process data (41). Several robotic devices have been designed and used successfully

by companies involved in the commercialization

of recombinant DNA products or processes. Genetics Institute’s (Cambridge, MA) Autoprep” Plas -

mid Isolation System provides small quantities of

plasmid DNA and vector DNA for DNA sequencing (22). Researchers at the same company also

developed a robot to purify and isolate synthetic

oligonucleotides for use as probes in cloning and

DNA sequencing (38).

Technical advances are occurring rapidly and

simultaneously in biology, robotics, and computer

science, so it is difficult to predict what the future will bring in the development of automated

technology. Some yet-to-bedeveloped technology

could make many of the current physical mapping procedures obsolete.

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Watson, J.D., and Crick, F. H. C., “Genetic Implications of the Structure of Deoxyribonucleic Acid, ”

Nature 171:964-967, 1953.

Watson, J.D., and Crick, F. H. C., “Molecular Structure of Nucleic Acids: A Structure for Deoxyribose

Nucleic Acid,” Nature 171:737-738, 1953.

Weiss, M., and Green, H., “Human-Mouse Hvbrid , , -./ --
51

Cell Lines Containing Partial Complements of

Human Chromosomes and Functioning Human

Genes,” Proceedings of the National Academy of

Sciences USA 58:1104-1111, 1967.

76. White, R., and Lalouel, J.-M., “Chromosome Mapping With DNA Markers,” Scientific American

258:40-48, 1988.

77. White, R., Lippert, M., Bishop, D. T., et al., “Construction of Linkage Maps with DNA Markers for

Human Chromosomes, ’’Nature 313:101-105, 1985.

78. Wieschaus, E. C., Niisslein-Volhard, C., and Jikgens,

G., “Mutations Affecting the Pattern of the Larval

Cuticle in Drosophila Melanogaster III: Zygotic Loci

on the X-Chromosome and Fourth Chromosome, ”

Roux’s Archive of Developmental Biology 193:296-

307, 1984.

79. Williams, B. G., and Blattner, F. R., “Bacteriophage

Lambda Vectors for DNA Cloning,” in Genetic Engineering, vol. 2, J.K. Setlow and A. Hollaender (eds.),

(New York, NY: Plenum Press, 1980).

80. Wilson, E. B., ‘

(

The Sex Chromosomes, ” Arch.

Mikrosk. Anat. Entw”cklungsmech. 77:249, 1911.

81. Yunis, J.J., Sawyer, J. R., and Dunham, K., ‘(The

Striking Resemblance of High-Resolution G-Banded

Chromosomes of Man and Chimpanzee, ” Science

208:1125-1148, 1980.
chapter 3

Applications to Research in

Biology and Medicine
CONTENTS

Page

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55

Applicationsin Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56

Developing Diagnostic Tools . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56

Isolating Genes Associated With Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59

Developing Human Therapeutics +. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62

Prospects for Human Gene Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64

Applications in Human Physiology and Development . . . . . . . . . . . . . . . . . . . . . . . 65

Identification of Protein-Coding Sequences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65

Approachesto Understanding Gene Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66

Applications in Molecular Evolution. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68

Applications in Population Biology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72

Chapter p references. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73

Boxes

Box Page

3-A.Why Sequence Entire Genomes?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57

3-B. Duchenne and Becker’s Muscular Dystrophies . . . . . . . . . . . . . . . . . . . . . . . . . 63

3-C. From Gene Structure to Protein Structure: The Protein-Folding Problem. . . 66

3-D.Constructing the Evolutionary Tree: Morphology v. Molecular Genetics in

3-E

3-F

3G

the Search for Human Origins . . . . . . . . . . . . . . . . . . . . . . . . ., . . . . . . . . . . . . 70

The Origin of Human Beings: Clues From the Mitochondrial Genome . . . . . 71

Molecular Anthropology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72

Imphcations of Genome Mapping for Agriculture. . . . . . . . . . . . . . . . . . . . . . . 73

Figures

Figure Page

3-1.Mappingat Different Leve]sof Resolution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56

3-2.The Use of Synthetic DNA probes To Clone Genes . . . . . . . . . . . . . . . . . . . . . 60

Tables

Table Page

3-l. Examples of Single-Gene Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57

3-2. Some Companies Developing DNA Probes for Diagnosis of Genetic Diseases 58

3-3.The Size of Human Genes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61

3-4. Some Human Gene Products With Potentialas Therapeutic Agents. . . . . . . . 64

3-5. Classification of Human Proteinsby Invention Period . . . . . . . . . . . . . . . . . . . 69
Chapter 3

Applications to Research in

Biology and Medicine

“[physical and genetic maps 1 will certainly be very useful [but] you have to interpret

that sequence, and that’s going to be a lot of work. It will be like having a whole history

of the world written in a language you can’t read. ”

Joseph Gall

American Scientist 76:17-18,

February 1988

INTRODUCTION

Research efforts aimed at creating genetic linkage and physical maps of chromosomes or entire

genomes are collectively referred to in this report

as genome projects (see chs. 1 and 2). The goals

of genome projects are to develop technologies

and tools for mapping and sequencing DNA and

to complete maps of human and other genomes.

Proponents expect that the products and processes generated from genome projects will enable

researchers to answer important questions in biology and medicine. Meeting this objective, however, will depend on the success of concurrent

projects aimed at analyzing the information generated from mapping genomes. Interpreting genome maps will require the combined efforts of

individuals with expertise in structural biology,

cell biology, population biology, biochemistry,

genetics, computer science, and other fields.

Biology and medicine have already benefited

from efforts to map and sequence specific genes

from human and other organisms. Some questions

might be addressed sooner or better, however,

if more extensive genetic linkage maps, cDNA

maps, contig maps, and DNA sequences were available (figure 3-1). (See ch. 2 for detailed discussion

of the types of genetic linkage and physical maps,)

Research on inherited and nongenetic diseases,

the physiology and development of organisms, the

molecular basis of evolution, and other fundamental problems in biology could all be facilitated in

the long run by genome projects.

Scientists continue to debate about which applications depend on information from maps of

entire genomes and which require only maps of

specific regions. The value of a complete DNA sequence of a reference human genome is the most

hotly contended scientific issue (see box 3-A). Focused research has been the mode of molecular

genetics to date: Scientists have targeted specific

regions of genomes for intensive study. Many of

the potential applications of genome mapping summarized in this chapter have already been and

will continue to be achieved by targeted research

projects. Wherever possible, therefore, this chapter attempts to differentiate between the uses for

which extensive maps will be necessary and those

for which partial maps are adequate.

55
— . ——.—

56

Figure 3-1 .—Mapping at Different Levels of Resolution

“’’’’’’’’’’” “’’’’’’’’’’’’” “’’’’’’’’’’’” “’’’’’’’’’’’” “’’’’ ’’’1’ 1’’’’’’” “’’’’’’’’’’’” “

Disease

Gene

t

MAPPING GENES TO WHOLE CHROMOSOMES

Chromosome Banding

DNA Hybridization to Somatic Cell Hybrids

or Sorted Chromosomes

In Situ Hybridization

PHYSICAL MAPPING OF LARGE DNA FRAGMENTS

Yeast Artificial Chromosome Cloning

(Up to 1 Million Base Pairs)

Pulsed Field Gel Electrophoresis

(Up to 10 Million Base Pairs)

APPLICATIONS

Genome projects have accelerated the production of new technologies, research tools, and basic

knowledge. At current or perhaps increased levels

of effort, they may eventually make possible control of many human diseases—first through more

effective methods of detecting disease, then, in

some cases, through development of effective therapies based on improved understanding of disease mechanisms. Advances in human genetics

and molecular biology have already provided insight into the origins of such diseases as hemophilia, sickle cell disease, and hypercholesterolemia.

The new technologies for genetics research will

also help in the assessment of public health needs.

Techniques for sequencing DNA rapidly, for example, should permit the detection of mutations

following exposure to radiation or environmental

IN

PHYSICAL MAPPING OF SMALL DNA FRAGMENTS

Cosmid Cloning (Up to 45,000 Base Pairs)

Plasmid and Phage Cloning

(Up to 23,000 Base Pairs)

MEDICINE

agents. Susceptibilities to environmental and work

place toxins might be identified as more detailed

genetic linkage maps are developed, and special

methods of surveillance can be used to monitor

individuals at risk. By providing tools for determining the presence or absence of pathogens (e.g.,

bacteria and viruses) in large numbers of individuals as well as identifying genetic factors that render some human beings more susceptible to infection than others, genome projects might also

yield methods for tracking epidemics through populations.

Developing Diagnostic Tools

The use of DNA hybridization probes for detecting changes, such as restriction fragment

length polymorphisms (RFLPs), in the DNA of in-
—

57

—

Box 3-A.—Why Sequence Entire Genomes?

Rapid advances in technology have made it feasible to sequence the entire genome of an organism, at

least a small one such as bacteria or yeast. Researchers do not yet agree, however, on the value of a complete DNA sequence of a genome the size of the human genome. Several types of arguments have been

made in favor of sequencing entire genomes:

. The information in a genome is the fundamental description of a living system—it is what the cell

uses to construct a copy of itself—and so is of fundamental concern to biologists.

. Genome sequences provide a conceptual framework within which much future research in biology

will be structured. Questions concerning control of gene expression (signals for control of gene expression, genome replication, development mechanisms, and so on) ultimately depend on knowing genome

sequences.

. The genomes of some higher organisms, including those of human beings, have repeated DNA sequences, sequences of unknown function, and some sequences which are likely to have no function,

comprising nearly 90 percent of the total DNA content. Without the complete DNA sequence of several

genomes, it will be impossible to determine whether such sequences have meaning or are ancestral

“junk” sequences.

. Genome sequences are important for addressing questions concerning evolutionary biology. The reconstruction of the history of life on this planet, the definition of gene families (also critical to other areas

of biology), and the search for a universal ancestor all require an understanding of the organization

of genomes.

. Genomes are natural information storage and processing sytems; unraveling them may be of general

interest to computer and physical scientists.

Other scientists would argue that these possible applications can be derived from sequences of single

genes or larger regions of chromosomes. They believe it is a waste of time and money to sequence the

entire human genome, particularly because some regions have no known or essential function. Many of

these researchers favor sequencing only those regions believed to be clinically or scientifically important,

including expressed sequences and sequences involved in the control of gene expression, and putting the

others off indefinitely.

SOURCES:

National Research Council, Mapping and Sequencing the Human Genome (Washington, DC: National Academy Press, 1988).

C. Woese, LJniversity of Illinois, Urbana, personal communication, June 1987.

Table 3-1 .—Examples of Single-Gene Diseases

Disease Description

Duchenne muscular dystrophy Progressive muscle deterioration

Cystic fibrosis Lung and gastrointestinal degeneration

Huntington’s disease Late-onset disorder with progressive physical

and mental deterioration

Sickle cell anemia Deformed red blood cells block blood flow

Genetic marker Gene Protein

Hemophilia Defect in clotting factor Vlll causes uncontrolled

bleeding

Beta-Thalassemia Failure to produce sufficient hemoglobin

Chronic granulomatous disease Frequent bacterial and fungal infections

involving lungs, liver, and other organs

Pherrylketonuria Enzyme deficiency that causes brain damage

and mental retardation

Polycystic kidney disease Pain, hypertension, kidney failure in half of

victims

Retinoblastoma Cancer of the eye

identified cloned

Yes Yes

Yes No

Yes No

Yes Yes

Yes Yes

Yes Yes

Yes Yes

Yes Yes

Yes No

Yes Yes

identified

Yes

No

No

Y e s

Y e s

Yes

Yes—

tentative

Yes

No

Yes

SOURCE: Office of Technology Assessment, 198S.
58

I

M

Photo credit: Ray White, The University of Utah Medical Center, Salt Lake City,

UT. Repr/nted with permission from American Journal of Human Genetics 39:3(B

306, 1986.

Identification of a genetic marker showing linkage between high levels of low-density lipoprotein (LDL) cholesterol and the genetic locus for the LDL receptor gene

using restriction fragment length polymorphism (RFLP)

analysis of the LDL receptor genes from a multigenerational family with inherited hypercholesterolemia. A

radioactively labeled DNA fragment from the cloned

LDL receptor gene was used as a probe to observe

differences among affected and unaffected individuals

in the numbers of electrophoretically separated DNA

fragments after cutting the DNA with a restriction enzyme. Individuals without the polymorphism are represented as unfilled squares (males) or circles (females)

and show only one DNA fragment. Hal f-f illed symbols

represent individuals with one allele for the defective

gene and one for the normal gene and show two DNA

fragments. The lane marked “M” is a set of

DNA fragment size markers.

dividuals with genetic diseases is described in detail in chapter 2. Such methods of DNA analysis

offer several advantages over traditional approaches to the study of human disease. Knowing the organization of genes on chromosomes

and their DNA sequences could enable clinicians

to detect mutant genes before a disease manifests

itself in the form of damaged cells or tissues and

will eventually lead to a more complete understanding of the pathogenesis of human disease

[Friedmann, see app. A].

The study of randomly selected RFLP markers

in human families has revealed linkages to a number of genetic diseases (table 3-1) (1,3,6, 10,16,17,

23)25,29,32,37,38,41,42,46,52,55,56), As the chromosomal locations of more disease-causing genes

are identified, more probes for diagnosing genetic

diseases will become available. A genetic linkage

map saturated with RFLP markers (or one

with other polymorphic markers) is viewed by

many molecular geneticists as crucial to the

development of diagnostic reagents for there

maining human genetic diseases [Friedmann,

see app. A]. (See table 3-2 for a list of companies

developing diagnostic probes for such diseases.)

It is important to recognize that DNA probes

for RFLP markers are not always reliable tools

for diagnosing genetic diseases before the onset

of symptoms. Without enough data from relatives

of potential disease carriers, it may not be possible to confirm the linkage between a particular

RFLP marker and a genetic disease. The main limitation to reliable diagnosis of most genetic diseases

is the lack of an adequate number of DNA samples from several generations of affected and unaffected individuals.

Many available RFLP markers can be used only

in a few families, and the RFLP marker map is

a cumulative one that aggregates the data from

many families. The largest standard data set is

derived from the Center for the Study of Human

Polymorphism (CEPH) in Paris (see ch. 7 on international efforts in genome mapping). The data collected by CEPH are taken from 40 families around

the world, most of which do not have any known

genetic disease. Materials from these families are

used to locate RFLP and other polymorphic markers. Once markers have been identified, they can

be tested for linkage to a particular genetic disease in families known to have that disease. The

Table 3-2.—Some Companies Developing DNA Probes

for Diagnosis of Genetic Diseases

Company Probes under development

California Biotechnology Susceptibility to heart

(Mountain View, CA) disease

Cetus Corporation sickle cell anemia

(Emeryville, CA)

Collaborative Research Cystic fibrosis

(Bedford, MA) Duchenne muscular

dystrophy

Polycystic kidney disease

Integrated Genetics Cystic fibrosis

(Framingham, MA) Hemophilia B

Huntington’s disease

Polycystic kidney disease

Sickle cell anemia

Lifecodes Cystic fibrosis

(Elmsford, NY) Down’s syndrome

Polycystic kidney disease

Sickle cell anemia

SOURCE: Office of Technology Assessment, 198S.
59

Photo credit: The Bettmann Archive, New York, NY

A large New England family of the early 1900s spanning three generations. Samples of genomic DNA from members

of such families are very useful for constructing genetic linkage maps, such as a RFLP map.

CEPH families are large, selected to enable scientists to trace DNA markers through at least three

generations.

Isolating Genes Associated With

Disease

Some inherited human diseases arise from or

cause differences in detectable proteins that circulate in the blood, such as human growth hormone and insulin. A research scheme called forward genetics has been used to isolate the genes

encoding these proteins. In this strategy, a gene

is cloned after the altered protein product has

been characterized. Other genetic diseases, such

as retinoblastoma, chronic granulomatous disease,

and Duchenne muscular dystrophy, involve protein products that were not identified before the

corresponding gene was cloned. An experimental

approach called reverse genetics was used to find

these genes. First the gene containing the mutation responsible for the disease is linked to a RFLP

or other polymorphic marker, then the gene and

its protein product are isolated and characterized

 [Friedmann, see app. A].

Forward Genetics

Until recently, most methods for cloning diseaseassociated genes required prior characterization

of the biochemical defect responsible for the disease. Using the forward genetics approach, researchers identify the mutant gene product—a

protein—then isolate a clone of the gene from a

library of cDNA clones (clones made from DNA

copies of the mRNA transcripts of genes—see ch.

2). If the protein has been purified, antibodies can

be made and used to select for clones of cells expressing the product. Alternatively, if part of the

protein’s amino acid sequence is known, synthetic

DNA prohes complementary to the exons, or

protein-coding sequences, of the gene can be designed, based on the genetic code (figure 3-2). Once

the cDNA clones are isolated, they can be used

as DNA probes to pick out clones from genomic

libraries.
60

Figure 3=2.-The Use of Synthetic DNA Probes To Clone Genes

An mRNA Sequence Predicted from AUG UAC AGG AUG CAA CUG UCU UGC

Amino Acid Codon Usage Frequencies

DNA PROBE Sequence Complementary TAC ATG TCC ATC GTT GAC AGA ACG

to Predicted mRNA Sequence

Culture Plate with

Cdonios of Bacteria

Carrying Cosmids with

cDNA Inserts

Fiitar
—

61

The difference between cDNA copies of genes

and genes on chromosomes is that the latter have

both exons and introns (noncoding sequences interrupting protein-coding sequences). The genes

in the human genome range from fewer than

1)000 base pairs to more than 2 million base pairs

in size and are thus typically too large to be contained on standard cloning vectors (table 3-3). The

cDNA clones, which are smaller because they contain only exons, are useful because they can be

introduced into bacteria, yeast, or mammalian tissue culture cells and transcribed and translated

into protein. The resulting proteins can be used

in studies of the physiology of diseases or in some

cases as human therapeutics.

The utility of the various types of physical

maps in the forward genetics strategy depends

on the purpose of isolating the gene. If only

cDNA copies of a particular gene are needed for

making large quantities of the protein product,

then extensive genomic maps would not be necessary. If the cDNA copy of the gene is to be used

as a DNA probe for isolating the whole gene from

a collection of genomic DNA clones, or for studying the organization of the genome in the region

of interest, then a contig map illustrating the order of DNA segments from the relevant portion

of the genome would be very useful.

Reverse Genetics

Reverse genetics has made it possible to isolate

genes associated with inherited diseases for which

no specific biochemical defect has been established. To do this, the genetic disease is usually

linked first to a particular chromosome by studying inheritance patterns at the DNA level. The general region of the gene on the chromosome is identified using DNA probes for RFLP markers on that

chromosome. Samples of DNA from families of

individuals afflicted with the genetic disease are

tested with a set of DNA probes which hybridize

to markers spaced throughout the chromosome

until a linkage between the mutant gene that

causes the disease and the RFLP is detected. The

location of the gene is then identified more preTable 3.3.—The Size of Human Genes

Gene size mRNA size

(in thousands (in thousands Number of

Gene of nucleotides) of nucleotides) introns

Small:

Alpha-globin . . . . . . . . . . . . . . .

Beta-globin. . . . . . . . . . . . . . . . .

Insulin. . . . . . . . . . . . . . . . . . . . .

Apoliproprotein E . . . . . . . . . . .

Parathyroid. . . . . . . . . . . . . . . . .

Protein kinase C . . . . . . . . . . . .

Medium:

Collagen I

Pro-alpha-l(1) . . . . . . . . . . . . .

Pro-alpha-2(1) . . . . . . . . . . . . .

Albumin . . . . . . . . . . . . . . . . . . .

High-mobility group

COA reductase . . . . . . . . . . .

Adenosine deaminase . . . . . . .

Factor IX . . . . . . . . . . . . . . . . . .

Catalase . . . . . . . . . . . . . . . . . . .

Low-de nsity-lipoprotei n

receptor . . . . . . . . . . . . . . . . .

Large:

Phenylalanine hydroxylase . . .

Factor Vll . . . . . . . . . . . . . . . . . .

Thyroglobulin . . . . . . . . . . . . . .

Very large:

Duchenne muscular dystrophy

0.8

1.5

1.7

3.6

4.2

11.0

18.0

38.0

25.0

25.0

32.0

34.0

34.0

45.0

90.0

186.0

300.0

2,000<0

0.5

0.6

0.4

1.2

1.0

1.4

5.0

5.0

2.1

4.2

1.5

2.8

1.6

5.5

2.4

9.0

8.7

17.0

2

2

2

3

2

7

50

50

14

19

11

7

12

1 7

50

SOURCE: Victor McKusick, The Johns Hopkins University, Baltimore, MD.
62

cisely by using additional probes for closely spaced

markers that cover the region of interest.

In order to distinguish the gene locus that actually causes the disease from nearby, but unrelated,

genes, it is generally necessary to demonstrate

that the identified gene is expressed abnormally

in tissues from patients with the disease. A

genomic region 1 million base pairs in length, for

example, could contain as many as 100 genes. In

such cases, it is necessary to use biochemical methods to identify the gene that is responsible for the

disease. Techniques for detecting messenger RNA

transcripts or proteins can be used to search for

differences in amounts of geneprociuct in the tissues of affected and unaffected individuals; these

differences can then be correlated with an alteration in a particular gene. Retinal cells were analyzed in this way as part of the search for the

retinoblastoma gene (18,28), as were muscle cells

in individuals with and without Duchenne muscular dystrophy (see box 3-B). Once the gene product has been identified, it is possible to study the

physiology of a particular disease with the aim

of identifying a therapy or preventive treatment.

Although reverse genetics is generic in concept,

the amount of effort involved in isolating and characterizing genes using genetic and physical map

data varies. Over 100 person-years have been

spent searching for the gene that causes cystic

fibrosis–an effort that has led to localizing the

gene on a small region of chromosome 7 but not

to finding the gene itself or determining how it

causes the disease (17). On the other hand, researchers identified and isolated the gene for

chronic granulomatous disease in far fewer

person-years (38). The existence of DNA probes

for RFLP markers has also made possible the identification of the genes for Duchenne muscular dystrophy (32) and retinoblastoma (18,28) [Friedmann,

see app. A].

The technical difficulty involved in locating the

gene responsible for a particular disease by reverse genetics usually depends on the physical

map distance between the nearest RFLP marker

and the linked gene. Existing RFLP maps of the

human genome have a resolution of only about

10 centimorgans (approximately 10 million base

pairs). A map with markers spaced every 1

centimorgan would make it much less

timeconsuming to locate the genes by reverse

genetics (7,33). Such a map would be constructed

using a pool of several thousand DNA probes that

detect RFLP markers spaced about every 1 million base pairs throughout the genome. A library

of clones made from overlapping segments of

the genome and a contig map illustrating the

relative position of each clone with respect to

its neighbors would also be useful in reverse

genetics. These tools would spare researchers

the labor-intensive step of isolating and characterizing all of the genomic clones between the

marker and the gene of interest; the only work

remaining would be to associate the characteristics of the disease with the correct clone or clones.

Identification of Genes Involved in

Polygenic Disorders

Genetic linkage maps of the human genome are

also useful for characterizing inherited diseases

caused by more than one factor, often referred

to as polygenic disorders. Among the diseases for

which more than one gene is likely to be responsible are certain cancers, diabetes, and coronary

heart disease (27). For example, in a complex disorder such as coronary heart disease, blood

plasma lipoproteins, the coagulation system, and

elements of the arterial walls all play a role, so

the number of genes involved can be very large

(40). Some scientists argue that the RFLP maps

currently available, with markers spaced an average of 10 centimorgans apart, area sufficient starting point for studies of polygenic diseases (11).

Highenresolution RFLP maps, such as a 1-

centimorgan map, would no doubt simplify

the job of identifying the genes responsible for

polygenic disorders.

Developing Human Therapeutics

Forward genetics has yielded important results

in the area of drug development. As stated earlier,

the ability to use cDNA clones has been crucial

to the development of commercial products such

as human growth hormone and insulin and to potential human therapeutics such as tumor necrosis factor and interleukin-2, therapeutics that

would not otherwise be available in the quantity

or quality necessary for effective use (table 3-4)
63

BOX 3-B.— Duchenne and Becker’s Muscular Dystrophies

Duchenne muscular dystrophy (DMD) is a genetic disease that affects 1 in 3,000 to 1 in 3,500 male

infants born. Becker’s muscular dystrophy is a similar but milder disorder with much lower incidence.

Both diseases begin in childhood and lead to muscle wasting. DMD typically results in death before age

20. The search for the gene causing these diseases and the protein encoded by that gene has been an exciting story of molecular biology in the 1980s. The effort in many ways typifies modern genetics, with extensive international collaboration, study of nonhuman species, and creative use of molecular methods.

The gene causing these diseases had been known for some time to be on the X chromosome because

of inheritance patterns. Duchenne and Becker’s muscular dystrophies affect primarily boys, who have only

one X chromosome, inherited from their mothers. Girls have two X chromosomes and therefore must,

as a rule, receive abormal genes from both parents in order to develop Duchenne or Becker’s muscular

dystrophy–a much less likely occurrence.

The search for the gene started with studies of families. DNA from persons with DMD, including several

girls and one boy, was collected in an effort to find a common area of the X chromosome that had been

lost or altered. once the correct region of the X chromosome had been identified (its absence was found

to cause DMD), DNA from that region was obtained and cloned. The clones were used as DNA probes

for complementary mRNA sequences in muscle tissue from affected and unaffected individuals. The purpose was to identify the mRNA gene transcript that was present in unaffected individuals but altered in

persons with DMD. The mRNA was located and subsequently shown to encode a large protein called dystrophin found in muscle cells.

The DMD search has uncovered some extraordinary facts. Duchenne and Becker’s muscular dystrophies

are caused by different changes in the same gene. That gene is the largest found to date, spanning over

2 million base pairs (table 3-3). It is broken into at least 60 exons.

The scientific collaboration that led to the discovery of dystrophin was notably efficient. One paper

alone listed 77 authors from 24 research institutions in 8 countries. Molecular probes, clones, and materials

from affected patients were openly exchanged, hastening researchers in their quest for the culprit gene.

so[TR(:h;s

K.H F]schheck, ,\. tt’ Ritter, 0.1. ‘1’irschwetl, et al., “Recombination W’ith pER’I’87 (DXS164) in Families With X-linked Muscular DystrophJ, [.ancef

2LJuly ) 104, 1986

E P H[}ffnlal], A P. Monaro, C C. Peenel, et al , “Conservation of the Duchenne hluscular Dystrophy Gene in Mice and Humans” Srirwre 238347-3.50, 1987

E.P Hoffman, R.H Brown, and I..hl Kunkel, “Dystrophin: The Protein Product of the Duchenne Muscular Dystroph?r Locus, ” (’e)] .51 919.928, 1987

\l Koenig, E P Hoffman, C.J, Bertelson, et al , “Complete Cloning of the Duchenne Muscular Dystrophy (DMD) cDNA and Preliminary (,enom]r organlzat]on of the DMD Gene in Normal and Affected Individuals, ” Cc// 50:509-517, 1987.

1,. M. Kunkel et al., “Analysis of Deletions From Patients With Becker and Duchenne Muscular Dystrophy, ” Nature 322 ”73-77, 198[;

A P k!onaco, R .1,. Neve, C. Colletti-Feener, et al., “Isolation of Candidate cDNAs for Portions of the Duchenne Muscular f)J strophj (km, “ ,\’.ifurt> :j~:j 646.

650, 1986,

A.P Monaco, C.J. Bertelson, C. Colletti-Feener, et al., “1.oca]ization and Cloning of Xp21 Deletion Breakpoints tmolved in Muscular L)jstrophJ ‘ ffuman

Genetics 75:221-227, 1987.

G J ~an Omenn, J .M. Verkerk, M .H. Hofker, et al., “A Physical Map of 4 Million Base Pairs Around the Duchenne Muscular D\;st ruph}, (+ne on the

X Chromosome,” Cell 47:499-504, 1986

(53). The cDNA clones isolated by forward genetics ural human proteins made from isolated human

could be used to make a cDNA map that illustrates

the chromosomal locations of expressed regions

of DNA. This cDNA map, plus a library of pre

viously ordered clones of genomic DNA, would

be valuable tools for studying the role of cep

tain genes in the manifestation of disease.

Knowledge of the mechanisms directing normal

cellular functions will probably lead to important

sources of new therapies for human diseases: nat -

genes, engineered proteins, and conventionally

synthesized drugs designed from a knowledge of

the structure of the proteins they target. A dvances in the development of human therapeutic products will be made more rapidly if research in the areas of protein engineering, the

relationship of protein structure to function,

rational drug design, and others parallels genome mapping efforts.
.—

64

Photo credit: Nancy Wexler, Columbia University, New York, NY

A Venezuelan man with Huntington’s disease, a rare,

late-onset genetic disease that causes degeneration

of nerve cells in the brain.

Prospects for Human Gene Therapy

Clinical use of human genetic linkage and physical maps, now largely restricted to diagnosis, may

eventually include the insertion of normal DNA

directly into human cells to correct a particular

genetic defect (54). This practice is called human

gene therapy. Advances in gene therapy will depend on development of ways to insert DNA into

cells safely and to ensure that the’ inserted DNA

corrects the defect (54). Gene mapping will not

improve gene therapy directly, and for most diseases the ability to make a diagnosis will precede

the availability of an effective treatment. The

knowledge gained through use of gene maps will,

however, enhance knowledge about the function

of genes and thus indirectly improve the prospects

for gene therapy [Friedmann, see app. Al.

Table 3=4.—Some Human Gene Products With

Potential as Therapeutic Agents

Gene product

● Actual or potential therapeutic application

Atrial Natluretic Factor

Ž Possible applications in treatment of hypertension

and other blood pressure disorders, and for some

kidney diseases affecting excretion of salts and

water.

Alpha Interferona

• Approved for treatment of hairy celI leukemia;

possible broader applications in other cancers.

Beta Interferon

● Inhibits viral infections and may be useful as an

anticancer treatment.

Epidermal Growth Factor

. Expected to have applications in wound healing,

including burns, and for cataract surgery.

Erythropoietin

. Anticipated treatment use for anemia resulting

from chronic kidney disease.

Factor Vlll:Cb

● Prevents bleeding in patients with hemophilia A

after injury.

Flbroblast Growth Factor

. Possible use in wound healing and treating burns.

Gamma Interferon

. Possible treatment for scleroderma and arthritis.

Granulocyte Colony Stimulating Factor

. Possible treatment for Acquired Immune Deficiency

Syndrome (AIDS) and leukemia.

Human Growth Hormonea

• Approved as a treatment for chiId hood dwarfism;

expected to have broader therapeutic potential in

treatment for short stature resulting from Turner’s

syndrome and for wound healing.

Insulina

. Approved for treatment of diabetes.

lnterleukin.2

● Possible treatment for various cancers.

Microphage Colony Stimulating Factor

. Potential applications are for treatment of

infectious diseases, primarily parasites; possible

cancer therapy.

Superoxide Dismutase

. Possible preventive treatment for damage caused

by oxygen-rich blood entry into oxygen-deprived

tissues (e.g., during organ transplants).

Tissue Plasminogen Activator

. Approved as treatment for dissolving blood clots

associated with heart attacks.

Tumor Necrosis Factor

● Possible anti-tumor therapy.

aApproved for commercial gale in the United States by the Food and Dru9

Administration.

%on-recombinant DNA version has been approved for sale, but the cloned gene

product has not.

SOURCE: Office of Technology Assessment, 1988.
65

APPLICATIONS IN HUMAN PHYSIOLOGY AND DEVELOPMENT

Studies aimed at understanding the molecular

basis of inherited diseases may yield information

that can be generalized to other physiological processes. Knowledge of the structure and function

of genes associated with Alzheimer’s disease, for

example, might give important clues to the cellular mechanisms regulating aging of brain tissue.

The organization of genes in genomes is another

fundamental issue in biology. Is it important for

genes to exist on a particular chromosome in a

particular order? Comparisons of physical maps

of the chromosomes of higher organisms could

shed some light on the extent to which gene organization is associated with gene expression and gene

function.

The nucleotide sequences of human genes have

been and will continue to be important research

tools for understanding the basic cellular processes underlying physiology and development.

Nevertheless, knowing the DNA sequences of

genes and how they translate into the amino acid

sequences of protein products is not sufficient to

establish how such genes are controlled or how

the gene products function in a particular cell or

in the organism as a whole. The genetic code that

guides the translation of DNA sequence into protein sequence offers only the first step in unraveling the mysteries of the human genome. Understanding the relationship between protein

structure and function is the crucial next step,

but it faces the greatest number of technical bottlenecks (see box 3-C).

Identification of Protein-Coding

Sequences

Individual efforts to clone particular genes

will not be eliminated by the availability of

genetic linkage and physical maps; rather they

will be redirected toward localizing a particular gene within a region of a chromosome or

within the DNA sequence of that region. Because human genes are more often interrupted

by introns, the identification of the exon and regulatory sequences in and around genes has proved

more difficult in human beings than in lower

organisms. The most reliable method of identifying exons is to know the amino acid sequence of

the protein product and, using the genetic code,

find the corresponding DNA sequence by inspecting the whole gene sequence. DNA sequences can

be determined at a faster rate than proteins can

be isolated and sequenced, however, so computerassisted methods offer a more practical approach.

There is a variety of computer software available for predicting exon sequences, some of it

more reliable than others (12,14,48) [Mount, see

app, A]. As more DNA sequences become available, methods for predicting exons can continue

to be refined. Computer scientists argue that

the analysis phase of whole genome sequencing projects will progress efficiently only if the

development of new computational and other

theory-based predictive methods that can accommodate large sequences is emphasized.

Photo credit: Shirley Ti/ghman, Princeton University, Princeton, NJ

Electron micrograph revealing an intron sequence interrupting the protein-coding sequences of the mouse

beta-g lobin gene. DNA containing the gene (including

intron sequences) was allowed to hybridize (base pair)

with beta-globin mRNA that had been isolated from

cells in its mature form with no intron sequences. A

loop appears in the region of the intron where no complementary sequences exist between the two

molecules (see arrow).
66

Box 3-C.— From Gene Structure to Protein Structure: The Protein-Folding Problem

“Protein-folding is the genetic code expressed in three dimensions,” according to Fetrow and co-workers.

How does the linear sequence of amino acids code for a protein’s structure? How does the three dimensional

conformation of a protein drive its function? Sometimes the amino acid sequence of a protein with an

unknown function is similar to that of a protein with a known function; in many such cases, the similarity

is a valid indicator of comparable jobs. In other cases, the threedimensional structure of a protein (the

amino acid sequence folded into the actual structure of the protein) gives more reliable clues about function. It is therefore important to develop experimental and theoretical means for determining the threedimensional structures of proteins. Because proteins are so large, often consisting of multiple domains (discrete portions) with different functions, this generally involves analysis of how each part of a protein contributes to its overall structure.

There is experimental evidence that certain structural domains can serve similar functions in a number

of different proteins. It is the combination of domains that gives a protein its unique overall function. A

stretch of amino acids in one protein can be nearly identical in sequence to that in another protein, but

if the surrounding amino acid sequences are different, then the sequences might fold into domains with

quite different threedimensional structures. At present, scientists cannot predict with certainty how the

linear sequence of amino acids in a protein will fold into the protein’s threedimensional structure—thus

the protein-folding problem. As genome mapping projects make more gene sequences available, the problem will take on even greater significance. The National Academy of Sciences in a recent report called

protein folding “the most fundamental problem at the chemistry-biology interface, and its solution has the

highest long-range priority.”

Most predictions of three-dimensional structure are based on theories of the behavior of amino acids

in certain chemical and physical environments and on information gleaned from viewing the atomic structures of proteins through X-ray diffraction. (X-ray diffraction of protein crystals is an important tool in

structural biology-the field dedicated to the study of proteins and other macromolecular structures. It

is the most important technique for determining the threedimensional structure of large proteins at the

atomic level. ) Existing methods for predicting structure are not reliable for all proteins or protein domains,

because structural data are available for only about zoo proteins and for even fewer classes of proteins.

There are few membrane proteins in the structure database, for example, and thus little experimental

basis for testing predictions about how such important proteins will fold. More structures of proteins need

to be determined, using X-ray crystallographic and other biophysical technologies, in order to provide a

solid foundation for protein-folding theories. Once the protein-folding problem is solved, the road from

gene sequence to gene function will be considerably shortened and will lead, in some cases, toward the

development of promising new human therapeutic products.

SC) URCES:

T, Blundell, B.L. Sibanda, M.J,E, Sternberg, and J.M. Thornton, “Knowledge-Based Prediction of Protein Structures and the Design of Novel Molecules, ”

,Vature 326:347-352, 1987.

J.S, Fetrow, M.H. Zehfus, and G.D, Rose, “Protein Folding: New Twists, ” Bio~echnology 6:167.171, 1988,

T Koetzle, Brookhaven National Laboratory, Upton, NY, personal communication, March 1987,

National Academy of Sciences, Research Briefings (tvashington, DC: 1986, National Academy Press, 1986).

Approaches to Understanding

Gene Function

Isolating a gene is not nearly as difficult as determining how the gene and its products function in the cell. The following are some experimental approaches to solving this problem:

Ž to modify or inactivate the normal function

of a gene by replacing it with a modified

version,

● to inhibit the function of a gene’s mRNA or

protein product by using antibodies to the

protein or an RNA complementary to the

mRNA, and
67

● to compare the DNA sequence of a cloned

gene of unknown function with those of genes

whose functions are known.

Using the first two methods, scientists have studied the function of gene products by identifying

alterations in the biochemical or physical characteristics of the affected cell or organism (2,15,

24,26,30,36,39,44,50,51 ). The third strategy is theoretical, using sequence data accumulated from

previously characterized gene products to predict a function for a newly identified gene. Such

predictions can then be tested experimentally.

Probably the most widely used first step in determining the role of a gene is to find similarities

between its DNA sequence and those of genes

from other organisms. Yeast, for example, shares

with animal cells many of the molecules and processes that are being studied intensively in modern cell biology, including the factors modulating

cell structure and dynamics, the components of

the machinery that modulates protein secretion

from cells, the constituents of basic chemical pathways, and analogs of several mammalian oncogenes (genes involved in controlling the rate of

cell growth). Many of these factors and processes

were first identified or characterized, or both, in

higher organisms, but the application of them to

yeast genetics has provided new insights (57).

A recent study reported the use of yeast cells

to isolate a human gene that can substitute for

a yeast gene in regulating the yeast cell’s life cycle (34). Plasmid vectors carrying cDNA were introduced into yeast cells to find a human gene

product that was similar enough to a yeast gene

to replace it in the regulation of the yeast cell’s

life cycle. This was accomplished by mutating the

yeast’s copy of the gene and then finding cells that,

upon introduction of the appropriate human gene,

appeared to regain their normal function. The human cDNA clone identified by this technique is

thus a candidate for a protein that regulates life

cycles in human cells. Studies of the genomic version of the human gene will be necessary to definitively establish the role of this product in human

cell cycle regulation. This example illustrates how

yeast genetics and biochemistry can be used to

Photo credit: Oonald Riddle, University of Missouri, Columbia, MO

Micrograph comparing the appearance of a short, fat

nematode mutant called “dumpy” (above) with that of

a normal nematode (below). The mutant grows to only

two-thirds of the normal body length because of a mutation in a gene for a type of collagen (a protein) needed

for normal development (magnified 80 times).

identify human genes with important functions

(57).

In fruit flies, genetic research and the tools of

recombinant DNA have made it clear that certain

DNA sequences are involved in regulating the development of the organism. Different sets of genes

appear to be expressed at different times in the

course of development, causing the patterns observed in the developing embryo. How gene expression is regulated to create developmental patterns is a central question in biological studies of

many organisms. Fruit flies are easy to dissect and

to manipulate genetically, and much is known

about their development; they have therefore

proven to be a very useful model. One DNA sequence, called the horneo box, was first identified in the genes of fruit flies and later in those

of higher organisms, including human beings (31).

There is substantial evidence that the homeo box,

a short stretch of nucleotides of nearly identical

sequence in the genes that contain it, determines

when the expression of particular groups of genes

is turned on and off during development of the

fruit fly (35). As more gene sequences from fruit

flies, human beings, and other organisms are determined, more knowledge about the signals

governing developmentally expressed genes is

likely to be acquired [Mount, see app. Al.
—

68

Photo credit: John Post/ethwalt, University of Oregon, Eugene

Mutations in the gene Antennapedia, a homeotic gene, cause the fruit fly to develop an extra pair of antennas. Pictured

at left is the normal fruit fly, and at right a fly with the mutation. Homeotic genes have counterparts in humans and

vertebrates; each gene has a characteristic DNA sequence within its protein-coding sequences called the homeo box.

APPLICATIONS IN MOLECULAR EVOLUTION

The disciplines of population biology, genetics,

molecular biology, and cellular biology merge in

the study of how species evolve, constituting the

field of molecular evolution. The construction of

a physical map of the human genome will permit

molecular analysis of several questions fundamental to evolution, including how genomes change

and what factors cause them to change, as well

as how small-scale changes relate to the overall

evolution of the organism (45).

Species with different degrees of relatedness

can be usefully compared because their genes,

and thus the proteins encoded by those genes,

will have differing rates of sequence divergence.

The course of human evolution can be read in

the sequences of proteins (14). Comparisons of

human and mouse DNA sequences are probably

the most useful in the identification of genes

unique to higher organisms because mice genes

are more homologous to human genes than are

the genes of any other well-characterized organism, Comparisons of human DNA sequences with

those of lower organisms such as the fruit fly or

nematode are most useful in the identification of

genes encoding proteins that are essential to all

multicellular organisms. Finally, since yeasts are

single-celled eukaryotes (cells whose chromosomes are contained in nuclei), their sequences

are most useful in the identification of genes that

make proteins whose functions are essential to

the life of all eukaryotic cells because such proteins would be least likely to have undergone major changes in the course of their evolution

IMount, see app. A]. Table 3-5 shows how human

proteins can be classified by their period of invention: from ancient, to middle-age, to modern

(14).
69

Table 3-5.—Classification of Human Proteins

by Invention Period

1. Ancient proteins

A. First editions. Direct-line descendancy to human

and contemporary prokaryotes. Mostly enzymes involved in metabolism.

B. Second editions. Homologous sequences in human

and prokaryotic proteins, but apparently different

functions.

Il. Middle-age proteins

Proteins found in most eukaryotes but prokaryotic

counterparts are as yet unknown.

Ill. Modern proteins

C. Recent vintage. Proteins found in animals or plants

but not both. Not found in prokaryotes.

D. Very recent inventions. Proteins found in vertebrate

animals but not elsewhere.

E. Recent mosiacs. Modern proteins clearly the result

of shuffling exons.

SOURCE: Adapted from Doollttle, R F., Feng, D, F., Johnson, MS., and McClure,

M.A , “Relationships of Human Protein Sequences to Those of Other

Organisms,” Cold Spring Harbor Symposia on Quantitative Biology

51 ”447-456, 1986.

Physical map and sequence data accumulated

from many species over the past 10 years have

led scientists to recognize patterns of genome

change quite different from those proposed

earlier. Now, molecular evolutionists are beginning to understand such patterns as the duplication and acquisition of new genes and their corresponding functions, differences in the use of

the genetic code among different organisms (48),

and differences in the occurrence of gene families in different species (45).

important questions in molecular evolution arise

from the fact that the genes of prokaryotes (organisms without nuclei, e.g., bacteria), as well as many

genes in yeast and some multicellular organisms,

are not interrupted by introns:
70

● Are the introns found in genes today descendants of extra or unused DNA from bacteria

and eukaryotes such as yeast?

● Did prokaryotes rid themselves of intron sequences, or did they never have them?

● How did intron sequences get into the genes

that code for modern proteins (14)?

By sequencing similar genes from many species,

scientists have found that some introns have been

in place for very long evolutionary periods and

that the positions of introns within genes divide

the genes in ways that correspond to the distinct

functional domains of the proteins’ structures

(5,22,49). These observations have led tO n ew

models of molecular evolution (8,13,19-21,47). The

availability of more gene sequence data should

facilitate the assessment of theories about the evolution of genes and gene structures.

Sequences of more human genes, high-level

understanding of variations in genomic organization among individuals, and analyses of

differences between human beings and other

organisms should aid in the evaluation of

molecular evolutionary theories on how spe

cies originate (see boxes 3-D) 3-E) and 3-F). Recognition of differences in rates of nucleotide substitution, recombination, and other mechanisms

responsible for variation in the human genome

will lead to a better understanding of the molecular basis of these processes and of the constraints

on each. Evaluation of proposed models for the

propagation and evolution of multigene families,

such as certain classes of cell surface receptors,

requires a detailed knowledge not only of the relatedness of the DNA sequences in these genes, but

also of their locations in the genome and the DNA

sequences of the regions surrounding them (45).

Box 3-D.—Constructing the Evolutionary Tree: Morphology v. Molecular Genetics

in the Search for Human Origins

Ever since Linnaeus, biologists have classified animals according to similarities and differences in form

and structure. When the concept of evolution took root, these morphological features were used to establish phylogenies—trees or lineages that indicate the evolutionary relationships among species. New and

sophisticated methods of genetic analysis have challenged morphology as the prime determinant of family

trees. Recent debates about human origins have revealed the potential power of genetic techniques for

evolutionary studies.

For the past two decades or so, anthropologists and biologists studying the problem of primate evolution have agreed that chimpanzees and gorillas are closely related enough to be classified in the same family, while humans stand alone in a separate, more distant family. Morphological evidence favors this view.

Both chimps and gorillas, for example, walk on their knuckles; humans do not, and the fossils of their

most direct ancestors show no features associated with knuckle walking. Chimps and gorillas also share

similarities in the thickness and structure of their tooth enamel which suggest a common ancestry separate

from humans.

Analyses of the DNA of chimps, apes, and human beings contradict this view, Scientists recently examined comparable segments of DNA in the region of the beta -globin gene from human beings, chimpanzees,

gorillas, and orangutans. They sequenced 4,900 base pairs of DNA from this region in each organism, then

appended data for nearby regions for which sequences had already been published. In all, they compared

a 7,100-base-pair region and concluded that chimpanzee and human gene sequences were the least divergent. The most parsimonious explanation of the data was that human and chimpanzee are more closely

related to each other than either is to the gorilla.

The beta-globin study, while it strongly suggests that chimpanzees are the closest cousins of human

beings, does not conclusively end the search for human origins. Contradictions remain in the evidence

gathered from comparative anatomy and from genetic analysis; studies of other gene loci will be necessary

to settle the matter.

SOURCES:

R.L. Cann, “in Search of Eve,” The Sciences (September/October) :30-37, 1987.

R. Lewin, ‘<My Close Cousin the Chimpanzee,” Science 239:273-275, 1987.

M.M. Miyamoto et al., “Phylogenetic Relations of Humans and African Apes From DNA Sequences in the Globin Region,” Science 239:369-373, 1987
71

B OX 3-E. —The Origin of Human Beings: Clues From the Mitochondrial Genome

For more than a century, archaeologists, anthropologists, and biologists have been digging through

layers of dirt and rock, sieving fossils and artifacts, in an attempt to figure out when, where, and how

human beings differentiated from other primates to become a unique species. These scientists have relied

on a variety of tools, everything from the picks and axes used to dig up fossils to sophisticated techniques

for determining the age of the bones they have unearthed. Unfortunately, archaeological digs do not always

yield perfect clues: Even well-preserved fossil remains are generally incomplete, and there are still missing

links, cases in which fossils that could hint at the genealogy of several precursor species have not been

found. Thus, it has been difficult to determine exactly when human beings diverged from prehistoric ancestors to become the species now known as Homo sapiens.

The development of molecular genetic techniques for analyzing DNA offers a new source of evidence

in the ongoing debate about human origins. Techniques for mapping and sequencing DNA allow researchers to compare different species and different individuals from the same species at the most basic le~’el.

These comparisons can aid evolutionary studies.

one promising approach is the study of the DNA sequences of mitochondria, small structures that are

found in the cells of all multicellular organisms. Mitochondria are the power plants of eukaryotic cells.

They produce energy for life processes by providing a site for the combination of oxygen and food molecules.

Without them, cells would depend on less efficient processes of energy production and could not survi~~e

in an environment containing oxygen. Mitochondria have much in common with bacteria: They are similar

in size and shape, they both contain DNA, and they each reproduce by dividing in two.

The DNA in mitochondria can be more useful for some evolutionary studies than the DNA in cell nuclei,

for several reasons. First, since it lies outside the cell nucleus and sexual recombination occurs only within

the nuclei of sperm and egg cells, mitochondrial DNA is not recombined during sexual reproduction. It

is inherited only from the mother. Consequently, changes in the nucleotide sequences are due only to mutation and not to the natural shuffling of DNA that occurs during reproduction. Second, DNA in the mitochon -

dria is not protected as well as DNA in the nucleus, nor does it have the same kinds of mechanisms for

repair. Thus, mitochondrial DNA mutates about 10 times as fast as the chromosomal DNA in the cell’s nucleus, which means that the mitochondrial genome has evolved more rapidly than the chromosomal genome. Finally, mitochondria are relatively small: They contain approximately 16,000 base pairs, considerably fewer than the 3 billion base pairs in the entire set of human chromosomes, making them easier to analyze.

These three characteristics of mitochondrial DNA—absence of sexual recombination, a high natural

mutation rate, and small size—have helped scientists construct a “molecular clock” that can be used to

help establish the approximate time and place of human origins. By calculating the rate at which mitochon -

drial DNA changes and then comparing the DNA sequences of mitochondria from many individuals, researchers have begun to formulate genealogical trees. For example, scientists sequenced samples of mitochon -

drial DNA from 140 people around the world and used the information to propose that the first Homo

sapiens lived .200,000 years ago on the African continent. Prior to these findings, anthropologists speculated

that human beings originated nearly 1 million years ago. Debate continues among scientists about the validitv and proper application of mitochondrial DNA sequences in evolutionary studies, but it is clear that molecu -

lar genetics will play a growing role in this area.

soLIRct’s

B. Alberts, D Braj, J. Lew’is, et al., “’l’he E~olution of the Cell, ” in AfofecularBiology of the Cell (New York, NY: Garland Publishing 1983)

R.L Cann, “In Search of El e,” The Sciences (September fOctober):30-37, 1987.

RI.. Cann, M. Stoneking, and A C, Wilson, “Mitochondrial DNA and Human Evolution,” Nature 325:31-36, 1986.

R Lew’in, “k[olecular Clocks Turn a Quarter Century, ” Science 239:561 -56~, 1988.

J Tierney, 1. t$’right, and K Springen, ‘ The Search for Adam and El’e, ” Newsweek, Jan. 11, 1988, pp. 46-52.

J Wainscot, ‘[)ut of the Garden of Eden, ” ,Wttme 32,5.13, 1986.

J D. W’atson, N H Hopkins, J \\’. Roberts, et al , ,$ folecdar Bio/o@’ of the Gmw (hlenlo Park, NJ: f3en)amin (’umrnings Publishing, 1987)
72

Box 3-F.—Molecular Anthropology

Anthropologists working in a central Florida bog recently discovered 8,000-year-old human skeletons

with well-preserved brains, some of which have provided the oldest available samples of human DNA. Before this discovery, samples of DNA had been available only from the dried tissue remains of archaeological

specimens from more arid regions. The fact that DNA can be preserved in other than excessively dry conditions greatly increases the number of archaeological sites at which more ancient DNA samples may be

discovered. DNA fragments have also been prepared from Egyptian mummies, from an extinct animal called

a quagga, and from a 35,0()()-year-old bison from Alaska. Biologists have been trying to clone these DNA

fragments for use in studies of evolution. The sample from the extinct bison is likely to be old enough

for comparison with modern buffalo DNA; this comparison may provide clues to the mechanisms of genome evolution. The human DNA samples, although important discoveries, are too recent to be particularly

informative in studies of molecular evolution. As methods for working with the DNA extracted from these

ancient species are improved, and as more specimens are uncovered, the application of gene mapping and

sequencing technologies to anthropology and archaeology will be more feasible.

SOURCES:

B. Bower, “Human DNA Intact After 8,000 Years,” Science News, Nov. 8, 1986, p, 293,

G,H. Doran, D. A’. Dickel, W.E. Ballinger, et al., “Anatomical, Cellular and Molecular Analysis of 8,000-Year-Old Brain Tissue From the Windover Archaeological Site,” Nature 323:803-806, 1986.

APPLICATIONS IN POPULATION BIOLOGY

Population biologists study populations by

analyzing many individuals. They are interested

in similarities and differences among individuals,

among groups, among varieties, and among species. To address such questions as how geography and environment affect inheritance patterns of certain traits, a physical map and a

complete sequence of a single reference genome are not particularly valuable. It would

be more useful to have corresponding sequence

information from widely diverse geographical

areas, from various religious and ethnic subgroups, and from all races (9).

Population geneticists studying human beings,

plants, or animals make great use of molecular

markers—RFLPs and, increasingly, sequences of

specific regions—to assess the extent of genetic

variability (see box 3-G). Information on the same

small chromosomal region (e.g., a gene or a region important for gene expression) from many

individuals might be more useful than information on larger chromosomal regions from a few

persons (43), Genes for rare diseases are not all

found in a single human genome: Sickle cell hemoglobin, for instance, might not have been discovered if only Northern Europeans had been

studied (4,9).

Problems in population genetics that bear on

public health involve finding means for estimating human mutation rates,l for studying susceptibility to pathogens such as the virus responsible for acquired immune deficiency syndrome

(AIDS), and for assessing possible environmental

influences on these phenomena. The mechanisms

generating physical variability among human beings are by no means well understood and involve

not only genetic factors, but, among other things,

a complex set of environmental factors. DNA sequences from representative portions of many

human genomes would also be of more immediate use than whole genome sequences for

monitoring the effects of specific environmental factors on the structure of the human

genome (9).

‘An OTA report assesses these scientific issues: U.S. Congress, Office of Technology Assessment, Technologies for Detecting Heritable Mutations in Human Beings, OTA-H-298 (Washington, DC: U.S.

Government Printing Office, September 1986).
73

BOX 3-G.—Implications of Genome Mapping for Agriculture

Since the dawn of agriculture, people have manipulated plants to enhance desired traits simply by

observing the results of breeding, with no true understanding of the genetic principles involved. Many

scientists working in the field of plant molecular biology believe that genome projects will have important

implications for agriculture, by increasing knowledge about the genes that control or influence yield, time

to maturation, nutritional content, resistance to disease, insects, and drought, and other factors in the production of crops.

The first gene maps ever constructed were assembled as a result of a series of painstakingly detailed

crosses of pea plants and statistical analyses of data carried out by Austrian monk Gregor Mendel. Mendel

was the first to recognize that some traits could be transmitted according to regular hereditary patterns.

All modern genetics and much of modern biology build upon the foundation laid by Mendel.

Construction of RFLP marker maps has begun for corn, tomatoes, cabbage, and other crop plants. Such

genetic maps give plant breeders the ability to use gene structure rather than observable characteristics

to develop new varieties of plants. This ability should facilitate the development of intricate strategies for

manipulating complex traits controlled by multiple, interacting genes.

The availability of RFLP maps makes it possible to select for several unrelated traits simultaneously

or to manipulate traits controlled by clusters of genes that interact in complex ways. Researchers have

mapped three genes that control efficiency of water use (drought tolerance) and five genes that have a

major impact on flavor and soluble solids in tomatoes. Three genes that make a major contribution to insect

resistance in tomatoes have also been mapped. A group of genes that influences yield has been found in

corn. RFLP maps of genes influencing equally important traits are being developed for alfalfa, azaleas,

cucumbers, onions, roses, sugar beets, and grasses.

Recently, there has been renewed interest in a small flowering plant called Arabidopsis thaliana, a duckweed in the mustard family. Although this plant has no obvious economic or nutritional value, it is a valuable research tool for plant molecular biologists. The Arabidopsis genome, at about 70 million base pairs,

is about 10 percent or less the size of some of the major crop plant genomes, such as cotton, tobacco,

or wheat. The small size of this plant makes it an important model system for studying general mechanisms

of gene regulation that may be directly applicable to economically important but genetically less tractable

plants. For these reasons, work has already begun on making complete genetic linkage and contig maps

of the Arabidopsis genome.

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chapter 4

Social and Ethical

Considerations
CONTENTS

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Basic Research ., . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Levels of Resolution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Access and Ownership. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Commercialization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Diagnostic~herapeutic Gap. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Physician Practice. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Reproductive Choices. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Eugenic Implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Positive Eugenics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Negative Eugenics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Eugenics of Normalcy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Attitudes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Role of Government . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Duties Beyond Borders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Chapter 4 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Boxes

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Box Page

A.DNA Fingerprints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .......80

B. Determinism and the Human Genome. . . . . . . . . . . . . . . . . . . . . . . . . . . . .......86
Chapter 4

Social and Ethical Considerations

“Science is a match that man has just gotta light. He thought he was in a room—in

moments of devotion, a temple—and that his light would be reflected from and display

walls inscribed with wonderful secrets and pillars carved with philosophical systems

wrought into harmony. It is a curious sensation, now that the preliminary sputter is

over and the flame burns up clear, to see his hands lit and just a glimpse of himself

and the patch he stands on visible, and around him, in place of all that human comfort

and beauty he anticipated—darkness still. ”

H.G. Wells, 1891

“The moral significance of humankind is no more threatened by peeking at the underlying musical notation, the base sequences, than is reading the score of Beethoven’s

last symphony diminishing to that piece of work.”

Thomas H. Murray,

Case Western Reserve University, 1987

INTRODUCTION

As projects to map and sequence the human ge -

nome are undertaken, their long-range social and

ethical implications need to be considered as part

of policy analysis, yet further knowledge is needed

before many of these implications emerge. Some

will arise in the course of deciding what priority

to give genome projects and what level of resolution (coarse genetic linkage map, complete DNA

sequence) is most appropriate. More profound

ethical questions are posed by possible applications of genetic data for altering the basis of human disease, human talents, and social behavior.

Questions about personal freedom, privacy, and

societal versus individual rights of access to genetic

information are among the most important. A full

picture of the human genome will of necessity

raise questions about the desirability of using

genetic information to control and shape the future of human society. The complexity and urgency of these issues will increase in proportion

to advances in mapping and sequencing.

Part of the reason for studying genomes is to

see how variations in genes account for differences among people. Some of the issues raised

in this chapter relate specifically to these variations: What will be the impact of discovering that,

in their genetic endowment, human beings are

either more equal or more unequal than we now

suppose? other problems do not concern genetic

differences, but rather the impact of discovering

the extent to which genes do or do not limit the

options of human beings in general. One commentator has argued that scientists bear a responsibility for using “moral imagination” to anticipate

the full range of uses and consequences of their

work, especially when that work is in the basic

sciences (2).

The social considerations raised by genome projects include ethical issues. Ethical issues often arise

in the context of debates about values, principles,

or human actions that have had particular merit

in the past. Such debates about what ought to be

done often cannot be resolved by empirical inquiry. Specific genetic information such as the

location of a gene along a chromosome or the sequence of nucleotide bases composing a specific

gene is value-neutral and as such is not ethically

troublesome. However, questions about private

investment versus the allocation of Federal resources or about the proper use and availability

of genetic information are ethical questions because they involve choices among actions based

upon competing notions about what is good, right,

or desirable.

79
—

80

Competing ideas about the desirable course of

human action are developed from considerations

about the greater good, personal freedom, benefiting others, avoiding harm, and fairness and

equality. It is important to note that the ethical

issues surrounding the use of and access to genetic

information are not unique to the enterprise of

mapping and sequencing the human genome (10)

(see box 4-A). The existing uses of genetic screening, which in most cases are based on incomplete

information about the location of a specific gene,

already raise ethical questions. In addition, some

general ethical questions are moot because of contemporary realities, for example, the question of

whether there should be any human genome mapping and sequencing activities at all. This question is moot because mapping and sequencing projects have been underway for over a decade and

BOX 4-A.—DNA Fingerprints

DNA fingerprints are derived from traces of human biological material such as blood, semen, hair,

or other tissue. Recombinant DNA technology is applied to these samples to identify patterns of genetic

sequence that are unique to each human being. Matched DNA fingerprints can establish the identity of

a given individual with near certainty. DNA fingerprints, therefore, have great practical use in establishing

the identity of criminals, family members, or bodily remains.

Genetic fingerprinting raises ethical issues such as the maintenance of personal autonomy when tissue

samples are requested for identification purposes and the maintenance of confidentiality of individual genetic

profiles. Even after tissue specimens have been discarded, there is considerable fear that genetic records

will be retained in spite of the wishes of the human source of the tissue. California requires convicted

sex offenders to give blood and saliva samples before their release from prison. The provision of such

samples also makes it possible to discover information that may be incidental to past criminal records (e.g.,

XYY chromosome, drug use) but that could be used against the present or former inmates.

In the United States to date, practical applications of DNA fingerprinting have involved tests of specific

suspects or known criminals. There are plans in California to store this information in the world’s first

computerized data bank of DNA fingerprints. In Great Britain, however, a DNA analysis of blood samples

from all men and boys between the ages of 13 and 30 in Leicester County was conducted in an attempt

to identify the person who raped and murdered two teenage girls. A 17-year-oId boy originally charged

with the crimes was released when his genetic profile did not match that derived from the semen left

in the victims. More conventional investigative methods were later used to catch a suspect, a local baker

who had avoided the test. The mass screening effort left investigators with a genetic profile on every young

man in the county, information they later destroyed.

DNA fingerprinting has also been used as proof of paternity for immigration purposes. In 1986, Britain’s Home Office received 12,000 immigration applications from the wives and children of Bangladeshi

and Pakistani men residing in the United Kingdom. The burden of proof is on the applicant, but establishing the family identity can be difficult because of sketchy documentary evidence. Blood tests can also be

inconclusive, but DNA fingerprinting results are accepted as proof of paternity by the Home Office.

Testing of extended families has been used in Argentina to identify the children of at least 9,OOO Argentineans who disappeared between 1975 and 1983, abducted by special units of the ruling military and

police. Many of the children born to the disappeared adults were kidnapped and adopted by military “parents, ” who claimed to be their biological parents. Once genetic testing of the extended family revealed

the true identity of the child in question, the child was placed back in the home of its biological relatives.

It was initially feared that transferring a child from its military “parents” who were kidnappers but who

had nevertheless reared the child for years would be agonizing. In practice, the transferred children became integrated into their biological families with minimal trauma,

St) LIRCES’

Offwe of ‘rechnolo&v Assessment, based on Herman, R , “British Police Embrace ‘DNA’ Ihngerprints, ” The Washington Post, Xov 24, 1987

A J Jeffreys, J F Y Brookfiekf, and R. Semeonoff, “Positive Identification of an Imm]gratlon Test<ase [Jsmg Human DNA Fmgerprmts, ” ,Vature 317818.819, 1985.

J M Diamond, “Abducted orpbans [dentlfied by Grandpatwnity Testing,” Nature 327552.553 1987
81

there has been no concerted effort to prohibit

them. The more immediate questions, therefore,

are how these projects should best proceed from

now on and what use should be made of new

genetic information.

Each of the following sections begins with a list

of important social and ethical questions, followed

by a short general discussion establishing the context of these issues and, in some cases, outlining

opposing arguments. Decisions about mapping

and sequencing rest in part on arguments about

appropriate allocation of resources, Arguments

about access to versus control of knowledge turn

on debates about the relative importance of ethical principles such as autonomy (that is, selfdetermination or personal freedom of action) and

beneficence (the duty to act in ways that benefit

and do not inflict harm on others). There is general concern about the ways in which personal

freedom of action might be either enhanced or

diminished by increased knowledge about human

genetics. Finally, there is significant concern about

the possibility of eugenics, that is, that new and

existing information will be used in attempts to

improve hereditary qualities. The social and ethical arguments relevant to mapping and sequencing the human genome reveal the tension between

an attempt to arrive at some clear insight about

duties and obligations and an attempt to weigh

benefits versus harms. The purpose of this chapter is to describe and clarify important points of

social and ethical controversy, not to resolve them.

BASIC RESEARCH

●

●

How should the conduct of research in the

basic sciences, such as genome mapping and

sequencing, be influenced by a concern for

the social good?

What are the considerations when basic research in the biological sciences seems to take

resources away from areas of research that

might have more immediate social benefit?

A genetic linkage map of the human genome

already exists and progress has been made in the

development of a physical map. Practical debate,

therefore, centers on questions about the most

efficient and effective way to develop the complete physical map, that is, whether the whole human genome should be sequenced in a systemLEVELS OF

● What level of resolution of the physical map

is really needed, and for what purposes?

while even a rough genetic map, permitting the

identification of markers linked with major diseases, might prove useful to insurers or others

bent on identifying high-risk individuals, it would

have less value for basic researchers than a more

precise map. From an ethical standpoint, the key

arguments about levels of resolution, or molecular detail, are based on the distribution of costs

and benefits involved. If the public is asked to pay

atic way and how new genetic information should

be applied.

How these questions are answered depends

upon the values attached to scientific progress and

the relationship between scientific progress and

human good, There is a strong argument that basic

scientific research is valuable in and of itself and

should be pursued for its own sake. Coordinated,

systematic mapping of the human genome is consistent with this view, and proponents argue for

resources and against constraints in the name of

conducting good science. Others argue that scientists need to be responsive to and sometimes

even constrained by the public interest (7).

RESOLUTION

an appreciable portion of the cost, then it deserves

to participate in the political debate about embarking on an expensive, full-scale project. Scientific

and technical factors being equal, chromosomal

regions in which greater clarity would benefit

many people (e.g., those associated with prevalent genetic diseases) might be addressed first. If

the largest share of the costs is borne by the private sector, then few, if any, questions of priority

will be posed, other than those chosen by the persons investing in the projects.
82

●

●

●

●

●

●

ACCESS AND

What are the ethical considerations pertaining to control of knowledge and access to information generated by mapping and sequencing efforts?

Who should have access to map and sequence

information in data banks?

Do scientists have a duty to share information; what are the practical extent and limits

of such an obligation?

Who owns genetic information?

Do property rights to individuals’ genetic identities adhere to them or to the human species (14)?

Is genetic information merely a more detailed

account of an individual’s vital statistics, or

should this information be treated as intrinsically private, not to be sought or disclosed

without the individual’s express consent (10)?

There is a method in scientific research that allows investigators to pursue their hunches, test

their hypotheses, replicate their results, and publish their findings in roughly that order. Careful

adherence to this process ensures accuracy and

the orderly development of knowledge. The time

lag between discovery of new information and

communication of it, however, has caused some

commentators to question whether scientists have

the right to withhold information about genetic

markers that might be of great interest to the public at large.

OWNERSHIP

From an ethical perspective, it may be argued

that genetic information is by definition in the public domain: The human genome is a collective property that should be held in common among all

persons of human heritage (8). An opposing argument is that, since gene sequences are not commonly knowable and understanding them requires the use of expensive and often patentable

machinery, discovery of sequences and the fruits

that derive from them belong to the person who

uncovered them. By this reasoning, it does not

matter whether the sequences are unique or how

they might be used, it is the labor and inventiveness associated with the discovery of them that

makes them valid intellectual property. Current

patent law takes the latter tack but limits patentability by preventing the patenting of a person

or an idea.

One prominent scientist has acknowledged the

public’s special claim to the genome but argues

that a public enterprise may not be the best way

to satisfy this claim and that delay on so urgent

a project serves no one (5). A significant portion

of the value of the genetic information gathered

through human genome projects will not be fully

realized until some decades after the projects are

completed, but there is little doubt that it will help

elucidate the function and physical location of

genes that cause or predispose to illness and disease. For this reason alone, the sequences will have

substantial commercial value.

COMMERCIALIZATION

● What facets, if any, of human genome map- which are held by individual companies. The ethi -

ping and sequencing activities should be com- cal issues of privatization of this knowledge turn

mercialized? on the importance of sequences lost to others by

The commercial value of genome sequences has

already been recognized by companies that have

applied for patents on a number of specific materials and techniques. At least one company has

argued that it has the right to copyright and control the materials and maps that it develops (5).

academic - communities ‘or corporations which

have restricted the use of them. On one level, the

problem is largely academic, since the data needed

for a complete map and sequence could be assembled by the public sector, with duplication or purchase of the data held by private parties. On

another level, however, the Potential loss of critiThe selective forces of the marketplace have cal data, the duplication of effort, and the control

generated a database network, some portions of of knowledge raise serious questions about a com -

which are in the public domain and others of bined scheme of public versus proprietary hold-
83

ing of fundamental knowledge. There is a strong lowing scientists and others to retain the beneargument that parts of research that are funded fits of commercial exploitation of inventions.

publicly should yield public information, while alDIAGNOSTIC/THERAPEUTIC GAP

●

●

What are the ethical implications of the growing gap between diagnostic and therapeutic

capabilities?

Should diagnostic information about genetic

disorders for which there is no therapeutic

remedy be handled differently from that

about disorders for which there are therapeutic interventions?

There is no doubt that continuing scientific advances in mapping and sequencing the human

genome accelerate diagnostic applications. One

philosopher has noted that the ability to map the

human genome yields information about susceptibility that is more precise, more certain, and

PHYSICIAN

● Do physicians and other health care providers

face a conflict between an increasingly reductive approach to medical science and a focus

on holistic patient care (17)?

Increased information about human genetics

changes attitudes and alters the knowledge that

serves as a basis for health care interventions. Physicians and other health care providers must constantly alter their views and understanding of human behavior, health, and disease. There are many

examples of diseases that were once thought to

be amenable to preventive health care that are

potentially more threatening to individual freedom and privacy than earlier methods of presymptomatic diagnosis and vague hypotheses about

familial traits (10). A related issue is the need to

protect information that may be available to or

sought by third parties such as insurance companies or employers. Progress to date indicates that

the ability to diagnose a genetic abnormality precedes the development of therapeutic interventions and that this gap may be growing. This is

true for many genetic diseases, an important example being Huntington’s disease (see box 7-A in

ch. 7).

PRACTICE

now known to have a genetic component or cause.

On a practical level this presents obvious difficulties, as health care providers are increasingly uncertain whether they are dealing with patterns

of health and illness in individuals that can be

ameliorated by changes in life style and medical

treatment or if such patterns are in large part a

matter of genetic destiny. In addition, the ethical

principle of respect for persons indicates that individuals must be treated with care, compassion,

and hope because they are persons and not merely

the embodiments of a genetic formula or code,

REPRODUCTIVE CHOICES

● What ethical considerations arise from the The ethical question of one generation’s duties

increased ability of parents to determine the and obligations to another becomes more evident

genetic endowment of their children (through as genome mapping generates data pointing to the

such practices as selective termination of serious consequences of certain cultural practices

pregnancy, selective discarding of human em- or mating patterns. For example, it has been

bryos created in vitro, or selection of X- or demonstrated that, if it were possible to choose

Y-bearing sperm to determine the sex of the the sex of their children, many individuals and

child)? couples would prefer that their firstborn be male
84

(18). It has also been demonstrated that firstborn

children benefit from their early period of exclusive parental attention. If firstborn boys became

the norm, it might further compromise equality

of opportunity between men and women (16). In

such circumstances, the conflicts among values

and ethical principles such as autonomy, justice,

and beneficence will be strong. Human mating

that proceeds without the use of genetic data

about the risks of transmitting diseases will

produce greater mortality and medical costs than

if carriers of potentially deleterious genes are

alerted to their status and encouraged to mate

with noncarriers or to use artificial insemination

or other reproductive strategies (3).

On a practical level, the availability of information that couples might use to select embryos created in vitro has been hampered by an absence

of federally funded research concerning many aspects of human fertilization. There has been a de

facto moratorium on such research since 1980

(13).

EUGENIC IMPLICATIONS

● What ethical concerns arise from possible eugenic applications of mapping and sequencing data?

The possibility of mastery and control over human DNA once again raises the highly charged

issue of genetic selection. One major difference

between current and previous attempts at eugenic

manipulation is that any potential eugenicist will

have substantially more powerful techniques to

effect desired ends and more data with which to

muster support. With even the modest knowledge

achieved in their first century, genetic techniques

have become sophisticated enough to permit the

use of selective breeding to produce animals with

desired qualities.

When Francis Galton defined eugenics in 1883

as the science of improving the “stock)” he intended the concept to extend to any techniques

that might serve to increase the representation

of those with “good genes.” Thus, he indicated

that eugenics was “by no means confined to questions of judicious mating, but takes cognizance of

all the influences that tend, in however remote

a degree, to give the more suitable races or strains

of blood a better chance of prevailing speedily over

the less suitable than they otherwise would have

had” (4). Prior to the development of recombinant

DNA technology, eugenic aims were primarily

achieved by attempting to control social practices

such as marriage. New technologies for identifying traits and altering genes make it possible for

eugenic goals to be achieved through technological as opposed to social control.

Knowledge of human genetics will amplify the

power to intervene in the diagnosis and treatment

of disease. Each time a person who would otherwise have died of a disease caused or influenced

by a gene is treated successfully by genetic or nongenetic means, the frequency of that gene in the

population increases [Lappe, see app. A]. Human

genome projects will intensify and accelerate the

already difficult debates about who should have

access to one’s genetic information by providing

faster and cheaper methods of testing for genetic

variations, by making much more information

available, and by increasing the specificity of

genetic information (15). The ethical debate about

eugenic applications more properly focuses on

how to use new information rather than on

whether to discover it. Eugenic programs are

offensive because they single out particular people and therefore can be socially coercive and

threatening to the ideas that human beings have

dignity and are free agents.

Positive Eugenics

Beginning with Plato, philosophers have recognized that eugenic ends could be achieved through

subtle or direct incentives to bring together

presumptively fit human beings. Positive eugenics

is defined here as the achievement of systematic

or planned genetic changes in individuals or their

offspring that improve overall human life and

health and that can be achieved by programs that
85

do not require direct manipulation of genetic material.

Most commentators have rejected or cast doubt

on any uses of genetic engineering to enhance or

directly improve the human condition. The President’s Commission for the Study of Ethical Prob -

lems in Medicine and Biomedical and Behavioral

Research declared that efforts to improve or enhance normal people, as opposed to ameliorating

the deleterious effects of genes, is at best problematic (11).

It may well be that the problem with positive

eugenics has more to do with the means than with

the ends. The basic objective of improving the human condition is generally supported, although

debates about just what constitutes such improvement continue. Many concerns about eugenic policies in the past focused on the methods used to

attain them, such as sterilization, rather than on

the ends themselves.

Negative Eugenics

Negative eugenics refers to policies and programs that are intended to reduce the occurrence

of genetically determined disease. It implies the

selective elimination of gametes (ova or sperm)

and fetuses that carry deleterious genes, as well

as the discouraging of carriers of markers for

genetic disease from procreation. There are few

technical obstacles to karyotyping human beings

for eugenic reasons. Verbal genetic histories of

sperm donors, for example, are designed to exclude donors carrying some genetic diseases. Such

a screening process, accompanied by a physical

examination and laboratory tests, has already been

recommended by the Ethics Committee of the

American Fertility Society (l). The development

of specific genetic tests could make gamete screening easier and more specific and will also expand

existing capabilities to conduct prenatal tests.

Eugenics of Normalcy

The third eugenic use of genetic information

would be to ensure not merely that a person lacks

severe incapacitating genetic conditions, but that

each individual has at least a modicum of normal

genes. One commentator has argued that individuals have a paramount right to be born with a

normal, adequate hereditary endowment (6). This

argument is based on the idea that there can be

some consensus about the nature of a normal

genetic endowment for different groups of the

human species. The idea of genetic normalcy, once

far-fetched, is drawing closer with the development of a full genetic map and sequence; however, concepts of what is normal will always be

influenced by cultural variations and subject to

considerable debate.

ATTITUDES

● How will a complete map and sequence of It will also depend on how important human gethe human genome transform attitudes and nome projects are to understanding genetic facperceptions of ourselves and others? tors for complex traits. Whether higher human

One of the strongest arguments for supporting

human genome projects is that they will provide

knowledge about the determinants of the human

condition. One group of scientists has urged support of human genome projects because sequencing the human genome will provide one of the

most powerful tools humankind has ever had for

deciphering the mysteries of its own existence (12).

attributes are reducible to molecular constructs

is a topic of considerable debate in the philosophy of biology, and human genome projects would

doubtless enlarge and intensify this debate. A reasonable hypothesis is that, while little information of director immediate value regarding complex behaviors is likely to result from human

genome projects, insights into the possible construction of control regions for the development

The relevance of this proposition will depend of the human embryo, the genetic basis for orga -

on the degree to which complex human behaviors nizing neuronal pathways, and the genetic conare determined by understandable genetic factors. trol of sexual differentiation will all be significantly
86

enhanced. In the long run, knowledge of human

genetics will make scientific understanding of human life more sophisticated.

A greatly increased understanding of how genes

shape characteristics could influence human beings’ attitudes toward themselves and others

[Glover, see app. A]. Such increased understanding might highlight the degree to which genetic

factors are equal or unequal for traits that confer social advantage. This information might reveal that human beings have fewer options than

they suppose and could thereby encourage a determinist view of human choices (see box 4-B), or

it could reveal just the opposite. A general increase

in genetic information might also alter social customs based on erroneous scientific assumptions.

Many individuals have general beliefs about

their genetic potential for achievement in certain

spheres of activity, about the limits of possible

improvement through effort or environmental

change. These intuitive beliefs are often vague and

inaccurate. often, it is only in regard to a few skills

or characteristics that individuals have pushed

against the limits of their potential. When science

makes it possible to trace the actual limits of individuals, intuitive perceptions may turn out to be

wrong. This has the potential of both enhancing

and limiting personal liberty.

BOX 4-B.—Determinism and the Human Genome

Determinism in biology is the general thesis that, for every action taken, there are causal mechanisms

that preclude any other action. Mapping and sequencing the human genome will not alone impose a determinist view of human nature. Seeing where genes are located, or knowing the order of bases in the DNA,

will not alone make behavior predictable.

But mapping and sequencing together with tracing the pathways between genes and behavior will start

to paint a determinist picture. Scientists are now starting to work out these pathways. Take, for example,

the pattern of behavior classified by psychiatrists as sensation seeking, which involves a disposition toward

gambling and alcoholism. This behavior is correlated with low levels of activity of the platelet monoamine

oxidase. These levels of activity have been shown by studies of twins to be largely under genetic control.

In a determinist model, human actions can be explained in terms of causal mechanisms, even though

those mechanisms may be very complex. If this model is right, it seems that what human beings do, just

as much as what billiard balls do, is the product of a set of laws operating in particular circumstances.

This view of human nature is disturbing. It suggests that a Godlike scientist, with complete knowledge

of all the relevant causal laws and of the circumstances in which they operate, could successfully predict

human action. In two different ways, determinism is at least an apparent threat to our attitudes. First,

the elimination of genuine choice would leave no room for the belief that we can partly create, actualize,

or modify ourselves. Second, undermining choice may also undermine many emotional reactions to others.

The determinist picture may not leave room for justifiable resentment of what people do or for justifiable

feelings of blame or guilt.

There are alternative views within determinism. Hard determinism is the view that individual choice

is entirely ruled out, along with the emotional responses linked to holding people responsible for what

they do. Soft determinism asserts that free choice and responsibility are compatible with determinism.

The issue is whether the soft determinist can resist the hard determinist’s argument against freedom

and the reactive attitudes. There are two strategies for resisting: 1) to point out that determinism is not

the same as fatalism, that even in a deterministic world what human beings do influences the future; and

2) to disagree that determinism eliminates genuine choice, attempting to work out a model of free action

that is compatible with determinism.

SOURCES

Office of Technology Assessment, 1988

Clover, see app A.
87

ROLE OF GOVERNMENT

●

●

what is the proper role of government in

mapping and sequencing the human genome?

Specifically, does the government have a role

in deciding what data should be collected in

gene mapping and sequencing? How should

this information be disseminated and guarded

from abuse?

The lines of power, coercion, and authority in

the public and private scientific sectors are blurred

because the first genetic maps are being made in

corporations (e.g., Collaborative Research, Inc.)

and in private philanthropies based in universities (e.g., the Howard Hughes Medical Institute

at the University of Utah).

The ethical arguments for involving the Federal

Government in the process of genome mapping,

whether by shaping, constraining, blocking, or

doing nothing, center on the public interest in

making resources available in ways that are consistent with the considerations of beneficence, justice, and autonomy. These issues encompass academic freedom or freedom of scientific inquiry

because the projects have universal and lasting

implications. Once the human genome is mapped

and sequenced, the resulting data will have widespread implications for generations to come

[Lappe, see app. A].

The precise boundary between basic and applied science is hard to draw, but there is enough

understanding of where it lies to be able to use

it as a basis for policy. A case might very well be

made for a government policy that would leave

●

●

●

basic research unrestricted but that would place

some stringent controls on applied research and

technological applications, for example, by ensuring that genetic testing is voluntary and access

to data is controlled.

All research carries with it the likelihood of

changing one’s conception of the world and so

of changing one’s attitudes. For these reasons,

there is a strong case against government intervention to stop research. There are four main

arguments:

1.

2.

3.

4.

Stopping research might be opting for comfortable ignorance or illusion rather than uncomfortable truth. The growth of science has

rested on the preference for uncomfortable

truth. Those who view science as one of mankind’s finest creations will be dismayed at any

wholesale repudiation of this preference.

It is unlikely that existing world views, beliefs, and attitudes can be protected by shutting down basic research. The knowledge that

such protection was needed might itself start

to undermine existing views.

As a practical matter, it maybe that government cannot stop basic research, It is not easy

to monitor what goes on in laboratories, and

what is stopped in one country may take place

in another [Glover, see app. A].

Stopping research blocks both possible ben -

efits and risks. The belief that research can

be performed to permit benefits while coping with and occasionally avoiding risks is a

matter of historical precedent.

DUTIES BEYOND BORDERS

What, if any, ethical issues are raised when and sequencing information?

considerations of international competitive- . what issues are involved when applications

ness influence basic scientific research? of genetic information or biotechnology that

What, if any, are the duties and obligations are of great use to Third World countries are

of the United States to disseminate mapping not developed or fully exploited because they

and sequencing information abroad? are less profitable for industrialized counWhat are the implications of shared informa - tries?

tion for international competitiveness?

What are the international implications of The United States has recently proposed an insharing technological applications of mapping ternational framework of rules for science. The
88

purpose of this framework is to see that all nations do their fair share of basic research and that

all the results of such research be made public,

except for those with strategic implications (9).

The increased protection of intellectual property

and patent rights for technological innovations

formed the basis of this proposal; these rights were

also central to recent international trade talks.

There is some sentiment that barriers to the transfer of technology would continue even if there

were no reward for intellectual property. one

commentator has noted that, unless products are

protected by a set of principles now, basic scientific results could become increasingly restricted;

some nations might do less basic research and instead emphasize applying other nations’ results (9).

The most common single-gene defects, disorders

of the hemoglobin molecules that carry oxygen

in red blood cells, are highly prevalent in many

nations in Southern Europe, Africa, the Middle

East, and Asia. Such nations would benefit most

if research tools became widely available as they

were developed and if priorities for which chromosomal regions are mapped first took world

prevalence of disorders into account. Use of map

and sequence information by developing nations

may also require special attention to devising

screening tests that are cheap and simple, and

might entail access to services (e.g., sequencing

or mapping) located in developed nations

[Weatherall, see app. A].

CONCLUSION

All human beings have a vital interest in the social and ethical implications of mapping and sequencing the human genome. It is not surprising,

therefore, that there are debates about how genome projects should proceed. These extend beyond considerations of scientific efficacy and involve the interests of patients, research subjects,

physicians, academicians, lawyers, entrepreneurs,

and politicians. Mapping the human genome accelerates our rate of understanding—and the distance between increased understanding and direct intervention to alter the human genome is

shrinking. Add to this the development of scientific tools such as gene probes, and immediate

practical questions are posed: How should basic

research be conducted? What level of resolution

in mapping is necessary? Who should have access

to and ownership of data banks and clone repositories? How should thorny questions surrounding commercialization be handled? Long-range

questions about eugenics, reproductive choices,

the role of government, and possible duties and

obligations beyond national borders also arise.

These questions are complex and are not likely

to be resolved in the near future. It will therefore

be necessary to ensure that some means for explicitly addressing ethicaI issues attends scientific

work.

CHAPTER 4 REFERENCES

1. American Fertility Society, Ethics Committee, “Ethical Considerations of the New Reproductive Technologies,” Fertility and Sterility 46:1 S–94S, 1986.

2. Callahan, D., “Ethical Responsibility in Science in

the Face of Uncertain Consequences,” Annals of

the New York Academy of Sciences 265:1-12, 1976.

3. Campbell, R. B., “The Effects of Genetic Screening

and Assortative Mating on Lethal Recessive-Allele

Frequencies and Homozygote Incidence, ’’American

Journal of Human Genetics 41:671-677, 1987.

4. Galton, F., Inquiries Into Human Faculty (London:

Macmillan, 1883).

5. Gilbert, W., quoted in Roberts, L., “Who Owns the

Human Genome?” Science 237:358-361, 1987,

6. Glass, B., “Ethical Problems Raised by Genetics)”

in Genetics and the Quality of Life, Charles Birch

and Paul Abrecht (eds.) (New York, NY: Pergamon

Press, 1974), pp. 51-57.

7. Institute of Medicine, Responding to Health Needs

and Scientific Opportunity: The Organizational

Structure of the National Institutes of Health (Washington, DC: National Academy Press, 1984).

8. Issues of Collaboration for Human Genome

Projects, OTA workshop, June 26, 1987.

9. MacKenzie, D., “US Advocates a ‘World Code’ for

Science)” New Scientist 5 (November): 245, 1987.

10. Macklin, R., “Mapping the Human Genome: Problems of Privacy and Free Choice,” Genetics and the
89

Law III, A. Milunsky and G.J. Annas (eds.) (New

York, NY: Plenum Press, 1985), pp. 107-114.

11. President’s Commission for the Study of Ethical

Problems in Medicine and Biomedical and Behavioral Research, Screening and Counseling for

Genetic Conditions: A Report on the Ethical, Social, and Legal Implications for Genetic Screening,

Counseling and Education Programs (Washington,

DC: U.S. Government Printing Office, 1983).

12. Smith, L., and Hood, L., “Mapping and Sequencing

the Human Genome: How To Proceed, ” Biotechnology 5:933-939, 1987.

13. U.S. Congress, Office of Technology Assessment,

Infertility: Medical and Social Choices, OTA-BA-358

(Washington, DC: U.S. Government Printing Office,

May 1988).

14. U.S. Congress, Office of Technology Assessment,

New Developments in Biotechnology: Ownership

of Human Tissues and Cells, OTA-BA-337 (Washington, DC: U.S. Government Printing Office,

March 1987).

15. U.S. Congress, Office of Technology Assessment,

Human Gene Therapy, OTA-BP-BA-32 (Washington,

DC: U.S. Government Printing Office, December,

1984), app. B.

16. Walters, L., “Is Sex Selection a Frivolous Practice?

Yes,” Washington Post, Apr. 7, 1987, p. 11.

17. Weatherall, D., “Molecules and Man, ” Nature 328:

771-772, 1987.

18. Westoff, C. F., “Sex Preelection in the United States,

Some Implications,” Science 184:633-636, 1974.
chapter 5

Agencies and Organizations

in the United States
CONTENTS

Page

National Institutes of Health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93

The Institutes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95

Funding Mechanisms . . . . . . . . . . . . . . . . . . . . , . . . . . . . . . . . . . . . . . . . . . . . . . . . 95

Research Infrastructure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96

Peer Review. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98

Department of Energy ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99

The Office of Heakh and Environmental Research. . . . . . . . . . . . . . . . . . . . . . . . 99

Health and Environmental Research Advisory Committee Report . ..........101

National Science Foundation ..., . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ....102

National Bureau of Standards . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...103

Centers for Disease Control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ....103

Department of Defense . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...104

Office of Science and Technology Policy . . . . . . . . . . . . . . . . . . . . . . . . . . . . ... ...104

Domestic Policy Council . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ., ....105

Office of Management and Budget . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. ....105

Howard Hughes Medical Institute . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ....105

National Research Council. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...106

Private Corporations . . . . . . . . . . . . . . . . . . . . . . , . . . . . . . . . . . . . . . . . . . . . ......107

Private Foundations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..........109

Summary. .. .. .. .. .. .. ... ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. ....109

Chapter 5 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ........110

Figures

Figure Page

5-1.Organization of NIH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94

5-2, organization of DOE. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99

5-3. Howard Hughes Medical Institute Genomics Resources . .................106

Tables

Table Page

5-1.NIH Support for Mapping and Sequencing, Fiscal Year 1986 . . . . . . . . . . . . . 94

5-2. Division of Research Resources Activities Related to Molecular Genetics. . . . 97

5-3. Budget for Proposed DOE Human Genome Initiative . . . . . . . . . . , . . . . . . . . .101
Chapter 5

Agencies and Organizations

in the United States

“Science has been a formative factor in making both the Federal Government and

the American mind what they are today. The relation of the government to science

has been a meeting point of American political practice and the nation’s intellectual life.”

A. Hunter Dupree,

Science and the Federal Got~ernment

(Baltimore: Johns Hopkins University Press, 1986), p. 2.

Projects involving or related to mapping or sequencing the human genome can be found in several Federal agencies and nongovernment organizations in the United States. Activities at the

principal agencies and organizations will be briefly reviewed in this chapter. They include:

● Federal agencies:

—the National Institutes of Health,

—Department of Energy,

—the National Science Foundation,

—the National Bureau of Standards,

—the Centers for Disease Control,

—the Department of Defense,

—the office of Science and Technology Policy,

—the Office of Management and Budget,

—the Domestic Policy Council;

● Nongovernment organizations:

—the Howard Hughes Medical Institute,

—the National Research Council,

—private corporations,

—private biomedical research foundations and

other philanthropies.

NATIONAL INSTITUTES OF HEALTH

The National Institutes of Health (NIH) form one

branch of the Public Health Service of the U.S.

Department of Health and Human Services. They

are administered by a director, currently James

Wyngaarden. NIH is a highly decentralized confederation of institutes, divisions, bureaus, and

the National Library of Medicine (see figure 5-l).

The principal mission of NIH is to conduct and

support biomedical research to improve human

health.

NIH was established in 1887. Since World War II,

it has become “the foremost biomedical research

facility not only in the United States but in the

world” and “a brilliant jewel in the crown” of the

Federal Government, according to Wilbur Cohen,

former Secretary of the Department of Health,

Education, and Welfare (10).

The institutes with the largest budgets for

genetic mapping and DNA sequencing are the National Institute of General Medical Sciences, the

National Cancer Institute, the National Institute

of Allergy and Infectious Diseases, the National

Institute of Child Health and Human Development,

and the National Institute of Neurological and Communicative Disorders and Stroke (see table 5-l).

In fiscal year 1986, NIH supported approximately

3,000 projects that involved mapping or sequencing, with a combined budget of $294 million (out

of a total budget of $5.26 billion, of which all but

5 percent went for research activities) (18). NIH

estimated it spent $313 million for such projects

in fiscal year 1987 (18).

Planning at NIH is decentralized. The Office of

the Director has responsibility for overall direction, but most programmatic decisions are made

in the institutes, which are autonomous and

largely control their own budgets. A 1984 report

by the Institute of Medicine remarked on the “absence of the trappings of bureaucratic authority;

hence the Director manages largely on the basis

of persuasion, consensus, and knowledge” (11).

93
94

Figure 5-1.–Organization of NIH

Table 5.1 .—NIH Support for Mapping and Sequencing,

Fiscal Year 1986 (millions of dollars)

Human Nonhuman

Institute research research Total

NIGMS . . . . . . . . . . . . . . . . . . 12.4 99.6 112.0

NCI . . . . . . . . . . . . . . . . . . . . 18.3 24.2 42.5

NIAID . . . . . . . . . . . . . . . . . . . 6.0 28.0 34.0

NICHE . . . . . . . . . . . . . . . . . . 11.8 18.2 30.0

NINCDS . . . . . . . . . . . . . . . . 10.7 10.6 21.3

Other institutes and

divisions and the NLM . . 31. 9 22.1 54.0

Total . . . . . . . . . . . . . . . . . 91.1 203.0 294.0

Abbreviations: NIGMS = institute of General Medical Sciences; NCl = National

Cancer Institute; NIAID= National lnstituteof Allergyand Infectious Diseases;

NICHD= National lnstituteof Child Health and Human Development; NINCDS

= National Institute of Neurological and Communicative Disorders and Stroke;

NLM = Library of Medicine.

SOURCE’ Office of the Director, National Institutes of Health, May 1987, as modified by the Office of Technology Assessment.

National Institute

of Child Health and

Human

Development

National Institute

on Aging

policy were presented by many experts. Statements both in favor of and against special initiatives were aired (22). A working group of NIH administrators was formed subsequent to that

meeting. The working group is chaired by the director; other members represent several of the

institutes and divisions most directly involved.l

This working group is responsible for setting overall policies for NIH in connection with human ge -

nome projects, and it initiated two program announcements in 1987 (17). Included in NIH’s

related research figures are several grants to produce physical maps of other organisms or parts

of human chromosomes, to develop cloning or

DNA detection techniques, and to develop other

Coordination of the various institutes is accomplished largely by the Office of the Director. In

October 1986, the Advisory Committee to the Director held a meeting at NIH entitled “The Human Genome)” at which views about setting NIH

‘Other members of the NIH working group on the human genome

are Ruth Kirschstein (Director of the National Institute of General

Medical Sciences), Betty Pickett (Director of the Division of Research

Resources), Duane Alexander (Director of the National Institute of

Child Health and Human Development), Donald A.B. Lindberg (Director of the National Library of Medicine), Jay Moskowitz (Associate Director for Program Planning and Evaluation), and George Palade

(Yale University). Rachel Levinson (Office of the Director) is executive secretary.
95

relevant technologies. The new genome programs

are to develop new methods for analysis of complex genomes and to improve computer representation and analysis of information derived from

molecular biology (12), These solicitations for

proposals were not associated with any new or

additional funding in 1987, but Congress has set

aside $17.2 million for them in 1988. The budget

request for fiscal year 1989 is $28 million. To review complex genome and informatics proposals,

NIH will convene new peer review committees.

The NIH also plans to seek advice from outside

scientists and to keep congressional staff abreast

of genome projects through a series of workshops,

the first of which was held February 29 and March

1, 1988.

The Institutes

The National Institute of General Medical Sciences (NIGMS) supports research and training in

the basic biomedical sciences fundamental to understanding health and disease. Its primary function is to support research projects conducted by

scientists throughout the nation and the world

that can serve as the bases for the more diseaseoriented research undertaken by the other NIH

institutes. NIGMS will administer the funds set

aside for characterization of complex genomes.

Unlike most of the other NIH institutes, NIGMS

has no intramural research program–its funding is for work done by non-NIH scientists.

NIGMS supports a major share of basic research

in genetics, including research on nonhuman species. Such work is concentrated at NIGMS because

the institute is responsible for research related

to fundamental biology or a broad array of disorders rather than to a disease group, developmental stage, or organ system. Genetics underlies many physiological processes and can explain

many disease states, but most fundamental

genetics research is not designed to elucidate a

single disease; rather, it elucidates general mechanisms or illuminates how human diseases might

occur by showing how other organisms function.

Understanding other organisms is often the first

and most important step in understanding human

health and disease, but the details of how knowledge about bacteria, yeast, or animals will relate

to human biology is rarely known in advance.

These are some of the reasons that NIGMS supports such a large share of the work on genetics

of nonhuman organisms.

Each NIH institute other than NIGMS has as its

mission the support of research on a range of diseases. The range of diseases may be defined by

organ system, developmental stage, explicitly

named disease group, or other criteria (see figure 5-1). The distinction between the kinds of work

supported by NIGMS and by the other institutes

is not hard and fast; in fact, support extends over

abroad range of scientific projects that could come

under the aegis of NIGMS or one of the other institutes. The National Institute of Child Health and

Human Development (NICHD), for example, has

a program that investigates the basic molecular

biology of development. In connection with this,

NICHD convened in May 1987a meeting of scientists working on human chromosome 21. Chromosome 21 is of special interest to persons doing

research on Down’s syndrome, Alzheimer’s disease, and several other diseases; it is also of interest because it contains the genes underlying several important and well+ haracterized biochemical

processes.

All of the institutes support genetic research (in

fact, other institutes support more of it in the aggregate than NIGMS), but this research is often

directed at finding the location of a particular

disease-associated gene. (For example, study of the

familial form of Alzheimer’s disease is supported

by the National Institute of Neurological and Communicative Disorders and Stroke, the National Institute on Aging, and the National Institute on Mental Health.) Institutes develop preventive diagnostic

tests and therapies for genetic diseases.

Funding Mechanisms

Spending at NIH is predominantly for investigator-initiated, basic, undirected research. Most

projects are related to human diseases, animal

models of human disease, or fundamental research on biological questions that might illuminate human biology in health and disease,

NIH’s primary funding mechanism is the investigator-initiated scientific grant (classified as RO1 by

the NIH bureaucracy and widely known by that
term) awarded to a single investigator or small

group. The typical RO1 grant (and there are now

more than 6)100 of them) is given to a research

scientist at a university or other research center

in response to a proposal submitted by that scientist. The proposal outlines the research question addressed, the approach to the question, the

people who would work on the project, and the

budget for the project. The average grant amount

for projects that involved mapping or sequencing was $130)000 in 1986 (5).

Some efforts-those with a specific purpose—

are more amenable to funding by contract. The

Gen.Bank” database of nucleic acid sequences, for

example, is supported by this mechanism under

a $17.2 million 5-year contract with Intelligenetics

Corp. of Mountain View, California (with a subcontract to the Los Alamos National Laboratory,

where GenBank” is housed). NIGMS administers

the GenBank” contract and is the principal funding unit, with contributions from other NIH institutes and divisions, the Department of Energy, and

the National Science Foundation. NIGMS also maintains the Human Mutant Cell Repository under

contract. This is a resource for persons attempting to use genetic techniques to understand diseases or physiological processes. In these instances

and others, NIH can contract with a provider to

deliver a service.

Each NIH institute other than NIGMS administers a program of intramural research, in most

cases located on the NIH campus. Investigators

are employed directly by NIH. The intramural research programs of NIH collectively constitute the

largest biomedical research facility in the world.

NIH’s intramural research complements its extramural support of university and research center scientists. Components of human genome

projects that require direct management by NIH

or that would be best integrated into existing programs could be added to the intramural research

programs.

NIH is not often associated with large, centrally

administered programs, but it does support many.

The National Cancer Institute, for example, supports a number of centers that bring research,

training, information dissemination, and clinical

application under one roof or administrative arrangement in order to accelerate the communication of ideas among normally disparate groups.

Program and center grants are typically larger

than investigator-initiated grants and can include

funds for training as well as for equipment and

research materials. A concerted research program

has recently begun to combat AIDS (acquired im -

munodeficiency syndrome). NIH has the capacity to direct a research program that requires coordination and some central planning.

Research Infrastructure

A small but important fraction of NIH funding

goes to support a research infrastructure–

resources used by a wide array of scientists and

clinical investigators to facilitate their research.

Much of the support for a research infrastructure comes from the Division of Research Resources (DRR) at NIH. Databases for genetic information, funding for repositories (e.g., for

human cell lines, DNA clones, and probes), and

support of the National Library of Medicine are

also important components of the research infrastructure for mapping and sequencing.

The DRR supports regional and national centers

with various purposes. It is divided into five programs, several of which support projects relevant

to mapping and sequencing. one of the purposes

of DRR-supported resources is to provide scientists and clinicians with access to advanced research technologies. This involves support of several databases, materials repositories, computer

resource centers, and grants to generate and analyze biomedical research data (see table 5-2). DRR

cofunds with NICHD the Repository of Human

DNA Probes and Libraries. This repository facilitates exchange of research materials crucial to

genome projects. DRR also supports a grants program to apply artificial intelligence and other sophisticated approaches of information science to

understanding sequence data and managing large

masses of biological information, Several databases, repositories, and activities supported by

DRR are cofunded by other NIH institutes or agencies of the Federal Government. DRR funds its resources through grants and contracts, primarily

to nongovernment scientists. It has helped fund

two workshops directly related to human genome
97

Table 5“2.—Division of Research Resources Activities Related to Molecular Genetics

Resource Function Location

Protein Identification Resource Database for protein sequences and Georgetown University

software Washington, DC

Sequences of Proteins of Annotated protein sequence file Bolt, Beranek, & Newman, Inc.

Immunological Interest Boston, MA

BIONET Network, database linkage, and Intelligenetics

software for use in molecular Mountain View, CA

biology

Dana Farber Cancer Institute and DNA sequence analysis software Boston, MA and Houston, TX,

Baylor College of Medicine (with and other computer resources respectively

other NIH institutes)

National Flow Cytometry Resource Chromosome and cell sorting Los Alamos National Laboratory Los

(with DOE, other NIH Institutes) Alamos, NM

DNA Segment Library Distribution center for cloned American Type Culture Collection

(with NICHD, DOE) human DNA made by Los Alamos Rockvilie, MD

and Lawrence Livermore national

laboratories

Cell Line Two-Dimensional Gel Cell line analysis by protein Cold Spring Harbor Laboratory Cold

Electrophoresis Database elect rophoresis in two dimensions Spring, NY

SOURCE Office of Technology Assessment, 1988.

projects-one with the Department of Energy

(DOE) on materials repositories and databases, the

other with DOE, the National Library of Medicine,

and the Sloan Foundation on applying information management systems to analysis of complex

biological problems.

The National Library of Medicine (NLM) is the

largest and most comprehensive collection of medical information in the world. The library also supports an extensive medical bibliographic resource

—the published Index Medicus and MEDLARS/

MEDLINE, the most widely used on-line computer

reference service for medicine and biomedical research. The NLM has been called “the foremost

biomedical communications center in the world”

(10) and the ‘(central nervous system of American

medical thought and research” (16).

The library was started in 1818 as a few books

in the office of the Surgeon General of the Army,

Joseph Lovell. Its great flowering occurred under John Shaw Billings in the period after the Civil

War, when it became an internationally recognized medical library. The library was transferred

from the military to the civilian sector in 1956,

and its name was changed to the National Library

of Medicine through legislation sponsored by Senators Lister Hill and John Kennedy. A new building for the collection was constructed on the NIH

campus in 1962, and in 1980 the 10-story Lister

Hill Center was dedicated. The library became part

of NIH in 1968 (16).

The NLM’s expertise lies in managing clinical

and biomedical research information. This includes not only storage of books and journals, but

the publication of reference works that list the

extensive international biomedical literature and

the maintenance of computer databases that make

access to the medical information more efficient.

In recent years, the Board of Regents of the NLM

has pointed to biotechnology databases as an area

of expected future growth and has encouraged

library staff to provide improved access to databases relevant to genetics, molecular biology, and

other aspects of the “new biology. ”

Late in the 99th Congress, Senator Claude Pepper introduced a bill, the National Center for Biotechnology Information Act of 1986, that would

give NLM responsibility to “develop new communications tools and serve as a repository and as

a center for the distribution of molecular biology

information” (H.R. 99-5271), The bill was reintroduced early in the 100th Congress with minormodifications (H. R. 100-393), and a companion

measure with very similar provisions (S. 100-1354)

was introduced in the Senate by Lawton Chiles.

The bill was further amended and introduced as
98

S. 100-1966 jointly by Senators Chiles, Kennedy,

Domenici, Leahy, Graham, and Wilson in December 1987. These bills would make the NLM responsible for improving access to the numerous

databases used in molecular biology and clinical

genetics, with funding authorized at $10 million

per year for fiscal years 1988 through 1992. Appropriations for fiscal year 1988 included $3,83

million for these purposes (13).

The NLM has been conducting research on how

to make human genetic information available to

the medical community for several years. It has

made Victor McKusick’s Mendelian Inheritance

in Man (15), the pivotal catalog of human genetic

loci identified by analysis of pedigrees, available

on-line through its Information Retrieval Experiment program, and it has linked the data in this

volume to information available in GenBank@ and

the Protein Identification Resource databank. The

library has also begun an experimental program

to link molecular biology databases, using researchers on the NIH campus in Bethesda to test

the system. It plans to make DNA sequence and

protein database analysis possible through a computer link to the National Cancer Institute’s supercomputer center in Frederick, Maryland. The

Howard Hughes Medical Institute and the NLM

have been discussing ways to link access to the

various databases supported by NIH and the institute.

Peer Review

The National Cancer Institute became the first

American institution to routinely employ peer review when it established the National Cancer Advisory Council in 1937 (26). Since then, peer review

has become an essential element in allocating

funds for research grants at NIH. The review system is two-tiered: The initial review is done by

study sections of scientific experts; the second tier

involves recommendations for funding made by

an institute advisory council.

Review of the typical grant involves several

steps. A grant application is received by the Division of Research Grants at NIH from an investigator (or from a program or center) under sponsorship of an institution. The application is then

assigned to a group of scientists from a particu -

lar discipline appointed by the Director of NIH.

These groups meet three times a year to review

grant applications. They assess applications for

their scientific merit (including originality, feasibility, and importance), the competence of the investigators to do the work, and the appropriateness of the proposed budget (4). The study section

votes to approve, disapprove, or defer consideration of an application. For grant applications that

are not defended, a priority score ranging from

100 (best) to 500 is assigned, based on the rankings of the individual members of the study section. This priority score is then included in a summary statement for each application that briefly

states reviewers’ opinions. The summary (and

where necessary the full documentation) is then

passed on to the appropriate advisory council.

Each institute at NIH has an advisory council,

composed of eminent scientists and informed lay

members, that recommends applications for funding. Advisory councils monitor the quality and fairness of review by the study sections and assess

special relevance to important national health

needs and the mission of the institute. Members

of advisory councils are appointed by the Secretary of Health and Human Services, except those

on the National Cancer Advisory Board, who are

appointed by the President. Inmost cases, the advisory council approves the actions of the study sections. Fewer than 10 percent of grant applications

are singled out for special discussion or action by

the advisory councils (26).

Staff of the NIH institutes then rank the approved proposals. Priority scores are the main,

but not the sole, determinants of funding: An estimated 1 to 2 percent of proposals are funded because of their particular relevance to a pressing

health need, the need to start research in areas

of future importance, a desire for balance in the

portfolio of grants supported by an institute, ethical considerations, or importance to NIH program

needs (26). Roughly one in five grant applications

is referred to more than one institute by the study

section (11). A small proportion of applications is

funded by more than one institute; typically, however, they are funded by one institute or are not

awarded.

Contracts and special programs also receive peer

review, usually through program review commit -
99

tees organized by the institutes or divisions. The

intramural research programs are reviewed by

non-NIH scientists who serve on boards administered by the institutes. Special review committees

are also constituted by the institutes to review

center or program grants.

In its 1984 report on the organization of NIH,

the Institute of Medicine noted that “the genius

of the institution in shaping scientific excellence

to health needs is found in the interplay between

the categorical research institutes and the disciplinary study sections” (11). This statement refers

to the fact that except for NIGMS, the NIH institutes focus on a category of diseases or organ systems. Study sections, in contrast, are composed

of scientists from a particular discipline or area

of expertise (e.g., genetics, pharmacology, pathology). These may overlap, but they often do not.

Institutes consider applications from different

study sections, sometimes from as many as 18 (11).

In 1986, there were 2,700 scientists and lay representatives serving on 155 review committees

at NIH (4,26).

DEPARTMENT OF ENERGY

Much of the attention devoted to mapping and

sequencing the human genome can be traced to

activities in the Department of Energy. DOE has

already begun a program of targeted research on

the human genome —the Human Genome

Initiative—to construct physical maps of several

human chromosomes and to develop relevant

technologies. The part of DOE responsible for the

Human Genome Initiative is the Office of Health

and Environmental Research in the Office of

Energy Research (see figure 5-2).

The Office of Health and

Environmental Research

The history of the Office of Health and Environmental Research (OHER) goes back to the Manhattan Project of World War II, which was organized to develop fission bombs. OHER began as

the Health Division, started in 1942 by Nobel laureate Arthur Holly Compton, a physicist at the

University of Chicago. The division focused on protecting people from the effects of radiation and

on the use of radioactive chemicals in medicine

and biomedical research. The research base was

broadened to include fossil fuels and renewable

energy sources by the Energy Reorganization Act

of 1974. These functions were retained when the

Energy Research and Development Administration became the Department of Energy in 1977

and OHER was established (21). The primary mission of OHER has been to study sources of radiation, pollution, and other environmental toxins

(particularly those related to the generation of

Figure 5-2.—Organization of DOE

Secretary,

Department of

Energy

Biochemistry Coordination

Management

Genetics Molecular Biology
100

energy), to trace them through the environment,

and to determine their effects. Another mission

is to exploit the resources of DOE-administered

national laboratories to the maximum benefit of

the nation.

Research at OHER is conducted largely through

the system of national laboratories. There are eight

general-purpose laboratories that conduct OHER

research as well as research in physical sciences

and mathematics, and there are nine dedicated

OHER laboratories located near national laboratories or universities. In addition, OHER supports

research at 100 universities and research centers.

OHER’S involvement in the human genome debate is traced by its former director, Charles

DeLisi, to an idea that occurred to him late in 1985

when he was reading a draft of the OTA report

Technologies for Detecting Heritable Mutations

in Human Beings (23)27). He realized the importance of having a reference human sequence for

OHER’S work. Subsequent discussions disclosed

that researchers at the Lawrence Livermore and

Los Alamos National Laboratories were thinking

about ordering DNA clones to make a physical

map as an extension of ongoing work. Robert Sinsheimer, chancellor of the University of California at Santa Cruz, had hosted a workshop on the

feasibility of sequencing the human genome the

previous year and was very interested. During

this period, Nobel laureate Renatto Dulbecco published a brief article in Science urging that the

human genome be sequenced (8).

DOE sponsored the Human Sequencing Workshop in Santa Fe, New Mexico, in March 1986,

and DeLisi outlined a three-point strategy in a May

1986 memo: 1) to produce a set of overlapping

DNA clones related to a physical map of human

chromosomes (see ch. 2), 2) to develop high-speed

automated sequencing methods, and 3) to improve

methods for computer analysis of map and sequence information. DOE also funded a second

workshop, Exploring the Role of Robotics and

Automation in the Decoding of the Human Genome, in January 1987. Funding for the DOE initiative, based on the three-pronged attack, began

in fiscal year 1987, with $4.2 million going to 10

projects at three national laboratories and at Harvard and Columbia Universities (6). DOE plans to

spend $12 million on human genome projects in

fiscal year 1988 and has requested $18.5 million

for 1989. A special appropriation of $12.7 million

was added to the Office of Energy Research budget to construct a building for an Institute of Human Genomic Studies at Mount Sinai Medical Center in New York. This resulted from a congressional initiative, and operations of that institute

are not part of human genome projects sponsored

by DOE. The reason for the name of the institute

is unclear, but the institute will apparently house

clinical genetic services for its region (24).

OHER projects include assembling an ordered

set of overlapping DNA clones spanning human

chromosome 19 at the Lawrence Livermore National Laboratory, making a similar clone set for

chromosome 16 at the Los Alamos National Laboratory (using somewhat different techniques),

and constructing a physical map of chromosome

21 and chromosome X at Columbia University. Efforts in 1988 will expand to include more university groups and the Lawrence Berkeley National

Laboratory and other national laboratories. An

effort to sequence the genome of the bacterium

Escherichia coli by a new method is being supported at Harvard University. Other projects include construction of DNA clones covering the

full set of human chromosomes (not cataloged in

order) and development of new technologies for

sequencing, detecting, and analyzing DNA.

Early enthusiasm for mapping and sequencing

at the national laboratories stemmed largely from

existing OHER projects. In one set of projects, laseractivated cell sorting was used to separate individual chromosomes. Cell sorting began naturally

in the national laboratories because of easy access to high-technology instrumentation and a

multidisciplinary blend of scientists, including biologists, chemists, physicists, computer scientists,

engineers, and mathematicians. The first fluorescence-activated cell sorter was developed at the

Los Alamos National Laboratory. This instrument

was used at the Lawrence Livermore and Los

Alamos National Laboratories to sort human chromosomes, and these chromosomes were used to

produce sets of DNA clones. The effort was divided

into two phases.

The first phase was to make sets of small fragments of cloned DNA (up to several thousand base

pairs) in lambda phage. This phase has been com -
701

pleted, and the clone sets have been turned over

to the American Type Culture Collection in Rockville, Maryland. (Preparation of the clones is

funded by DOE; storage and distribution of the

clone sets are funded jointly by NICHD and DRR.

DRR also supports the cell-sorter facility at the

Los Alamos National Laboratory.) The second

phase is to develop clone sets of up to 45,000 base

pairs using cosmids and other vectors (see ch. 2

for details). The next logical step is to order the

clone sets.

In future years, DOE plans to expand its efforts

substantially. A report recently written by a subcommittee of the Health and Environmental Research Advisory Committee is the main public

planning document for DOE work on human genome projects.

Health and Environmental Research

Advisory Committee Report

The Health and Environmental Research Advisory Committee (HERAC) is a group of scientists

from universities, national laboratories, and private corporations which reports to the Director

of the Office of Energy Research. Its main function is to advise the Director of OHER on the scientific program supported by OHER. In late 1986,

HERAC formed a subcommittee on the human genome to make recommendations about DOE’s Human Genome Initiative. The subcommittee was

chaired by Ignacio Tinoco and included members

from the Howard Hughes Medical Institute, universities, biotechnology companies, and one scientist from a national laboratory. The subcommittee’s document was approved and was submitted by HERAC to Alvin Trivelpiece, then Director of the Office of Energy Research, in April

1987 (25).

The subcommittee report urges DOE to develop

two important tools for research in molecular biology: a reference human DNA sequence and the

means to interpret and use it. These would be

created by a new research program divided into

two stages. The first phase (5 to 7 years) would

focus on:

● assembling ordered DNA clone sets of the human chromosomes;

● locating genes and other markers on a physi-

●

●

●

●

●

●

cal map based on these sets;

producing sequences of selected clones and

distributing that information;

developing new techniques for mapping and

sequencing;

applying automation and robotics to mapping

and sequencing;

creating computational and other methods

for identifying genes;

finding new algorithms for analyzing DNA

sequences; and

establishing computer facilit~es, databases,

materials repositories, networks, and other

resources to promote use of the methods and

resources produced by the projects.

Budget recommendations for the first phase are

noted in table 5-3. The second phase would provide a complete sequence for each human chromosome and would make new technologies available for use in addressing the central questions

of medicine and biology.

The subcommittee recommends that the work

be widely distributed among national laboratories,

universities, and companies because of the “highly

creative nature” of the science needed to meet

the objectives. The research program would include work by many small groups funded through

investigator-initiated grants, as well as larger multidisciplinary centers or consortia. The report also

recommends that DOE establish a two-tiered system of peer review: one or two initial review committees to assess technical merit and feasibility,

and a policy committee to determine overall strategy, develop policy, and oversee scientific review.

Table 5=3.—Budget Proposed for DOE Human

Genome Initiative (millions of dollars)

Fiscal year Amount that year Cumulative amount

1988 . . . . . . . . . 20 20

1989 ..., . . . . . 40 40

1990 ........, 80 140

1991 . . . . . . . . . 120 260

1992 .., . . . . . . 160 420

1993 .., . . . . . . 200 620

1994 . . . . . . . . . 200 820

1995 . . . . . . . . . 200 1,020

SOURCE: Subcommittee on the Human Genome, Health and Environmental

Research Advisory Committee, Repofl on the Human Gerrorne kritiatke, prepared for the Office of Health and Environmental Research,

Office of Energy Research (Germantown, MD Department of Energy.

April 1987).
102

The subcommittee urges DOE to ensure that

the results of the projects be in the public domain

and that the efforts be made in cooperation with

those of other agencies in the United States and

abroad, within the constraints of Federal law

governing technology transfer and concern for

national competitiveness in biotechnology.

A broad-based research program to foster development of technology is outlined, followed by

the rationale for DOE involvement, namely: 1) the

historical relation to ongoing work at the national

laboratories; 2) DOE’s experience with directed

research programs (as opposed to the much larger

and more diverse human and animal research supported by NIH); 3) the relation to the mission of

OHER (in assessing mutational damage from radiation and environmental exposure or developing new energy resources); and 4) access to multidisciplinary teams in the national laboratory

system. The potential utility of DNA sequencing

for monitoring exposure to radiation and toxic

The primary justification for the new initiative

is its potential utility. The technologies and information deriving from it would make future research more efficient (less costly and more powerful), would directly improve human health, and

would aid economic growth of industries dependent on biotechnology. A final section of the report warns that, although the program is of the

highest priority, it should not be permitted to hinder worthwhile ongoing programs, including research on nonhuman organisms. Concern that a

large new program at DOE would impede development in other fields is countered with the observation that large new sums of money have already been introduced into molecular biology:

HHMI has increased its annual spending on biomedical research by over $150 million during the

last decade, with primarily beneficial results. The

subcommittee ends by stating its opposition to creating any large, inflexible organization to execute

or supervise the work.

chemicals is noted as a principal reason

veloping sequencing technologies.

for deNATIONAL SCIENCE FOUNDATION

The blueprint for the National Science Foundation (NSF) grew from the report Science—The Endless Frontier, written by Vannevar Bush in 1945

(2). The original ideas for NSF, as propounded by

Bush and Senator Harley Kilgore, were modified

by postwar events and eventually led to legislation creating the foundation in 1950. The principal purpose of the NSF was to continue the Federal Government’s role in sponsoring basic

research, a role that developed during World

War II (9,14). Biology at NSF is supported through

its Directorate of Biological, Behavioral, and Social Sciences. In fiscal year 1987, NSF spent an

estimated $32.7 million on research related to gene

mapping and sequencing. Of this amount, only

$200,000 went for focused projects on gene mapping and sequencing of nonhuman organisms; the

bulk was for basic research ($13.7 million) and

for the research infrastructure, such as development of methods, new scientific instruments, databases, and repositories and support of instrumentation centers ($19 million). Planned spending for

1988 was $37.9 million. These figures are part of

the $206 million spent by NSF in support of biological science in fiscal year 1987, out of the total

NSF budget of $1.62 billion (12).

NSF supports primarily basic research in all sciences. Support of basic research grants is the

largest single component of NSF funding related

to human genome projects. In recent years, NSF

has increased its emphasis on engineering and

technology development (e.g., it partially supported development of the California Institute of

Technology’s DNA sequenator). In 1987, NSF announced a Biological Centers Program intended

to stimulate the growth of knowledge in biological research areas important to the continued development of biotechnology. Support for these

centers, estimated at $12 million for fiscal years

1987 and 1988, constitutes the second largest component of NSF funding of genome-related activities. A center for bioprocess engineering has been

functioning at the Massachusetts Institute of Technology for several years. (NIH has also supported

this center, for research training.) Two types of
103

centers are to be created under the Biological instrumentation and funds individual grants for

Centers Program: One will focus upon sharing basic biological science. Although the NSF budcapital-intensive instrumentation and developing get for biology is small relative to its support for

new instruments; the other will host large-scale other areas and to DOE and NIH support, it

multidisciplinary research. Either could be used nonetheless supports mapping and sequencing

by groups mapping and sequencing various organ- through bioengineering, basic biology research,

isms. NSF also sponsors a program on biological and the centers programs.

NATIONAL BUREAU OF STANDARDS

The National Bureau of Standards (NBS) was created in 1900 as the National Standardizing Bureau.

It is part of the Department of Commerce, and

its primary mission since its inception has been

to develop standards in scientific and technical

fields in order to facilitate industrial progress and

to prevent incompatibilities that could hamper research or technological applications. NBS also has

a program of research in methods and instrumentation that has grown naturally out of tracking

diverse and rapidly advancing technologies. Its

main technical expertise lies in the physical, chemical, and information sciences, but it is now developing expertise in biotechnology. It has joined

with the Montgomery County Government and

the University of Maryland, for example, in support of the Center for Advanced Research in Biotechnology in Gaithersburg, Maryland.

NBS has been suggested as a candidate agency

for quality control and research on measurements

for DNA mapping and sequencing. This would give

it the function in biology that it has for physics

and chemistry but would entail a considerable expansion of its expertise and resources devoted to

molecular biology. Its role could include checking data for accuracy, assessing the accuracy of

the machines used in the multicenter mapping and

sequencing efforts, and setting standards for the

reporting of results. NBS might also conceivably

develop technical standards for automated machines and computers used in creating or analyzing data about DNA. If NBS undertakes a function in quality control and standard setting, it will

need close collaboration with NIH and DOE, where

the bulk of expertise currently lies.

CENTERS FOR DISEASE CONTROL

The Centers for Disease Control (CDC) are situated in the Public Health Service of the Department of Health and Human Services. The main

offices are located in Atlanta, Georgia. CDC is the

Nation’s primary resource for tracking the incidence and prevalence of diseases and for intervening to thwart the spread of infectious agents

and preventable diseases. Related to this mission,

CDC maintains databases, disseminates information, and provides materials widely used in clinical research.

CDC could have a role in quality control and

in monitoring scientific activities involved in mapping and sequencing the human genome. It has

performed this function in the past, through its

Lipid Standardization Program. This program began more than 25 years ago to provide quantitative measurements for laboratories engaged in

lipid research related to diseases of the heart and

blood vessels. Since the program was initiated,

over 500 national and international laboratories

have received and analyzed reference materials

provided by CDC (3). Quality control and standard setting may become important as map and

sequence data become more plentiful and as more

laboratories come to rely on a common set of data.

If such measures prove necessary, CDC is a possible agency for determining or confirming the

chromosomal location or origin of DNA fragments

or for orienting new DNA fragments on the emerging physical maps. If this function were to be undertaken by CDC, close communication with NIH

and DOE would be necessary.
--

104

DEPARTMENT OF DEFENSE

While biological research is not the main mission of the Department of Defense (DoD), some

components of mapping and sequencing DNA

might be shared with or conducted by various

components of DoD. Each military service (particularly the Army and Navy) conducts some research in biology, primarily that related to the

health needs of military personnel or to defenses

against chemical and biological warfare. DoD

reports that all such research is unclassified: Much

of it is conducted at military facilities or contractoradministered laboratories, but some of it is conducted in universities as well. DoD supports some

generally useful resources in biomedical research.

The Armed Forces Institute of Pathology (AFIP)

is an international treasure house of tissue samples and microscopic slides spanning the full range

of human disease. Its tissue collection is used by

pathologists and biomedical researchers throughout the world. AFIP began as the Army Medical

Museum in 1862. It became the AFIP in 1949,

when the Navy and Air Force joined with the Army

in support of it, and the role of the institute has

expanded steadily since then. Today AFIP constitutes the largest organization of research and diagnostic pathologists in the world, The institute has

received more than 2.2 million cases (tissue or

slides from patients) from over 50,000 pathologists affiliated with more than 19,000 hospitals

and clinical facilities. AFIP’s unique capabilities as

a tissue repository have been expanded to include

modern storage techniques. Through further expansion of its capabilities, the staff and facilities

of AFIP could be used as a national tissue repository and assessment center for the full spectrum

of human diseases, The institute could play a role

in linking map and sequence data to human diseases. The availability of systematically classified

human tissues could facilitate development and

testing of medical products and diagnostic methods to probe the molecular basis of various

diseases.

The military biomedical research community

would have an interest in map and sequence data

because investigations of the effects of chemical

and biological weapons would include the study

of genes that are particularly vulnerable to attack

and the construction of vaccines or other defensive measures.

OFFICE OF SCIENCE AND TECHNOLOGY POLICY

The Office of Science and Technology Policy Representatives of OSTP followed the human ge -

(OSTP) is headed by the President’s Science Advi- nome debate and spoke at several national meetsor. OSTP’s primary responsibility is to advise the ings in 1986 and 1987.

President on science policy, on matters where scientific or technical information is relevant to Federal policy decisions, and on national policies for OSTP recently announced plans to reorganize

technology development. OSTP can on occasion its oversight of life sciences. It plans to form a

form coordinating councils under the Federal Co- Committee on Life Sciences for interagency coordinating Council for Science, Engineering and munication and coordination, and it tentatively

Technology. An example of OSTP coordination in plans to establish subcommittees on specific topics.

life sciences is the Biotechnology Science Coordi- Genome projects have been noted as likely tonenation Committee, which started as an OSTP ini- cessitate such a subcommittee, although the extiative responsible primarily for devising guide- act role and composition of it is not yet determined

lines for regulation of biotechnology products. (7).
105

DOMESTIC POLICY COUNCIL

The Domestic Policy Council (DPC) is a cabinetlevel group that reviews government activities.

David Kingsbury of NSF, as acting chairman of

the Biotechnology Working Group, gave a brief

presentation on human gene mapping to the DPC

in February 1987. An interagency subcommittee

of this working group, chaired by NIH Director

James Wyngaarden, was formed and met in May

1987 to exchange information on agency activities. NIH, DOE, NSF, the Food and Drug Administration, the U.S. Department of Agriculture, the

Environmental Protection Agency, and the Office

of Management and Budget were represented.

The purpose of the subcommittee was to minimize duplication of effort among the agencies and

to promote interagency communication. The subcommittee has subsequently been disbanded, to

be replaced by the OSTP group noted above. The

DPC will continue to keep abreast of developments

on genome projects through the President’s Science Advisor, who will administer the OSTP group

(l).

OFFICE OF MANAGEMENT AND BUDGET

The Office of Management and Budget (OMB)

monitors and coordinates the annual budget process for executive agencies of the Federal Government and oversees management of the agencies.

Each year, every Federal agency prepares a budget request that is reviewed within the agency

and then submitted to OMB. OMB reviews the requests and develops a budget for the President;

this budget is submitted to Congress in January

for the fiscal year beginning that October (although the process is late for fiscal year 1989 because of delay in passing the 1988 budget). OMB’S

budget-coordinating function places it in the position of arbiter among different agencies if there

are conflicting priorities or potential duplications.

By this mechanism, and by monitoring other activities in multiple departments, OMB can encourage

communication and coordination of activities.

OMB has one budget officer for NSF, another for

NIH, and a third for DOE. These officers are responsible for other agencies as well, and the activities related to human mapping and sequencing

constitute only a small fraction of their total budget responsibility. Two officers in the OMB science office have taken primary responsibility for

tracking the human genome budget submissions

of all agencies (20).

HOWARD HUGHES MEDICAL INSTITUTE

The Howard Hughes Medical Institute (HHMI)

was created in 1953 by aviator-industrialist Howard Hughes. It is a medical research organization

with an endowment of approximately $5 billion.

HHMI has increased its research funding dramatically over the last decade, from roughly $15 million in 1977 to approximately $240 million in 1987.

HHMI operates three programs (see figure 5-3).

The first and largest is scientific research in 27

laboratories located in hospitals, academic medical centers, and universities throughout the United

States. The second program, which supports the

first research program and is integrated with it,

includes a genome resources project, a research

training program for medical students (jointly with

NIH), and sponsorship of HHMI meetings and reviews. A third program will provide $500 million

over the next decade through grants and special

programs to support education in the medical and

biological sciences.

Under its first program, HHMI conducts research in five basic scientific areas: genetics, im -
106

Figure 5-3.—Howard Hughes Medical Institute

Genomics

\

Resources

munology, neuroscience, cell biology and regulation, and structural biology. Several HHMI

investigators are involved in genetic mapping and

related computational research, physical mapping,

and medical genetics. The principal HHMI centers

for genetics are located at the University of Utah

(Salt Lake City, Utah), the Baylor College of Medicine (Houston, Texas), the University of Michigan

(Ann Arbor, Michigan), the University of California (San Francisco, California), The Johns Hopkins

University (Baltimore, Maryland), the University

of Pennsylvania (Philadelphia, Pennsylvania),

Brigham Hospital (Boston, Massachusetts), and

Childrens’ Hospital (Boston, Massachusetts). HHMI

estimates that it expended $40 million for genetics

research in 1987, of which $2 million to $4 million were devoted to finding and using DNA markers and constructing genetic maps.

The HHMI genome resources project has a current annual budget of over $2 million. Through

that project, HHMI supports consequence databases relating to human genetics, including the

Human Gene Mapping Library (New Haven, Connecticut) and the On-Line Mendelian Inheritance

in Man (Baltimore, Maryland) (see figure 5-2).

HHMI also helps maintain a mouse genetics database at Jackson Laboratory (Bar Harbor, Maine)

and collaborates with the Center for the Study

of Human Polymorphism (CEPH) headquartered

in Paris, France. CEPH is a critical collaborative

institution that links several large groups working on construction of human genetic maps. HHMI

has participated in a large number of meetings

on the human genome, including one it sponsored

directly in July 1986 at NIH; at that workshop,

strategies and policies for mapping and sequencing were discussed. HHMI partially supported the

ninth Human Gene Mapping Workshop, held in

Paris in September 1987, which compiled data on

international gene mapping activities since the previous meeting in 1985.

NATIONAL RESEARCH COUNCIL

The National Academy of Sciences was estab- Research Council now conducts many studies on

lished by Congress in 1863. President Lincoln issues relating to science and technology. It is orga -

signed the law that brought it into existence. The nized into several disciplinary groups.

National Research Council (NRC) was established

in 1916 to provide advice to the Federal Govern- In August 1986, a group of scientists interested

ment about issues involving science. The principal in issues surrounding genome projects met in

impetus was the increasing relevance of science Woods Hole, Massachusetts. This group agreed

to preparations for World War I. The National to formulate a proposal for a study by the NRC,
107

which was presented to and approved by the Basic

Biology Board of the Commission on Life Sciences

in September 1986. A committee of distinguished

scientists, chaired by Bruce Alberts, was appointed

to consider the scientific issues connected with

genome projects. The committee on mapping and

sequencing the human genome held several public meetings in 1987 and released its report in February 1988 (19).

The Alberts committee was composed of scientists of different backgrounds, with varying degrees of direct involvement in mapping and sequencing projects and with initially divergent

views on genome projects. The committee reached

consensus on several points during the course of

its deliberations. The committee concluded that

mapping, sequencing, and understanding the human genome merited a special effort funded and

organized specifically for this purpose.

The committee’s report recommends that the

projects should begin with “a diversified, sustained

effort to improve our ability to analyze complex

DNA molecules, ” with a “focused effort that emphasizes pilot projects and technological development .“ It lists the specific types of maps that would

be useful as early genome projects, notes the importance of mapping and sequencing genomes of

nonhuman organisms, and stresses the need for

thorough peer review. The proposed projects differ from ongoing research by focusing on methods that would improve mapping, sequencing,

analyzing, or interpreting the biological significan c

vere- to ten-fold. The committee also notes the need

for central databases, repositories, and quality control facilities.

Research projects that merit special support are

explained in some detail. The committee favors

development and refinement of techniques in the

early years, with most support going to work on

mapping large genomes. One specific goal in early

years, for example, would be to enable sequencing of 1 million continuous base pairs. The need

for technological progress is noted for several additional areas: to isolate chromosomes, to create

cell lines, to clone substantial portions of DNA

from genomes of whole organisms, to clone DNA

in large fragments, to isolate large DNA fragments,

to order DNA clones derived from genomes, to

automate many steps involved in mapping and sequencing DNA, and to improve the collection, storage, dissemination, and analysis of information

and materials. Administration of these centralized

functions would be conducted by a scientific advisory board, including at least one full-time scientist appointed as chairman. This scientific advisory committee would also serve to advise the

agencies and to act as the focal point for international cooperation.

The committee recommended that $2OO million

per year be appropriated specifically for genome

projects, increasing to this level over the first 3

years. In the first 5 years, this might be spent to

fund work at 10 medium-sized multidisciplinary

centers and to support a program of grants to

many more small research groups. An estimated

1,200 scientists would be involved, with roughly

half located at the multidisciplinary centers, The

research component would account for $120 million per year. The remainder of the budget would

be used for construction ($55 million per year initially, decreasing in later years) and to pay for the

repository, database, quality control, and administrative functions of the scientific advisory committee ($25 million per year). The funding for construction in early years would be reassigned to

production of maps and sequence data as technologies matured.

A majority of the committee recommended that

a single agency be designated and given funding

to lead the effort. Other options were also discussed, including an interagency structure much

like the task force option discussed in the next

chapter. A final option was to have an interagency

body for planning and funding, but a single agency

for administration.

PRIVATE CORPORATIONS

private corporations in several fields have ex- in academic or national laboratories are now

pertise relevant to mapping and sequencing the produced commercially. Pharmaceutical and biohuman genome. Many instruments first developed technology companies could use map and se-
108

quence information to develop new products, and

many are themselves developing research techniques. Companies that market scientific instruments are also keenly interested. The role of the

private sector appears to be primarily to:

●

●

●

advise in planning the mapping and sequencing research program,

commercialize products that result from the

research, and

ensure that technology transfer from federally funded research projects to commercially

exploitable products is smooth and rapid.

Private corporations view human genome projects, with a few exceptions, as long-term research

that is best supported by the Federal Government.

Corporations are unlikely to lend financial support to a national program to map and sequence

the human genome, although they might well invest in particular projects that involve development of technology. Private firms could perform

specified functions under contract from the Federal Government (e.g., genetic mapping, physical

mapping, DNA preparation, or DNA sequencing)

once the technologies are available.

Several American companies already produce

DNA sequenators and other analytical instruments

used in mapping and sequencing projects. The

Lawrence Livermore National Laboratory group,

which is constructing ordered sets of DNA clones

under DOE sponsorship, is modifying an instrument initially designed for DNA sequencing by

Applied Biosystems of Foster City, California, Private corporations have likewise participated in

building the existing genetic map of human chromosomes. Collaborative Research and Integrated

Genetics are two companies based in the Boston

area that have contributed substantially to the effort to find new DNA markers and to Iink those

markers to human diseases. A few biotechnology

companies have been at the forefront in developing automated technologies for handling DNA. The

Genetics Institute (Cambridge, Massachusetts), for

example, developed a robotic system that extracts

DNA from bacteria and cells.

At least two companies—the Genome Corp. in

Boston and SeQ, Ltd., in Cohasset, Massachusetts

—are being started specifically to map and sequence the human genome. These companies plan

to construct a physical map and subsequently sequence the human genome over the next decade,

using private funds. They would offer access to

the materials and to the map and sequence information for a price. The process would be much

like that used currently by researchers, who pay

repositories for DNA clones, probes, and vectors

or who pay companies for enzymes and other materials used in molecular biology. The argument

behind this is that, while each laboratory could

conceivably develop the information independently, it is cheaper and faster simply to buy it from

a private firm that has developed it already. Those

purchasing the information would be free to use

it, but not to copy or sell it.

Private corporations could also play a role in

the development of technology related to mapping and sequencing. This could include company

access to government facilities, exchange of corporate and academic personnel, multicompany

consortia, individual corporate agreements with

universities or national laboratories, or some combination of these.

Members of the Industrial Biotechnology Association were recently polled regarding their support of Federal initiatives in mapping and sequencing the human genome. Those responding

indicated that:

●

●

●

●

•

●

The work should be funded entirely by the

Federal Government and should not interfere

with ongoing biomedical research.

NIH, DOE, and NSF should all participate (NIH

should take the lead).

A national planning committee, composed of

50 percent university scientists, 30 percent

government representatives, and 20 percent

industry representatives, should be set up.

Work should be carried out at dispersed

university and federally supported laboratories, not a center created for the purpose.

International cooperation should be encouraged if it does not entail delays.

Physical mapping should precede sequencing.

Respondents clearly support a role for industry

in planning and using the results of mapping and

sequencing projects, while indicating that the Federal Government should pay the bill.
109

PRIVATE FOUNDATIONS

Several private foundations support research

in human genetics. These include such diseaseoriented foundations as the March of Dimes, the

Hereditary Disease Foundation, the Muscular Dystrophy Association, and the Cystic Fibrosis Foundation, Other foundations support work on human genetics as part of a broader research

program, among them the American Cancer Society, the American Heart Association, and the Alz -

heimer’s Disease and Related Disorders Association. These foundations, while relatively small in

total funding, often act as catalysts in focusing

research on a problem of particular interest. They

are also highly effective at publicizing research

results, educating the public about the consequences of disease, and generating public support

for biomedical research.

SUMMARY

NIH, DOE, HHMI, and NSF have already made

substantial commitments to projects related to the

study of the human genome. Government activities are currently being coordinated by informal

communication among the agencies. A previous

coordinating group under the Domestic Policy

Council will likely be replaced by one organized

under the Office of Science and Technology Policy in the White House, with budget submissions

coordinated by the Office of Management and

Budget, Each research agency has its own means

of funding research and providing peer review

of programs. NIH and DOE have created special

planning groups to review genome projects. NIH

funding is over $313 million each year for human

and nonhuman research involving mapping or sequencing. In 1987, NIH announced two new programs in methods development; it has budgeted

$17.2 million for those projects in 1988 and requested $28 million for 1989.

In 1987, DOE allocated $4.2 million for 10

projects on physical mapping and technology development, It plans another $12 million in 1988

and has received recommendations from an outside scientific panel to ask for over $1 billion over

the following 7 years. The former director of

OHER stated that at least half the funds would

be distributed to researchers at universities and

research centers other than national laboratories

(3) and that the work will be reviewed prospectively and retrospectively by peers. DOE officials

have stated that their budget requests will be more

modest than those recommended.

NSF spent over $32.7 million on research related to genome projects in 1987, although only

$200,000 was considered to be for genome

projects per se. NSF’s new Biological Centers Program is likely to be relevant to genome projects,

particularly those involving new instrumentation.

HHMI funded $40 million of genetics research in

1987, including several million for construction

of genetic maps. HHMI also administers and funds

a genomics resource program of $2 million annually to support databases and other elements of

the research infrastructure.

To date, actions of the principal organizations

can be described as cooperative. NIH and DOE

have supported many joint efforts related to human genome projects. The GenBank” database

has been administered by NIH and located at a

DOE-supported national laboratory for over 5

years, and the two agencies also jointly support

DNA clone and probe repositories, computer analysis methods, and flow-sorting facilities. NIH and

DOE sponsored a meeting on database and repository needs of human genome projects in August

1987, and there has been an exchange of project

officers and extensive informal cooperation among

staff at NIH, DOE, NSF, and other executive

agencies.

The strengths of NIH and DOE are more complementary than competitive. Each believes it

could successfully mount and sustain the scientific and technical effort necessary for the contemplated mapping and sequencing projects. Both

support relevant work already, although with

different emphases. A decision to delegate the en-
110

tire effort to one agency would require that current efforts in other agencies be shut down.

The mapping and sequencing effort will more

likely continue to include NIH, DOE, NSF, HHMI,

and other agencies and organizations covered in

this chapter. The key question then becomes how

much and which part each agency should perform. Such decisions will be made in a general

sense by Congress, through authorization and ap -

propriation, with more detailed planning left to

executive agencies. There may be informal cooperation or some more formal means of coordinating the planning and execution of agency projects

under OSTP. Joint nongovernment advisory

groups could be formed to bring in expertise from

academia and industry. There are many options

for organizing an interagency effort and for incorporating outside advice into research planning.

These issues of organization and advisory structure are discussed in chapter 6.

CHAPTER 5 REFERENCES

1. Bledsoe, R., White House Domestic Policy Council,

personal communication, December 1987.

2. Bush, V., Science—The Endless Frontier: A Report

to the President (Washington, DC: reprinted by the

National Science Foundation, 1980).

3. Chen, A., Centers for Disease Control, personal

communication, August 1987.

4. Committee Management Staff, National Institutes

of Health, NIH Public Advisory Groups, NIH Pub.

87-10 (Bethesda, MD: NIH, October 1986).

5. DeLisi, C., comments at a meeting of the Human

Genome Subcommittee, Health and Environmental

Research Advisory Committee, Department of

Energy, Denver, CO, December 1986.

6. Department of Energy, material submitted to the

Domestic Policy Council, May 1987.

7. Dorigan, J., White House Office of Science and

Technology Policy, personal communication, December 1987.

8. Dulbecco, R., “A Turning Point in Cancer Research:

Sequencing the Human Genome,’’Science 231:1055-

1056, 1986.

9. England, J. M., A Patron for Pure Science: The National Science Foundation Formative Years, 1945-

1957 (Washington, DC: NSF, 1982).

10. Harden, V. A., Inventing the NIH: Federal Biomedical Research Policy, 1887-1937 (Baltimore, MD: The

Johns Hopkins University Press, 1986).

11. Institute of Medicine, Responding to Health Needs

and Scientific Opportunity: The Organizational

Structure of the National Institutes of Health (Washington, DC: National Academy Press, October 1984),

p. 76.

12. Kingsbury, D., National Science Foundation, personal communication, October 1987.

13. Levinson, R., Directors Office, National Institutes

of Health, persona] communication, January 1988.

14. Mazuzan, G. F., “National Science Foundation: A

15

16

17.

18.

19.

20.

21. Office of Energy Research, Department of Energy,

Brief History,” unpublished manuscript, September 1987.

McKusick, V. A., Mendelian Inheritance in Man, 7th

ed. (Baltimore, MD: The Johns Hopkins University

Press, 1986).

Miles, W. D., A History of the National Library of

Medicine: The Nation Treasury of Medical Knowledge, NIH Pub. 82-1904 (Washington, DC: U.S. Government Printing Office, 1982).

National Institutes of Health, NIH Guide to Grants

and Contracts, vol. 16, May 29, 1987, pp. 9-14; Oct.

16, 1987, pp. 6-10.

National Institutes of Health, Office of the Director, background information and information provided to the Domestic Policy Council, May 1987.

National Research Council, Mapping and Sequencing the Human Genome (Washington, DC: National

Academy Press, 1988).

Noonan, N., White House Office of Management

and Budget, personal communication, October

1987.

22

23

24

25

Health and Environmental Research: Summary of

Accomplishments, vol. 1, DOE Pub. ER-0194, April

1984; vol. 2, DOE Pub, ER-0275, August 1986

(Washington, DC: DOE, 1984, 1986).

Office of Program Planning and Evaluation, National Institutes of Health, The Human Genome,

proceedings of the 54th meeting of the Advisory

Committee to the Director, Oct. 16-17, 1986 (Bethesda, MD: NIH, 1987).

Science and the Citizen, “Geneshot,” Scientific

American, May 1987, pp. 58-58a.

Smith, D., Office of Health and Environmental Research, Department of Energy, personal communication, January 1988.

Subcommittee on the Human Genome, Health and

Environmental Research Advisory Committee, Re-
111

port on the Human Genome Initiative, prepared

for the Office of Health and Environmental Research, Office of Energy Research, Department of

Energy (Germantown, MD: DOE, April 1987).

26. U.S. Congress, General Accounting Office, University Funding: Information on the Role of Peer Re -

view at NSF and NIH, GAO pub, REED-87-87F S

(Washington, DC: U.S. Government Printing Office,

March 1987).

27. U.S. Congress, Office of Technology Assessment,

Technologies for Detecting Heritable Mutations in

Human Beings, OTA-H-298 (Washington, DC: U.S.

Government Printing Office, September 1986),
Chapter 6

Organization of Projects
CONTENTS

Page

Administrative Structures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. ....115

Single-Agency Leadership . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. ... ... ... .116

Interagency Agreement and Consultation . . . . . . . . . . . . . . . . . . . . . ..........118

Interagency Task Force . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. ...119

Consortium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...............121

Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..123

Advisory Structure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..........123

Responsibilities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...........123

Composition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. ...124

Structure and Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .................124

Big Science v. Small-Group Science . . . . . . . . . . . . . . . . . . . . . .................125

Displacement of Higher-Priority Science . . . . . . . . . . . . . . . . . . . . . ...........125

Style and Efficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..................125

Politicization. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. ....127

Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............128

Chapter 6 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ........128

Boxes

Box Page

6-A. Acid Precipitation Task Force . . . . . . . . . . . . . . . . . . . . . ..................120

6-B. Midwest Plant Biotechnology Consortium . . . . . . . . . . . . . . . . . . . . . ........122

6-C. Quotes on Genome Controversies. . . . . . . . . . . . . . . . . . . . . . ..............126

Figures

Figure Page

6-1. Lead Agency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. ....116

6-2. Interagency Agreement and Consultation . . . . . . . . . . . . . . . . . . . . . . . . . . ...118

6-3. Interagency Task Force . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ....119

6-4. Consortium. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .............121
Chapter 6

Organization of Projects

“Organization is a means to an end rather than an end in itself. Such structure is

a prerequisite to organizational health; but it is not health itself. The test of a health

business is not the beauty, clarity, or perfection of its organization structure. It is the

performance of people. ”

Peter Drucker,

Management: Tasks, Responsibilities, Practices

(New York: Harper & Row, 1974), p. 602.

ADMINISTRATIVE STRUCTURES

Chapter 5 presented the history, current involvement, and future plans of the many government

and nongovernment parties interested in genome

research. This chapter assumes the continued interest and participation of the current actors, and

it discusses the options for organizing those actors at the Federal level.

A properly designed administrative or organizational structure for genome projects is important.

As form so perfectly matches function in DNA,

so the organizational form of the project should

match its function and goals. These include rapid

accumulation of knowledge about the genome,

efficient storage and distribution of that information, and conversion of this knowledge into

productive theories, tools, reference materials,

and medicines. The political consequences of a

poorly administered group of projects are not only

failure to achieve potential intellectual and economic contributions, but also negative impacts on

the organization and funding of other scientific

investigations. A genome project blueprint cannot be drawn without taking into consideration

the abutting structures as well as the internal constraints.

Three major funding agencies must be included

in any consideration of organizational design: the

National Institutes of Health (NIH), the Department

of Energy (DOE), and the National Science Foundation (NSF). Nongovernmental bodies such as the

National Academy of Sciences (NAS) and the Howard Hughes Medical Institute (HHMI) are already

participating in organizational and advisory roles,

and commercial firms anxious for sequencing

technology and data seek input as well.

There are at least five possible administrative

structures a human genome project could develop:

●

●

●

●

●

One agency—a project performed exclusively

by one of the expert agencies.

Single-agency leadership—a project in which

Congress would designate one agency to coordinate and oversee the research.

Interagenccv agreement and consultation—a

cooperative project among the agencies in

which no additional authority structure

would be created.

Interagency task force—a project in which

a committee with the authority to direct research planning among the agencies would

be chartered.

Consortium-a project in which the private

sector as well as the Federal Government

would plan research, with possible cofund -

ing from the corporate partners.

The first alternative, a project organized and

executed solely by one agency, may be dismissed

as unnecessary and politically unworkable. A

single-agency project could only result from cutting out others, and several agencies have already

made substantial investments in genome research

and related technologies. Further, the current genome infrastructure, including GenBank” and

DNA clone repositories, is already interagency.

The other four proposals have unique strengths

and weaknesses. For any of them to be successful, however, the administrative structure must

at least organize communications at the scientific,

interagency, and international levels. At most, it

should be capable of planning a research program

115
116

involving many partners and funding them accordingly. Congressional decisions on the organizational structure can be based on perceptions of

the necessary patterns of authority, of quality and

scope of experience in research and development,

and of fiscal and economic priorities.

Single-Agency Leadership

One possible beginning for genome projects

would be the designation by Congress of a lead

agency to coordinate ongoing activities in various

agencies (see figure 6-l). This option was the one

favored by a majority of those on the National Research Council committee that issued a report on

mapping and sequencing the human genome (18).

The strengths of this organizational option derive

from its clear designation of authority. Such

leadership can be dynamic, and research would

follow the theme established by the lead agency.

A lead agency, and thus a lead administrator, focuses the project in all its aspects: It provides a

communications link among researchers, domestic

and foreign; a contact for media; and a target of

criticism and politicking. Drawbacks to designating a lead agency are the possibility of incomplete

commitment by the lead agency and the potential inability of the lead agency to command the

resources of other agencies effectively. Choosing

this option would necessarily entail choosing

which agency should lead,

Among NIH, DOE, and NSF–the three funding

agencies—NIH and DOE are the most appropriate candidates to lead a genome project, NSF is

an unlikely leader because its mandate excludes

the investigation of human health and disease, the

ultimate focus of the projects. Further, a largescale operation conducted by NSF would inevitably detract from other research of which NSF may

Figure 6-1 .—Lead Agency

be the sole patron. Such a loss would occur in

each of the funding agencies involved, but NSF

may be most sensitive because it funds much less

biology than NIH, and the research it supports

is more basic as a rule than that supported by

DOE or NIH (30). NSF can contribute to genome

projects by stimulating interest in automation and

robotics (which it has done), in animal models of

human disease (by gathering animal and microorganism sequence data for comparison), and in

instrumentation (through its biology centers).

Choosing between NIH and DOE is troublesome

because these agencies have complementary

strengths and weaknesses. The project would have

a different face with different leadership.

Because of its mandate to support investigations

to improve the Nation’s health, NIH dominates biomedical research. The institutes spent an estimated $313 million in 1987 for projects that involved mapping or sequencing, over $90 million

of which funded projects to characterize the human genome (13,15). NIH has conducted, funded,

and administered genetics research expertly for

years, and the institutes would seem to be a natural home for genome projects. The theme of an

NIH-led project would likely be a renewed commitment to the peer review system and to small,

or cottage industry, science, with some added attention to the research infrastructure.

One great strength of NIH is its decentralized

administration: Quality projects uninteresting to

one institute may well be funded by another. This

flexibility is achieved at a cost, however. Critics

have scrutinized this process and concluded that,

among other faults, it cannot support a large,

directed project (28). NIH leadership can have difficulty imposing the priority decisions needed for

a concerted effort. A distinction is often made between the operating styles of NIH and NASA (the

National Aeronautics and Space Administration),

with NASA having much greater central authority and NIH exemplifying a decentralized process

for setting priorities. To manage some of the proposed genome projects, mechanisms beyond NIH’s

standard researcher-riginated format may be required. This could “require a change in NIH’s philosophical outlook and its approach)” according

to George Cahill of HHMI (23).
117

NIH could conduct a directed research program,

It has done so in the past for the study of particular diseases (e.g., polio and cancer) and is now doing so for AIDS. While NIH has not previously

mounted a major project to develop a set of tools

for biology (as mapping and sequencing projects

are often characterized), it has the funding mechanisms and expertise necessary to do so. The mapping and sequencing projects have been described

as a library of information awaiting translation,

and NIH administers the National Library of Medicine (see ch. 5). To facilitate special genome

projects, NIH has created new study sections to

review grants that focus on methods; NIH could

also convene a new scientific advisory body in an

existing institute to direct a focused project, set

aside funds for special projects in one or more

institutes, and begin new centers or multidisciplinary programs analogous to existing ones. It already has a multi-institute coordinating body to

develop special initiatives like those announced

in May and October 1987 for analyzing complex

genomes and for informatics in molecular biology. NIH is currently in the process of establishing a mechanism for obtaining outside advice.

The high capital needs in some areas, the diverse expertise (extending beyond biomedical research) needed on some research teams, and the

standardized and repetitive work of mapping and

sequencing may render small research groups unable or unwilling to do such work (8). Experience

at the National Cancer Institute with the Special

Virus Cancer Program has suggested that the

standard grant mechanism is insufficient for such

tasks as the production of standardized tools, the

distribution of clinical materials, and the increased

coordination of investigators (33). If the institutes

were to assign high priority to genome projects,

those projects could conflict with other major research efforts, for example research on AIDS.

Some persons, among them Ruth Kirschstein, Director of the National Institute of General Medical Sciences, have questioned whether “it would

be appropriate to have a specifically targeted program that would compete with all the extraordinarily important programs NIH funds” (23). The

danger is that a targeted program would become

an instead-of program rather than an in-addition.

to program, as was the case with the Special Virus

Cancer Program (33).

As a lead agency, DOE would endow the genome

project with different characteristics of organization and expertise. DOE has long supported research on human mutations and DNA damage and

repair through the Office of Health and Environmental Research. The mission of OHER is to understand the effects of radiation and other means

of energy generation on human health and the

environment. OHER views ignorance of the genome and the inability to sequence and analyze

DNA rapidly as major limitations on its research.

As NIH might emphasize the human disease aspects of genome research, DOE would emphasize

the investigation of mutagenesis and other areas

closely related to OHER’s mission. Critics have

characterized OHER’s rationale as “clearly impractical” (17) and “forced and . . . disingenuous” (30).

But because of OHER’s interest in human genetic

material, DOE already has established expertise

in crucial technologies such as automated chromosome and cell sorting, and in the computer storage of genetic data. DOE believes that, through

its national laboratory structure, it should develop

methods and tools useful to the entire commu -

nity of molecular biologists (27).

The strengths and weaknesses of DOE are

largely complementary to those of NIH. DOE’s

strength is its familiarity with the administration

of focused research programs, It manages many

large facilities for research in physics and chemistry—such as accelerators for high-energy

physics—and the scientists whom DOE funds in

these areas are among the best in the world. DOE

also maintains excellent computing resources. Yet

DOE does not have the same stature within the

community of molecular biologists that NIH does

(11,16,24,30).

The national laboratories have long provided

services to the community of molecular biologists

that are not provided by other agencies. The national laboratories have pioneered many hightechnology instruments useful in biology: zonal

centrifuges, high-pressure liquid chromatography,

fluorescence-activated cell sorters, and chromosome sorting. Teams at national laboratories have

prepared sets of DNA clones from individual human chromosomes, and current mapping projects

are logical extensions of this work. Even though

the national laboratories are not renowned for
118

their expertise in molecular biology, some of the

technology, analytical software, and new methods that need to be developed will not be in biological disciplines—they will involve engineering,

physics, and mathematics, all areas of acknowledged national laboratory expertise.

DOE enjoys the reputation of being a proficient

organizer of projects among government, university, and industry researchers. As an agency, it

is experienced in managing large projects and disbursing large sums of money, extramurally to

universities and research centers and intramurally

to the national laboratories. Critics fear that, if

DOE assumes leadership of genome projects, its

bias toward central management will corrupt research and stifle the more traditional, perhaps

more creative, cottage industry approach.

DOE’s review process for genome projects

would involve prospective and retrospective peer

review. The degree of scrutiny is not likely to differ

substantially from that at NIH. Funding through

DOE would be less likely to sap other biomedical

funds, but other biological research programs at

DOE could suffer. Designating DOE as the lead

agency would give the organizational lead to an

agency that supports only a small fraction of related research and thus only a small fraction of

the user community. Having DOE administratively

lead all genome projects could prove unmanageable in the long term.

The controversy over which agency should lead

—DOE or NIH—may be misguided. Each agency

has a role to play, and discussion should focus

instead on how to encourage cooperation and to

ensure that the research program of one agency

does not inhibit that of the other. One observer

has asserted that a major directed program at NIH

alone would soon be politically incorporated into

the overall NIH budget and would thereafter displace untargeted research. The corollary is that

“DOE could find the leadership excellence more

easily than NIH could provide the budgetary insulation” (14). Nonetheless, NIH is the logical choice

for lead agency if Congress chooses to designate

one—its mission is most directly affected, and the

scientific community now supported by NIH is by

far the largest of the intended beneficiaries of genome projects. If NIH leads, then the expertise

and multidisciplinary research already supported

by NSF and DOE should be explicitly taken into

account in future planning. Difficulties in designating a lead agency are discussed under options

for action by Congress in chapter 1.

Interagency Agreement and

Consultation

The lack of a lead agency implies no favored

research strategy or funding mechanism, but a

balanced program to take advantage of NIH, DOE,

NSF, and other agencies’ strengths. Agencies could

be left to themselves to cooperate and communicate among themselves and with other interested

organizations in the United States and abroad (see

figure 6-2). A group of agency principals–agreed

to by the agencies or under the Office of Science

and Technology Policy—could meet to achieve

these goals and exchange details of research directions and developments.

An interagency agreement and consultation

framework eschews any formal creation of authority and relies on the good will of the participants to exchange information freely. Such an arrangement allows each agency autonomous, and

presumably efficient, use of its resources and permits each agency to address those research topics

most closely associated with its institutional interest. Interest may not always correspond to expertise, however, and it may conflict with or overlap other agencies’ programs. This would act

against one ostensible goal of the cooperative

effort—to streamline projects by eliminating unnecessary duplication of research. An informal

or ad hoc framework may also be inappropriate

for very expensive, long-term projects because

evolving and potentially diverging priorities may

diminish rapport among the agencies.

A communications and consultation committee

could be responsible for these cooperative, comFigure 6-2.—interagency Agreement and Consultation
119

munications, and streamlining functions, but the

institutional focus would be scattered and the

project would exist without clear leadership. Although in the best scenario such a committee

would be completely abreast of all the domestic

research, it might be too diffuse a body to support international organization of a project.

Decentralized authority is not without benefits,

however, for pluralism of funding sources and

flexible, decentralized organization are strengths

of American science. Genome projects may be

compelling enough to turn the organizational

gears without creating a special bureaucracy for

the task. A cooperative effort also permits a flexible mix of funding options, and each agency would

retain control over its research planning.

The subcommittee on the human genome of the

Biotechnology Working Group of the Domestic

Policy Council acted as “a mechanism for exchanging information . . . [with] the right people at the

right level, ” according to David Kingsbury of NSF

(23). This coordinating group will now be located

under a life sciences committee at the Office of

Science and Technology Policy. Such a group of

government administrators facilitates interagency

communication but may not address other needs.

A purely government body is open to the criticism that scientists and not government administrators must provide direction or at least participate directly in planning (31). This conflict is

similar to that found in creating an advisory body,

which generally reflects the question of how much

influence scientists should have on the science policy process (discussed below).

The merit of informal agreement and consultation is that each agency would have the flexibility

to follow its own research agenda. Agreement and

consultation would not require legislation by Congress and would make interagency cooperation

a matter of congressional oversight. A disadvantage is that flexibility maybe achieved at the cost

of clear authority and accountability. Further,

there might be no mechanism for resolving conflicts among agencies. The appropriateness of informal interagency cooperation turns on a judgment of which is more efficient—a directed and

planned effort or a pluralistic and decentralized

process.

Interagency Task Force

A genome initiative might require more active

leadership than that described above. An interagency task force dedicated to pursuing the genome project and wielding some authority over

funding and research might provide such leadership (see figure 6-3).

The task force could be constituted much like

an interagency committee, with principals from

the participating agencies; however, the task force

would possess authority in certain areas, such as

gathering of information from participating agencies, preparation of reports, formulation of recommendations, and interagency planning. It could

design and direct a genome project, drawing on

each of the participating organizations (see box

6-A).

A task force would be much like a lead agency

in its ability to draw the attention of foreign researchers, the media, and domestic political interests. And like a lead agency, the task force

would present a central character—its chairperson —who would act as spokesperson for the project. If the chairperson of the task force were

selected from the agency representatives, however, the appointment would likely carry with it

the same kind of political difficulties as selecting

a lead agency.

Establishing a functional authority may require

substantial political investment, but the cost of

subsequent decisions is negligible because they

can be immediate and final. With a committee

authorized only to facilitate communication, a

dilemma in the assignment of a particular research

project, for example, could be costly in any number of ways, from the time it takes to reach a cooperative solution to the money required to duplicate the research should no equitable distribution

Figure 6-3.—interagency Task Force
120

Box 6-A.—Acid Precipitation Task Force

The Acid Precipitation Act of 1980 (Public Law

96-294), Title VII of the Energy Security Act, established a lo-year program to reduce or eliminate the

sources of acid precipitation. To implement this program, Congress mandated the formation of the Acid

Precipitation Task Force, composed of members

from the national energy laboratories, the agencies,

and four presidential appointees, and chaired jointly

by representatives from the National Oceanic and

Atmospheric Administration (NOAA), the U.S. Department of Agriculture (USDA), and the Environmental Protection Agency (EPA). The task force is

thus a truly interagency body, drawing on a variety of agency expertise for leadership.

The legislative history describes the task force as

being charged with preparing a comprehensive research plan, to include individual research, economic assessment, Federal coordination, international cooperation, and management requirements.

The comprehensive plan is implemented and managed by the task force. The Acid Precipitation Task

Force could thus serve as a model for an interagency

task force dedicated to genome projects.

In 1985, representatives from the various agencies signed a memorandum of understanding that

fixed the structure for administering the act. The

memorandum assigns authority and responsibility

to: 1) a Joint Chairs Council, consisting of principals

from USDA, DOE, EPA, NOAA, the Department of

the Interior, and the Council for Environmental

Quality, and responsible for approving the annual

research program and the corresponding portions

of the budgets of the participating agencies; 2) the

task force, to review the annual research program

and budget and to provide advice and recommendations to the council; 3) the Director of Research

(appointed by the Joint Chairs Council), to formulate the research program and budget; 4) the Interagency Scientific Committee and the Interagency

Policy Committee, consisting of senior scientific and

policy executives, respectively, from the agencies,

to advise and recommend; 5) an External Scientific

Review Panel; 6) ‘the Office of the Director of Research, consisting of scientists and support staff;

and 7) research task groups, each under the lead

of a specific agency, to develop a research plan and

budget for a particular task.

Shortly after the 1985 reorganization, the General Accounting Office reviewed the program at the

request of Congress, because management changes

and delays in reporting had become constant. The

General Accounting Office’s recommendations are

more functional than structural, and they relate to

the difficulty of issuing public reports under great

scientific uncertainty. The almost intractable nature

of some of the acid precipitation problems is apparently issue-specific and not related to the organization of the project.

The authority under the new organization is significantly vested in the Joint Chairs Council, the Director of Research, and divided between a scientific column and a policy column, The fine structure

is fascinating: It attempts to permit each participanting agency to retain authority over its research expertise by creating research task groups. For example, Interior is responsible for monitoring

deposition, NOAA for atmospheric processes, and

DOE for emissions and control technology. In genome projects, distribution according to expertise

would have NIH focus on mapping techniques and

biological technologies, and DOE focus on automation and robotics and computation. This could be

useful as long as it did not assign tasks to the wrong

agency and did not inhibit flexible interagency planning for areas of legitimate overlap. The agencies

participating in the Acid Precipitation Task Force

are working on a scale similar in magnitude to that

of a genome project; from fiscal years 1982 to 1987,

the agencies spent just over $300 million for acid

precipitation research.

The joint chair arrangement, among NIH, DOE,

and NSF in a genome project, would represent a

smooth distribution of authority. The appointment

of a director of research might prove the only bone

of contention, as the selection might imply what

style of research—small-group science v. Big Science—is to be funded. The Acid Precipitation Task

Force also balances the concerns of policy specialists

with those of scientists and seeks the input of

nonagency scientists as well (it does neglect nonagency policy specialists, however). This interagency task force approach attempts to combine

the dynamic properties of an authoritative leader

with the efficiency of agencies pursuing their own

research expertise.

SOLIRCE: Office of Technology Assessment, 1987, based in part on U.S. Congress, General Accounting Office, Acid Rain: Delays and Management Changes

in the Federal Research Program, GAO Pub. RCED-87-89 (Washington, DC: GAO, 1987).
121

be achieved. A task force or lead agency could

eliminate some of this cost.

A task force may not be able to match efficiency

in decision making with efficiency in administering the agencies’ resources. Its recommendations

could be ignored by agencies, or it could prove

an obstruction or source of delays. A task force

is a bureaucratic solution, identifying a person

or group with the goal of genome analysis and

building upon the existing authority structure.

Such authority may be necessary to direct research and provide a focus for international communications, but it adds another layer to the

bureaucracy that separates the administrators of

science from the investigators.

Consortium

Like the task force approach, a consortium

would involve the creation of a new authoritative entity. Unlike the organizational structures

discussed previously, however, this approach

would require the active participation of private

firms (see figure 6-4). The introduction of this new

factor complicates the staging of a genome project.

The typical consortium is a close working association between a university research group and

one or more private firms interested in the pursuit and economic development of that research.

Government involvement in consortia is often

limited to financial support during the initial stages

of basic research, while industry waits to fund

the development stage. State government is frequently more active than Federal, because the

projects are perceived to be closely linked to local economic development (see box 6-B).

Figure 6-4. —Consortium

A consortium of universities, businesses, and

government is directed toward several mutually

enriching goals: strengthening universities, stimulating (competitive) economic growth, engaging

in basic research, creating generic technologies,

and developing and delivering specific products

(6). These goals correspond to those of some genome projects, which some persons hope will

maintain America’s competitive position in biotechnology against challenges from Asia and Europe. Genome projects would, for example, seek

both to create generic biotechnology tools (such

as techniques for handling very large DNA fragments, detecting very small amounts of DNA, and

designing software for analysis) and to develop

specific products (such as vectors for cloning DNA

or automated DNA sequencers). Such results

would benefit university researchers and corporate investors alike.

The question of setting the research agenda (in

other instances the responsibility of the individuals conducting the research and the agencies

funding it or of the task force established to oversee it) is complicated by private firms’ need to emphasize technology development and not necessarily free inquiry. Profit-seeking firms often have

shorter-term goals than are practical for the support of basic research and therefore focus on the

development of short-term technologies over longterm ones. Not all industries have a short-term

perspective, however: Pharmaceutical firms are

accustomed to basic research and long-term payoffs—investments requiring more than a decade

to bear fruit.

A private emphasis on development is closely

associated with the effective transfer of technology into the marketplace. A consortium would

no doubt speed technology transfer to participating firms, but firms might suppress the spread

of scientific information to protect their investment (5). The phenomenon of sitting on data is

not restricted to industry—academic scientists

may delay dissemination of information in order

to consolidate results for their own financial or

reputational benefit (12)—but proprietary interest will not help the free exchange of data. Thus,

the question of proprietary rights versus information in the public domain is a sticky one for
122

genome projects, where a naturally occurring

DNA sequence can translate into a muhi-milliondollar product. Thus the presence of commercial

firms in academia is two-sided: Goals of technology transfer and economic development may be

more easily reached, but the control exerted by

industry over the planning of the research agenda

of private firms might corrupt the atmosphere

of academia may be overstated now, since only

a few businesses have shown any interest in the

genome project; but the possibilities of reaping

economic benefits, especially in the current environment of international competitiveness, are

likely to attract more private sector involvement

and the dissemination of results might be too self- in the future.

interested. Concern that the economic aspirations

Box 6-B.— Midwest Plant Biotechnology Consortium

Representing a large number of university, industry, and government partners, the Midwest Plant Biotechnology Consortium is an experiment in basic research and technology transfer among agricultural sectors. Its purpose is to increase the competitiveness of American agriculture and agribusiness through the

development of basic plant biotechnology research.

The idea for the consortium began at DOE’s Argonne National Laboratory (ANL), which has a historical

research interest in photochemistry and photosynthesis. ANL determined that a coordinated program in

plant science could contribute to biotechnology applications of interest to both industry and government

agencies.

When ANL invited participation from universities and industry, it specified a number of principles that

would guide the consortium. The continued importance of both industrial and scientific peer review processes was stressed, and the intellectual property rights were established from the outset. ANL also emphasized the regional nature of the consortium, encouraging the participation of Midwest institutions to investigate for Midwest agribusiness. Aside from these initial guidelines, the original organization of the consortium

remained informal until recently, when it sought incorporation as a 501(c)(3) (tax-exempt) corporation and

developed a more formal budget process.

Government interest in the consortium comes from those agencies involved in the genome discussion—

DOE, NSF, and NIH—with the addition of USDA. A secretariat operates the consortium, determining policy

and procedure with informal involvement of government officials. More formal arrangements may be possible in the future. An executive board of corporate and university officers oversees the technical and

administrative operations. A number of research topic subgroups (e.g., plant growth, pesticides-herbicides)

also exists, and the primary interaction for technology transfer occurs at this level.

The consortium solves the problem of research direction by a two-tiered system: The industrial partners first select proposals on the basis of commercial potential, and then a peer review system selects on

the basis of technical merit. The consortium expects the Federal Government (with some State funds) to

support research through the initial stages, that is, until the industrial partners can see around the development corner to a commercial application. Research proposals developed as part of the consortium will

be subjected to normal competitive grant review at the Federal agencies. Industry would then fund the

final steps.

Organizationally, the Midwest Plant Biotechnology Consortium offers a number of useful parallels to

a genome project. The Federal agencies overlap similarly, as does DOE’s attempt to link the research program to related research at the national laboratories. Intellectual property rights are sensitive in both projects;

the consortium provided from the outset that each research participant would retain rights according to

institutional policy and that the industrial participants would have the right to first disclosure, The consortium retains the integrity of the peer review system while allowing industry to set some of its own research

priorities based on commercial potential. The parallels break down where some of the short-term commercial interest in a genome project focuses on automated tools and machinery in addition to the results of

biotechnical manipulation. Funding for the consortium is also considerably less than what is expected to

be necessary for a genome project.

SOURCE” Office of Technology Assessment, 1987
123

If consortia related to one or more genome

projects are formed, several issues will have to

be resolved. First, terms of participation must enable a broad spectrum of private firms to participate. Small firms with limited resources have had

difficulty, for example, in paying entry fees to some

biotechnology consortia (22). And nonprofit organizations, which must make their information available on a nondiscriminatory basis under U.S. tax

laws, might have difficulty in participating if there

are preferential terms for industrial partners.

Discussion

None of the four workable administrative

structures—the lead agency approach, which requires a choice between DOE and NIH; the cooperative approach, which requires no new legislation; the task force, which creates a formal

authority; or the consortium, which adds a dose

of private sector assistance—is static. Administrative forms may overlap: For example, the consortium may require a lead agency, or the cooperative effort may create consortia or task forces to

attain specific objectives. The administrative structure at the national level does require explicit

choices, however. Congressional action will vary

according to the option chosen. Interagency agreement and consultation would require no new legislation, only oversight. Designation of a lead

agency, establishment of a task force, or creation

of a single national consortium would require new

legislation.

Administration of genome projects will require

monitoring of some central services and facilities,

some services and functions performed at centers,

and many grants to small groups. This raises several concerns about communication among agencies and among the scientists whose work they

support. The diffusion of research among a large

number of groups complicates communication,

but it permits the most flexible organization of

research; the investigator may be as focused or

interdisciplinary as the research demands. A reduction in the number of groups reduces the difficulty of communication but limits the number

of people trying wholly new approaches to the

scientific or technical objective. The pace of innovation may be directly proportional to the number of groups: A commitment to a single center

or institute might fix the relevant technology

prematurely. When innovation is less important

than production, then specialized facilities are logical because they simplify the organization of

work. Problems of communication for centrally

administered projects are of a different variety.

Often the most difficult problem is ensuring that

services are appropriate and tailored to the needs

of those using them. Different genome projects

will have different modes of communication. Projects that rely on many small groups will need communication networks or frequent meetings of scientists; central services will require feedback from

user communities.

ADVISORY STRUCTURE

Second to the administrative structure in organizational hierarchy, though not in importance,

is the structure of an appropriate advisory body

or bodies. Agencies supporting genome projects

will benefit from tapping the academic and industrial sectors for the requisite expert wisdom. Similarly, academia and industry wish to ensure their

input into the decision-making process and to exercise some control over the research that affects

their livelihood. The responsibilities, composition,

structure, and funding of advisory groups then

become issues.

Responsibilities

The primary responsibility of the independent

advisory board (or boards) would be to follow the

research plan and budget envisioned by the agencies, task force, or consortium and to make recommendations where appropriate. Such recommendations might include identification of

promising research initiatives in need of funding

or oversight of standards necessary to ensure quality control. The board could be granted budget

authority to enact these recommendations, or its
124

role could be strictly advisory. Consideration of

broad overarching issues–such as the ethical implications of using some newly developed technologies or the economic benefits of targeted technology development-could also be a function of

the board.

The advisory board would naturally have a

reporting duty: to the participating agencies, to

Congress, to the public, and perhaps to the international community of scientists. The advisory

board would be an organ of communication

among the agencies, supplementing their informal direct contact. Congress would probably want

to be kept abreast of research progress and could

require periodic assessments in order to plan genome projects and other research initiatives. Annual or biannual reporting to Congress on progress and the distribution of funds could be fit into

the budget process, for this will be one way in

which genome projects are held accountable to

the taxpayers. The executive branch could be kept

up to date by the advisory board or through the

Office of Science and Technology Policy. An advisory board not composed entirely of Federal

officers would fall under the Federal Advisory

Committee Act (Public Law 92-463). Pursuant to

the act, the advisory board’s meetings and papers

must be open to the public. The advisory board

could also be the contact for international communication.

Composition

An advisory board would require members with

varied backgrounds. Scientists with experience

in the planning of mapping and sequencing work

would be needed for technical advice. Scientists

with database expertise would also be required,

as the storage and dissemination of the project’s

information is as central as the generation of it.

Scientists could be chosen from universities, industry, and federally supported laboratories.

Choosing the board involves the same issues as

the consortium decision: how much influence development- and profit-minded industry experts

should have on the project. One suggestion, from

an industrial association, is to set up an advisory

board with 50 percent university, 30 percent government, and 20 percent industry representatives

(9). This would in fact be an extension of current

practice, as university and industry representatives often work together productively. The selection of scientists from abroad to serve on the advisory board, perhaps as nonvoting members, would

help it assume an international role.

Since the project’s impact would extend into general science policy, economic competitiveness,

medical care delivery, and the like, experts from

such fields might be included. The board might

want, for example, to ensure that other areas of

biomedical research do not suffer from a drain

of funds or personnel, and policy experts and

economists would be helpful in this. Lawyers

might be necessary to address questions of intellectual property. Ethicists might be included to

help the board address such issues as confidentiality of data on research subjects or whether

to investigate the chromosome containing disease

gene A before that containing disease gene B. Representatives of interested private philanthropies,

particularly those supporting research in human

genetics, might also be included, An advisory

board would logically include at least a representative of the Howard Hughes Medical Institute, as

it funds a substantial portion of genome projects.

Structure and Funding

Scientists and nonscientists could serve together

on a single advisory body or on separate bodies.

The choice will influence the method of research

planning and science policy formation: In a single body, the procedure is multifaceted but

essentially unitary; in separate bodies, the procedure is separated into scientific and policy components. Another possible division of advisors

would be government representatives on one

panel and private representatives, from academia,

industry, and other backgrounds, on another.

Appointments to a policy board could be made

by the President, with the advice and consent of

the Senate. The choice of members could be assigned to a nongovernmental body, such as the

National Academy of Sciences, to ensure the

board’s independence and its technical competence. As an alternative, the task of selection could

be delegated to the Office of Technology

Assessment.
125

BIG SCIENCE V. SMALL-GROUP SCIENCE

The likelihood that Big Science will invade

molecular biology has often been cited in opposition to a concerted government program of genome projects. Small science is largely conceived

and executed by a principal investigator directing a small laboratory group funded by a grant.

Big Science can refer to many things. It can mean

large and expensive facilities. It can refer to large,

multidisciplinary team efforts that entail cooperative planning and therefore require individual

scientists to sacrifice some freedom in choosing

goals and methods. Or it can refer to bureaucratic

central management by government administrators. These different meanings have been intermingled in the emotionally charged debate about

genome projects. (For further insight into that debate, see box 6-C.)

Three lines of argument have been made against

conducting molecular biology research on one of

these Big Science models: style, efficiency, and political interference.

Displacement of Higher-Priority

Science

Some scientists worry that a major Federal program to map the human genome and sequence

a significant portion of it would detract from the

conduct of more important science (2)3)20). The

argument is that special appropriations for human genome projects could well go to projects

that do not present the most immediate obstacles

to scientific progress and might supplant funds

that would be allocated differently by the peer

review processes of scientific agencies. If genome

projects were not of the same scientific caliber

as projects in other areas of science, agencies

would nonetheless be precluded from reassigning those funds.

Other scientists argue that some genome projects do not lend themselves easily to current review procedures and merit a special effort (7,10,

19,25,30). Genome projects will involve not only

science, they say, but also technology development

and production. Some aver that existing peer review committees give short shrift to projects intended to develop methodology (as opposed to

answering a scientific question) and tend to underfund shared research resources. They believe that

the value of genome projects warrants a special

effort, including new peer review committees and

increased resources for a research infrastructure.

A related issue concerns the details of funding

mechanisms. Those who believe strongly in the

superiority of investigator-initiated small-group

research urge caution in supporting large projects

that are administered by institutions rather than

individuals. The agencies most directly involved—

namely, NIH and DOE—are adopting policies that

answer both arguments by promising to use a system of peer review that gives the scientific community substantial power to direct genome projects but that differs from current peer review by

adding new review groups to focus on component genome projects.

Style and Efficiency

Some scientists have objected to a Big Science

approach to genome projects because it goes

against the tradition of science as a cottage industry conducted by small, largely autonomous

groups. The underlying assumption is that Big Science management would undercut the motivation

and circumscribe the freedom of investigators by

making them beholden to administrators in a scientific bureaucracy. Yet team effort is likely to

be cheaper and faster in the long run for genome

projects that focus on developing instruments or

producing maps. It would be unwise and wasteful to shun all projects that do not conform to

the small-group mode. One science administrator advised scientists that:

. . . insofar as what they do is part of the war

against human suffering, their desires and

tastes are not all that matter. Biomedical science is not done, or, more important, is not

supported by the public, simply because it

gives intense satisfaction to the dedicated and

successful biomedical researcher (32).

Large and expensive projects must meet certain criteria, otherwise they could indeed supplant

other research. They must meet needs that cannot be met by small-group research (e.g., produc-
126

Box 6-C.—Quotes on Genome Controversies

Proposals for genoxne projects, particularly sequencing the human genome, have provoked considerable controversy among luminaries in molecular biology and related disciplines. The following quotations

illustrate the liveliness of the debate over the past 2 years.

“Sequencing the human genome is like pursuing the holy grail.” Walter Gilbert, Harvard University,

at several national meetings, March 1986 to August 1987.

“[sequencing the genome now] is like Lewis and Clark going to the Pacific one millimeter at a time.

If they had done that, they would still be looking.” David Botstein, Whitehead Institute, Cold Spring Harbor

Symposium on the Molecular Biology of Homo sapiens, June 1986.

“Humans deserve a genetic linkage map. It is part of the description of Homo sapiens .“ Raymond White,

Howard Hughes Medical Institute, University of Utah, in Science 233:158, 1986.

“The idea is gaining momentum. I shiver at the thought.” David Baltimore, Director, Whitehead Institute, in Science 232:1600, 1986.

“Of course we are interested in having the sequence, but the important question is the route we take

to getting it. ” Maxine Singer, Director, Carnegie Institution of Washington, in Science 232:1600, 1986.

“Sequencing the human genome would be about as useful as translating the complete works of

Shakespeare into cuneiform, but not quite as feasible or as easy to interpret. ” James Walsh, University

of Arizona, and Jon Marks, University of California, Davis, in Nature 322:590, 1986.

“I believe such a conclusion [against special efforts to sequence the human genomel represents a failure

of vision, an unwarranted fear of (not very) ‘big’ science .“ Robert Sinsheimer, University of California, Santa

Cruz, in Science 233:1246, 1986.

“My plea is simply that we think about this project in light of what we already know about eukaryotic

genetics and not set in motion a scientifically ill-advised Juggernaut.” Joseph Gall, Carnegie Institution of

Washington, in Science 233:1368, 1986.

“Too bad that it needs such fancy wrappings to attract public attention for an obvious good. ” Joshua

Lederberg, “The Gift Wrapped Gene, “ in The Scientist, Nov. 17, 1986, p. 12.

“The sequence will give us a new window into human biology.” Renatto Dulbecco, Salk Institute, interview with OTA staff member, January 1987.

“Of course, if you have the clones, you’re going to want to sequence them. The question is which ones

to do first. I think it is scientifically arrogant to prejudge what will be important and what will not.” Paul

Berg, Stanford University, interview with OTA staff member, January 1987.

“I’m surprised consenting adults have been caught in public talking about it [sequencing the genome] . . . it

makes no sense.” Robert Weinberg, Whitehead Institute, in The New Scientist, Mar. 5, 1987, p. 35.

“The sequence of the human genome would be perhaps the most powerful tool ever developed to explore the mysteries of human development and disease.” Leroy Hood and Lloyd Smith, California Institute

of Technology, in Issues in Science and Technology 3:37, 1987.

“The main reason that research in other species is so strongly supported by Congress is its applicability

to human beings. Therefore, the obvious answer as to whether the human genome should be sequenced

is ‘Yes. Why do you ask?’ “ Daniel Koshland, Editor, Science 236:505, 1987.

“The real problem that faces us is not the cost of the Human Genome Program, but how to get it going,

seeing both that the right people are in charge and that they work under an administrative umbrella that

will not tolerate uncritical thinking and so will never promise more than the facts warrant.” James D. Watson, Director’s Report, Cold Spring Harbor Laboratories, September 1987.

“We will see a new dawn of understanding about evolution and human origins, and totally new approaches to old scientific questions.” Allan Wilson, University of California, Berkeley, at a symposium for

the director, National Institutes of Health, Nov. 3, 1987.
—

127

tion, service, or targeted technology development).

They must not merely be useful, but fill critical

resource gaps as well (4). These criteria are likely

to be met by many databases, repositories, and

mapping projects. They have not yet been met by

proposals to sequence the entire human genome.

Some argue that, while it may appear that certain projects are best conducted by large, multidisciplinary teams, in the long run science progresses faster if large, targeted projects are not

begun (20). That is, small-group science is so much

more productive in the long run that attempts to

direct science will inevitably go astray.

Similar debates preceded the approval of costly

projects in other fields. Construction of cyclotrons

and other particle accelerators was resisted by

many physicists in the 1930s IHeilbron and Kevles,

see app. A], and space-based instruments were

opposed by many astronomers in the 1960s (26).

Yet these facilities permitted scientific advances

that would otherwise have been impossible, and

they were (and are) most often used by small research groups. The issue is not that expensive facilities should not be built, but that they should

address critical needs and be carefully planned.

Politicization

One way in which concerted projects are believed to drift into inefficiency is through political interference. This can be on a small scale (haggling that impedes progress among members of

a research team) or a large scale (e.g., pork barrel

science at the national level), One scientist has observed, “a megaproject like sequencing the human

genome is certain to increase the political control

over scientific decisionmaking” (3), and the American Society for Biochemistry and Molecular Biology warns against ‘(the establishment of one or

a few large centers that are designed to map

and/or sequence the human genome” (1). Large

research institutions can drift once their missions

have been accomplished, and it can be difficult

to close down unproductive efforts (32).

Molecular biology has been remarkably productive for three decades without the management

style of Big Science. In the recent inventory of

275 Big Science facilities compiled by the House

Committee on Science and Technology, none was

biological (29). Yet some human genome projects,

for example developing new instruments or pooling results from many different groups, will require multidisciplinary teams concentrating on a

technical problem. This situation is analogous in

many ways to the situations faced earlier by other

sciences in their transition to Big Science IHeilbron and Kevles, see app. A] (32). It is difficult

to imagine, for example, automating the steps in

cloning DNA, sequencing it, or mapping it without combining optics, chemistry, physics, engineering, and electronics. If the end products of

genome projects—materials and information—are

to be reliable and used internationally, there must

be quality control and standardization.

Clearly, some important functions require central coordination or multidisciplinary team research, although not necessarily centralized administration; some tasks cannot be forced into the

mold of small-group science. Technological developments will determine the pace and extent to

which Big Science becomes part of biological research. The question will be how to decide which

projects merit special effort and which do not.

Decisions of several types will be necessary in conducting genome projects. The advantages of decentralized planning must be balanced against the

need for some centralized resources. The importance of mapping, sequencing, and technology development must be compared to other research

and services. Such decisions will require an administrative structure to make them.

Biomedical investigations are now, and in the

foreseeable future will continue to be, conducted

primarily by small groups, although Big Science

facilities and services can amplify and complement

them. Small groups will remain the principal

means of studying physiology and disease. When

new institutions are created for elements of human genome projects, special attention must be

paid to making results useful to small scientific

groups. It would be ironic if genome projects

starved small-group research efforts in order to

create new tools.

The costs of database, repository, and map projects are not large relative to the costs of other

biomedical research, so planned projects are un-
128

likely to have any measurable adverse impact on search faster and less costly. If genome projects

other research. Moreover, genome projects in- threaten the health of small-group biomedical retended to bolster the research infrastructure search, then genome projects should take a back seat.

should free funds for new work by making reSUMMARY

The Howard Hughes Medical Institute recently

issued a short report on efforts to map the human genome; it observed:

The sooner the entire genome is mapped and

sequenced once and for all, the sooner scientists

can get on with the real work of human biology:

understanding what the genes do (2 I).

Databases and repositories must be centrally

administered, although not necessarily centrally

located, in order to be widely accessible. TechCHAPTER 6

1. American Society for Biochemistry and Molecular

Biology, policy statement, April 1987.

2. Ayala, F., “Two Frontiers of Human Biology: What

the Sequence Won’t Tell Us,” Zssues in Science and

Technology 3:51-56, 1987.

3. Baltimore, D., “Genome Sequencing: A Small-Scale

Approach)” Issues in Science and Technology 3:48-

50, 1987.

4. Baltimore, D., Whitehead Institute, personal communication, December 1987.

5. Cahill, G., comments at Issues of Collaboration for

Human Genome Projects, OTA workshop, June 26,

1987.

6. Dimancescu, D., and Botkin, J., The New Alliance:

America’s R&D Consortia (Cambridge, MA: Ballinger, 1986).

7. Gilbert, W., comments at Costs of Human Genome

Projects, OTA workshop, Aug. 7, 1987.

8. Gilbert W., ‘( Genome Sequencing: Creating a New

Biology for the Twenty-First Century,” Issues in Science and Technology 3:26-35, 1987.

9. Godown, R. D., testimony on Title II of S.1480 before the Subcommittee on Energy Research and

Development, Senate Energy and Natural Resources Committee, Sept. 17, 1987.

10. Hood, L., and Smith, L., “Genome Sequencing: How

To Proceed, ’’Zssues in Science and Technology 3:36-

46, 1987.

11. Joyce, C., “The Race To Map the Human Genome,”

New Scientist, Mar. 5, 1987, pp. 35-40.

nology will most likely determine whether and

when large facilities and coordinated administration are necessary to conduct genome projects.

If large facilities prove to be more efficient, this

will not necessarily be incompatible with research

by small groups; it could in fact enhance it. If,

however, large facilities and centrally organized

research programs threaten the lifeblood of biomedical research—investigator-initiated grants—

then the projects should be reevaluated and, if

necessary, cut back.

REFERENCES

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

Karny, G., comments at Issues of Collaboration for

Human Genome Projects, OTA workshop, June 26,

1987,

Kirschstein, R. L., letter in Issues in Science and

Technology, summer 1987, p. 5.

Koshland, D. E., “Sequencing the Human Genome,”

Science 236:505, 1987.

Levinson, R., NIH, personal communication, June

1987,

Lewin, R., News and Comment, Science 235:1453,

1987.

Mitra, S., Oak Ridge National Laboratory, personal

communication, March 1986.

National Research Council, Mapping and Sequencing the Human Genome (Washington, DC: National

Academy Press, 1988).

Office of Technology Assessment interviews with

R. Dulbecco, L. Smith, T. Friedmann, M. Bitensky,

R. Davis, and P. Berg, January 1987; W. Gilbert,

July 1987.

Office of Technology Assessment interviews with

A. Kornberg and S. Cohen, January 1987; D. Baltimore, July 1987.

Pines, M., Mapping the Human Genome (Bethesda,

MD: Howard Hughes Medical Institute, 1987).

Raines, L., Industrial Biotechnology Association,

personal communication, November 1987.

Roberts, L., “Agencies Vie Over Human Genome

Project,” Science 237:486-487, 1987.

Science and the Citizen, “Geneshot,” Scientific
129

American, May 1987, pp. 58-58a.

25. Smith, L., and Hood, L., “Mapping and Sequencing

the Human Genome: How To Proceed, ” Bio/Tech -

nology 5:933-939, 1987.

26. Smith, R., The Johns Hopkins University, personal

communication, December 1987.

27. Subcommittee on the Human Genome, Health and

Environmental Research Advisory Committee, Report on the Human Genome Initiative, prepared

for the Office of Health and Environmental Research, Office of Energy Research, Department of

Energy (Germantown, MD: DOE, April 1987).

28. U.S. Congress, General Accounting Office, University Funding: Information on the Role of Peer Review at NSF and NIH, GAO Pub. RCED-87-87 FS

(washinwon, DC: U.S. Government printing office,

March 1987).

29. U.S. Congress, House Committee on Science and

Technology, World Inventoruv of “Big Science” Instruments and Facilities (Washington, DC: U.S. Government Printing Office, 1986), cited in Heilbron

and Kevles, see app. A.

30. Watson, J. D., director’s report, Cold Spring Harbor Laboratories, in press.

31. Watson, J. D., comments at Costs of Human Genome

Projects, OTA workshop, Aug. 7, 1976.

32. Weinberg, A. M., Reflections on Big Science (Cambridge, MA: MIT Press, 1967), esp. pp. 113-114.

33. zinder, N. D., report of the ad hoc committee reviewing the Special Virus Cancer Program of the

National Cancer Institute, March 1974.
chapter 7

International Efforts
CONTENTS

Page

Introduction . . . . . . . . . . . . . . . . , . . . . . . . . . , . . . . . . . . . . . . . . . . . . . . . . . . . . . . , . , . . .133

Japan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .........136

Mapping and Sequencing Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .136

Potentials for Cooperation and Conflict With the United States . . . . . . . ..........138

Europe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. ...,139

European Organizations ..., . . . . . . . . . . . . . . . . . . . . ..., . . . . . . . . . . . . . . . . . . ..139

National Research Efforts in Europe. . . . . . . . . . . . . . . . . . . . . . ..................143

Other International Efforts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ........148

Australia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...148

Canada . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ......148

Latin America . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .149

South Africa. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...........149

The Union of Soviet Socialist Republics and Eastern Europe. . ..................149

International Collaboration and Cooperation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .150

Precedents for International Scientific Programs . . . . . . . . . . . . . . . . . . . . . . . . . . . . .150

Options for International Organization of Genome Research. . . . . . . . . . . . . . . .....1.52

Existing Collaborative Frameworks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .155

Chapter 7 References , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .159

Boxes

Box Page

7-A. The Venezuelan Pedigree Project . . . . . . . . . . . . . . . . . . . . . ...................134

7-B. The Center for the Study of Human Polymorphism (CEPH): An International

Gene Mapping Center. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ........146

7-C. The International Geophysical Year . . . . . . . . . . . . . . . . . . . . . . . . . . ...........151

7-D. Views on International Cooperation and Collaboration in Genome Research . . . .152

7-E. Large Centers v. Networking. . . . . . . . . , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .156

Figures

Figure Page

?-I. Distribution of Publications in Human Gene Mapping and Sequencing . ........133

7-2. Human Gene Mapping and Sequencing Articles Published Annually . ..........158

Table

Table Page

7-1. International Distribution of Human Genome Research . . . . . . . . . . . . . . . . . . . . . .133
Chapter 7

International Efforts

INTRODUCTION

The expected health benefits of genome projects—and their commercial potential—have attracted international as well as national attention.

The United States is the clear leader in basic

research, publishing more articles on mapping

and sequencing than European or Asian nations

(see figure 7-1, table 7-l). U.S. companies have also

marketed more instruments for DNA research

than any others (see ch. 2). Productivity in basic

and applied research does not, however, guarantee the United States the lead in developing or

producing commercial products and processes,

nor does it ensure market competitiveness. Japan

has also encouraged the commercial development

of technologies associated with the mapping and

sequencing of DNA, Countries such as Switzerland

and West Germany are home base for multinational pharmaceutical and chemical companies that are

poised to commercialize developing products.

Some nations not supporting much basic genome

research at present have strong biotechnology or

high-technology resources and policies and might

Figure 7-1 .—Distribution of Publications in

Human Gene Mapping and Sequencing

Compiled from a bibliometric analysis of literature on human

gene mapping and sequencing conducted for the Office of

Technology Assessment by Computer Horizons, Inc. [see

apps. A and E]. The differences between the annual percentages displayed and the total annual research (100°/0) can be

attributed either to countries not included in the listing or

to the absence of sufficient bibliographic information to determine the country or region from which the publication

originated.

SOURCE: Office of Technology Assessment, 1988

Table 7-1 .—International Distribution of Human Genome Research

(percent of articles published annually on human gene maps or markers)

Year 1977 1978 1979 1980 1981 1982 1983 1984 1985 1986

United States. . . . . . . . . . . . . . . 45 ”/0 420/o 380/o 43% 420/o 40% 460/o 44 ”/0 420/o 43 ”/0

Japan . . . . . . . . . . . . . . . . . . . . . 2 2 3 3 4 5 4 4 4 5

Western Europe

Denmark . . . . . . . . . . . . . . . . . 1 3 1 1 2 1 1 1 1 1

Federal Republic of

Germany. . . . . . . . . . . . . . . 5 4 2 4 6 5 5 5 5 5

Finland . . . . . . . . . . . . . . . . . . <1 1 1 1 1 <1 <1 1 1 <1

France . . . . . . . . . . . . . . . . . . 5 7 6 6 8 6 6 5 6 6

Italy . . . . . . . . . . . . . . . . . . . . . 2 2 1 2 3 2 4 3 3 4

Netherlands . . . . . . . . . . . . . . 4 5 3 3 2 2 2 2 3 2

United Kingdom . . . . . . . . . . 8 9 9 6 9 10 9 10 11 10

Other. . . . . . . . . . . . . . . . . . . . 7 4 7 4 6 5 6 5 4 5

Other non-European countries

Australia. . . . . . . . . . . . . . . . . <1 1 2 2 2 2 2 2 1 2

Canada . . . . . . . . . . . . . . . . . . 3 3 3 4 2 3 2 3 4 4

Eastern Europe and

U. S. S. R.. . . . . . . . . . . . . . . . 5 3 3 5 5 4 3 4 4 3

South Africa . . . . . . . . . . . . . 0 1 1 <1 <1 <1 <1 1 <1

Other. . . . . . . . . . . . . . . . . . . . 5 4 : 4 4 5 3 3 5 3

SOURCE: Office of Technology Assessment, 1988, compiled from a literature search and bibliometric analysis conducted for the OTA by Computer Horizons, Inc The

key words used in the search are described in app. E,

133
134

be well positioned to commercialize technologies

that are developed for and spun off from human

genome research. ’ The OTA has found that

Government agencies in the United States are further along in developing policies for genome

projects than are comparable agencies in other

countries, although a number of other countries

have well-established basic research efforts in

mapping and sequencing human and nonhuman

genomes-efforts that could either complement

or compete with U.S. efforts.

Gene mapping is perhaps the most common international research activity in human genetics,

and it is likely to be an area to which many nations will contribute. Human genes are highly

polymorphic, and populations from different

regions exhibit considerable genetic variation.

These regional differences will allow researchers

to contribute to comparative studies, as well as

to characterize and map genes of particular

regional interest (e.g., the thalassemias in the

Mediterranean and Oudtshoorn skin disease in

the Afrikaner population in South Africa). The

study of DNA from diverse peoples will shed light

on the nature of polymorphisms and genetic disorders, even if it does not lead immediately to improved health care (8).

The large scope of genome projects invites international cooperation. Informal cooperation and

collaboration are already underway through a va -

IIt is not within the scope of this assessment to provide a detailed

analysis of biotechnological capabilities and industrial funding; suffice it to say that genome research is part of a much larger arena

of Federal, university, and industrial research and development.

A forthcoming OTA assessment, New Developments in Bidechndogy, 4: [ ~.S. Int’estment in Biotechnology (81), covers this in great

detail for the United States. A previous OTA assessment, Commercial Biotechnology: An International Ana[vsis (79), describes the state

of biotechnolo~v in Western Europe and Japan; the more recent

Department of Commerce reports, Biotechnoiogv in Western Europe (91 ) and Biotechnology in Japan (39), offer updated information

on international efforts.

riety of mechanisms. Formal collaboration could

speed research and reduce the financial burden

on each country. Maintenance of international

databases and repositories is particularly important to provide timely access to information from research conducted around the

world. Many scientists encourage international

cooperation in genome research, but any effort

to conduct genome mapping and sequencing projects on an international scale must be based on

a realistic assessment of the capabilities and interests of the countries involved.

Countries that do not themselves carry out the

kinds of research involved in mapping and sequencing can play an important role by collecting genetic material from families for comparative studies. One such project, a collection of

genetic material from a group of Venezuelan families, was a key factor in the successful search for

the gene that causes Huntington’s disease (see box

7-A). Similar pedigree collections are being established and maintained in Egypt and Denmark, as

well as in isolated populations in the United States

such as Mormon and Amish communities. These

pedigrees provide valuable source material for the

study of polymorphisms and genetic disease in

human beings.

This chapter summarizes the state of DNA mapping and sequencing research in Japan, Western

Europe, and elsewhere. Issues of international cooperation and competition and precedents for international cooperation in science are examined.

Some organizational options for the international

management of genome projects are proposed,

specifying areas in which cooperation might best

be achieved and describing cooperative frameworks already in existence. Chapter 8 outlines

questions about international technology transfer that might emerge in collaborative or cooperative situations.

BOX 7-A. —The Venezuelan Pedigree Project

In the small fishing villages that line the coast of years the residents of these villages were ostracized,

Lake Maracaibo in Venezuela lives an unusual group considered to be chronically drunk. But in the early

of families. If you walk into any of these villages, 1970s a doctor from a nearby military base realyou may be met by residents who do a characteris- ized that the dance was not due to alcoholism but

tic dance down the streets—large, jerky motions, to Huntington’s disease, a rare, dominant genetic

staggering and weaving from side to side. For many disease that causes degeneration of nerve cells in
135

the brain. The onset of Huntington’s disease is generally late: In those who carry the gene, symptoms

begin at age 35 or older. The disease leads to loss

of control of the voluntary muscles, first causing

twitches and jerks, then dementia, and finally death.

A preliminary study describing the case histories

and pedigrees of approximately 100 patients from

Lake Maracaibo families was presented at a meeting of the American Neurological Association in

1972. It was an interesting case: an interrelated set

of families, along whose pedigree could be traced

an extraordinarily high incidence of a genetic disease that is rare in the general population. At the

time, however, no one knew what to do about it.

The case remained an interesting anecdote in the

memories of the researchers who attended the

meeting.

One of those researchers was Nancy Wexler, a

clinical psychologist. Wexler had both a professional

and a personal interest in Huntington ’s-her mother

had died of the disease, so she and her sister each

have a 50:50 chance of developing it.

Wexler and her colleagues remembered the case

of the Venezuelan families 5 years later, when writing a report on Huntington’s disease for a congressional commission. One of their recommendations

was to initiate a genetic study of the Venezuelan

pedigree. Starting in 1979, the National Institutes

of Health appointed Wexler to direct a program that

would implement the recommendations and set

aside funding for the Venezuelan genetic study. The

first team of researchers went to Lake Maracaibo

in 1981 to collect blood samples from which to extract DNA. At the same time, they compiled a careful record of the pedigrees of the volunteers from

whom the blood was extracted. Research teams

have gone every year since. The pedigree has grown

to include over 7)000 family members; the diagram

of it occupies a 100-foot-long section of a corridor

near Wexler’s Columbia University office. DNA samples have been collected from nearly 1,50() family

members, some with Huntington’s and some

without.

At the same time the genetic study got underway,

advances in recombinant DNA technolo~v, specifically the elaboration of techniques for finding

genetic markers using RFLPs (see ch. 2), increased

the power of analytical methods that could be used

on the collected family materials. In 1982, Jim

Gusella and others began to screen the DNA from

the Venezuelan collection for genetic markers

linked to the gene for Huntington’s disease. They

tested DNA from normal and affected members of

the Venezuelan families, comparing the different

patterns cut by restriction enzymes on the samples

from different family members. The fact that the

pedigree included large extended families wvas useful in locating informative markers. By 1983, the

researchers had figured out which chromosome

contains the Huntington’s gene and had identified

a linked marker, paving the way for a diagnostic

test—an extraordinary breakthrough, says Wexler,

in such a short time. The search for the actual

gene is not yet over, however, since locating more

closely linked markers has presented unforeseen

difficulties.

A cure is not in sight for the families of Lake

Maracaibo, but they have made an extremely important contribution to the study of Huntington’s.

Photo credit: Nick Kelsh/Kelsh.Marr Studios

Huntington’s patient being rowed across Lake

Maracaibo.

Photo credit: frank Micelotta/Time magazine

Nancy Wexler going over Huntington’s disease

pedigrees. -
136

Moreover, their genetic materials are a valuable resource for other genetic studies, including searches

for other disease genes, as well as for the development of genetic maps. Indeed, some of the DNA has

been contributed to the international mapping collaboration coordinated by CEPH (see box 7-B). Wexler suggests that “the pedigree is a big genetic

playground–whatever idea you have, you could

probably test it there.”

The Venezuelan pedigree project highlights an important role that developing countries can play in

human genome projects, even if they do not yet have

the capability to carry out human genome research

on their own. A similar collection of genetic materials from patients with genetic diseases (primarily

the anemias and thalassemias) and their families was

started in Egypt in 1964 and has proceeded since

in collaboration with scientists from NIH and several universities---Oxford, London, Harvard, Columbia, New York University, and the University of California, San Francisco. The scientists who manage

this collection are eager to cooperate in international

efforts to map and sequence the human genome.

As Wexler points out:

In many cases, the countries are eager to collaborate, but they don’t know what they have

to offer. The patient populations are a valuable

resource. And once the working relationships are

established between Third World countries with

health problems and the high-tech labs in the developed countries, the connections are there for

advice and assistance if those countries get to the

point of starting their own labs.

Sf)[lRCES’

J Guse[la, ‘(-fine, Mapping and Disorders of the Nervous System, lecture at Amer.

wan Association for the Advancement of Scwnce annual rmwtmg, Boston Feb Is

1988

N Hashem, Ain Shams (Inii ersq Medmal Center, Cairo, E@Ipt, personal communl.

cation, July 1987

S $Vexler, Columhla L’niverslty, personal communication october 1987

JAPAN

Japan’s efforts to develop automated DNA sequencing technologies have been highly publicized

over the past year, causing concern that Japan

will capture the market for sequencing technology and that it will realize most of the potential

profits from genome projects. Japan does not,

however, have well-defined government policies

for human genome mapping. Instead, funding for

mapping and sequencing research is under the

jurisdiction of half-a-dozen government agencies

that often compete for prestige rather than attempt to coordinate efforts.

Mapping and Sequencing Research

The general framework for science policy in Japan is formulated by a small group of bureaucrats

in the various agencies and by an inner cabinet

group, the Council on Science and Technology,

chaired by the prime minister. Programs for human genome research have been divided among

the Ministry of Education, Science, and Culture

(MESC), the Science and Technology Agency (STA),

and the Ministry of International Trade and Industry (MITI). The Ministry of Agriculture, Forestry,

and Fisheries supports some research on nonhuman genomes, notably a $500,000 feasibility study

on sequencing the entire genome of rice (77).

The Ministry of Education, Science,

and Culture

Most mapping and sequencing research falls under the domain of MESC, the primary supporter

of basic research in Japan. Like the National Institutes of Health in the United States, MESC supports research projects selected by peer review;

it provides grants and funds for universities and

university-based researchers and for several national research institutes. In addition, the ministry can encourage research in specific, targeted

areas on the recommendation of its advisory

committees.

The ministry does not yet have an official policy regarding genome research but has appointed

an advisory committee to study the situation.

Members of the committee visited the United

States in early 1988 to gather information on US.

policies on human genome research and to ascertain what the US. expects of Japan. The committee’s recommendations will be implemented beginning in fiscal year 1989 or 1990 (58).

Japan is often criticized for not doing enough

basic research; many observers have questioned

whether Japanese scientists have enough expertise in basic molecular biology to support a major
137

gene mapping or sequencing effort [Yoshikawa,

see app. A]. Bibliometric analysis [see app. E] indicates that while Japan’s research output in DNA

mapping is far below that of the United States (figure 7-I, table 7-1), its proportion of research relative to other countries has consistently increased

over the last decade. Its share of publications on

human gene mapping and sequencing rose from

2 percent in 1977 to 5 percent in 1986, compared

to a U.S. share that varied from 40 to 46 percent

during those years. In addition, MESC supported

the research of a scientist that led to the publication of a complete genetic map of E. coli in the

prestigious magazine Cell in 1987 (53). U.S. researchers published a map of E. coli at about the

same time, but the Japanese research was notable for the speed with which it was done and for

the use of automated technologies.

The Science and Technology Agenc y

STA supports mostly mission-oriented basic research. It has played a leading role in the development of automated sequencing technology.

Since 1981, STA’s Special Coordination Fund for

the Promotion of Science and Technology has underwritten a program entitled Extraction, Analysis, and Synthesis of DNA, with a total funding

of $3.8 million (40). The project, led by Akiyoshi

Wada of the University of Tokyo, aims to “to reduce the burden of time demanded of researchers working on the analysis of DNA base sequences

by developing automatic machinery,” utilizing the

knowledge and resources of companies with expertise in electronics, robotics, computers, and

material science [Wada quoted in Yoshikawa, app.

A]. The project scientists are adapting robotic techniques and mass production machines to automate

the time-consuming steps in the Maxam and Gilbert sequencing process (see ch. 2) rather than

developing new processes. The project has resulted in a prototype of a microchemical robot,

made by Seiko, but it is not yet on the market.

The goal of the project has been to increase the

rate of DNA sequencing output in general, not to

sequence the entire human genome. Wada has

repeatedly emphasized the necessity for international cooperation in the project and would like

to develop a supersequencing center to operate

as a service facility for scientific groups around

the world (84,87).

STA and a private foundation sponsored an international conference in Okayama in July 1987

to discuss the state of DNA sequencing technologies and possible strategies for genome sequencing in the future; the conference gave no clear

indication of the pace or direction of future STA

efforts. Some scientists expressed doubts about

the STA project, noting that there has been no

public discussion in Japan about whether or not

to support Wada’s conception of the project and

that the project is not actively supported by many

other Japanese scientists [Yoshikawa, see app. A].

Still, a quiet consensus has emerged that sequencing technology should be developed regardless of

whether a full-scale project to sequence the human genome is launched.

Oversight of the project has now shifted from

the Special Coordination Fund to STA’s Council

for Aeronautics, Electronics, and Other Advanced

Technologies (CAEOAT); a decision on the status

of future directions of the sequencing research

should be made by spring 1988, The publicity and

momentum of the project are undoubtedly attributable in part to the active role that ex-Prime Minister Nakasone played in advocating biotechnology and related projects [Yoshikawa, see app. A].

Whether the momentum will continue now, after Nakasone’s retirement, remains to be seen.

The Ministry of International

Trade and Industry and the

Human Frontiers Science Program

MITI coordinates applied research, linking

university researchers with industry to encourage

technology development and commercialization.

It does not now play a major role in genome research, but its influence may increase if the Human Frontiers Science Program is fully funded.

A human genome sequencing project may become

a focal point for the program.

The Human Frontiers Science Program (HFSP)

is a proposal for an international, cooperative pragram of research in basic biology and the development of related “key technologies. ” The proposal originated in 1985 in MITI’s Agency of

Industrial Science and Technology (AIST). The proposal came about partly in response to interna-
138

tional criticism that Japan does little basic research

itself, but capitalizes on the research of others

(4,23), and partly to emphasize international cooperation in the face of persistent foreign trade

frictions [Yoshikawa, see app. A]. The HFSP proposal met with a lukewarm reception during early

outings and international conferences, however,

and Nakasone’s mention of it at the June 1987 Economic Summit meeting roused little enthusiasm

[Yoshikawa, see app. A] (46,76).

If implemented, HFSP would probably enhance

Japan’s sequencing effort, since DNA sequencing

technology has been identified as a key area for

development. The program was granted an initial budget of 197 million yen (approximately $1.5

million) for fiscal year 1987, to conduct a feasibility study, but the amount to be spent on development of sequencing technologies is not yet clear.

Some observers speculate that the proposal will

be shelved now that Nakasone has retired. MITI

officials contend, however, that the program is

still viable (4,90). A December 1987 planning meeting again endorsed human genome sequencing

as a focus for HFSP, but the Ministry of Finance

probably will not decide on the program’s budget until 1989 (75).

Commercialization of Mapping and

Sequencing Technologie s

potentially marketable technologies that are developed for genome projects have been supported

by the several mechanisms through which the government aids industrial research in technology

development. STA’s Special Coordination Fund,

established in 1981, provides incentives for basic

research for new technologies in accordance with

the long-term goals for science and technology

development set by its Policy Committee. STA’s

Research Development Corp. promotes commercial uses of government-developed technologies

that might not be used otherwise. The prototype

of Seiko’s microchemical machine was developed

with assistance from the Special Coordination

Fund, while the Research Development Corp. has

supported its commercialization. In addition,

Hitachi, Fuji Photo Film, Toyo Soda, and Mitsui

Knowledge Industries have all undertaken research into the automation of DNA sequencing,

and some relevant products are being commercialized. DNA extractors developed by Toyo Soda

are already on the market, as is a gel preparation

by Fuji and autoradiograph readers by Seiko and

Hitachi.

Potentials for Cooperation and

Conflict With the United States

Many Japanese scientists are willing to cooperate in an international genome sequencing project,

but collaboration will clearly be accompanied by

economic tensions and competitive posturing both

by the United States and by Japan.

The development of similar automated technologies by U.S. and Japanese companies may pose

difficult trade issues. The Japanese concentration

on sequencing hardware has drawn criticism from

American companies, which fear that the Japanese could take the lead in developing technologies for the analysis of DNA (89). At present, however, U.S. manufacturers are clearly ahead in the

development and manufacture of equipment for

manipulating and analyzing DNA (see ch. 2). Japanese companies are not as far along in marketing relevant products as is often reported—while

the Seiko machine has been touted in the Western press, few scientists in Japan have even heard

of it (40). In addition, the machine’s economy has

been overrated: One frequently quoted estimate

for the sequencing systems is $0.17 per base pair,

with a target of $0.01 or less, but Wada himself

states that the system is still far from reaching

even the $0.17 goal (86), (The present cost of sequencing is approximately $1.00 per base pair.)

Finally, despite the customary preference of Japanese officials for buying Japanese machines, officials of U.S.-based Applied Biosystems, Inc. (ABI,

Foster City, CA) in Japan have reported no difficulty in marketing their DNA sequencing machines

and other instruments used by molecular biologists [Yoshikawa, see app. A]. To date, Japan is the

largest market for ABI’s sequencing machine (47).

One frequently voiced fear is that Japanese companies are focusing on automating parts of the

sequencing process that companies in the United

States have not yet automated (although several

U.S. firms have begun development). Thus far,

however, the STA-sponsored technology development effort is based on automating machines that
7JY

use conventional methodology rather than developing or using new molecular biology techniques.

Scientists at some U.S. companies have commented

that it may have been a mistake for Japan to invest so much in automating existing methodologies when there are new technologies emerging

that may make the old methods obsolete.

Databases, which are generally considered useful and politically straightforward areas for cooperation on genome projects, present knotty

problems of ownership of information. Despite

support within the scientific community, the development of shared databases—even within

Japan—is problematic. The Japanese Government

has recognized that Japanese databases and repositories are insufficient to handle even its own

research and development, and it is trying to establish the database infrastructure necessary for a

While Japan is often viewed as a prime competitor, many European countries have stronger

research traditions in molecular genetics and the

developrnent of related technologies. There are

notable genome mapping and sequencing activities in France, Italy, and the United Kingdom, and

significant research in gene mapping and technology development in Denmark, the Federal

Republic of Germany, and others. In addition, several supranational organizations in Europe have

developed targeted programs to encourage biotechnology development; human genome projects

can be and are being included. The following sections describe research activities underway in the

European community as a whole and in selected

countries, in alphabetical order.Z

‘The information presented in the sections on selected countries

is based on several sources. The OT.A contracted a report on research efforts in key countries in Western Europe [Newmark, see

app. Al. Some information was gleaned from scientific journals and

international news sources. In late 1986 and throughout 1987, OTA

conducted an informal suri’ey of international efforts, contacting

embassy officials, science attaches, and scientists from numerous

countries to request information about the types and funding Ietels

of genome mapping and sequencing research undertaken in those

countries and asking whether any specific policies governed genome

research. The information gathered from this effort varied considerably in focus, depth, and detail. The countries represented here—

other than those with targeted or particularly well known research

programs–are thus self-selected and self-reported. ‘1’he result is a

descripti~’e account rather than a cornprehensi~e analvsis.

European Organizations

Over the past two decades, many European nations have supported scientific collaboration in

principle, but in practice funding has been a persistent problem:

Most European governments have become increasingly reluctant to invest large sums of public money in domestic and citilian R&D, and this

is reflected at the European level. . . As domes -

tic science budgets in Europe have become hardpressed for cash, governments are asking whether

they are getting value for money from international projects. Scientists in some fields have also

come to view such projects as unwelcome competitors for their domestic research budgets (29).

Nonetheless, several existing organizations in Europe either support genome research now or could

do so in the future.

The European Economic Community

The founding treaties that established the institutions of the European Economic Community

(EEC) made little explicit provision for research

and development beyond that needed for Eura -

tom (which dealt with nuclear energy, including

radiation biology), the Coal and Steel Community)

and some coordination of agricultural research
140

under the Treaty of Rome founding the EEC. In

January 1974, the Council of Ministers agreed on

the general need for an EEC research and development policy, and in the mid-1970s, the EEC’S

advisory commission began proposing programs,

including a program of research and training in

selected areas of genetics and enzymology (bimolecular engineering). It was not until 1981 that

this proposal was approved, since Article 235 of

the Treaty of Rome specifies that such programs

can only be adopted by unanimous agreement of

all member states (11).

Support of research and technological development has been enhanced by the adoption of the

Single European Act, which took effect on July 1,

1987. This act modifies and extends the Treaty

of Rome by adding provisions for precompetitive

research to strengthen “the scientific and technology basis of European industry and to encourage it to become more competitive at the international level” (19). Once a multiyear framework

program is unanimously agreed on by member

states, the individual research and development

programs within its agreed areas and financial

limits can be approved by a qualified majority

(member state votes are weighted roughly by size).

The current framework program, an initiative to

help create collaboration in targeted areas in science and technology, was adopted on September

28, 1987, and runs until 1991, with a global limit

of 5.396 million ECUs (European currency units,

which in recent years have had approximately the

same value as the U.S. dollar). Framework programs must be proposed by the commission and

approved by the governing Council of Ministers

and the European Parliament (11).

Most relevant to genome research is a series

of research programs in biotechnology: the Bimolecular Engineering Programme, 1981-85; the

Biotechnology Action Programme (BAP), 1985-89;

and Biotechnology Research and Innovation for

Development and Growth in Europe (BRIDGE),

1990-93, A Concertation Unit for Biotechnology

in Europe was established in 1984 to coordinate

the various activities in biotechnology [Newmark,

see app. A]. These programs have been designed

to complement national research programs while

promoting the development of European biotechnology (83).

The budget for BAP has been substantially reduced from the original proposal; as of spring

1987, it appeared that approximately $300 million of the proposed $6 billion budget would be

earmarked for biotechnology research, with

another $100 million for health, including some

funds for human genome mapping and sequencing work, under the heading of “predictive medicine” [Newmark, see app. A]. “Within the biotechnology program(s), active consideration is being

given to mapping and sequencing technology, and

in particular with respect to the genome of yeast,”

although “given the range of topics within the current biotechnology program, it would be surprising if genome work gained more than a small fraction of the total” (11). However, “Community

research expenditures have a catalytic role that

mobilizes other funds, and a political significance

that enhances the coherence and consequent effectiveness with which national funds are deployed” (11). BAP encourages proposals that include at least one industrial partner in the research

effort or that provide specific evidence of interest on the part of industry.

When BAP expires, it will be replaced by

BRIDGE, which is likely to place even more emphasis on industrial participation. While not yet

finalized, BRIDGE is likely to include a project to

sequence the genome of yeast, which is more feasible than sequencing the human genome [Newmark, see app, A]. The tentative plan is to undertake a 2-year pilot project in which perhaps 15

laboratories will concentrate on sequencing one

yeast chromosome; eventually, a large number of

European yeast laboratories would be involved.

The pilot project might be launched under BAP,

but the full project would be part of BRIDGE and

is provisionally estimated to cost $50 million. The

project would also try to create a market for sequencing equipment [Newmark, see app, A]. Research on the project will begin soon at some participating laboratories in the United Kingdom

[Mount, see app. Al.

A subprogram of BAP, Contextual Measures for

R&D in Biotechnology, aims to enhance EEC capabilities in bio-informatics (the use of computers

and information science in biology), data capture

techniques (including advanced instrumentation

and automated reading), data banks, computer
141

modeling, computer software, and the “collection

of biotic materials” (repositories), along with the

“development of information and communication

techniques for enhancing the quality and usefulness of such collections” and “the development

of techniques for the identification, characterization, conservation, and resuscitation of the materials held in such collections” (20). Development

of a biotechnology infrastructure has obvious potential for researchers in human genetics.

Another EEC activity that aids genome research

is the Task Force for Biotechnology Information.

Created in 1982, the task force has produced discussion papers and has provided small sums of

money, totaling $200,000, to support databases

(including a contribution to software development

at the database of nucleotide sequences run by

the EMBL, discussed below and in app. D), and

the launching of the European branch of the

CODATA Hybridoma Databank, centered at the

American Type Culture Collection in Rockville,

Maryland. The task force work plan for 1987-90

maintains support for databases, communications,

and computational research. The commission of

the EEC also supported a series of workshops and

studies (1984-86) investigating the interface between biotechnology and information technology

in a planning exercise known as Bioinformatics:

Collaborative European Programs and Strategy

(BICEPS), which “aims to formulate a mid- to longterm strategy for Europe in bio- and medical informatics” and “overall, to improve the European

competitive position in the rapidly developing

world market for these technologies and applications” (18). Documents for BICEPS refer to the informatics requirements of human genome sequencing and have contributed to plans for

bio-informatics in BAP and BRIDGE and to a proposal for a program of Advanced Informatics in

Medicine (17). The proposed pilot phase, 1988-90,

at 25 million ECUS) was presented by the commission to the European Parliament and the Council of Ministers in September 1987. It includes

plans for the development of advanced sequencing instruments and related computational facilities required in genome and other areas of biochemical and protein engineering research, The

European chemical industry trade association has

endorsed some of the BICEPS proposals and has

indicated a willingness to help support an infrastructure such as sequence databases (11,21).

Apart from biotechnology programs, EEC funds

research and development in health. The commission’s original proposals for the framework

program envisaged a Program of Predictive Medicine and Novel Therapy, which would seek “development of predictive medicine and novel therapy oriented towards better knowledge of the

human genome, and genetic engineering processes aiming at the repair of DNA defects (e.g.,

in congenital diseases of genetic origin)” (11). The

program was designed to support research in four

areas from 1987 through 1991: study of the human genome (including mapping the genome as

an aid in the diagnosis and prevention of genetic

disease), nucleic acid probes, genetic therapy, and

monoclinal antibodies. Funding for the program,

originally proposed at $75 million, has been revised downwards to $25 million; both budget and

content may be further revised before the program is approved.

The European Molecular Biology

Organization

Funded by 17 European countries, EMBO serves

primarily to strengthen the training of European

molecular biologists. It supports fellowships, workshops and training courses, occasional scientific

meetings, and a journal, but it does not directly

support research. EMBO sponsored a meeting of

Europeans with an interest in human genome research in spring 1987. Few of the scientists present

expressed an interest in mounting a major European mapping or sequencing project; instead, most

favored informal cooperation between individual

laboratories. The group was pessimistic about

whether public funds could be found for a largescale project and raised the possibility of seeking

private funds [Newmark, see app, A].

The European Molecular

Biology Laboratory

Located in Heidelberg, West Germany, EMBL

is financed by contributions from 10 of the 17

member nations of EMBO. It houses the administrative offices of EMBO, but the organizations have

separate budgets and purposes. EMBL’s staff of
142

about 250 scientists and technicians, drawn from

member nations and from West Germany, work

on a scientific program proposed by its directorgeneral, at present Lennart Philipson, and subject to the approval of a council composed of representatives from contributing countries. The laboratory was founded with the notion that

molecular biology would require facilities that

would be too expensive for any national research

program to support. For the most part, however,

research in molecular biology has not required

large centralized facilities, and member nations

have tended to interact less with EMBL as they

have become proficient at molecular biology in

their own laboratories (28). consequently) members have often been grudging in their support,

which limits the projects that EMBL can undertake. EMBL’s annual budget is approximately 45

million deutschmarks (about $26.5 million), 25 to

30 percent of which is paid by West Germany (W.

EMBL sponsors research in instrumentation,

biocomputing, and gene mapping and sequencing as well as other areas of biology. EMBL’s researchers have been active in technology development for mapping and sequencing and have

produced prototypes of machines for automating some of the steps in DNA sequencing (see ch. 2).

EMBL also operates the major European database of nucleotide sequences, which works in cooperation with GenBank” to gather and disseminate sequence data. For EMBL to undertake a

major human genome project would require a considerable increase in budget —unlikely under current circumstances—and sustained enthusiasm

from its members [Newmark, see app. A]. DirectorGeneral Philipson is eager to promote collaboration on a genome sequencing project, which he

believes will increase the need for a centralized

European data-handling facility. In the 1986 director’s report, Philipson encouraged the establishment of new support programs for a human

genome project:

If the American plan to launch a programme

on the human genome materializes, the EMBL

may be a natural collaborative partner in this

project. It might, therefore, be worthwhile to plan

for at least one new Programme in one of those

fields to be initiated in Heidelberg at the end of

the proposed Scientific Programme (1990). To fa -

cilitate recruitment and the launching of this Programme, plans should be available by 1990 but we

do not foresee any cost during the next 4 years (36).

The European Science Foundation

Headquartered in Strasbourg, France, the ESF

is subscribed to by 49 research councils and

equivalent bodies from 18 European countries (33).

It supports projects on a special funding basis from

a small central fund; in the past, the ESF has not

sponsored much research in biology, although recently it has supported some protein engineering work. One of the foundation’s standing committees, the European Medical Research Council,

enables the heads of national medical research

bodies to meet once a year. The council has no

budget, however, and little influence outside the

ESF. At its 1987 meeting, the council decided not

to attempt to coordinate European research on

human genome mapping and sequencing [Newmark, see app. A].

The European Research Coordination

Agency

A French-initiated response to the U.S. Strategic Defense Initiative, EUREKA was set up in 1985

to encourage development of advanced technologies in Western Europe. Participating in EUREKA

are the 18 democracies of Western Europe: the

12 member states of the EEC (Belgium, Denmark,

France, the Federal Republic of Germany, Greece,

Ireland, Italy, Luxembourg, The Netherlands, Portugal, Spain, and the United Kingdom); the 5 member states of the European Free Trade Association (Austria, Finland, Norway, Sweden, and

Switzerland); and Iceland.

EUREKA promotes industry-led technological

collaboration among its members in several areas,

including biotechnology and advanced information technology. It supplements EEC’S efforts by

funding research beyond the precompetitive

stage. A EUREKA project must involve at least two

industrial laboratories in two different European

countries. Governments vary in their financial support of EUREKA projects: Some offer little more

than token support and assistance in administering an international collaboration; others, such

as France, pay up to 50 percent of a EUREKA

project. Coordinated by a small secretariat in Brus -
143

sels, EUREKA’s performance has impressed many

observers. Still, maintaining consistent funding is

difficult, since most of the governments supporting EUREKA have not created procedures for

funding the program (34), There are no EUREKA

projects for human genome mapping and sequencing yet, but the program might be used to link

French researchers to industrial partners in Europe, particularly in the development of sequencing technologies [Newmark, see app. A].

National Research Efforts in Europe

Denmark

The National Health Authority, the primary

funding agency for biomedical research, supports

some gene mapping studies, although there is at

present no centralized effort. Other funds for gene

mapping and sequencing come from general allotments to universities and research institutes,

from the government, and from research councils, notably the Danish Research Council. Special projects can be funded by applying to the

appropriate research council. The Institute of

Medical Genetics of the University of Copenhagen is the most prominent Danish effort in the

field. It has the longest tradition and the greatest

interest in gene mapping; sequencing is not yet

a major concern, although it may be in the future. A University of Copenhagen scientist is the

editor of the international journal Clinical Genetics,

which publishes mapping studies and similar research. There are several ongoing projects at the

institute on various genetic diseases, but there is

no concerted effort or government policy on mapping and sequencing (70).

One project of interest is a family pedigree

project that has been underway for more than

10 years, Like the Venezuelan pedigree project

(box 7-A), this is a collection of genetic material

from families with many children; the collection

contains “samples of red cells, serum, plasma,

thrombocytes [parts of the blood that help in clotting], lymphocytes [cells important in the immune

system], as well as skin biopsies” (59). Unlike the

Venezuelan material, the genetic material in the

Danish project was collected from apparently normal families; over the years it has been tested by

classical genetic markers to help establish poly -

morphic regions for genes of different blood

groups, enzyme types, and so on. Extensive RFLP

mapping (see ch, 2) of the material has not been

done because of limited resources, but negotiations are underway to contribute material to the

Center for the Study of Human Polymorphism

(CEPH), an international gene mapping center located in Paris, for further mapping. There is as

yet no clear policy in Denmark on whether to sequence large portions of the family material, especially because resources are limited, but the research group is exploring the possibility of

collaborative arrangements within Denmark, with

other countries, and with the United States. The

goal is to establish a Danish center for human gene

mapping, LINK, starting with the family material

that has already been gathered and expanding the

collection, as well as drawing in researchers from

other institutes. LINK is envisioned as a Scandinavian counterpart to the French CEPH effort (59).

The Danish Government has established 10 new

biotechnological centers and allocated D.kr. 500

million (about $80 million) for their operating expenses over the next 5 years (6)59); 410 million

will be used to establish new research centers at

technical universities and private firms (24). The

biggest center, at Aarhus, is already supporting

some gene mapping research in collaboration with

CEPH.

Federal Republic of Germany

The emergence of the environmentally oriented

Green party in West Germany, combined with a

general wariness about research with possible eugenic applications, has made molecular genetics

research a sensitive political issues Nonetheless,

research in molecular biology is well funded by

federal, state, and private monies. There are four

K)ne indication of this attitude is that a feclerall~ appointed commission of government and outside experts on genetic engineering

recommended, in early 1987, that there be “tight limits drawn for

analyses of human hereditary factors (genomic anal~rsis) as well as

for gene therapy” (2). The commission published an extensive report entitled Chances and Risks of Genetic Engineering after two

years of study. An English translation of the foreword and recommendations of the report, entitled Gene Technology: Opportunities

and Risks (16) has been made a~’ailable by the EEC. The DFG criticized the recommendations of the commission in the case of genome analysis, arguing that the search for causes and cures for

genetic defects is a scientific duty and serves the public interest

(42).
144

main sources of funds for basic research in

molecular genetics. The Max Planck Society, which

receives a substantial allotment from the federal

government but is legally independent, supports

the Max Planck Institutes, each of which is devoted

to a particular area of research (72). The German

Research Association (DFG) obtains approximately

half of its funds from the federal government and

half from state governments and supports research in the universities. The German Ministry

for Research and Technology (BMFT) supports

projects in universities as well as funding the Institute for Biotechnology Research and other research institutes. Individual states contribute to

some science research through the universities.

Another source of potential support for genome

research is the prestigious Society for Biotechno -

logical Research (GBF), a government-funded research center (78).

At present, West Germany does not have a coordinated genome mapping or sequencing project.

At a meeting in September 1987, representatives

of the DFG decided not to endorse a concerted

genome project, although the agency does support a research program targeting molecular

methodology for studying the genome (52).

West Germans are strong supporters of international cooperation. They consistently contribute to EMBL, and several laboratories are carrying out research that could be extended at little

expense and aligned with an international collaboration in genome research.

Biotechnology is being actively promoted by the

federal and state governments in West Germany.

The Federal Ministry of Research and Technology’s Biotechnology Research Program, initiated

in 1985, includes as an objective the promotion

of “research and development projects in public

life care, including health, nutrition, and environmental protection”; one of its high-priority research areas is a program of “genetic engineering with a focus on the investigation of gene

structures, research on gene functions, and on

controlling of genetic processes” (68). The ministry has also encouraged the establishment of research centers in which university and industry

would participate and has set up seven “gene

centers” to study areas including gene expression

and differentiation and the correlation between

gene structure and function. Human genome mapping and sequencing are not explicitly included

in either the Biotechnology Research Program or

the genetic research centers, but both support

related research and could provide an institutional

infrastructure and funding framework for genome research.

Finland

In January 1987, scientists at the Finnish Academy proposed a 5-year plan to improve biotechnology and molecular biology research, in order

to promote industry and increase industrial capabilities. The proposal included a request for the

equivalent of $37 million per year for research,

training, and equipment (48). Finland has established several genetic engineering research centers and has plans for half-adozen more; the institute associated with the University of Helsinki

is perhaps the best known.

Human genome mapping in Finland is being

done by about 10 large and small individual research groups in medicine and science. They are

primarily funded by government sources, namely,

university budgets and the Academy of Finland,

which is the main funding source other than

universities. The University of Helsinki hosted the

eighth international Human Gene Mapping Workshop (HGM 8) (5). Finland has no concerted effort

nor any specific policies; as in most countries, however, sequencing efforts have focused on particular genes. Finnish groups are involved in collaborative projects with groups in other countries,

notably the United States, and have contributed

to and received materials from international databases and repositories.

France

Since 1981, the French Government has sought

to make France a world power in science and technology by increasing both funding and political

interest in research and development. The Government has encouraged collaboration between

university and industry researchers, both within

the country and with the rest of Europe (e.g., the

EUREKA program).
145

The French Ministry of Research is directly or

indirectly in charge of nearly all governmentfunded research. Most is carried out within

universities, often in units set up by the research

organizations, the largest of which is the National

Center of Scientific Research (CNRS). The CNRS

and the much smaller National Institute of Health

and Medical Research (INSERM) are the only two

government organizations that support research

related to human genome mapping and sequencing. The Pasteur Institute in Paris, a semiautonomous institute that receives half its funds

from the government, carries out related research.

None of these organizations has announced a firm

plan for human genome mapping or sequencing,

but each is considering what part it might play

[Newmark, see app. A].

An important focus of genome studies in France

is the CEPH (see box 7-B). organized in 1983 by

Jean Dausset to “hasten the mapping of the human genome by linkage analysis with DNA polymorphisms)” CEPH is a privately funded center

that collects and distributes genetic materials for

use in mapping studies. It acts as an informal coordinator for approximately 40 investigators in Europe, North America, and Africa who use CEPH

materials in exchange for reporting their data

(25,26).

France has not initiated a coordinated genome

project, but there is a strong undercurrent of opinion favoring a substantial program in human genome mapping and sequencing as long as it is not

funded at the expense of other research. Genome

researchers may try to work through EUREKA

to involve other European companies with an interest in instrumentation or information technology. The French Government (usually through its

Ministry of Industry) is prepared to provide 50

percent funding for EUREKA projects, and there

are indications that it would consider CEPH’s human genome work eligible for EUREKA funding

[Newmark, see app. A].

Italy

Recent administrations have given priority to

improving Italy’s scientific performance in hopes

of sparking a technology-led revitalization of the

country’s ailing economy. Considerable extra

funds for technology-related research have been

made available in the past few years, with biotechnology as one focus. The Italian Government

announced in April 1987 that it would allocate

209 billion lire (approximately $156 million) over

a 5-year period for a national biotechnology

project involving both public research centers and

industry (64); the following month Italy’s National

Research Council (CNR) announced a special research project in biotechnology for which it will

spend 84 billion lire (about $63 million) over the

5-year period (51).

In May 1987, the CNR announced its decision

to initiate a project devoted to human genome sequencing, to be run as a cooperative effort of all

CNR institutes and laboratories working in biology (22). Nobel laureate Renato Dulbecco is C oordinating the project, in which CNR has started

investing 20 billion lire (about $15 million) and

75 to 100 person-years (51). A 2-year pilot project

with a budget of $1 million per year will be undertaken first, to determine whether a large-scale

project will be funded at around $10 million a year.

(These sums are to cover only specific materials,

machines, travel, meetings, and so on—not salaries and general overhead—since only the existing number of personnel will be involved. )

A key question in the pilot project is whether

it is possible to isolate a single chromosome without damaging it so much that sequencing would

be impossible, The ability to separate the chromosomes would offer a shortcut to sequencing,

and researchers could begin sequencing with one

of the smaller chromosomes (but one with genes

of particular interest), probably chromosome 21,

22, or Y (73). otherwise) researchers will consider

continuing the project using conventional techniques. Research institutes and laboratories in

Rome, Naples, Pavia, and Milan will participate

in the project. Databases and information retrieval

will be managed by research units in Rome, Turin,

Milan, and Bari, with the aim of making the national databases compatible with and complementary to existing international ones (57)73).

The pilot human genome project is still expkmatory, so no attempt is being made yet to coordinate work with researchers outside Italy. Project

scientists anticipate that the final project would

be complementary to, if not an integral part of,

any international project that arises [Newmark,
146

see app. A]. In the meantime, Italian scientists are ian scientists are not the only ones interested in

enthusiastic about Italy’s role in genome mapping; chromosome 21, however; it is a popular target

“there is good reason to believe that, for once, for research because it contains genes for Alzthis country will perhaps succeed in reaching the heimer’s disease and for Down’s syndrome, and

starting line ahead of &her countries” (73). Ital- it is likely to be an early focus of U.S. efforts.

BOX 7-B.— The Center for the Study of Human polymorphism (CEPH):

An International Gene Mapping Center

The Centre d’Etude du Polymorphism Humain (CEPH) has become an important focus of international

scientific cooperation in the drive to map the human genome. CEPH is a private research foundation established in 1983 by French Nobel laureate Jean Dausset with the bequest of an anonymous donor. Its aim

is to “hasten the mapping of the human genome by linkage analysis with DNA polymorphisms. ”

The basic premise behind CEPH’S activities is that a genetic linkage map (see ch. 2) will be more easily

constructed if researchers study genetic material from a common group of families—a reference panel.

The most useful family pedigrees consist of four living grandparents with many children and grandchildren

so that the inheritance of DNA can be traced through three generations. CEPH maintains DNA from a panel

of 40 families, each with 5 to 15 children; in most cases, all grandparents are living. The DNA from 29

of the 40 families in the CEPH collection was contributed by Ray White and his collaborators from the

Howard Hughes Medical Institute (HHMI) in Utah. Dausset also solicited family materials gathered by other

researchers in the United States and Europe, including some material from normal families identified in

the Venezuelan pedigree project. In contrast to that project (see box 7-A), in which researchers collected

material from families with Huntington’s disease in order to trace the gene responsible, CEPH maintains

material from families with no known genetic diseases. The markers mapped to chromosomal locations

in normal CEPH families can then be used to accelerate the search for disease genes in other families.

CEPH coordinates an international collaboration of researchers from laboratories in Europe, North

America, and Africa. In order to obtain material from CEPH, collaborating investigators must first possess

DNA probes that detect genetic markers, generally RFLPs. They must agree to use the probes to test the

entire panel of 40 families and to provide CEPH with all of their data. There are no enforcement mechanisms, but so far researchers have cooperated.

Dausset’s work is supplemented by the efforts of Jean-Marc Lalouel, a mathematical geneticist at HHMI

in Utah who has designed a variety of computer programs to record and analyze the data contributed

by CEPH investigators. Lalouel and his collaborators have written programs that analyze genetic linkages

and automatically sketch out gene maps from the results. These programs are sent out on disk with the

CEPH DNA samples. Researchers can record and analyze their data using the programs on the disk, then

send the disk back to CEPH for inclusion in a central database. HHMI supports a database station at CEPH

that will be linked to its Utah station and may soon include interactions with other databases as well.

An important factor in CEPH’s success at fostering cooperative research is the two-tiered database it

maintains. One database, available only to collaborators, contains all data that investigators produce. At

the end of a year’s time or when the results have been published, whichever comes first, data from the

collaborative database is moved into a public database, where it is accessible to any qualified researcher.

This system of having both a private and a public database ensures the timely sharing of information while

affording investigators some proprietary protection for their results. The fact that the collaboration requires sharing of data–but not the actual probes, which could prove to be patentable–reduces potential

competitive tensions.

st)l’it( *.S

H M Cann, Centre d’Etude du Polynorphtsme Humam K’F, PHI (’ollaboratn e Mapp[rrg of thr Human (,enome paper submitted In preparation for the ()[ [ 16. I ? IY86 nw,etlng

of the ,.ldvisory Committee to the Director, NIH

H M Cann, fXPH personal commumcation, December 1987

C’entre d’Etude du Polymorphlsme Humaln, unpublished report, 1986

J Dausset, H Cann, and D Cohen, “Centre d’Etude du Polymorphlsme Humam (fXPHJ (krllaboratrw Mapping of the Human Genome ‘ unpublished manuscript Apri 198?

J 1, Marx, “Putting the Human Genome on the Map, ” Scienre 229150-151, 1985

M Pines, .tfappmg the Human Genome (Bethesda, MD Howard Hughes Medical bwANute, 1987)

It W’hlte, M I.eppert D ‘I Bishop, et al , ‘(construction of I.rnkage Maps wrth DNA Markers for Human ( hromowmes Safure 313 101.105 198.5
— . —

147

Industry is not playing a role in the pilot project,

since few Italian companies have the technological interest or capability. But scientists involved

in the research believe that “the automation required for the project will act as a major incentive for industry” and hope that industry would

help finance the final project (73). At least one Italian pharmaceutical company has expressed a willingness to participate and contribute.

The United Kingdom

The United Kingdom has a strong research tradition in molecular biology and genetics, and it

has done pioneering work in the mapping of nonhuman genomes and in the development of sequencing techniques. The United Kingdom has

consistently ranked second to the United States

in the number of articles on human gene mapping and sequencing published annually in international journals (see figure 7-1) table 7-l). The

United Kingdom also ranks high in the development of physical mapping techniques and of automated technologies for DNA manipulation and

analysis. Thus the United Kingdom is well placed

intellectually, if not financially, to contribute significantly to mapping the human genome.

Basic biomedical research is funded mostly by

the government through the Department of Education and Science, although both the Department

of Health and Social Security and the Department

of Trade and Industry have funds available for

contract research. The Department of Education

and Science distributes research monies through

universities and through five research councils,

The research councils provide support for scientific programs carried out in universities; some

councils also support research within their own

institutes. Biotechnology is an area of overlap for

the Science and Engineering Research Council

(SERC) and the Medical Research Council (MRC),

the two councils whose areas of interest are most

closely related to human genome research. The

science and engineering council supports basic

biological research outside the medical field, although it has supported some work on automated

DNA sequencing through a biotechnology directorate established to link academic research to

industrial needs. The MRC is undoubtedly the

leading supporter of mapping and sequencing research. Its total expenditure for genome-related

research for the 1985-1986 fiscal year, both direct and indirect, was approximately 4.2 million ($7.4 million) [Newmark, see app. A] (88).

The MRC is similar to the NIH in supporting highquality, investigator-initiated proposals, although

the council also establishes targeted programs in

particular areas. It has a longstanding commitment

to molecular biology and has the power to set up

new units devoted to particular areas of research

when a suitable director and sufficient funds are

available. Although the MRC supports a good deal

of relevant research and its various units and grant

holders have the expertise and instrumentation

necessary for the study of genetic disease, the MRC

does not now plan a targeted program of research

on human genome mapping or sequencing. At a

1987 meeting, however, the MRC did endorse the

plan of an employee, well-known scientist Sydney Brenner, to map the human genome (largely

with private funds) as long as the research proceeded at no extra cost to the research unit Brenner directs (66). At Brenner’s request, the MRC

has also agreed to set up a committee that will

consider questions such as who owns the clones

produced in mapping efforts and how best to provide public access to them.4

Brenner’s project will be financed in part by a

4300,000 (about $525,000) prize award he received from the Louis Jeantet Foundation; the

MRC and other sources will provide another

<200,000 to +250,000 (about $350,000 to

$440,000) per year (56). The project will build on

a mapping technique developed by Alan Coulson,

John Sulston, and co-workers in the MRC research

unit at Cambridge. They compiled a genetic linkage map of the nematode Caenorhabditis elegans

4“It has been agreed by the MRCI that the human ,genome work

should constitute a separate project to be carried out as an extension of the work of the [Molecular Genetics] L1nit [in Cambridge],

It was also considered that the longer term future of this work could

not be tied to the finite tenure of a personal LJnit. The project might

evohe into a reference laboratory with a major service component

and would then need a different funding structure. A central aim

would be to ensure that the collection of clones and information

remained in the public domain. It \\’as therefore agreed that an Ad\isory Board be established to consider these and other policy matters” (66).
——

148

genome, the smallest genome known for any multicellular creature (it is estimated to be 80 million

base pairs, compared with approximately 3 billion base pairs for the human genome—see ch.

2). Brenner expects that perhaps half of the genome could be mapped by a few people within

5 years. The project will include research on datahandling methods and parallel processors, since

the mapping techniques require sophisticated

computing capabilities.

The Imperial Cancer Research Fund (ICRF), a

charitable organization financed solely by donations, has recently recruited scientists to work on

the development of a different technique for human genome mapping, as well as related software

and instrumentation [Newmark, see app. Al. The

MRC and ICRF plan to explore the possibility of

collaboration in areas of common interest.

Other efforts in the United Kingdom include

technology development in automated systems for

genome sequencing at the University of Manchester Institute of Science and Technology

(UMIST) (1) and biocomputing research at the

University of Edinburgh. The Edinburgh Biocom -

puting Research Unit has considerable experience

in database searching and related problems and

is undertaking a variety of studies into the informatics needed for analysis of map and sequence

data (15).

The United Kingdom contributes to international research efforts such as EMBL, to which

the MRC provided 2.72 million (about $4.7 million) in 1987, The MRC maintains a level contribution to EMBL in real terms, after supporting

some growth of the organization in 1982, when

the new director was appointed (66).

OTHER INTERNATIONAL EFFORTS

Australia

The largest research institution in Australia is

the Commonwealth Scientific and Industrial Research Organization (CSIRO), which is conducting pertinent research through its Division of

Molecular Biology. Biomedical research is primarily the province of the National Health and Medical Research Council, which at present funds a

number of researchers working on gene mapping

and sequencing. The Department of Human Genetics and the Medical Molecular Biology Unit at

the Australian National University in Canberra are

sites of some relevant research activity. In particular, chromosomes 6 and 9 are the foci of investigation because several genes have been localized

to them (43,82). Researchers at the Cytogenetics

Unit Department of the Adelaide Children’s Hospital in North Adelaide are constructing maps of

chromosome 16 and part of the X chromosome.

They have collaborated with scientists from the

U.S. Department of Energy’s Lawrence Livermore

and Los Alamos National Laboratories.

The Department of Industry, Technology and

Commerce administers a system of research

grants under its National Biotechnology Program,

with priority areas including genetic engineering

and cell manipulation and culture, which could

provide support for genome research.

Canada

Canada does not yet have a national policy on

genome sequencing. The National Research Council (NRC) is considering the creation of a task force

to address this subject within its laboratories. A

national network of biotechnology laboratories

supported by the council has been set up, including the Biotechnology Research Institute in Montreal, the Plant Biotechnology Research Institute

in Saskatoon, and the Division of Biological Sciences in Ottawa, which focuses on protein engineering.

In addition to the expertise that the government

research institutes might lend to genome research,

Canada has 15 to 25 university laboratories with

the necessary skills and equipment to participate

in a human genome project. To date, however,

there has been little effort to coordinate the activities of these various groups. Canadian scientists

and government officials are paying close attention to international developments in human genome sequencing and are hopeful that opportunities for international collaboration will develop

(67).
149

Latin America

Relatively few laboratories are involved in human genome research; of those that are, the primary interest is generally mapping genes for diseases of particular national significance. As one

observer pointed out, “Brazil has its share of good

scientists, but they are hampered by lack of funding and difficulties importing equipment and materials”; presumably the same holds true in other

Latin countries (13).

Many Latin American countries realize the commercial potential of biotechnology; Brazil and Argentina, among others, have initiated programs

to encourage biotechnology research and development. Argentina has a biotechnology program

under the aegis of its Secretariat of Science and

Technology (60), and Brazil has a Biotechnology

Secretariat in its Ministry of Science and Technology (13). Scattered throughout Latin America

are individual laboratories doing relevant research.

In Mexico, “scientists are pushing the Mexican

government to consider the development of genetic research a priority. They don’t want to fall

behind on this kind of research, because the

pathology index in the Mexican population is approaching that of developed countries. With epidemics and infections decreasing, greater attention can be paid to genetic problems” (69). Like

Brazil, however, Mexico has a low research budget (less than 0.6 percent of the gross national

product is spent on research) and can neither afford sophisticated equipment nor train enough

scientists; both countries are interested in international cooperation. The Organization of American States reports that its Department of Scientific and Technological Affairs, which runs a

Regional Program for the Development of Science

and Technology in Latin America and the Caribbean, includes projects in plant and animal

genetics but none in human genetics (65).

South Africa

Gene mapping and sequencing research is supported by the Medical Research Council (MRC),

the Council for Scientific and Industrial Research

(CSIR), and the National Cancer Association, None

has initiated a formal or coordinated attempt to

map or sequence the human genome, but there

are a number of laboratories at work in the field

of human genetics (30). Several researchers are

active in the CEPH collaboration, screening the

CEPH family materials and contributing their results. Researchers are examining genes for Huntington’s disease, cystic fibrosis, and neurofibromatosis in collaboration with laboratories in

the United States and the United Kingdom (10).

Research is also underway on several genes of

particular interest in the region–those for Oudtshoorn skin disease and familial hypercholesterolemia (conditions prevalent in Afrikaners) and

albinism, which is common in the Bantu population (50).

The Union of Soviet Socialist

Republics and Eastern Europe

Although the Soviet Union has not been a major contributor to mapping and sequencing studies

published in international journals, it has published some research on bacterial genomes (74)

and the barley genome (3). Soviet scientists are

also working on computational methods for analyzing DNA sequences (7). The Central Institute

for Molecular Biology in East Berlin has undertaken a variety of studies in gene mapping and

sequencing and has collaborated with researchers in the United Kingdom (45). Bibliometric analyses (see figure 7-1 and app. C) show that the Soviet Union and Eastern European countries have

not published a significant number of research

articles on human gene mapping and sequencing.

These figures tend to select items from international journals, however, so internal publications

are not as thoroughly cataloged and accounted

for.
150

INTERNATIONAL COLLABORATION AND COOPERATION

The large size and humane mission of human

genome projects make them ideal candidates for

international collaboration. International databases have already been established and are being jointly maintained, which indicates some willingness to cooperate on gene mapping efforts, but

it remains to be seen how far that cooperation

will extend. The potential for commercial payoffs

raises difficult questions but does not preclude

successful collaboration as long as prior agreement on allocation of benefits is reached (32,49).

The following sections recount some precedents

for collaboration and cooperation in international

science projects and the role the United States has

played in them. Organizational options available

for international human genome projects are examined, and some collaborative efforts already

underway are described. The following chapter

outlines the questions of international technology

transfer that will undoubtedly arise in any coordinated international effort.

Precedents for International

Scientific Programs

The biological sciences have been organized into

international projects far less often than other sciences, but collaborations in the physical and space

sciences can provide useful organizational insights.

The International Geophysical Year, box 7-C, is

an example.

Since the 1940s, research in particle and highenergy physics has relied on complex and expensive equipment—notably, the particle accelerator—that is beyond the ability of any individual

investigator, or even any one institution, to construct and maintain. Consequently, a number of

large, specialized laboratories have emerged nationally and internationally. In the United States,

centralized facilities evolved into a network of national laboratories, now operated by DOE. These

laboratories house cyclotrons, synchrotrons, and

other advanced instruments and undertake research in a broad range of areas, cooperating in

limited ways with researchers from abroad.

The European Center for Nuclear Research

(CERN) was established in 1954 to advance knowledge in the field of particle physics. It is operated

by 14 European nations and has provided a framework for collaboration in instrumentation. Its

governing council consists of one technical advisor and one administrative advisor from each

member nation. Participants contribute to CERN

based on their gross national products, although

no nation can contribute more than onequarter

of CERN’S annual operating budget. CERN has enabled European nations to conduct research beyond the capabilities of any single member nation and has been widely recognized for its success

in the advancement of particle physics. It has restricted its efforts to basic research, however, and

so has avoided the complications that arise in collaborative work on applied research (80).

The enormity of the endeavor to explore and

study space spawned proportionately large agencies to manage the research. The founding legislation of the United States’ National Aeronautics

and Space Administration (NASA) included international cooperation as a major theme, and NASA

has carried out that mandate by negotiating and

implementing hundreds of cooperative projects.

Some NASA projects have established formal joint

working groups on a bilateral basis with other

national agencies. These groups meet several times

a year to ‘(discuss present and future projects of

mutual interest, and to exchange information on

scientific and management issues of concern” (61).

One of NASA’s major partners has been the

European Space Agency (ESA), a collaboration of

13 European nations. The Hubble Space Telescope

is an example of collaboration between the two

agencies. In 1977, officials from NASA and ESA

drew up an agreement to work together on the

project, citing specific contributions and responsibilities (37). An article on data rights directed

that scientific data from the telescope be reserved

for analysis for one year, then turned over to public data centers. Results were to be made available to the scientific community through publication as soon as possible and appropriate. No

specific provisions were made for patenting products or processes developed in the course of the

project.
151

Box 7-C.—The International Geophysical Year

The International Geophysical Year (IGY) was originally conceived as the third in a series of international polar years-earlier cooperative investigations into the phenomena of the Arctic and Antarctic took

place in 1882-1883 and 1932-1933–but the scope was expanded to include the study of all aspects of the

physical environment. Sydney Chapman, one of the organizers, described the enormous undertaking as

it finally evolved:

The main aim is to learn more about the fluid envelope of our planet—the atmosphere and oceans-over all

the earth and at all heights and depths. The atmosphere, especially at its upper levels, is much affected by disturbances on the Sun; hence this also will be observed more closely and continuously than hitherto. Weather, the

ionosphere, the earth’s magnetism, the polar lights, cosmic rays, glaciers all over the world, the size and form of

the earth, natural and man-made radioactivity in the air and the seas, earthquake waves in remote places, will

be among the subjects studied. These researches demand widespread simultaneous observation.

To accomplish this, teams of scientists from 67 nations—60,000 in all-observed, measured, and recorded

data in meteorology, geomagnetism, auroras and airglow, the ionosphere, solar activity, cosmic rays,

oceanography, glaciology, gravity measurements, and other disciplines over a period of 18 months in

1957 and 1958.

The effort was coordinated by the Special Committee of the IGY (CSAGI) under the auspices of the

International Council of Scientific Unions. Planning committees were appointed to organize research

programs in 14 different disciplines. Participating nations generally had their own planning commissions

or advisory boards as well.

An essential feature of IGY was the operation of world data centers. Participants agreed to send

all of their data to three major centers, in the United States, the U. S. S. R., and Western Europe. Organizations or investigators from any country could obtain copies of the deposited materials free of charge

(other than the price of reproduction and transmission). In addition, the data were summarized and

presented in more than 30 volumes in the Annals of the International Geophysical Year, an information

resource that provided the raw material for subsequent research in geology, meteorology, oceanography, and other fields.

SOLIRCES

S Chapman Anrra/.s of rhe InIernaIiona/ Geophwmal Year, forward quoted m H Newell, Beyond the Atmosphere E+srfy Years of Space Scwnce (W’ashmgkm [X’ N 4S.!, 1980)

S (’hapman /[;} }’ear of Dwco\e~~ L4nn Arbor, MI Llnwersity of Michigan Press, 1959)

J M England, ,4 Patron for Pure Science “I%e National Science Foundation’s Formatwe }’ears (Washington, DC National Scuvw Founcfatum 19821 pp 297..{O4

H F. Newell Beyond rhe Atmosphere Earfy Years of Space Science (Washington, DC NASA, 1980)

W’ Sullnan, .4sMu/t on fhe 1‘nknown rhe hrternatlonal Geophysical Year (New York NY McGraw’ Hill, 19611

NASA’s operating principles for international potential: ‘

(Astronomical data have no commercollaboration are a useful starting point for draw- cial value” (71). The gap between research in

ing up collaborative agreements.s One key dif - molecular genetics and the market has narrowed

ference, however, between human genome proj - rapidly in recent years, making the boundary beects and most space research is the commercial tween basic and applied or development-oriented

research nearly impossible to draw. Consequently,

‘NASA has never formally encoded its mechanisms for interna- agreements si-mila~ to those negotiated by NASA

tional collaboration, but it has developed an informal set of guidelines:

● Cooperation is on a project-by-project basis, not on a program and ESA regarding data rights and publication of

or other open-ended agreement. results could prove insufficient for human genome

• Each project must be of mutual interest and have clear scien- projects. A second difference is that the instrumen- tific value.

Technical agreement is necessary before political commitment. tation required for human genome projects is nei -

Each side bears full financial responsibility for its share of the ther as large nor as expensive as that used in par-

●

project. ticle physics and space research.

Each side must have the technical and managerial capabilities

to carry out its share of the project; NASA does not_ provide In spite of a stated desire for international cosubstantial technical assistance to its partners, and little or no

U.S. technology is transferred. operation, the United States has generally acted

Scientific results are made public (55). as the primary partner in large science projects,
152

defining them and then inviting other nations to

join in, rather than planning, funding, and implementing projects jointly (54). In the present era

of constrained funding, however, the United States

may not always be able to carry out major research projects on its own.

Collaborative projects can offer significant savings for participating countries by splitting the

financial burden (although some observers have

pointed out that the costs of negotiating and the

loss of jobs if a project is located outside the United

States may reduce the savings). Collaboration creates a paradox, however: On the one hand, it might

reduce the cost for each member, making the project more feasible; on the other, it might reduce

each nation’s potential economic gain from the

project. The world economic situation has led to

an increasing desire for scientific research to produce commercially valuable products, thereby

fostering a protective, nationalistic attitude toward

research (see box 7-D).

Options for International

Organization of Genome Research

A decision to pursue human genome projects

on the international level, emphasizing cooperation and participation, will entail considerable organizational effort. It will have the same organizational goals as a domestic effort: to eliminate

redundancy in research and to expedite the spread

of scientific and commercial knowledge of the geBOX 7-D.— Views on International Cooperation and Collaboration in Genome Research

“Too many promising international research collaborations, from AIDS research to the sequencing of

the human genome, languish for lack of a workable framework for tangible and short-term research. . . .

The U.S. Department of Energy and the Japanese Science and Technology Agency have an interest in organizing and supporting the @enomel project; each seems sensibly to have decided that two independent

projects would be a waste of resources and a source of confusion, but [they] differ sufficiently in their

objectives as to impede agreement between themselves, let alone with others. ” Editorial in Nature 328:187,

1987.

“There’s a task to be done here, and we need to get on with the task. If we try to take into account

every country’s interest and concerns, we can only serve to delay it. ” J. McConnell, Johnson & Johnson,

Science Writers’ Workshop, Brookhaven National Laboratories, Upton, NY, Sept. 14, 1987.

“An international DNA analysis center or centers equipped with super sequencing systems which are

connected to a worldwide data-network should be developed. ” A. Wada, “Many Small-Scale or a Few LargeScale DNA Sequencers?” unpublished report, Japan, 1987.

“It is highly desirable that the U.S. continue to be the leader of the @enome mapping and sequencing]

effort, but it must be consciously and effectively run as an international quest for knowledge having universal importance. No single purse nor administrative center, in either the U.S. or the world, can or should

be created to fund or attempt to direct the task.” D. Fredrickson, National Institutes of Health, personal

communication, December 1987.

“There is . . . a growing awareness in Europe that the first megaproject in biology is shortly being

launched. Europe ought to participate in it alongside the USA and Japan to ensure access to the information

and all that it implies for medical and biological science, as well as the technological spinoffs that will surely

arise. . . . There is now an opportunity to ensure that the project involves international collaboration from

its outset which should not be missed. ” L. Philipson and J. Tooze, “The Human Genome Project, ” Biofutur,

June 1987, pp. 94-101.

“If they wished, either Western Europe or Japan could by themselves take on this project and it must

be assumed that they will initiate their own efforts. So a new international body should soon be formed

to ensure that collaboration, not competition, marks the relationship between these efforts in various parts

of the world. In a real sense, the exact sequence of the human genome will be a resource that should

belong to all mankind. So it is a perfect project for us to pool our talents, as opposed to increasing still

further the competitive tensions between the major nations of the world.” J.D. Watson, director’s report

for Cold Spring Harbor Laboratories, in press.
153

“The principle of ‘mutual self-interest’ . , . lies at the heart of successful cooperation. ” D. Dickson and

C. Norman, “Science and Mutual Self-Interest,” Science 237:1102, 1987.

“If a sequencing factory can be built, Wada emphasizes that it would not be ‘Japan Incorporated’ against

the rest of the world. He wants an international centre that would be open to scientists of all nationalities

and intended for the benefit of all mankind. ” D. Swinbanks, “Human Genome: No Consensus on Sequence, ”

Nature 322:397, 1986.

“This project is so vast that it necessarily requires international cooperation. Since there are 3 billion

bases to be sequenced, the project will not create problems of competition.” P. Vezzoni, Consiglio Nazionale

di Richerche, Milan, quoted in A. Sommariva, “And Italy Will Study Chromosome 22,” Italia Oggi (Milan),

May 22, 1987, p. 36.

“There’s considerable interest in the commercial spinoffs, and I expect each country would want to

keep those. I would hate to see U.S. tax dollars used to kill yet another U.S. industry. ” J. McConnell, Science

Writers’ Workshop, 1987.

“On the one hand, the climate for international collaboration in science . . . is warmer than ever. In

virtually every major field, U.S. scientists can point to significant work being done in Europe, the Soviet

Union, Japan, Canada, or Israel that needs to be read closely, argued about, and replicated as much as

does work done in the United States. On the other hand, the new era is chillier, for governments and

businesses here and abroad will continue to try to squeeze economic value out of every bit of science to

win the international high-tech sweepstakes. ” D. Shapley and R. Roy, Lost at the Frontier: U.S. Science

and Technology Policy Adrift (Philadelphia, PA: ISI Press, 1985), p. 116.

“The creation of a sequence database is the major goal of the project, whether it is done nationally

or internationally or privately. . . . I don’t think an international project as an organized scheme will emerge,

. . . I expect a set of private ones will emerge, with some level of cooperation,” W. Gilbert, Harvard University, Science Writers’ Workshop, Brookhaven National Laboratories, Upton, NY, Sept. 15, 1987.

“I am convinced that an international advisory body must be formed to oversee the data bases. . . .

International cooperation [is] as important as interagency coordination in the U.S.A. But I do not think

that a special institution would be useful at the national and at the international level.” A. Lafontaine, Office

of the Secretary General, Brussels, Belgium, personal communication, June 1987,

“There is a strong belief here that practical collaborations on actual, welldefined projects are very

helpful, and probably more meaningful than large-scale collaboration between governments. Cell banks,

gene banks, and databases are very important in this regard.” A. de la Chapelle, University of Helsinki,

personal communication, August 1987.

“International cooperation is not something that should be imposed by government agencies. . . . Real

cooperation comes from individual scientists communicating with each other. ” C. DeLisi, Mount Sinai School

of Medicine, Science Writers’ Workshop, Brookhaven National Laboratories, Upton, NY, Sept. 15, 1987.

“I’m just concerned that if we focus on trying to set up an international effort, we will delay decisions

of the United States in proceeding with this. I’d like to see a willingness to cooperate at the international

level, but setting U.S. national priorities.” G. Cahill, Howard Hughes Medical Institute, comments at Issues

of Collaboration for Human Genome Projects, OTA workshop, June 26, 1987.

“[Tlhe United States does not and cannot expect to monopolize information and innovation in this field.

Moreover, the initiation of a human genome project in the United States will probably not deter work

in other countries, but rather will stimulate it. Given this assumption, the importance of past traditions,

and the magnitude of the task of mapping and sequencing the entire human genome, every effort should

be made to enhance the existing contacts between the United States laboratories and those overseas, so

as to speed the work. Indeed, we believe it will become necessary to have some major organized mechanism

for international cooperation, In particular, its objective would be to collate data and ensure rapid accessibility to it, as well as to distribute materials, such as cloned DNA fragments.” National Research Council,

Mapping and Sequencing the Human Genome (Washington, DC: National Academy Press, 1988), p. 85.
nome. Just as the issues in domestic organization

revolve around distribution of authority and tasks

among interested government agencies and private firms (described in ch. 5), the issues in international organization involve coordination of interested sovereign nations.

An international organization could be either

passive or active. A passive organization would

serve primarily as a clearinghouse of research information among participating nations. This task

would require the formulation and oversight of

standard nomenclature and the translation of research reports. The organization would need to

keep track of research in progress and any technological innovations reported by individual laboratories, and it might be intimately associated

with databases such as GenBank” and the EMBL

data bank and with collaborative organizations

such as CEPH. Although participation in this type

of passive organization would have to be voluntary, all academic researchers would stand to benefit from the free flow of information. The proprietary interests of commercial researchers

might limit their participation, but collaborative

arrangements could be made (12,49). The success

of a passive international organization depends

primarily on the good will of the participants.

An active international organization along the

lines of the interagency task force described in

chapter 6 could plan and distribute genome research among participating countries. There are

at least three ways in which the tasks of an international genome project may be distributed: 1) by physical units, such as chromosomes

or genes, in which each country would analyze

one unit or a group of units; 2) by project aspect,

such as sequencing, informatics, or cloning, in

which each country would focus on one aspect;

and 3) by geography, in which each country or

group of countries with similar resources would

establish a genome center.

Distribution by physical units would require

each participating nation to possess the entire

spectrum of technical specialties associated with

the project—mapping, sequencing, data management, and so on, This requirement would probably limit involvement to those nations that are

already scientifically advanced, regardless of any

interest among nations attempting to develop bio -

technical capabilities. The requirement could,

however, spur developing nations to acquire technologies, and it might provide an economic incentive for commercial firms to assist in the start-up

efforts. Assignment by chromosome would most

likely cause intense politicking among the top nations for the most “interesting” chromosomes. Certain countries or regions might be more interested

in chromosomes known to contain genes that affect a large portion of their populations. Such a

method of assignment would also identify a specific nation with a specific achievement, effectively

placing flags on the map of the genome. The realization of this would inject an element of competition for national prestige into the context of an

international science project. In effect, the cooperative partners would be establishing the arenas

and ground rules for competition.

An international project divided by project

aspect would require participating countries to

adopt a specialty, which would accelerate development and commercial profit in that field but

could preclude achievement in related fields, Japan, for example, might contribute a large share

of DNA sequencing because of its interest in automating sequencing technologies. The component

tasks of a genome project are not equivalent nor

easily evaluated in terms of necessary resources,

so distributing them may prove difficult. Further,

some aspects of the project are more visible and

economically valuable than others. To map or sequence an important gene is noteworthy and profitable; to create a database is to provide a common good but to receive little of value in return.

An international division of labor is an attractive

idea, but only clearly defined special talents among

the nations would justify it.

The third possible distribution of international

efforts is geographical—several genome centers

could be established and supported by a nation

or group of nations. The vocation of these centers

might become a point of debate, however: Should

each cover the full spectrum of genome technology, or should they specialize?6 If each center attempted to cover all technologies, a division of

The idea of setting up large centers has been promoted by American scientist and entrepreneur Walter Gilbert (44) and by .lapan

Akiyoshi Wada (84,85,87). Both have referred specifically to sequencing rather than to genome research in general.
155

labor might evolve based on specialized innovation. This might keep the centers complementary

and competitive, but not necessarily cooperative.

Establishing specialized centers would predetermine each center’s scientific and economic success. Focusing all of them on a single aspect, for

example sequencing, would siphon funds and attention from the other aspects, A center arrangement involving only countries with state-of-theart research capabilities might lock out interested

countries just beginning to develop biotechnology capabilities, unless the centers were amenable to taking on minor partners. Few scientists

other than the two who have proposed the sequencing center idea seem to be enthusiastic about

the prospect of establishing large centralized institutions (see box 7-D).

If an international project is to be pursued, issues of participation and underlying motivations

should be recognized clearly and early. Without

specific guidelines for initial and future participation, any organization is likely to become entrenched and inaccessible to latecomers. If the

motivation for an international distribution of ef -

fort is purely economic, then participation might

be restricted to nations already able to demonstrate their ability to contribute. Should an international effort be tied to political goals such as

assisting the growth of biological research and

biotechnology in the developing world, then widespread participation and an organization capable

of coordinating both advanced and developing

countries would be necessary. If political motives

are acknowledged, then the international organization might seek to encourage the association

of national goals and priorities with genome research. Political motivations are probably inherent in international projects, but they could be

used to elicit widespread participation and continuing commitment. By using enticements such

as distribution of physical units of the genome

by political units of the participants, it may be possible to guide nationalistic forces into a workable

international effort.

An important factor in any international] collaborative or cooperative agreement will be the

participants’ domestic organization of human genome projects. The agencies involved speak with

many voices, depending on their respective mis -

sions. Formal collaboration would be difficult to

negotiate without some domestic coordination (see

chs. 5 and 6) to harmonize goals. Otherwise, less

formal cooperative arrangements will probably

prevail.

Even if there emerges no formal international

organization that can satisfy national and proprietary goals, the United States could establish an

international advisory board to solicit suggestions

and recommendations from the international scientific community regarding human genome projects. Domestic advisory boards could include

nonvoting members from Europe and Japan, An

international advisory committee for database

oversight already exists; it has two members from

the United States, two from Japan, and several

from Western Europe (14). Members of the committee issue recommendations that, although not

binding, help coordinate the various national

efforts,

Existing Collaborative Frameworks

Lack of an international organizational structure does not preclude informal collaboration or

cooperation. Scientific laboratories exchange

views, visits, and materials as a matter of daily

practice; many scientists prefer informal networking to prescribed arrangements and institutions

(see box 7-E). Policymakers in Europe are finding

that increasing support for laboratory networks,

rather than establishing centers, can be an effective way to conduct research on a limited budget, Many of the scientists involved in human genome research host visiting foreign scientists and

graduate students regularly.

The United States already finances international

collaboration in biomedical research to a certain

extent through the normal funding mechanisms

of the National Institutes of Health, which may

award grants to U.S. investigators “whose work

involves substantial collaboration with foreign institutions” (63). Researchers affiliated with foreign

institutions are eligible for grants and contracts;

in fiscal year 1984, NIH spent $35 million on foreign grants, roughly half the budget allotted to

international activities, NIH also gives grants for

foreign or international conferences and for international research fellowships.
156

Box 7-E.—Large Centers v. Networking

The development of international sequencing centers draws enthusiastic response from some quarters

and skepticism from others. Proponents such as Walter Gilbert and Akiyoshi Wada advocate the creation

of several international centers containing advanced sequencing equipment as the most efficient way to

sequence the genome, if not to map it. Critics contend that establishing large central institutions reduces

the innovation spawned by small research laboratories doing investigator-initiated projects. Other critics,

including many industrialists, argue against “naive internationalism,” stating that the task at hand should

be done posthaste, without lengthy delays while international negotiations decide on the division of labor,

responsibilities, and benefits.

One solution that could satisfy critics of both stripes is networking—strengthening the links between

existing laboratories-rather than starting up new research centers. Networking has recently gained popularity in the European community; indeed, Dickson has written that “the top political priority given to the

idea that governments should focus their efforts on linking together scientists in existing laboratories—

rather than on creating major centers or research facilities –has become perhaps the most important shift

in European-level science policy in the 1980s.”

Various research programs supported by such organizations as the European Science Foundation and

the European Economic Community (EEC) have adopted networking strategies in lieu of costlier and more

contentious decisions to set up central collaborative facilities. The ESF has supported laboratory networks

for research in areas including polar science and individual psychological development. Particularly relevant for genome research is a network on the molecular neurobiology of mental illness, in which scientists

are hunting for pedigrees of families with psychiatric problems in order to locate informative genetic polymorphisms for linkage analysis studies (see ch. 2 and box 7-A). The EEC supports research under the Stimulation Program, providing money to allow scientists from different countries working on the same project

to meet, perform joint experiments, and so on. One successful project that the Stimulation Program funded,

according to Dickson, was “a research program into the development of new high-field magnets, which

now links together scientists working in 58 research institutions in the 12 member states of the EEC. The

EEC’s Biotechnology Action Program, which encourages a translational approach to the research it sponsors, has developed a similar networking approach-European Laboratories Without Walls (ELWWS). ELWWs

link individual researchers from laboratories in different institutions (preferably in more than one country)

together for multidisciplinary but focused, precompetitive research projects. The ELWW program emphasizes rapid, open flow of information and material between participants and incorporates joint planning

and evaluation of the scheduled experiments.

Perhaps because European laboratories have traditionally been poor at communicating beyond their

national borders—European scientists are more likely to collaborate or cooperate with American scientists

than with other Europeans—the networking strategy has met with increasing enthusiasm and has fostered

notable successes. Whether the strategy would work to link Europe, Japan, and the United States is not

certain. Even within Europe there are potential problems. Networking could lead to the support of elite

research groups and exclude those from poorer countries that do not yet have the facilities to be desirable

research partners. For projects with potential commercial value, proprietary rights and the open exchange

of information can become troublesome issues. Dickson reports that some policymakers argue that “the

relative absence of centralized strategic thinking could turn out to be a major weakness. ” Despite these

caveats, networking is a model for international organization that could reduce the anxieties accompanying

the planning and implementation of international cooperative or collaborative projects.

SOURCES:

D. Dickson, “Networking: Better Than Cr8ating New Centers?” Science 237:1106.1107, 1987.

J. HeiIbron and D. Kevles, we app. A.

J Maddox, “New Eurupean Colbhmations,” Nature 330:417, 1987.

J. McConnell, Johnson & Johnson, 6cience Writers’ Workshop, Brookhaven National Laboratories, Upton, NY, Sept 14, 1987

R van der Meer, E Magnien, and D de Nettancourt, “European Laboratories Without Walla: Focused Precompetitive Researth,” Trends in Biotechno&y 5318.321, 1987
157

DOE also engages, to a limited extent, in international research cooperation and collaboration

through its national laboratories. It has been criticized, however, for earning ‘(a poor reputation

abroad for long-term commitment to international

collaborations,” which “will make it extremely difficuh for DOE to attract foreign countries into significant new partnerships” (3 I). So far, however,

DOE scientists working on genome projects have

collaborated freely with researchers from other

countries (82).

Existing research organizations can also become

centers of collaboration. CEPH coordinates over

40 international investigators and research laboratories for mapping studies (see box 7-B). It sends

genetic materials to major gene mapping laboratories around the world; in exchange, the laboratories share their results and data.

Washington UniversityRIKEN Collaboration

A recent agreement between researchers from

Washington University in St. Louis, Missouri, and

the Institute of Physical and Chemical Research

(RIKEN) in Tsukuba, Japan, illustrates the potential of international collaboration at the level of

individual institutions (38). The 3-year program,

effective November 1, 1987, enables researchers

from Washington University’s new Center for

Genetics in Medicine (founded by a donation from

philanthropist James McDonnell) to work with researchers from the Tsukuba Life Sciences Center of RIKEN. The research will combine the expertise of the university’s scientists in cloning yeast

cells with the technological know-how of the

RIKEN scientists, who have developed automated

DNA analysis equipment. The initial focus of the

research will be to sequence the entire yeast genome and to improve techniques for cloning human chromosomes into yeast cells.

This collaboration, the first bilateral agreement

between American and Japanese scientists in the

field of genetics, also provides for information and

personnel exchanges with the Pasteur Institute

in Paris and the Academia Sinica in Shanghai,

China. Data and results from the collaboration will

be disseminated freely to the international community.

International Human Gene

Mapping Workshops

A series of biannual international gene mapping

workshops—the ninth (HGM 9) was held in Paris

in September 1987—has provided a mechanism

for extensive international interaction. Prior to

each workshop, committees are appointed for

each of the human chromosomes. The committees are in charge of evaluating the research that

has been done on the chromosome; they solicit

papers from the international research community and select the ones to be presented. At the

workshop, the committee for each particular chromosome works toward a consensus on which

mapping data will be accepted as the standard.

The committees also decide upon the official

nomenclature for map sites and for probes, and

their deliberations provide a measure of quality

control for the research. Data accepted at the

workshop are submitted to the Human Gene Mapping Library in New Haven, Connecticut, and subsequently entered into that database (see app. D).

In 1987, a new database, Genatlas, was initiated

specifically for the purpose of managing the mapping data from HGM 9. The conference proceedings are published in the Journal of Cytogenetics

and Cell Genetics. Proceedings of some of the conferences have been independently published.

The growth in the size of the HGM workshops

is one indication of the overall growth of the field

of human genetics. Early conferences attracted

an exclusive group of participants, but the ninth

drew hundreds. Data are accumulating so rapidly that biannual conferences may not be sufficient; plans are already underway for an informal workshop, dubbed HGM 9.5, to be held in

1988 (9).

International Journals

The scientific publication process is the most

important form of data sharing within and across

national borders—an ongoing form of international cooperation. A bibliometric analysis of the

international literature showed a rapid rise in the

number of mapping and sequencing articles published in international journals between 1977 and

1986 (see figure 7-2). U.S. researchers have con-
158

Fi~ure 7-2.—Human Gene Mapping and Sequencing

2000

1500

1000

Articles Published ‘Annually

m

1977 1978 1979 1980 1981 1982 1983 1984 1985 1986

A bibliometric analysis conducted for the Office of Technology Assessment by Computer Horizons, Inc. [app. A] showed

a steady increase in the total number of articles published

annually in international journals on human gene mapping,

gene markers, nucleotide sequences, and related topics from

1977 through 1986. [See app. E for details on the key words

used in the literature search.]

SOURCE: Office of Technology Assessment, 19S8,

sistently contributed the largest number—from

38 to 46 percent of all articles with genetic map

or linkage results (see figure 7-I, table 7-1, and

app. E) [Computer Horizons, Inc., see app. Al. The

United Kingdom is the next largest contributor,

publishing 8 to 11 percent of the articles annually, while France and West Germany are next

with 5 to 8 percent and 2 to 5 percent, respectively. Japan’s share of the basic research has increased fairly steadily, from 2 percent to 5 percent of the total. These data show the international

nature of genome research and of the medical and

scientific literature in general. There exists some

segregation of Eastern European journals due to

restrictions on export of information, and language may pose a barrier for non-English-speaking

scientists (since many international journals are

published in English), but for the most part scientific journals are thoroughly international. Scientists from one nation freely report data in journals from another.

Databases and Repositories

The operation of databases and repositories has

been a standard mode of international cooperation in many scientific fields, and human genome

projects are no exception; several databases and

repositories relevant for human genome projects

exist (see app. D). The cooperative arrangements

that have evolved among the international databases for nucleotide sequences and for protein

sequences are examples of effective international

collaboration.

Databases for nucleotide sequences were started

at Los Alamos National Laboratory (later funded

by NIH and operated under the name GenBank@

)

and EMBL (officially dubbed the EMBL Data Library) during the late 1970s. By the fall of 1980,

the database organizers recognized the need for

collaboration between the two, and from 1980

through 1982 the databases exchanged sequence

data on an informal basis until their first major

releases. In August 1982, GenBank@ and EMBL

held their first joint meeting and agreed to use

a similar system of accession numbers and to divide the journals each would scan for data. The

compatibility of the databases was further enhanced by agreements, reached in 1985 and 1986,

on common sets of data and annotation. The DNA

Data Bank of Japan formally joined the collaboration in May 1987, The division of responsibilities

for various aspects of the operation of the databases was formalized in meetings in the summer

and fall of 1987.

An international workshop on database needs

in molecular biology was convened in Heidelberg,

West Germany, in 1987. The participants recommended that an international advisory committee composed of experts from the fields of molecular biology and information sciences be formed

to provide advice and guidance for expanded cooperation among the databases (35). The funding

agencies that support the databases followed the

recommendation and appointed a committee,

which consists of three members from the United

States, three from Europe, and two from Japan.

The committee will meet yearly to advise database staff on matters such as format and annotation. Its recommendations are not binding, however, since each database is responsive primarily

to the agencies that support it. The first meeting

was held in February 1988.

Formal collaboration on protein sequence databases is more recent. The US. database, the Protein Identification Resource (formerly known as

the Dayhoff database, or NBRF), was started in
159

the late 1960s. The European and Japanese counterparts—the Martinsreid Institute for Protein Sequence Data (MIPS) (27) and the Japan International Protein Information Database (JIPID)–

began operations in 1987. The close collaboration

among the three includes use of the same format,

the same software, and a regional division of monitored journals (41).

The continued development and maintenance

of databases and repositories are the most commonly endorsed mode of international cooperation on human genome projects (see box 7-D). The

National Academy of Sciences supported the establishment of an international organization to gather

and distribute data and materials in its 1988 report on human genome mapping (62).

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Sorting of a Large Genomic Library,” Cell 50:495-

508, 1987.

54. Logsdon, J., George Washington University, personal communication, August 1987.

55. Logsdon, J., “U.S.-European Cooperation in Space

Science: A 25-Year Perspective,” Science 223:11-16,

1984.

56. Maddox, J., “Brenner Homes in on the Human Genome,” Nature 326:119, 1987.

57. Mannarino, E., Embassy of Italy, personal communication, July 1987.

58. Matsubara, K., Institute for Molecular and Cellular Biology, osaka University, Japan, personal communication, February 1987.

59. Mohr, J., University of Copenhagen, personal communication, August 1987.

60. Morris, R.G., U.S. Embassy, Argentina, personal

communication, September 1987.

61. National Aeronautics and Space Administration,

Life Sciences Report, 1987 (Washington, DC: NASA,

1987), p. 65.

62. National Research Council, Mapping and Sequencing the Human Genome (Washington, DC: National

Academy Press, 1988).

63. Novello, A.C., “National Institutes of Health Awards

to Institutions in Foreign Countries, 1976 -85,” The

Lancet, Sept. 6, 1986, pp. 561-563,

64. Oddo, G., “More Business Involvement in CNR’s

Finalized Programs, ’’ll Sole 240re (Milan), July 14,

1987, p. 6.

65. Organizaci6n de 10S Estados Americans) Situacion

de la Genetica en la Region: Informe Preliminary

(Washington, DC: OAS, 1986).
161

66. Probert, M., Medical Research Council, United

Kingdom, personal communications, July 1987; December 1987.

67. Roe, L., Ministry of State, Canada, personal communication, December 1987.

68. Schmitz, D., “Biotechnology in the Federal Republic of Germany (FRG),” report prepared for the U.S.

Department of State, December 1986.

69. Simpkins, L. C., U.S. Embassy, Mexico, personal

communication, September 1987.

70. Skou, B., Royal Danish Embassy, personal communications, November 1986; February 1987; April

1987.

71. Smith, R., The Johns Hopkins University, personal

communication, July 1987.

72. Soil, D., Yale University, personal communications,

August 1987; September 1987.

73. Sommariva, A., “And Italy Will Study Chromosome

22,” ltalia Oggi (Milan), May 22, 1987, p. 36.

74. Sukholdolets, V. V., “Bacterial Genome Construction: New Advances in Genetic Engineering,”

Genetika (Moscow) 22:901-903, 1986.

75. Swinbanks, D., “Human Frontiers Program Seeks

International Help,” Nature 330:683, 1987.

76. Swinbanks, D., “Japan’s Human Frontiers Project

Stays in the Doldrums,” Nature 328:100, 1987.

77. Swinbanks, D., “What Future Now for Japanese Biotechnology Research?” Nature 329:661, 1987.

78. Technologies Elettriche (Milan), January 1987, pp.

78-87.

79. U.S. Congress, Office of Technology Assessment,

Commercial Biotechnology: An International Analysis (Springfield, VA: National Technical Information Services, 1984).

80. U.S. Congress, Office of Technology Assessment,

Star Power: The U.S. and the International Quest

for Fusion Energy, OTA-E-338 (Washington, DC:

U.S. Government Printing Office, October 1987).

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New Developments in Biotechnology, 4: U.S. Investment in Biotechnology (Washington, DC: U .S. Government Printing Office, in press).

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83. van der Meer, R. R., “EC-biotechnology: European

Challenge,” Trends in Biotechnology 4:277-279,

1986.

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21, 1987.

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86. Wada, A., University of Tokyo, personal communication, September 1987.

87. Wada, A., “Strategy for Building an Automatic and

High Speed DNA-Sequencing System, ” in Proceedings of the 4th Congress of the Federation of Asian

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89. Yoder, S., “Japanese Tap Advanced Technologies

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91. Yuan, R., Biotechnology in Western Europe (Washington, DC: Department of Commerce, 1987).
chapter 8

Technology Transfer
CONTENTS

Pag e

Patent and Copyright Policies . . . . . . . . . . . . . . . . . . . . . . . . . .166

Patents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..........166

Copyrights . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..., . . . . . . . . . . . . . . . . . 170

Trade Secrets. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170

International Technology Transfer. . . . . . . . . . . . . . . . . . . . . . .................172

Economic Benefits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..........172

Humanitarian and Scientific Benefits . . . . . . . . . . . . . . . . . . . . . ..............173

National Prestige . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..........174

Military Applications. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .174

Chapter 8 References. . . . . . . . . . . . . . . . ..., . . . . . . . . . . , . . . . . . . . . . . . . . . . . .174
chapter 8

Technology Transfer

‘

(The politics of knowledge—the question of who owns and controls the distribution

and use of scientific information—is by no means a new issue. The pure scientist working in an ivory tower has long been extinct. ”

Dorothy Nelkin, Science as Intellectual Property: Who Controls Research?

(Washington, DC: American Association for the Advancement of Science, 1984), p. 92.

The economic impact of genome projects will

depend on how many new products and services

are created by them. Some large scientific projects

such as space programs and electronics research

facilities have been justified by their potential for

spinning off technologies. The magnitude of such

spinoffs is unpredictable, however. Often, there

emerge useful products that could not have been

foreseen IHeilbron and Kevles, see app. A], Given

the many surprises in molecular biology over the

past decade, it is impossible to predict exactly how

genome projects will result in products, but they

undoubtedly will yield many new applications in

pharmaceuticals, agriculture, and other industrial

sectors. Uncertainty about the magnitude of economic impact means that genome projects cannot be justified purely as an economic investment.

As the projects go forward for scientific and medical reasons, however, it makes sense to ensure

that their results are fully used. The process of

converting scientific knowledge into useful products is technology transfer.

The Federal Government influences the efficiency of technology transfer through its research

and development policies. Government has traditionally supported research that will have large

but unmeasurable noneconomic benefits (e.g., research aimed at improving health as a value in

itself rather than simply disease impact measured

in dollars) or that is too risky for individual firms

to support (e.g., projects that are expensive, highly

uncertain in outcome, or long-term). Arguments

for increased Federal support of biomedical research since World War II have generally emphasized improvements in health. Economic arguments for increased biomedical research funding

have typically been analyses of economic drag–

how much the Nation could save by avoiding disability or disease (18). This argument is changing

to concern for efficient translation of science into

products. Policymakers are shifting their attention to technology transfer as products derived

from molecular genetics find their way to the marketplace, international trade imbalances worsen,

and rising deficits intensify scrutiny of Federal

budgets.

A major effort is underway in many developed

and some developing nations to target biotechnology for investment because it is considered particularly likely to produce economic benefits

(3, 16,19,23). Most foreign governments’ efforts to

promote biotechnology include strategic planning

of national research programs and encouragement of research and development in private firms

(e.g., tax incentives, subsidies for industrial research centers, business grants, or government

risk capital). The United States has no deliberate

Federal policy to encourage biotechnology per se

(16,19,23), although legislation introduced late in

the first session of the looth Congress would create a national biotechnology policy board.

Most genome projects could produce both direct and indirect economic benefits. Some projects

are expected to yield directly marketable products (e.g., DNA sequenators, analytical instruments, DNA probes for diagnostic tests). Others

would accelerate development of products (e.g.,

maps, repositories, and databases).

Different groups have divergent concerns about

technology transfer. Scientists fear that corporate

participation will inhibit the free flow of information and impede scientific progress. Policymakers

want to ensure that a large Federal investment

in genome projects is translated efficiently into

new products and services, ultimately creating

new jobs and other economic benefits. They are

wary of projects in which U.S. taxpayers will fund

165
166

research that is commercialized and used by foreign interests. In this view, foreign governments

should support an equitable fraction of basic research, and American investments should not allow jobs and profits to migrate abroad. Industrial

representatives want a say in planning research

programs and access to scientific results as they

are produced. Individual companies wish to ensure that any funds they invest will earn sufficient returns.

Congress could encourage technology transfer

by funding personnel exchange among government, academic, and industrial sectors, with minimal bureaucratic strictures, and by supporting

symposia, journals, and other modes of information exchange. When advisory committees are

formed to guide Federal genome projects, industrial representatives could ensure that projects

are planned with an eye to economic exploitation.

These options are covered in chapter 6. The remaining options relate to protection of inventions

resulting from federally funded research, discussed below.

PATENT AND COPYRIGHT POLICIES

Ideas and know-how—intellectual property—

are granted many of the same legal protections

as tangible private property. Intellectual property

law traces its roots directly to the U.S. Constitution, which authorizes the Federal Government

“to promote the Progress of Science and the useful Arts, by securing for limited times to their

Authors and Inventors the exclusive Right to their

respective Writings and Discoveries,” The purpose

of intellectual property protection is to encourage

inventors and discoverers to share their knowledge, while ensuring that they benefit from the

fruits of their labors. Legal protections balance

the social good stemming from wide disclosure

of new knowledge against individuals’ or companies’ rights to gain from what would not have existed without their efforts.

Three types of intellectual property protection

are relevant to discussion of the technologies likely

to emerge from genome projects: patents, copyrights, and trade secrets.

Patents

patents grant inventors the right to exclude

others from producing, using, or marketing their

inventions (as defined in the patent claims) for

a specified period. The purpose of patent law is

to give inventors an incentive to risk their time

and money in research and development, while

requiring public disclosure. Patent laws in different countries vary in degree of protection, enforcement, penalties for violation, and criteria for

approval. In the United States, the period of protection is 17 years, with extensions for pharmaceuticals to cover some of the delay imposed by

regulation. Patents apply to inventions, but not

to ideas, mathematical formulas, or discoveries

of preexisting things. A patentable invention must

be new, useful, and not obvious. A patent holder

can permit others to use or make the invention

by licensing it.

Profit is only one of many motivations for patenting an invention. Another is to maintain control

over it. Leo Szilard filed a patent on the process

of nuclear fission, for example, hoping to bring

it to the attention of military authorities in the

United States and Great Britain (12). Cyclotrons

used in nuclear physics were patented to ensure

their proper medical applications, yet this did not

inhibit research (in fact, most physicists were not

even aware of the patents) IHeilbron and Kevles,

see app. A]. The Rockefeller Institute patented the

sphygmomanometer (blood pressure cuff) to ensure that clinicians would have ready access to

it and that later discoverers could not limit its use

(11). Nonprofit organizations supporting genome

projects are likely to encourage patents when they

would ensure broad public use (9).

U.S. patents are obtained from the Patent and

Trademark Office in the Department of Commerce (other nations have analogous institutions).

The patentability of inventions is initially determined by this office. The scope of protection and

more refined factors for granting patents are defined by case law, when patents are challenged
167

in court, The principles for determining patentability do not depend on any particular type of technology, but interpretation of them does. Uncertainty about the patentability of inventions is

greater in biotechnology than in most other areas

because the techniques are new and complex. Interpretation of criteria for granting patents, defining the scope of patent claims, and determining

what constitutes infringement have not been clarified by case law, because the case law does not

yet exist.

Patent Policies for Federally

Funded Research

Uncertainty about patentability need not paralyze research efforts, because interpretation of

patent law does not interfere with most federally

supported research (as explained below). Patent

policies of Federal agencies will nonetheless influence how genome research is commercialized,

and these patent policies have changed dramatically over the past decade. The changes are intended to promote commercial application of federally funded research by permitting private

ownership and control of its results. The reasoning is that research will be more broadly disseminated and effectively used if those who conduct

it are granted title to the patents on resulting inventions, thus providing an incentive to commercialize the inventions [Rosenfeld, see app. A].

Changes in patent policy resulted from studies

showing that, while the Federal Government held

title to roughly 28,000 inventions in 1975, fewer

than 5 percent had been licensed to businesses

(15). The Patent and Trademarks Amendments

of 1980 (Public Law 96-517) were passed to grant

title to small businesses and nonprofit organizations funded to do research by the Federal Government. These were further amended in the

Trademark Clarification Act of 1984 (Public Law

98-620), most significantly by removing restrictions on licensing. Regulations implementing these

laws were made final by the Department of

Commerce in March 1987.

The policies applying to small businesses and

nonprofit organizations were extended to large

businesses, with some exceptions, by a memorandum from President Ronald Reagan dated February 18, 1983, The Technology Transfer Act of 1986

(Public Law 99-502) permitted new licensing and

joint venture arrangements, and granted agencies authority to form consortia with private concerns. Executive Order 12591, issued by President

Reagan in April 1987, encouraged technology

transfer of federally funded research. The order

was based on existing statutes and promoted consortium formation, exchange of research personnel between government laboratories and industrial firms, special technology transfer programs

at federally owned laboratories, and transfer of

patent rights to government grantees and contractors,

The policies embodied in these statutes, regulations, and executive orders constrain the authority of Federal agencies to force sharing of data

if sharing would conflict with recipients’ taking

title to inventions [Rosenfeld, see app. A], The government can override recipients and take title to

patents only in special situations. One of these is

when an agency determines that retaining title

‘(will better promote the policy and objectives” of

the patent statutes. This clause has been narrowly

interpreted and has rarely been used by the research agencies involved in genome projects

IRosenfeld, see app. Al. The Federal Government

can also impose licensing requirements to ‘(alleviate health and safety needs,” “meet requirements

for public use specified by Federal regulations, ”

or meet “certain statutory provisions requiring

products to be manufactured in the United States.”

These provisions have also been narrowly interpreted and impose such a daunting burden of

proof on agencies that they are unlikely to be used.

They could conceivably be invoked if patent rights

interfered with the pooling of data that must be

collective to be useful or if clinical benefits were

delayed (e.g., slow commercialization of genetic

tests or therapies), but only if problems were severe and obvious.

Federal research agencies’ patent policies need

not unduly slow exchange of information. The degree to which information flow is impeded will

depend on when grant recipients and contractors

file patent applications. Many genome projects will

result in patentable inventions, particularly those

focused on technology development. Recipients

of Federal funds may follow one of three courses

of action: file applications early and subsequently
168

release data; file early and do not take extra actions to release data (relying on the patent process to do so); or decide not to patent.

Filing patent applications early and publishing

data soon thereafter are optimal for encouraging

rapid dissemination of knowledge, protecting inventors’ rights, and preserving economic benefits in the United States. Early patenting and subsequent disclosure would release data for public

use but would help inventors maintain control of

their inventions and assure them and their sponsoring institutions of any financial rewards. Early

patent application would also protect the Nation

because statutes give a preference to U.S. manufacture of any resulting products or services. Early

patent application not followed by special efforts

to disseminate data would ensure benefits for the

grant recipient or contractor but would needlessly

delay exchange of useful information-patents are

often not published for several years, and it has

taken over 7 years for some biotechnology patents

to be awarded.

Investigators may decide not to apply for a patent because they wish to avoid substantial legal

costs and bureaucratic entanglements or because

they believe that science should not become commercially oriented. This can make new methods

freely available to all, but it can also inhibit full

exploitation of an invention. It is also against the

intent of Federal statutes, which require recipients of Federal funds to report patentable inventions. An inventor can lose control of an invention if he or she does not file a patent and another

inventor does so. A product or process that is not

patented is unlikely to be used commercially, because any firm investing in manufacture will want

a guarantee that its investment will be protected.

Failure to patent also invites foreign exploitation

of research funded at U.S. taxpayers’ expense: Patent rights could be claimed by a foreign company,

research institution, or individual; U.S. firms

would not be given manufacturing preference;

and the US. inventor could be prevented from

use of the invention. Export of economic benefits

has occurred frequently in biological sciences

when initial discoveries have not been patented.

Penicillin was discovered in England, for example, but the patent was obtained by U.S. corporations. The cell fusion process for making monoclinal antibodies was developed in London, but

many of its applications were exploited first in

the United States. In both cases, the United Kingdom claimed the Nobel Prize, but the United States

reaped most of the economic benefits.

Federal agencies and Congress may wish to oversee patent practices of grantees and contractors

closely to ensure that patents are filed early and

data exchanged soon thereafter. Disclosure of data

should not be long delayed by policies designed

to encourage patenting of inventions, because data

per se are not inventions eligible for patent protection. There is a gray area, however, between

invention of new methods and the data that result from using them.

Scientists may be reticent to disclose details of

methods used to generate data if doing so endangers patentability. An invention must be novel

to be patented: that is, it must not be widely used

by parties other than the inventor for more than

one year, and publication of the method cannot

precede filing the patent by more than one year.

(Some foreign countries do not permit even the

one-year grace period.) If investigators are uncertain whether disclosing details of method would

threaten a patent, they may choose not to publish those details. Uncertainty over patentability

can indeed inhibit the free exchange of information. It has led one commentator to list three possible ways of altering patent laws: 1) making the

definition of novelty more flexible; 2) establishing an intellectual property protection that is analogous to but more limited than patents and that

requires less rigorous proof of novelty and nonob -

viousness; or 3) legislating special intellectual property protections for biotechnology (8). Further

study is needed “to determine whether and how

biotechnology demands special treatment as intellectual property before legislative reform will

be in order” (8). This suggests that patent policies

might be high on the agenda for congressional

oversight but low on the legislative calendar.

Filing patents early and then disclosing the results could worsen an already considerable backlog of pending patents. Approximately 7,000 biotechnology patents have been filed at the Patent

and Trademark Office and await final action (20).

If the benefits of patent protection are judged im-
169

portant by Congress, then one option would be

to increase the resources in the biotechnology sections of the Patent and Trademark Office. This

could include higher salaries, more opportunities

for training to keep abreast of technological developments, easier access to technical databases,

and more examiners. Increased resources could

not only reduce uncertainty by diminishing the

backlog of pending patents, but also increase the

attention devoted to each application and reduce

subsequent litigation.

Patent Policies at Research Agencies

The Department of Commerce recently promulgated final regulations for Federal agencies to use

when funding research at small businesses,

universities, and nonprofit organizations [37 CFR

401]. While these regulations, issued in March

1987, have had little time to take effect, the National Science Foundation (NSF) and the National

Institutes of Health (NIH) have followed similar

policies since the late 1970s,

The General Accounting Office found that university administrators, industry representatives,

and small businesses all reported a “significant

positive impact on research and innovation” from

taking title to inventions that resulted from federally funded research, University and industry

officials also reported benefits from the 1984 law

that removed licensing restrictions (15). Agencies

likewise reported a generally positive assessment,

with greater potential for licensing patents than

when title was retained by the Federal Government.

The situation at the Department of Energy (DOE)

is more complex. A substantial fraction of DOE

research funding goes to national laboratories,

which are owned by the Federal Government and

operated by private contractors. At most of the

laboratories, the contractor can elect to take title

to inventions. Title rights are restricted, however,

at facilities that conduct research on weapons and

naval propulsion systems. This could prove relevant to genome projects because several of the

groups that have been directly engaged in DOE’s

Human Genome Initiative are located at laboratories with restricted title policies—namely, Lawrence Livermore National Laboratory and Los

Alamos National Laboratory, both operated by the

University of California. Regulations state that limitations on the contractor’s right to take title should

be restricted to ‘(inventions occurring under” naval nuclear propulsion or weapons-related programs [37 CFR Part 401.3(a)(4)]. This should permit the contractor to take title to inventions from

human genome projects because the projects

would not be conducted under restricted programs, even at the affected laboratories. Negotiations between DOE and contractors are more complicated, however, when restrictions differ among

programs at the same facility. Legislation has been

proposed to mandate patent policies for genome

projects at the national laboratories; the policies

would be modeled on those of other research

agencies.

The regulations and executive orders implementing patent policies at research agencies are

quite recent. It would be premature to alter those

policies fundamentally until the results of current

law can be assessed (with the possible exception

of DOE policies regarding national laboratories,

noted above).

There are additional roles for Congress. First,

Congress could monitor the practices of Federal

agencies and funding recipients to ensure that the

intent of existing statutes is carried out. Second,

Congress could increase resources to the Patent

and Trademark Office to enable more efficient

processing of patents. Third, Congress could increase resources for universities and other recipients in order to manage patent filing in the United

States and abroad. Finally, Congress could ask

agencies engaged in genome projects to specify

their patent policies more clearly, At present, written material on patent policies at NIH, DOE, and

NSF is difficult to obtain, and there is no single

source for information on patent policies at all

agencies involved in genome projects [Rosenfeld,

see app. A]. The interagency nature of genome

projects means that recipient institutions will often

be funded by more than one agency. A clear presentation of patent guidelines at various agencies,

with explanations of the advantages of early patent filing and the implications of doing so (and

not doing so), might diminish confusion and promote commercial application.
170

Copyrights

Copyright law is intended to protect works of

authorship. It has traditionally been applied to

works of art, books, and articles but has had to

adapt to technological change. Copyrights now

extend to computer software and electronic entertainment media, for example (6, 17). Copyright

is intended to protect the expression of ideas, not

the ideas themselves—a difficult but crucial distinction.

The Copyright Act of 1976 is the most recent

statute relevant to genome projects, extending protections to nontraditional media such as computer

software. The extensions may also prove relevant

for research in molecular biology (6). Case law

has evolved doctrines to test the distinction between idea and expression and to define the scope

of protection. An author can prohibit others from

copying his or her book, for example, but the concepts and methods described in the book are not

protected. Arguments have been made that copyright could apply to DNA (6), but this line of argument is not widely accepted and the scope of protection (if it exists) is quite narrow (5). The ability

to copyright a native DNA sequence derived from

a human chromosome or other natural source is

particularly uncertain (5). A preliminary communication from the Copyright Registration Office

indicates that such sequences would not be accepted, although the book or printed map containing them—the particular expression of map

or sequence data—would (10).

Even if DNA maps can be copyrighted, such

copyrights are unlikely to inhibit research substantially. In normal circumstances, obtaining a

copyright does not require extra time and is thus

not a justification for delaying disclosure of results. A company could charge for access to map

or sequence information in much the same way

that commercial databases charge for information sharing. Access and service charges are not

new—molecular biologists routinely pay for services that are less expensively or more rapidly performed by others. They buy copyrighted books

and read copyrighted journals. Many materials

used in biological research (clones, enzymes,

chemicals) can be made by individual investigators, but it is easier to purchase such materials

from a company set up to make them.

The type of research conducted by a private

company engaged in mapping and sequencing

DNA would be feasible in a large number of laboratories. Copyrights would not prevent investigators from using information published or otherwise provided by a company or from duplicating

the work. A company that has developed extensive map and sequence information would either

charge so little that it is cheaper for a researcher

to obtain it from the company than to do the work,

or the researcher would in fact repeat the work.

In either case, the community of researchers is

no worse off than if the company had not mapped

or sequenced.

If copyright practices prove to impede research,

then agencies can take steps to correct the deficiencies. Agencies have much broader discretion

for copyright policies than for patents IRosenfeld,

see app. A].

Trade Secrets

Information held by one company that is useful in its business and unavailable to competitors

is called a trade secret. Trade secrets can be protected from misappropriation—that is, improper

disclosure–through the courts, which award

monetary damages for unauthorized use. A trade

secret must be in continual use, be well established

in practice, and have actual or potential commercial value (19). The holder must take steps to guard

it. Trade secrets do not involve slow and costly

legal steps for registration, their duration is not

limited by law, and they need not meet patentor

copyright criteria. Uncertainties about patents and

copyrights are not relevant (although legal criteria

for protection under trade secret laws must be

met). Trade secret protections are principally secured under State rather than Federal laws, and

there is some variation among the States. Trade

secrets have limited scope: In a rapidly moving

field they may not last long. Trade secret laws

cannot ensure returns on a research investment

if another inventor discovers the secret method

or finds a new way to do the same thing. Protection does not apply, even if competitors figure out

the secret by examining a product (reverse engineering). Most important, trade secrets must be

kept secret. This would be quite difficult to justify

for federally funded research.
171

The scientific equivalent of a trade secret is nondisclosure. This is referred to pejoratively as sitting on data and is widely viewed as improper

beyond the period needed to confirm accuracy

of results and take advantage of a lead for further research. The period of nondisclosure varies

widely among researchers, even those in the same

field, Researchers who share data and materials

early and freely are widely praised, such as the

many collaborators who worked to find the muscular dystrophy gene (see ch. 3). But nondisclosure—for a few months to a year—is not uncommon in order to maintain a research advantage

or to establish first discovery, even in research

leading to Nobel Prizes (or perhaps especially in

such research) (21,22). Permanent nondisclosure

of an important result is, however, inimical to the

purpose of scientific inquiry—the discovery and

dissemination of new knowledge.

Nondisclosure is of particular concern when the

results must be pooled in order to be useful (e.g.,

maps derived from data contributed by various

groups). The need for pooled data can create a

situation known as the prisoner’s dilemma: when

cooperation of all parties yields the maximum benefits, but one party can benefit if he does not cooperate and the others do, (So called because

prisoners planning a jail break all benefit from

cooperation, but one stooge can benefit individually by telling the guard of the plans.) An investigator searching for the location of an unknown

gene stands to gain if other groups with markers

make them freely available but he does not. He

can then use both his and others’ work to speed

the search, while denying others access to his markers. Similar situations will arise in connection

with submitting information to databases, sending materials to other researchers or central repositories, and other cases directly related to genome projects. Agencies will need to monitor the

free exchange of data and materials, particularly

when the efforts must be collective, and take steps

to correct inequities. The need for joint efforts

highlights the importance and fragility of collaborative institutions such as the Center for the

Study of Human Polymorphism (CEPH) (see ch. 7).

Many journals have either explicit or unwritten policies that research data and materials described in an article must be made available to

other researchers at the time of publication. Researchers preserve their option for exclusive use

from the time of discovery until publication. Many

scientists make materials available even before

publication, which can require many months.

Linking availability of materials to publication is

a powerful mechanism, because one measure of

scientific prestige is priority—who discovered

something first. Priority is generally determined

by date of publication. In large collaborative scientific projects, mechanisms have evolved to permit scientists time to pursue hot research leads

while ensuring that others gain fair access. (CEPH’S

policy of sharing one set of data only among collaborators and making another set publicly available is an example.)

An informal policy of disclosure operates in Federal agencies through the process of peer review,

If a researcher is known to hoard data—and such

information spreads rapidly through scientific

communities—then proposals submitted by that

individual are unlikely to be given high priority

by study sections (7). Review groups withhold support from research whose results they cannot see.

This mechanism is slow—it can only be used when

a grant is up for renewal, every 3 years or more—

but it can be quite effective. If further measures

are needed, Federal agencies could require submission of materials and data—map positions or

DNA sequence data, for example—to the appropriate database. Such a policy would not be easily enforceable, however, and would be constrained by investigators’ patent rights. Some

journals now require submission of DNA sequences in proper form to GenBank” or its sister

database in Europe at the time a paper is accepted.

Agencies could devise incentives to make contribution of data and materials attractive, an alternative that is more easily implemented and less

politically troublesome than negative sanctions.

Those submitting data to CEPH, for example, benefit from knowing the position of their markers

relative to markers found by others. Persons managing the DNA sequence databases have contemplated giving researchers a similar incentive,

Federal agencies have substantial power to require disclosure when it does not impede grantees’ and contractors’ intellectual property rights.

Grant recipients and contractors need ample time

to file patent applications, but legal protections
172

of intellectual property are unlikely to inhibit when broad access to data is necessary to fulfill

agency policies promoting disclosure, particularly the agency’s mission.

INTERNATIONAL TECHNOLOGY TRANSFER

Human gene mapping is inherently international

in scope. Recent breakthroughs in assembling

rough genetic maps, for example, have depended

on an international collaboration of investigators

from Europe, North America, and Africa using

family data from four continents. Several current

technologies for sequencing and physical mapping

were developed in the United Kingdom and other

European nations, not the United States; however,

recent years have seen increased emphasis on retaining the economic benefits of federally funded

research for the United States.

International technology transfer is the movement of inventions and know-how across national

borders. Concerns about international technology

transfer fall into four areas: economic benefits,

humanitarian and scientific benefits, national prestige, and military applications.

Economic Benefits

Concerns about economic implications of international technology transfer focus primarily on

the export of jobs and services generated by research funded at public expense, Policies to combat this fall into three main areas: patent policies,

restrictions on flow of information and materials, and promotion of domestic technology transfer so that benefits remain within national

borders,

The patent policies described above have several provisions on international technology transfer that are relevant to genome projects. For foreign recipients of Federal funds or those subject

to a foreign government, agencies must consider

whether the recipient’s government or company

enters into international cooperative funding

agreements on a “comparable basis” and whether

the recipient’s government protects U.S. intellectual property rights [Executive Order 12591, Apr.

10, 1987]. Recipients of Federal R&D funds must

ensure that the products of the invention will be

“manufactured substantially in the United States”

[35 U.S.C. 204]. Since jobs and economic wealth

are linked more tightly to manufacturing than to

initial research and development, even foreignheld U.S. patents resulting from Federal funding

would have economic benefits in the United States.

Moreover, Federal agencies are not required to

grant patent rights to foreign recipients or those

subject to control of a foreign government, even

if they are universities or nonprofit organizations

[37 CFR 401.14(a)(l)]. Foreign recipients are thus

managed differently than their U.S, counterparts.

Agencies could conceivably require foreign recipients to assign title to the U.S. Government or require that U.S. research partners take title,

Exploiting federally funded research inventions

abroad will usually entail seeking foreign patents.

Several international conventions govern patents,

but conditions for granting patents differ among

nations. The United States permits a grace period

of one year from the date of publication to file

a patent application, for example, but many other

governments do not. If investigators wish to ensure worldwide patentability, therefore, they must

file foreign patents before publication, The period

of patent protection also differs. Researcher institutions accepting Federal funds must know

about these and other differences when making

decisions about foreign patents, Disseminating

knowledge about such differences could be encouraged by research agencies in concert with

the Department of Commerce. Agencies could also

encourage institutions receiving Federal funds to

pursue foreign patents.

The current necessity for filing patents individually in many countries is expensive and wasteful

for all nations. International patent policies have

been discussed several times at meetings of the

Organization for Economic Cooperation and Development. Attempts are being made to harmonize

international practices (14).
173

Humanitarian and Scientific

Benefits

The humanitarian and scientific benefits of genome projects will be great. The United States has

consistently performed a significantly higher fraction of the total mapping and sequencing effort

than any other nation (see ch. 7). The knowledge

resulting from these efforts has been freely shared

with the rest of the world, to the benefit of citizens

of all nations. The scientific knowledge generated

at Federal expense since World War II may well

prove to be one of the most significant international contributions of modern American culture.

Imposing restrictions on the flow of information and scientific materials from U.S. researchers to researchers abroad would be politically

troublesome and technically difficult. Details of

what to share and what to restrict would be difficult to describe in advance, and policies restricting the flow of data are against scientific traditions,

which transcend national borders. Withholding

map locations and DNA sequence information

would be a violation of scientific ideals, particularly when such information could be clinically

useful. Unilateral restrictions imposed by the

United States would invite reciprocation, to the

detriment of worldwide scientific progress.

The same tradition of free international exchange does not necessarily apply to the exchange

of services and products—for example, mapping

services, instruments, automation equipment, and

reagents—which is governed more by international trade agreements than by scientific practices. Many national governments wish to assist

their companies in developing goods and services

for export. Genome projects focused on technology development are likely to be seen in this light.

Nationalistic economic policies make projects to

develop instruments or other salable goods poor

candidates for international cooperation. European nations may be exceptions, because they

have a basis for cooperation through several biotechnology programs of the European Economic

Community.

Restrictions on international exchange of scientific personnel would disrupt many molecular

biology laboratories in the United States and

abroad. The United States has often reaped the

benefits of international scientific exchange, Senior scientists, postdoctoral fellows, and graduate

students from other nations work in U.S. laboratories and attend conferences. In exchange, U.S.

scientists visit and are occasionally educated at

universities and research centers abroad (12,22).

The team of scientists that developed the atomic

bomb for the U.S. Army, for example, was heavily dependent on scientists trained in Europe (1.2).

Molecular biologists from abroad have often settled in the United States because it is so conducive

to scientific research; several Nobel laureates at

American universities immigrated during their scientific careers. Many projects in molecular biology have depended heavily on foreign scientists

working in the United States, and many of the

best stay or eventually return (4). The United

States may in fact benefit from international personnel exchanges more than it is hurt by them.

The Federal Government could nonetheless limit

funding of foreign researchers at U.S. institutions,

although this would probably generate ill will and

provoke reciprocal actions by other governments.

One of the problems in assessing the potential

impact of policies to reduce funding of foreign

researchers in American laboratories is the absence of information about their research careers.

If most foreign researchers remain in the United

States or are particularly productive investigators

while receiving Federal funds, then policies to restrict their ingress would be counterproductive.

Extending current restrictions or use of Federal funds for American researchers to travel

abroad would be even less politically acceptable

and more difficult to implement. It would result

in direct loss of information to the United States,

because persons traveling abroad are as likely to

import information from their foreign collaborators as to export it. Policies designed to inhibit

the exchange of personnel, materials, and information across national borders threaten benefits

but gain little for the United States.

Promoting domestic exploitation and foreign

patenting of new technologies is a more positive
774

and less politically troublesome means to the same

end of improving U.S. economic competitiveness.

Such policies can preserve the U.S. lead in research

without provoking retaliation or tarnishing the

country’s prestige.

National Prestige

One argument for Federal sponsorship for genome projects is that they are highly conspicuous and beneficial: Other nations will do the work

if the United States does not, to the detriment of

US. prestige. Similar arguments have been proffered for the supersonic transport, space programs, and other technical projects. These arguments tie the stature of U.S. science and

technology to leadership of genome projects. The

international prestige attached to genome projects

is a purely political judgment; it cannot be assessed

technically.

What would be the consequences if Japan or

a European nation were to have the first complete set of ordered DNA clones representing all

human chromosomes, or the first reference sequence of the human genome? Such questions are

best answered primarily by the scientific and technical merits of the projects, not by an appeal to

a vague notion of national prestige. If projects are

technically unsound or uneconomical, then the

United States would not benefit from a commitment to them. Other countries could do so, but

CHAPTER 8

1. Dashiell, T.R., “The Department of Defense and Biotechnology,” Technology in Society 8:223-228, 1986.

2. Dashiell, T. R., comments at Issues of Collaboration

for Human Genome Projects, OTA workshop, June

26, 1987.

3. Fujimara, R. K., International Trade Administration,

U.S. Department of Commerce, Biotechnology in

Japan (Washington, DC: U.S. Government Printing

Office, in press).

4. Hall, S. S., Invisible Frontiers: The Race To Synthesize a Human Gene (New York, NY: Atlantic

Monthly Press, 1987).

5. Issues of Collaboration for Human Genome

Projects, OTA workshop, June 26, 1987.

6. Kayton, I., “Copyright in Living Genetically Engithey would only be hurting themselves. If the

projects are technically sound, then the United

States would do well to lead or at least participate in them, but national prestige would not be

the principal justification for involvement. National

prestige is not a useful basis for judging major

scientific or technical projects.

Military Applications

Military applications of results of genome

projects should not prove to be a major consideration in technology transfer. U.S. policies ban the

export of goods and technologies that could be

used for military purposes by specified hostile

countries. Such policies are administered by the

Department of Commerce in consultation with the

Department of Defense and the Department of

State. The export of some goods produced using

biological technologies could be affected (1), At

present, however, DNA mapping, sequencing, and

other means of analysis relevant to genome

projects are not on the list of controlled technologies, and this should remain true for the foreseeable future (2). The main reason is that the technologies and data resulting from genome projects

would not have immediate military applications.

Like other technologies and data, some could conceivably be used for a military purpose, such as

devising vaccines against biological warfare

agents, but genome projects would not in themselves promote biological warfare.

REFERENCES

7.

8.

9.

10.

neered Works, ” George Washington Law Review

50:191-218, 1982,

Kirschstein, R, comments at Issues of Collaboration for Human Genome Projects, OTA workshop,

June 26, 1987.

Kern, D., “Patent and Trade Secret Protection in

University-Industry Research Relationships in Bio -

technology, ’’Harvard Journal on Legislation 24(win -

ter):191-238, 1987.

Kumin, L., Howard Hughes Medical Institute, Bethesda, MD, personal communication, December

1987.

Library of Congress, Copyright Registration Office,

Washington, DC, personal communication, May

1987.
175

U.S. Government Printing Office, April 1986).

18. U.S. Congress, Office of Technology Assessment,

Research Funding As an Investment: Can J1’e Measure the Returns? OTA-TNI-SET-36 (Washington,

DC: U.S. Government Printing Office, April 1986).

19. U.S. Congress, Office of Technology Assessment,

Commercial Biotechnology: An international AnalYsis, OTA-BA-218 (Springfield, VA: National Tech11. Lowrance, W., comments at Issues of Collaboration for Human Genome Projects, OTA workshop,

June 26, 1987.

12. Rhodes, R., The Making of the Atomic Bomb (New

York, NY: Basic Books, 1986).

13. Rycroft, R. W., “International Cooperation in Science Policy: The U.S. Role in Macroprojects, ” Technology in Societhv 5:51-68, 1983.

14. Tusso, B., Office of Economic Development, Paris, nical Information Service, January 1984).

France, January 1988. 20.

15. U.S. Congress, General Accounting Office, Patent

Policy: Recent Changes in Federal Law Considered

Beneficial, GAO/RCED-87-44 (Washington, DC: Gen- 21.

era] Accounting Office, April 1987).

16. U.S. Congress, Office of Technolo&v Assessment, 22.

New Developments in Biotechnology, 4.- U.S. Investment in Biotechnology (Washington, DC: U.S. Gov- 23.

ernment Printing Office, in press).

17. U.S. Congress, Office of Technology Assessment,

Intellectual Property Rights in an Age of Electronics

and information, OTA-CIT-302 (Washington, DC:

Van Horn, C., personal communication, U.S. Patent and Trademark Office, Washington, DC, February 1988.

wade, N., The Nobel Duel (Garden City, NY: Anchor/Doubleday, 1981).

Watson, J. D., The Double HeZix (New York, NY:

New American Library, 1969).

Yuan, R.T., International Trade Administration,

U.S. Department of Commerce, Biotechnology in

IVestern Europe (Washington, DC: U.S. Government Printing Office, 1987),
Appendixes
Appendix A

Topics of OTA Contract Reports

The following reports were prepared by outside contractors for the Office of Technology Assessment for

this assessment. They are available on microfiche or

as hard copy from the National Technical Information

Service (NTIS), 5285 Port Royal Road, Springfield, VA

22161; te]: (703) 487-4650.

● Mapping Our Genes Contractor Reports, Vol.

1, Order No. PB 88-160 783/AS

—Bibliometric Analysis of Work on Human Gene

Mapping, Samuel R. Reisher and Michael B. Albert,

CHI Research/Computer Horizons, Inc.

—Medical Implications of Extensive Physical and Sequence Characterization of the Human Genome,

Theodore Friedmann, Center for Molecular Genetics, School of Medicine, University of California, San Diego

—Mapping the Human Genome: Some Ethical Implications, Jonathan Glover, New College, Oxford

University

—Mapping and Sequencing the Human Genome:

Considerations From the History of Particle Accelerators, John L. Heilbron, University of California, Berkeley, and Daniel J. Kevles, California

Institute of Technology

—Mapping the Human Genome: Historical Background, Horace Freeland Judson, The Johns Hopkins University

—Long-Term Implications of Mapping and Sequencing the Human Genome: Ethical and Philosophical Implications, Mark A. Lappe, College of Medicine, University of Illinois at Chicago

● Mapping Our Genes Contractor Reports, Vol.

2, Order No, PB 88-162 805/AS

—The Mapping and Sequencing of Genomes: A Comparative Analysis of Methods, Benefits and Disbenefits, Stephen M. Mount, Department of Biological Sciences, Columbia University

—Mapping the Human Genome: Experimental Approaches for Cloning and Ordering DNA Fragments, Richard M. Myers, Department of Physiology, University of California, San Francisco

—Mapping and Sequencing the Human Genome in

Europe, Peter A. Newmark, Nature

—Application of Human Genome Mapping for the

Global Control of Genetic Disease, Sir David J.

Weatherall, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford University

—In Search of the “Ultimate Map “of the Human Ge -

nome: The Japanese Efforts, Akihiro Yoshikawa,

Berkeley Roundtable on the International Economy, University of California

OTA also sponsored two workshops during this

assessment, and the transcripts of those workshops

have been submitted to NTIS as:

Mapping Our Genes, Transcript of Workshop ‘(Issues of Collaboration for Human Ge

nome Projects,)) June 26, 1987, Order No. PB 88-

162 797/AS; and

Mapping Our Genes, Transcript— of Workshop “Costs of Human Genome Projects,

Aug. 7, 1987, Order No. PB 88-162 813/AS.

The following report was written for OTA but was

not sent to NTIS because it will be available to the public

through a law journal article:

● “Sharing of Research Results in a Federally Sponsored Gene Mapping Project, ” Susan Rosenfeld, Science and the Law Committee, Association of the Bar

of the City of New York, August 1987; to be published by the Rutgers Computer and Technology

Law Journal, vol. 14, No. 2, 1988.

179
Appendix B

Estimated Costs of Human

Genome Projects

Congress has primary responsibility for funding research through Federal agencies because of its responsibility for the national budget each year. Appropriating Federal funds for any special genome projects will

therefore fall to Congress. These appropriations will

express Congress’ judgment regarding the relative

value of genome projects. In setting appropriation

levels, Congress will weigh the costs of the programs

against their anticipated benefits (in economic and social terms) and will balance the value of proceeding

against the costs of not doing so, as measured in lost

benefits or opportunities.

Proposals for genome projects are intended to support research, but research needs are inherently unpredictable: Technological breakthroughs could dramatically diminish budget needs, and unanticipated

obstacles could just as dramatically increase them. Estimates of near-term projects using existing technologies

are necessarily more accurate than future projects that

presume technological developments. Costs for some

of the larger components, such as sequencing significant portions of human or nonhuman DNA, hinge on

unit costs that are highly uncertain now and are rapidly changing due to technical advances (e.g., the cost

of sequencing a single base pair of DNA). These uncertainties suggest that a 5-year budget plan is the best

that can be produced, and projected costs for even

the first 5 years might need to be substantially revised.

The costs of human genome projects can be separated

by components, although the boundaries between

some of them are imprecise. The costs projected in

this appendix are based on a process followed by OTA

to generate estimates from internationally recognized

experts.

OTA Cost Estimates

In order to better estimate potential costs of human

genome projects, OTA held a workshop on August 7,

1987. At that workshop, there was apparent consensus

on rough estimated costs of several components and

confusion or disagreement about many others. A follow-up letter was sent to workshop participants and

over 150 experts from executive agencies, universities, and corporations to confirm estimates made at

the workshop and to expand them. Replies were received from over 70 persons. The revised cost estimates

were externally reviewed by over 100 individuals and

institutions in a draft report circulated in November

1987, and some minor revisions are based on comments received during this review. The resulting cost

projections attempt to include most of the direct costs

of research. They do not include indirect costs of

university administration (although they do include

administration in Federal agencies).

In some cases, it may prove possible to attract funding from the private sector—foundations, medical research institutes, or corporations. If so, Federal spending could be correspondingly reduced. In many cases,

however, the Federal Government will eventually pay

the full costs. If a company developed mapping and

sequencing information or new instruments, for example, the first-and for a longtime the predominant—

users would remain researchers funded to do biomedical research by the Federal Government. This would

be the case for most technologies developed as part

of human genome projects (use by researchers being

the primary goal of the enterprise). A company’s investment would thus be charged back to the government by charging for use of information or purchase

of instruments by the research community. In some

cases there may be a market for products outside the

biomedical research community. If so, the private sector funds could indeed displace government funds.

Funding from research foundations, medical institutes,

and other philanthropies would also, as a rule, substitute directly for government costs.

There was strong consensus about the importance

and feasibility of improving the research infrastructure (databases and repositories) and generating

genetic and physical maps of human and nonhuman

chromosomes; there was substantial uncertainty about

sequencing strategies and their associated costs. It is

agreed that the need for new technologies is paramount, but there is disagreement about how much it

would cost to develop them or how such efforts should

be organized.

Discussion in the following sections reviews costs

by component.

Computers and Computational Methods

Cost estimates for the necessary persomel, research,

and equipment are $12 million per year for the early

years, increasing to 15 percent of the overall budget

as it exceeds $80 million annually. This would be in

180
181

addition to continued support of existing databases and

computer facilities. Spending should be relatively flat

over time, because hardware will have to be purchased

in early years and research will take an increasing

proportion of the budget in later years. Hardware will

have to be upgraded, however, so cost estimates are

necessarily uncertain for future years. While it is logical to link computational needs to human genome

projects, funding devoted to storage of genetic data

and sophisticated analysis of DNA will prove impon

tant in molecular biology even if maps are not completed and other human genome projects are not

funded.

Genetic Maps

Genetic mapping has been conducted for several

years, and a rough map of human chromosomes already exists. Discussion at the OTA cost workshop centered on a map with two to four times the resolution

of current maps. Subsequent letters and discussions

have centered on a further increase in resolution,

preferably such that a gene being studied would be

separated from its closest DNA markers (on average)

in only 1 of 100 family members. (Geneticists call this

a l-entimorgan map. ) Estimates based on existing procedures yield annual costs of $6 million per year for

5 years. Since this is an existing technology and there

are already facilities to do the mapping, a startup

period is not needed. Funds saved from new methods

could be devoted to automating the processes so further refinements of maps in humans and other organisms would be easier to construct in the future.

The two principal groups constructing human

genetic marker maps to date have not been federally

supported. One has used private corporate funds, and

the other has been funded by the Howard Hughes Medical Institute (HHMI). HHMI-sponsored work is a nearly

direct substitute for goverment funding. Future work

would be of greater magnitude, however, and may require Federal investment. In the case of work supported by Collaborative Research (the largest corporate

group) and other companies, the Federal Government

will probably pay for access to the probes either as

a lump sum (to obtain access for all federally funded

researchers) or indirectly (as federally funded researchers pay for access to individual DNA markers

or mapping services).

Physical Maps

.

physical maps would be quite useful for future research. Ordered clone sets linked to them would be

even more useful. Pilot projects on selected human

chromosomes and on many lower organisms are in

progress, and a useful set of ordered clones from all

the human chromosomes may be feasible in the next

5 to 10 years.

Projections based on existing technolo~ yield costs

of $60 million for a usefully complete set of ordered

cosrnid clones over 5 years, New technologies may permit the creation of ordered sets of much larger DNA

fragments (using yeast artificial chromosomes, YACS),

and these would be extremely useful also. Costs of constructing ordered libraries composed of both cosmid

and YAC clones are estimated at $7o million.

There are substantial uncertainties regarding both

types of clones. Physical mapping of human chromosomes using cosmid clones has only begun in the last

year, and therefore the rate and completeness of such

mapping are highly uncertain. Mapping with yeast artificial chromosomes is much newer, although promising. The main uncertainty regarding YACS is not cost,

but feasibility: If such mapping is possible, it would

be substantially less expensive than mapping using cosmids (although cosmid maps might be needed for many

research applications).

Ordered clone libraries are difficult to complete.

Progress is rapid at first, but it is unlikely that a chromosomal region can be spanned without gaps between

groups of continuous clones. Maps complete enough

to be useful can be expected from several years’ effort, but if truly complete maps are necessary, then

efforts must be continued, perhaps at funding levels

equal to those for initial construction. Half or more

of the total effort maybe required for the last 10 percent of the maps. Clone libraries with gaps are quite

useful, however, because a chromosomal region of interest is likely to be represented even in incomplete

libraries.

Cost estimates start at $10 million for the first year

(building on current Federal expenditures), rise to $2o

million in $5 million increments over 2 years, and then

drop to $10 million (with the proviso that continued

higher funding may be necessary if complete maps are

deemed essential).

Projects To Link Genetic and

Physical Maps

Identifying the parts of DNA that carry the instructions for making protein and integrating them into

genetic and physical maps would be very useful. Which

stretches of DNA are actually used to produce protein

varies with the tissue (many genes are expressed differently in different tissues or stages of development).

The likely process would be to make DNA copies

(cDNA) of the RNA that is translated into protein from

a variety of tissues (’both healthy and diseased) and at
182

various stages of development. Locating cDNAs on

physical and genetic maps would result in cDNA maps.

Such maps could be used to pick out protein-coding

regions along stretches of DNA of unknown function.

This would make the physical map much more useful, by highlighting regions of particular interest, and

would provide a missing step in the search for genes

whose approximate location had been determined by

genetic linkage maps. DNA sequencing might also begin by using cDNAs to select regions likely to be of

interest (because they are known to produce protein).

Maps of cDNA would give clues to a gene’s function

if the pattern of expression related to a known biological process. Comparison of cDNAs from human and

other organisms can give clues to function by relating

expression to degree of evolutionary relatedness. If

a genetic disease is located in a certain chromosomal

region and cDNA maps show that one DNA segment

from that region is transcribed only in the tissue affected by the genetic disease, then the gene corresponding to the cDNA is a good candidate for the

gene causing the disease. Maps of cDNAs have been

suggested by several groups [2,3,11,12,13,15].

The first step in constructing cDNA maps would be

to collect and organize existing sets of cDNA clones.

New sets of cDNA clones could be made from missing

tissues, disease states, developmental stages, or organisms. The various cDNAs could then be located on

genetic linkage maps and physical maps. The cost of

this process is highly uncertain, in part because the

number of genes in human and many other organisms

is not known. Those specifically asked about this component estimated that its costs would likely range from

$2 million to $5 million per year, depending on how

much work could be done by merely cataloging existing cDNA clone sets; how many new sets would have

to be constructed; how many organisms, tissues, developmental stages, and disease states would be used

as sources; and the extent of genetic and physical maps.

The costs of cDNA mapping would increase with the

increasing detail of genetic and physical maps. OTA

estimates start from a base of $2 million, increasing

annually by $1 million increments.

Resource Material Repositories

Estimated costs of storing the clone sets linked to

physical maps, cell lines for genetic research, and the

various DNA analytical materials for genetic mapping

originally ran to over $250 million. The largest component, dwarfing all others, was the cost of storing

the DNA clones linked to physical maps. Such storage

costs are virtually prohibitive, and these estimates were

dropped, Subsequent discussions with experts on storage of materials for molecular biology, specifically with

persons at the American Type Culture Collection,

yielded storage estimates an order of magnitude lower.

The estimates summarized in table B-1 are for collection and storage of clone sets. Costs of dissemination

would be borne by users through user fees. Costs of

collecting and storing mutant cell lines and DNA analytical materials (such as probes) have not been included.

.

Sequencing

There is little consensus on how much DNA sequencing should be done as part of genome projects, particularly whether a complete human reference sequence should be an objective. There is consensus,

however, that sequencing technology is crucial and

ripe for innovation. Cost projections should become

easier in 2 to 3 years, as the first automated DNA sequencing machines are improved; massive sequencing would not begin in most schemes for several years,

Total. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47 68 131 186 228
183

except as part of pilot projects and for DNA regions

known to be of special interest [6]. The debate about

sequencing involves disagreement about the costs of

sequencing per base pair, the amount of redundancy

necessary to make a sequence useful, the expected

pace of technological improvements, which laboratory

preparation steps are included, and how much DNA

would be sequenced as part of human genome projects

(rather than through traditional funding mechanisms).

Estimates of the cost of sequencing vary widely, ranging from several pennies to several dollars per DNA

base [6,16], but there is some agreement that costs

would drop to $0.20 to $0.30 per base pair by the end

of 1988, based on existing technologies. Some of the

discrepancy in the estimates comes from including

different components. The costs of special cloning procedures, preparing DNA, use of reagents, technician

time, and capital costs of instrumentation should all

be included in cost estimates.

Judgments about which technologies to use and how

much sequencing should be performed are best made

each year by an advisory committee with access to

technical experts. Such judgments would presumably

be based on costs, the availability of material to sequence, and consensus on which regions to sequence

first. For OTA projections, a few assumptions have

been made. For the first 2 years’ budget, sequencing

would be covered as technology development—performed on lower organisms or human chromosomal

regions of known interest —for possible sequencing on

a larger scale. For years 3 to 5, it would be based on

sequencing one small chromosome per year at $0.20

per base pair ($30 million per year, based on threefold

redundancy and 50 megabases per year), permitting

a phase-in period for implementation of the technologies. This estimate is for purposes of budgeting only,

however, and could prove wildly high or low. If the

technologies for cloning, preparing DNA for sequencing, and finally determining a DNA sequence become

significantly cheaper, as some experts predicted at the

OTA workshop, the amount of DNA sequenced at that

cost could be increased. If costs remain high, only a

limited amount of DNA could be sequenced, according to priorities set by the oversight board. After the

fifth year, the budget could go up or down in proportion to need.

Quality Control and Reference

Standards

The large amounts of map and sequence information and new materials created by human genome

projects will be useful only if the information is accurate and resource materials are cataloged reliably.

If there are many different groups involved in the efforts, problems of quality control could impede useful applications. The scope and magnitude of this problem will become clear only when the technologies are

defined and the results of mapping and sequencing

efforts begin to accumulate. Special budget allocations

for comparing results from different groups or to

establish measurement standards may become necessary. Budget needs for quality control will be nil in the

first year and will grow in early years until they constitute 5 percent of the overall budget. For initial estimates, it is projected to grow by $1 million per year

from a base of zero.

Technology Development

Investments in methods and instruments associated

with genome projects are likely to lead quickly to commercial applications. The objective for technology development is open-ended, however, and it could be

either the largest component or a relatively small fraction of genome projects. Responses to OTA letters and

drafts showed no consensus on the proper budget.

Many scientists familiar with industrial development

encouraged higher figures, while academic molecular biologists set lower ones. A maximum figure of $500

million to be spent over 5 years was mentioned at the

OTA workshop, in line with recommendations of a

committee established by the Department of Enery

(DOE). There was some support for the alternative of

devoting 25 percent of the total budget to technology

development [6]. Minimum estimates were for a steady

state of $20 million to $30 million. Several individuals

noted the importance of developing technologies early

on, while recognizing the need to keep early budgets

realistically low because a new research program

would require the accumulation of trained personnel

and pilot work to provide a foundation for later work.

The approach used in OTA estimates is to increase

funding from $10 million the first year to a stable figure of $100 million by yearly increments. Funding for

biological instrumentation centers under the National

Science Foundation might account for part of this, and

methods or instruments of great interest to industry

might lead to some cost sharing with private firms.

If so, Federal funding could be reduced accordingly.

Technology development funding, like sequencing, is

among the most flexible of the proposed projects and

could be adjusted by the oversight board and the congressional appropriations process,

Training of Personnel

Training of investigators and scientific exchange

among participants are crucial and would include grad-
184

uate and postgraduate fellowships, scientific workshops, and national scientific meetings. Some persons

urge that fellowship funds be targeted to shortage

areas, but others believe that targeted programs are

less effective than untargeted ones for the best people in any relevant discipline. If training were targeted,

it might include development of dual expertise in computers and molecular biology, organic chemistry and

molecular biology, engineering and molecular biology,

and clinical medicine and informatics or molecular biology. Training would also be needed for technicians,

and for sabbaticals for scientists interested in shifting

from their fields to genome projects. Workshops

among participating groups and national symposiums

to communicate results would permit rapid dissemination of new methods and insights. Exchange programs among industrial, national laboratory, and academic scientists would promote technology transfer.

Training and personnel costs are estimated to merit

10 percent of each annual budget. For initial projections, funding might start at $4 million and increase

yearly by $2 million.

Administrative Costs

Participants in the August 1987 OTA workshop estimated that 1 to 3 percent of each year’s budget would

be needed for administrative overhead. That estimate

was subsequently increased to 5 percent in response

to letters and after analyzing administrative costs at

Federal research agencies. Administrative costs include

operation of a national advisory board; oversight of

databases, repositories, networks, and other services;

setting instrumentation standards for cloning, mapping, and sequencing technologies; administration of

grants and contracts; and other purposes. Some additional features would be unique to genome projects,

for example, analysis of likely social impacts and ethical dilemmas created or intensified by genome projects.

The need for such analysis has been explicitly noted

in hearings and has been highlighted by research

agency administrators and congressional staff. It could

be obtained through grants to bioethicists, lawyers,

economists, and social scientists for publications or

workshops on various topics.

Summary

The costs of the components of human genome projects are projected in table B-1. These would start from

a base of $47 million in fiscal year 1989 (if 1989 were

the first year) and increase to $228 million in fiscal

year 1993. It is not useful to project budgets beyond

then, because technological development is so uncertain. The projected figures do not attempt to assign

functions to particular agencies, merely to state overall direct research costs. Future budgets will need to

be revised in light of actual appropriations.

History of Earlier Estimates

Perhaps the earliest evidence of a human genome

project is found in a letter from Robert L. Sinsheimer,

then Chancellor of the University of California, Santa

Cruz (UCSC), to University of California President

David Pierpont Gardner, on November 19, 1984. A potential benefactor had withdrawn support from a

project, and Sinsheimer took the opportunity to provide a counterproposal that might interest the benefactor. In doing so, Sinsheimer suggested that a human

genome institute be founded at UCSC, with startup

costs of $25 million and an annual operating budget

of $5 million. This was, in effect, the first cost estimate for a human genome project.

The letter from Sinsheimer to Gardner referred to

an enclosure, later to be used as a basis for discussion

at the May 1985 Santa Cruz Human Genome Workshop, in which the institute was formally proposed [71.

The proposal assumes existing mapping technologies

and a continued rate of development of DNA sequencing speed equal to the exponential increase of the past

decade. The proposal then concludes that “within a

few years, the human genome could be reduced to

an ordered set of cloned fragments” and that “50 tech”

nicians could approach completion of the [sequencing]

project in 10-20 years.” The proposal estimates the

yearly support of each technician at $100,000, yielding an annual budget of $5 million and a total project

cost of about $100 million. The proposal also calls for

$25 million for startup facilities, and it distributes the

operating money among the mapping and sequencing

project itself (75 percent), developing techniques (10

percent), application to basic biology and medicine (10

percent), and education and training of students and

other personnel (5 percent).

The Santa Cruz workshop displays similar optimism

about the mapping aspect of a genome project, suggesting that a physical map could be completed by a

20-person group in 3 to 5 years [14]. The workshop

also included discussion of a restriction fragment

length polymorphism (RFLP), or genetic, map. This map

could be achieved in “a few years” at a resolution finer

than 50 centimorgans. Based on then current technologies, sequencing the 3 billion base pairs of the human genome was taken as “not feasible.” The workshop went beyond the initial proposal and discussed

details about the computer requirements for a project.

There was, however, no explicit cost estimate for these

details,
185

The next round of cost estimates came out of DOE’s

workshop in Sante Fe in March 1986. Appended to the

workshop notes and the correspondence the workshop

generated between the participants and DOE’s Mark

Bitensky was a cost estimate by Christian Burks of the

Los Alamos National Laboratory. Burks calculates the

person-years required for various aspects of the

project, which, for a physical mapping and sequencing endeavor, including computer and administrative

costs and assuming some sequencing advances, totals

3,505 person-years [5]. Allowing for hardware and

overruns of his estimate, Burks concludes a genome

project would cost between $0.5 and $2.5 billion.

The next major meeting, at Cold Spring Harbor, focused primarily on sequencing. The only estimate to

issue from the discussion was the oft-quoted 30,000

person-years required to sequence the human genome

one time through [8]. This estimate—translated into

$3 billion by either $1 per base pair or $100,000 per

person-year–was based solely on existing technology

and was therefore obsolete within days of the conference, when the automated sequencer at the California Institute of Technology was announced [18].

By the middle of 1986, the Caltech sequenator had

made it clear that advances in sequencing technology

would drive costs down. HHMI’s Informational Forum

at the National Institutes of Health in Washington, D. C.,

continued to quote the 30,000 person-year estimate,

but it also cautiously offered an estimate of 300 personyears, assuming a two-order-of-magnitude increase

from automation [17]. The HHMI forum likewise gave

a dual estimate for the physical map (200 person-years,

or 30 to 40 with automation advances) [4], and for computer storage of sequence information ($0.30 per base

pair, $0.03 with advances) [11.

Nine months later, DOE brought out its own cost estimates, presented as a yearly budget for a genome

project. In the Health and Environmental Research

Advisory Committee report, the subcommittee scientists estimate that sequencing, with redundancy for

accuracy, would cost $60 million, assuming advances

in automation [19]. Sufficient automation should be

available 5 years hence [10]. The remainder of the budget is not described in detail, but it does specify that

$500 million will go to various aspects of technological development, including mapping and informatics,

assuming $100,000 per person-year of research [9]. The

total for the DOE-proposed projects comes to $1.02

billion. Table B-2 presents a summary of estimates.

The National Research Council of the National Academy of Sciences established the Committee on Mapping and Sequencing the Human Genome, whose report was released in February 1988 [13]. That report

represents the views of an exceptionally distinguished

panel of experts from diverse scientific backgrounds,

The panel members began their deliberations with

widely differing knowledge of the state of gene mapping and divergent opinions about the merit of special

research efforts. While writing the report, the panel

reached a consensus that a special effort was merited

and recommended additional funding of $200 million

per year. This level would be reached over the initial

3 years. During the first few years, the budget would

be roughly divided into $120 million for research in

10 or so multidisciplinary centers and numerous small

research groups. Construction and materials would

cost $55 million per year, and $25 million would Operate repositories, databases, training, and administrative functions. In later years, the budget would increase

for dedicated production of map and sequence data.

This $200 million annual budget would continue until

at least the year 2000.

Appendix B Refemmces

1. Be]], George 1., comments at Informational Forum on the

Human Genome, sponsored by Howard Hughes Medical

Institute, July 23, 1986, at the National Institutes of Health,

Bethesda, MD.

2. Berg, Paul, comments at Costs of Human Genome Projects,

OTA workshop, Aug. 7, 1987.

3. Berg, P., Stanford University Medical Center, personal

communication, January 1987.

4. Brenner, Sydney, comments at Informational Forum on

the Human Genome, sponsored by Howard Hughes Medical Institute, July 23, 1986, at the National Institutes of

Health, Bethesda, MD.

5. Burks, Christian, “The Cost of Sequencing the Complete

Human Genome,” Santa Fe Genome Sequencing Workshop, Mar. 3-4, 1986.

6. Costs of Human Genome Projects, OTA workshop, Aug.

7, 1987.

7. Edgar, Bob, Noller, Harry, and Ludwig, Bob, “Human Genome Institute: A Position Paper, ” enclosure in personal

correspondence from Robert L. Sinsheimer, University

of California at Santa Cruz, to David Pierpont Gardner

(Nov. 19, 1984) distributed at the Santa Cruz Human Genome Workshop, May 24-25, 1985.

8. Gilbert, Waker, comments at Molecular Biology of Homo

sapiens, Cold Spring Harbor Laboratories symposium,

May 28-June 4, 1986.

9. Hood, L., California Institute of Technology, personal

communication, June 1987.

10. Hood, L. California Institute of Technology, personal communication to David Guston, June 1987.

11. Karnei, R., and Stocker, J.T., Armed Forces Institute of

Pathology, personal communication, December 1987.

12. McKusick, V. A., and Ruddle, F.H., “Toward a Complete

Map of the Human Genome,” Genornjcs 1:103-106, 1987.

13. National Research Council, National Academy of Sciences,

Report of the Committee on Mapping and Sequencing

the Human Genome (Washington, DC: National Academy

Press, 1988).
186

14. Notes and Conclusions, Santa Cruz Human Genome

Workshop, sponsored by Department of Energy and Los

Alamos National Laboratory, June 4, 1985.

15. Philipson, L., and Tooze, J., “The Human Genome Project,”

BioFutur, June 1987, pp. 94-101.

16. Roberts, L., “New Sequencers to Take on the Genome, ”

Science 238:271-273, 1987.

17. Smith, David, remarks at Informational Forum on the

Human Genome, sponsored by Howard Hughes Medical

Institute, July 23, 1986, at the National Institutes of Health,

Bethesda, MD.

18. Smith, Lloyd M., Sanders, Jane Z., Kaiser, Robert J., et

al., “Floumscence Detection in Automated DNA Sequence

Analysis,” Nature, 321:674-678, 1986.

19. Subcommittee on the Human Genome, Health and Environmental Research Advisory Committee, Report on the

Human Genome Initiative, prepared for the Office of

Health and Environmental Research, Office of Energy

Research, Department of Energy (Germantown, MD:

DOE, April 1987).

Table B-2.–Comparison of Genome Cost Estimates (millions of dollars (M) or person-years (py))

UCSCa position paper

1 1/19/64 . . . . . . . . . .

UCSC workshop

5124-5185 . . . . . . . . .

Sante Fe workshop

3186 . . . . . . . . . . . . .

Cold Spring Harbor

Symposium

5/28-6/2/66 . . . . . . . .

HHM1/NIH

150 py administration $50&2,500

OTAd

$500 M technology $1,020 M

$ 60 Mlyr 10 centersa

$3,000 M

$60 M&r grants and (over 15 yrs.)

technology

development for

small groups

$55 M/yrc facility

construction (early

years, decreasing

later)

$25 Mlyr

administration,

quality control,

advisory committee

functions

$200 M/yr
Appendix C

Participants in OTA workshops

ISSUES OF COLLABORATION FOR HUMAN GENOME PROJECTS

Workshop Sponsored by the

Office of Technology Assessment

and the

Howard Hughes Medical Institute

June 26, 1987

2322 Rayburn House Office Building

United States Congress

Washington, DC

Chairman

William W. Lowrance, Ph.D.

Director

Life Sciences and Public Policy Program

The Rockefeller University

Bernadette Alford, Ph.D. Susan Rosenfeld, Esq.

Legal and Regulatory Affairs Science and the Law Committee

Collaborative Research Association of the Bar of the

George F. Cahill, M.D. City of New York

Vice President for Scientific Training Frank Ruddle, M.D.

and Development Department of Biology

Howard Hughes Medical Institute Yale University

C. Thomas Caskey, M.D. Robert Smith, Ph.D.

Director History of Science Department

Institute for Molecular Genetics The Johns Hopkins University

Baylor College of Medicine Robert E. Stevenson, Ph.D.

James F. Childress, Ph.D. Director

Department of Religious Studies American Type Culture Collection

University of Virginia

Susan Cozzens, Ph.D.

Department of Social Sciences

Illinois Institute of Technology

George Gould, Esq.

Associate Patent Counsel

Hoffman LaRoche

Geoffrey M. Karny, Esq.

Dickstein, Shapiro & Morin

Charles E. Van Horn

Director

Organic Chemistry and Biotechnology

U.S. Department of Commerce, Group 120

Patent and Trademark Office

LeRoy Walters, Ph.D.

Director

Center for Bioethics

Kennedy Institute of Ethics

Georgetown University

187
188

COSTS OF HUMAN GENOME PROJECTS

Workshop Sponsored by the

Office of Technology Assessment

August 7, 1987

Office of Technology Assessment Conference Center

Washington, DC

Chairman

Paul Berg, M.D.

Willson Professor

Department of Biochemistry

Stanford University Medical Center

Christian Burks, Ph.D. Keith McKenney, Ph.D.

Los Alamos National Laboratory Center for Chemical Physics

George F. Cahill, M.D. National Bureau of Standards

Vice President for Scientific Training and Mark L. Pearson, Ph.D.

Development Director of Molecular Biology

Howard Hughes Medical Institute E.I. du Pent de Nemours & Co.

Anthony V. Carrano, Ph.D. Robert E. Stevenson, Ph.D.

Biomedical Sciences Division Director

Lawrence Livermore National Laboratory American Type Culture Collection

Helen Donis-Keller, Ph.D. John Sulston, D. Phil.

Collaborative Research, Inc. MRC Laboratory of Molecular Biology

Walter Gilbert, Ph.D. Cambridge, England

Biological Laboratories James D. Watson, Ph.D.

Harvard University Director

Leroy Hood, M.D.

Chairman

Division of Biology

California Institute

Cold Spring Harbor Laboratory

of Technology
Atmendix I)

Databases, Repositories, and

Informatics

Among the most useful products of genome projects

will be information and materials—information about

genes and their locations and sequences, and biological materials such as DNA fragments from chromosomes of known pedigree, ordered cosmids, and

clones. Proper management of data and materials is

essential to increase the efficiency and productivity

of research and to reduce duplication of efforts so that

genome projects can succeed in meeting the needs of

medical scientists and molecular biologists in this century and the next.

Existing databases and repositories that gather, maintain, analyze, and distribute data and materials are

already struggling to keep up with the exponential

growth of molecular biology. Present capabilities will

have to expand greatly to handle the increase of information resulting from a targeted set of genome projects. while it is logical to link computational needs

to genome projects, however, funding devoted to

storage of genetic data and materials and to sophisticated analysis of DNA will prove important in

molecular biology even if a major mapping and se

quencing initiative is not undertaken. Because the

essential databases, repositories, and linking computer

networks provide goods and services for the entire

research community, the Federal Government has a

long-standing tradition of supporting them and is in

a unique position to further enhance the resources.

This appendix describes some existing databases and

repositories and outlines present and future database

needs relevant for human genome projects specifically

and molecular biology in general.

Databases

Various databases exist that serve the needs of researchers in genome mapping and sequencing (see table D-l). One set of databases gathers, stores, and distributes information directly related to genetic maps

and physical maps. Some databases specialize in map

and sequence information from one specific genome—

for example, there are databases exclusively devoted

to the mouse, E. coli bacteria, drosophila, and nematode genomes—while others carry particular kinds of

information from all the relevant genomes. Other databases gather data on the sequences and structures of

proteins and amino acids that are not direct results

of mapping and sequencing research but are necessary for addressing basic research problems underpinning genome research. The data from the differ

ent types of maps and from different species have

important interconnections, so it is essential that

the information be linked for comparative studies.

Genetic Maps

Genetic maps can be generated in several ways (see

ch. 2). Pedigree analysis of linked traits yields a map

in which traits can be ordered sequentially and with

a rough estimate of the distance between them. RFLPs

and other DNA probes can help link the traits with

specific genes or regions of DNA to produce more refined maps. Maps of the functional regions within individual genes aid in the search for underlying causes

of genetic diseases and for the mechanisms by which

genes control development and function. several

different databases serve the different information

needs for specific kinds of maps.

On-Line Mendelian Inheritance in Man (OMIM).–

An atlas of human traits that are known to be inherited-expressed genes—has been compiled into a reference work known as Mendelian Inheritance in Man,

which has been published in seven editions. The listing has been edited by Victor McKusick of The Johns

Hopkins University since 1966. As of March 1, 1988,

4,336 traits had been identified as genetically based,

including over 2,000 diseases.

Since 1986, the Howard Hughes Medical Institute

(HHMI) has supported computerization of the list, and

it is now accessible for on-line searches free of charge

(4). It is cross-referenced in the Human Gene Mapping

Library so that information on expressed genes can

be linked to map data.

Human Gene Mapping Library (HGML).–A1so called

the New Haven Database, HGML consists of five linked

databases-one each for map information, relevant

literature, RFLP maps, DNA probes, and contacts (researchers with information on data or materials). In

addition, the map database is linked to OMIM. All of

the databases are cross-referenced, so that data about

a gene or probe of interest can be drawn from all five

during the same search (10).

DNA Nucleotide Sequences

Databases containing raw DNA sequences, information about the origin of the DNA segment sequenced

189
— .

190

Table D-- I.—Some Existing U.S. Databases and Repositories

Location Funding source Annual budgeta

Nucleotide sequence data:

GenBank @ Los Alamos National Laboratory,

Intelligenetics Corp., CA

Genetic map data:

On-Line Mendelian Johns Hopkins University

Inheritance in Man (OMIM) Baltimore, MD

Human Gene Mapping Library New Haven, CT

(HGML)

Protein and amino acid sequence and structure data:

Protein Identification National Biomedical Research

Resource (PIR) Foundation

Washington, DC

Protein Data Bank (PDB) Brookhaven National Laboratory

Upton, NY

Repositories:

American Type Culture Rockville, MD

Collection (ATCC)/Human

DNA Probe and

Chromosome Library

Human Genetic Mutant Cell Coriell Institute for Medical Research

ReDositorv Camden, NJ

NIH, b DOE, NSF, USDA $3,500,000

Johns Hopkins University, $ 550,000’

HHMI, NLM

HHMI $ 500,000

NIHd

$ 500,000

NSF, NIH,e DOE $ 260,000

NIHf

$ 300,000’

NIHg $ 750,000

aBudget figures are approximate. Several of the databases have multiyear contracts; amount listed Is the average YearlY allOtment.

%IH sponsors of GenBankQ, pact and present, include the National Institute of General Medical Sciences (N IGMS), the Division of Research Resources (DRR), the

National Institute for Allergy and Infectious Diseases, the National Cancer Institute, the National Library of Medicine, the National Eye Institute, and the National

Institute of Diabetes and Dlseaaes of the Kidney. The NIGMS administers the contract and coordinates the funding.

‘The Johns H@ins university contribution to OMIM is difficult to meagure, because it includes many indirect factors (Staff sIJppOrf, SpaCe, publication COStS, etC.).

HHMI contributes S318,000 and the NLM $100,000 annually.

dThe NIH sponsor iS DRR.

eNIH sponsors are NIGMS and DRR.

fNIH sponsors are the National Institute of Child Health and Human Development (NICHD) and DRR; DOE has contributed some funds through DRR.

gThe NIH sponsor is NIGMS.

SOURCE: Office of Technology Assessment, 1988.

(which gene, which organism), and various annotations

that summarize information about important features

in the sequence (sites cut by DNA-cutting enzymes, regulatory sequences, protein-coding regions) will be

directly affected by genome projects that emphasize

sequencing. The major databases for nucleotide sequences are GenBank@ and its European counterpart,

EMBL (8). Each carries sequence data and related information for the human genome as well as bacterial,

yeast, fruit fly, mouse, and other genomes. Since 1982,

GenBank@ and EMBL have split the task of data collection, with each database monitoring specific journals

in molecular biology to locate and enter sequence data,

and they cooperate closely in sharing and distributing

it. They have recently been joined by the DNA Data

Bank of Japan (DDBJ), which is in charge of monitoring Asian journals and contributing to the reciprocal

exchanges. (DDBJ served primarily as an access node

to GenBank” and EMBL starting in 1984, but did not

start gathering its own data until 1987.)

GenBank”.-GenBanko originated at the DOE’s Los

Alamos National Laboratory in 1979 and started to receive funding from the NIH in 1982. It is the major

U.S. database for nucleic acid sequence information

from humans and other organisms (3). GenBank” is

presently administered and receives a major portion

of its funds from the National Institute of General Medical Sciences (NIGMS) of NIH. Data are entered and updated by curators at Los Alamos and are distributed

by Intelligenetics Corp. (Mountain View, CA).

The amount of data contained in GenBank” has

grown exponentially since its inception. In addition,

the number of users has increased from a small set

of one hundred or so who accessed it when the first

NIH contract started to tens of thousands of scientists

who now access either directly or through commercial distributors. GenBank”’s new 5-year contract,

which took effect in October 1987, significantly increases funding to meet the growing demand.

Protein and Amino Acid

Sequences and Structures

Databases that gather information on protein and

amino acid structure and function are crucial for the

application of genomics research to clinical and pharmaceutical problems, as well as for advancing the understanding of basic problems in biology-how genes
191

function, how they code for proteins and enzymes,

and how their protein products are structured and

function (see ch. 2). The effects of map and sequence

data on these databases will depend on the strategy

followed for genome projects. For example, a concerted nucleotide sequencing effort would affect research on protein and amino acid structure more

slowly than increased funding to researchers studying specific genes and their gene products—generally

proteins (6).

Protein Identification Resource (PIR).-PIR is “a resource designed to aid the research community in the

identification and interpretation of protein sequence

information” (14). It contains sequence data for proteins and amino acids, with annotations that indicate

known functional regions. PIR is run by the nonprofit

National Biomedical Research Foundation and receives

most of its funding from NIH’s Division of Research

Resources. Modest user fees cover the distribution

costs; academic users pay a flat fee, while commercial

users are charged by the amount of computer time

they use. PIR has recently started cooperating with

the Japan International Protein Database (JIPID) and

the new European database, Martinsreid Institute for

Protein Sequence Data (MIPS), to establish an international data network for protein sequences.

Protein Data Bank (PDB).–The Protein Data Bank

was founded in 1971 as “an international computerized archive for structural data on biological macromolecules” (1), [t gathers information on the atomic

coordinates of the structure of nucleic acids, messenger RNA, amino acids, proteins, and carbohydrates

that have been derived from crystallographic studies.

Structural information is a vital link in the understanding of how proteins function, which eventually leads

to knowledge of the mechanisms of genetic disease and

suggests possible directions for rational drug design.

PDB is based at DOE’s Brookhaven National Laboratory and supported primarily by NSF, with additional

funds from the National Institute of General Medical

Sciences of NIH. Modest user fees help cover the costs

of distribution. Use of the database has been growing

rapidly and is predicted to continue growing in parallel with human genome projects. Linking PDB with

databases that contain genetic map and sequence information will enhance the long-term goals of human

genome research (12).

Present and Future Needs

The many types of information that are produced

in molecular biology necessitate the maintenance of

a ~’arietuv of specialized databases. At the same time,

however, the information in different databases must

often be combined in order to understand the full

dimensions of an-y specific research problem. It is crucial for the scientific community to be able to access information on a topic of interest from a variety of databases that may handle different aspects

of the problem. Thus databases must use standardized or easily translatable formats and they must be

interconnected. The problem of format has been recognized and is being addressed in scientific meetings,

by database advisers, and by funding agencies. Several programs are underway to improve the linkages

between databases. An experimental project at the National Library of Medicine, discussed below, will develop a system to link a variety of databases relevant

to molecular biology.

The speed with which data are entered into the databases has been a major concern. The exponential increase in data has not always been matched by increases in the support for databases and personnel to

operate them, causing a lag time of several months

or even years between the publication of data and their

entry, in fully annotated form, into databases. If the

lag time is excessive, the efficiencies of centralized data

management and retrieval are lost. One solution that

is being explored is the direct submission of data to

the databases by the researchers as a requirement for

publication in journals. At least one journal has already

agreed to cooperate with GenBank@ and EMBL in an

attempt to speed acquisitions in this way (19). Another

possibility is to encourage funding agencies to make

the submission of data or materials to the appropriate

databases a condition of receiving research grants. The

automation of data entry will be necessary as the

amount of data increases. Automated methods are already under development; the capacity to enter data

may be built into some automated sequencing machines.

The timely exchange of data is also affected by issues of intellectual property rights and technology

transfer. Open and rapid exchange of information and

materials speeds research and is particularly important when the data have medical or clinical implications. If the data and materials become commercially

valuable, however—and many researchers predict that

they will—the values of open access and free exchange

could clash with the desire to protect proprietary rights

on potentially patentable data or materials. Because

access to databases and repositories is international,

there are concerns that U.S.-funded research could

be commercialized by other countries. The problems

are not intractable, however: There are set’eral successful precedents of advance contracts that specifv

how data will be contributed to databases while protecting property rights (4,21). (See also ch. 8.)

A major problem faced by databases for the past decade has been insufficient funding for handling the exponential increase of data. Costs will continue to rise
——. .— —

792

as more map and sequence data are generated. The

government agencies and other organizations that support genome projects appear to recognize the importance of continued funding for relevant databases. For

example, the increased budget in the new GenBank@

contract (for 1987 through 1991) indicates that funding agencies are aware of the need to enhance database maintenance. An initiative within the National Library of Medicine to strengthen information resources

for molecular biology and biotechnology (discussed below) should lend further support to databases needed

for genome projects. The Howard Hughes Medical Institute has been particularly active in supporting database resources and networks to link them. It is essential that financial support continue to keep pace with

the growing body of data.

Repositories

Genome projects will generate biological materials

as well as sequence and map data. Access to these materials is a key element in making the map information useful. A scientist searching for a gene of unknown

location would want to have access to a panel of DNA

markers that could give an approximate location, then

a more closely spaced set of markers to locate it more

precisely. Once the gene’s location was established on

the genetic map, the investigator would select DNA

clones covering that region of the human chromosomes

from a repository, thus obtaining the DNA encoding

the gene. Each of these steps would require access to

a set of cloned DNA fragments. Existing repositories

are hardly sufficient, but how much must be invested

in them will depend on conclusions on the value of

centralized sources rather than housing materials in

individual labs.

Companies developing a new product derived from

or related to a human gene would also wish to have

access to such materials in many instances. Storage

and handling of such DNA resources is thus a crucial

function. The materials will be most widely useful if

they are stored at national collection and storage facilities. DNA probes, vectors, and some other materials are best maintained at a facility such as the American Type Culture Collection (ATCC). Others, such as

cell lines derived from individuals and families with

genetic diseases, are stored in the Human Genetic Mutant Cell Repository in Camden, New Jersey. Other materials that are unlikely to have substantial demand

from a wide variety of investigators might be stored

at the laboratories that generated them and distributed on a more informal basis to those requesting them.

Present methods and technologies for the amplification, characterization, storage, and distribution of materials are expensive and time-consuming; the costs

of storage could become a major component of mapping and sequencing projects. Newer and cheaper storage methods will have to be developed as production

of DNA fragments increases. The development of automated techniques for organizing, managing, and accessing materials will be necessary; research on automated repository management is already underway

at ATCC and at DOE’s Los Alamos National Laboratory (11, 21).

Even with the advent of automated repository management techniques, however, the high cost of storing and maintaining materials makes the selection of

materials to collect particularly crucial. While it might

be desirable to keep large collections of clones generated in an attempt to develop libraries of overlapping

clones or contigs (see ch. 2), the curators of repositories and the scientists who use them will have to

choose which materials are of utmost importance, and

these decisions should be periodically reviewed (22,23).

American Type Culture Collection

The ATCC maintains a variety of different collections

of animal, plant, and bacterial cell lines, hybridomas,

phage, and recombinant DNA vectors, as well as an

NIH-sponsored repository of human DNA probes and

chromosome libraries (20). The collection of chromosome libraries includes materials from DOE’s National

Gene Mapping Library (see ch. 5). The ATCC amplifies and stores samples and distributes them, along

with pertinent information, to investigators for a nominal fee. Investigators must agree not to use the materials for commercial purposes nor to sell them,

The repository maintains a database of information

on the source and characteristics of the material in

its collection. Its advisory committee has recommended

that the database be included in a mapping database

such as HGML.

Human Genetic Mutant Cell Repository

Sponsored by the National Institute of Genera] Medical Sciences of NIH, the Human Genetic Mutant Cell

Repository was founded in 1972 to maintain a collection of well-characterized human cell cultures (2,17).

The cultures are available to investigators worldwide

at a nominal fee. The repository contains over 4,OOO

individual cultures, which represent more than 400

genetic diseases and 700 to 800 chromosomal aberrations (7). The curators of the collection have increasingly sought to include material from multigenerational

family groups for linkage analysis; the repository now

maintains cell lines from the Venezuelan Huntington’s

pedigree (see box 7-A) and others such as cystic fibrosis families, families with fragile X-linked mental

retardation, and so on.
793

Data Analysis, In formatics, and

Computer Resources

Development of analysis methods to search for and

compare sequence information, to predict sequences

that code for proteins and the structures of those proteins, and to aid in other aspects of the analysis of data

from genome projects will eventually need to utilize

parallel processing techniques and the capacity of supercomputers. Most researchers agree that the hardware to tackle the complex problems of sequence analysis and comparison already exists but that satisfactory

software must be developed. The DOE, the NIH, the

NLM, and the NSF support various programs and

grants for the development of software to represent

and analyze data and for the development of computer

resources such as supercomputing centers and computer networks. Several of these resources are described below. Numerous private firms are developing or marketing computer programs that search

databases or analyze data on nucleic acid or protein

sequences.

BIONETTM

BIONETTM is a nonprofit computer network run by

Intelligenetics, Inc. [Mountain View, CA) and funded

by the Division of Research Resources of NIH and by

modest user fees (13). Its goals are to “provide computation assistance in data analysis and problem solving

to molecular biologists and researchers in related field,

to serve as a focus for the development and sharing

of new software, and to promote rapid sharing of information and collaboration among a national community of scientists” (9). BIONETTM provides access to

several major databases (GenBank”, EMBL, PIR, PDB,

and databases of restriction enzymes and plasmid vectors) as well as to software for analyzing nucleic acid

and protein sequences. The network also aids communication between its members through a series of

bulletin boards on topics of user interest and through

an electronic mail system. BIONETTM serves users in

the United States, Canada, and Europe.

National Biotechnology Information

Center

The National Biotechnology Information Center is

an initiative to develop and enhance a range of tools

for molecular biology information that is being sponsored by the National Library of Medicine (NLM) (18).

The project is presently the subject of several authorizations bills but has already received some appropriations for a range of projects, including the building

and maintenance of databases, developing a comprehensive listing of existing databases, and improving information retrieval systems. NLM has already developed a prototype of a retrieval system, called the

Information Retrieval Experiment (IRX) that connects

data from several different databases and graphic and

visual sources. For example, a database search for a

specific disease gene will yield information on whether

the gene has been mapped, the map of the gene in

graphic form, bibliographic information on publications about the map, as well as information on clinical

symptoms, diagnosis, and visual representations of affected patients (X-rays, diagrams, photos, and so on).

The NLM initiative will enhance the management of

data from genome projects and will forge links between

information from many areas of molecular biology to

aid in basic and biomedical research (15). The NLM

is in an advantageous position to coordinate database

activities through its expertise in handling information through existing literature databases such as

MEDLINE.

The Matrix of Biological Knowledge

Workshop

The Matrix of Biological Knowledge Workshop, a

month-long conference held during the summer of

1987, was an attempt to formulate models and make

recommendations for the organization of knowledge

and data from all disciplines in biology (16). R was sponsored by the NIH, the DOE, the Sloan Foundation, and

the Santa Fe Institute.

The workshop grew out of the efforts of a committee sponsored by the NIH that attempted to set forth

and evaluate models used in biomedical research. Several scientific meetings prior to the workshop had addressed the particular complexities of biological data;

at the workshop, biologists, computer scientists, and

database experts actually tried to work out some of

the problems raised at earlier meetings. Participants

at the workshop issued the following general recommendations:

. . . that support for a centrally coordinated effort to

establish a knowledge base of databases in the biological sciences be aggressively pursued; that the current

independent efforts to establish interdatabase structures and analysis tools be coordinated with a long-term

view towards maximum integration; . . . that these coordinated efforts incorporate the most up-todate computer science and analytical methods; and finally, that

these activities directly involve the experimental and

biotechnology communities in order to ensure the uti]-

ity of the ensuing developments (16).

These recommendations appear to reinforce the direction of ongoing efforts in agencies that sponsor databases. The specific recommendations issued by work-
194

ing groups in each of seven broad categories may prove

useful for the future management of databases in all

of biology.

1.

2.

3.

4.

5.

6.

7,

8.

9.

10.

Appendix D References

Abola, E. E., Bernstein, F.C., and Koetzle, T.F., “The Protein Data Bank,” in P.S. Glaeser (cd.), The Role of Data

in Scientific Progress (New York, NY: Elsevier Science

Publishers, 1985).

Aronson, M. M., Miller, R.C., Nichols, W .W., et al., “Breakpoint Map of Human Translocation Cell Cultures Available From the NIGMS Human Genetic Mutant Cell Repository,” Journal of Cytogenetics and Cell Genetics

30:179-189, 1981.

Burks, C., Fickett, J.W., Goad, W .B., et al., “The GenBank”

Nucleic Acid Sequence Database,” Computers Applications in Bioscience 1:225-233, 1985.

Cahill, G.C., Vice President for Scientific Training and

Development, Howard Hughes Medical Institute, Bethesda, MD, personal communication, December 1987.

Cassatt, J., National Institutes of Health, personal communication, April 1987.

George, D., Protein Identification Resource, National Biomedical Research Foundation, Washington, DC, personal

communication, December 1987.

Greene, A. E., Human Genetic Mutant Cell Repository,

Coriell Institute for Medical Research, Camden, NJ, personal communication, March 1988.

Harem, G., and Cameron, G., “The EMBL Data Library,”

Nucleic Acids Research 14:5-9, 1986.

Introduction to BZONET Mountain View, CA: Intelligenetics, Inc., 1987).

Kidd, K., Lecture at “Genomics Meeting: Assessing the

Repository, Informatics, and Quality Control Needs,” Lawrence Livermore National Laboratory, Livermore, CA,

Aug. 26-27, 1987.

11. Knobeloch, D., and Beugelsdijk, T.J., ‘(Automated Sample Management: Organizing, Managing, and Accessing

12.

13.

14.

15.

16.

17%

18.

19.

20.

21.

22.

23

the DNA Fragments Generated in the Process of Mapping and Sequencing the Human Genome,” in Repository,

Data Management, and Quality Assurance Needs for the

National Gene Library and Genome Ordering Projects,

see ref. 23.

Koetzle, T., Protein Data Bank, Brookhaven National Laboratory, Upton, New York, NY, personal communication,

September 1987.

Kristofferson, D., “The BIONETTM Electronic Network,”

Nature 325:555-556, 1987.

Ledley & Barker, Protein Identification Resource project

description, November 1987.

Masys, D., National Library of Medicine, Bethesda, MD,

personal communication, December 1987.

Morowitz, H.J., and Smith, T. (eds.), Report of the Matrix

of Biological Knowledge Workshop (Santa Fe, NM: Santa

Fe Institute, 1987).

“The National Institute of General Medical Sciences Human Genetic Mutant Cell Repository, ” Somatic Cell and

Molecular Genetics 12:421, 1986.

National Library of Medicine, “Biotechnology Information: A Plan for the National Library of Medicine,” unpublished report, 1987.

“A New System for Direct Submission of Data to the

Nucleotide Sequence Data Banks,” Nucleic Acids Reseamh

15, No. 18, 1987.

Nierman, W.C., Benade, L. E., and Maglott, D. R., American Type Culture Collection: NIH Repository of Human

DNA Probes and Libraries (Rockville, MD: American Type

Culture Collection, 1987).

Stevenson, R., American Type Culture Collection, Rockville, MD, personal communication, October 1987.

U.S. Congress, Office of Technology Assessment, “Costs

of Human Genome Projects,” workshop held Aug. 7, 1987

(see app. A).

U.S. Department of Energy, Office of Health and Environmental Research, and National Institutes of Health, Repository, Data Management, and Quality Assurance Needs

for the National Gene Library and Genome Ordering

Projects, unpublished report from a workshop, August

1987.
Appendix E

Bibliometric Analysis of

Human Genome Research

Computer Horizons, Inc. (CHI) was hired by the Office of Technology Assessment to conduct a bibliometric analysis of work on human gene mapping, including an international bibliography of the most relevant

literature. This bibliography centered on an examination of the growth of relevant scientific literature keyed

to the words “Gene or Genes or Genetic,” “Marker or

Linkage or Map,” and “Human. ” Additional key word

combinations included “Human Chromosome, ” “Human DNA Sequence, “ “Human Nucleic Acid Sequence, ”

“Human Restriction Fragment Length Polymorphism,”

and various combinations designed to select papers

on methods and techniques of DNA analysis.

The use of publication counts as a measure of research activity is part of the field of bibliometrics. A

growing body of research has demonstrated the usefulness of bibliometric techniques: Counts of scientific

papers and the numbers of citations to them have been

shown to be indicators of research productivity. Limitations to bibliometric techniques do exist, particularly

in balancing the treatment of non-English publications.

Since the literature of science is dominated by Englishspeaking researchers, there is an inherent bias against

citations of foreign-language publications. In the pres -

ent case, however, the primary purpose of the literature search was to provide indicators of growth rather

than to develop specific bibliographies. As such, the

analysis clearly demonstrated a rapid growth in the

scientific literature related to mapping and sequencing the human genome, and an acceleration of this

growth over very recent years.

Over 11,000 entries of relevant literature were presented in the bibliography, which scanned appropriate publications from 1977 through 1986. The literature search included journals published in English,

French, German, Dutch, Italian, Polish, Japanese, Spanish, Russian, Bulgarian, Swedish, Finnish, Norwegian,

Danish, and Hebrew. All entries were subsequently

grouped by OTA into the country or region of origin

to identify national and regional trends in research.

The regions included the United States, Western European countries, Japan, and other non-European countries. The table below presents the results. The data

were used as the basis for figures 7-1 and 7-2 and table 7-1 in chapter 7, which display the growth in the

total number of articles on human gene mapping and

sequencing and the breakdown by country or region.

Annual Publications in Human Genetics:

Articles Published on Human Genes or Genetic Markers and Linkage Maps

Year 1977 1978 1979 1980 1981 1982 1983 1984 1985 1986

United States. . . . . . . . . . . . . . . 187 218 235 314 308 364 487 577 689 818

Japan . . . . . . . . . . . . . . . . . . . . . 7 11 17 22 32 45 39 58 67 85

Western Europe

Denmark . . . . . . . . . . . . . . . . .

Federal Republic of

Germany. . . . . . . . . . . . . . .

Finland . . . . . . . . . . . . . . . . . .

France . . . . . . . . . . . . . . . . . .

Italy . . . . . . . . . . . . . . . . . . . . .

Netherlands . . . . . . . . . . . . . .

United Kingdom . . . . . . . . . .

Other. . . . . . . . . . . . . . . . . . . .

6 14 9 7 12 7 9 12 21 25

20

3

21

8

15

32

31

23

6

34

8

25

49

19

14

8

36

9

17

57

46

33

7

42

15

20

46

30

42

5 ;

24

13

66

45

41

5

57

15

18

88

44

51

9

64

44

25

97

62

69

12

70

39

25

126

69

78 100

15 14

94 114

44 66

50 45

184 185

70 92

Other Non-European countries

Australia. . . . . . . . . . . . . . . . .

Canada . . . . . . . . . . . . . . . . . .

Eastern Europe and

U.S.S.R. . . . . . . . . . . . . . . . .

South Africa . . . . . . . . . . . . .

Other. . . . . . . . . . . . . . . . . . . .

2

12

8

17

11

17

17

28

18

14

22

29

24

26

23

38

20 38

60 68

23

0

20

32

17

6

20

41

21

7

35

79

38

8

33

75

36

6

33

57

33

3

41

87

36

4

32

61

51

6

42

81

60 62

16 9

87 63

Uncertain . . . . . . . . . . . . . . . . . . 95 101

Total . . . . . . . . . . . . . . . . . . . . 419 516 618 735 772 899 1,070 1,298 1,650 1,885

SOURCE: Office of Technology Assessment, 19S8.

195
Appendix F

Acknowledgements

OTA wishes to acknowledge the many people contributed to the preparation of this report. Members of

the advisory panel and contractors are listed at the

front of the report. Workshop participants are listed

in appendix C. Others helped by commenting on drafts

of the report, providing information or advice, or consenting to interviews with OTA staff. OTA particularly

thanks those at the National Institutes of Health, the

Department of Energy, the National Science Foundation, the Howard Hughes Medical Institute, and other

organizations for their invaluable efforts to inform

OTA about their activities. Our gratitude is extended to:

Carlos Abella

Embassy of Spain

Bruce M. Alberts

University of California al

Duane Alexander

National Institute of Child

Development

Norman Anderson

Large Scale Biology

Wyatt Anderson

University of Georgia

David G. Baldwin

Tetrarch Inc.

David Baltimore

Whitehead Institute

Phil Beachy

San Francisco

Health and Human

Carnegie Institution of Washington

George I. Bell

Los Alamos National Laboratory

Celeste Berg

Carnegie Institution of Washington

Fred Bergmann

National Institute of General Medical Sciences

Michel Bernon

Embassy of France

Ralph Bledsoe

Domestic Policy Council

Lars Bolund

University of Aarhus, Denmark

Judith Bostock

Office of Management and Budget

David Botstein

Genentech, Inc.

James E. Bowman

University of Chicago

Elbert Branscomb

Lawrence Livermore National Laboratory

Douglas Brutlag

Stanford University

Martin Buechi

Embassy of Switzerland

John Burris

National Academy of Sciences

Andrew Bush

U.S. Senate

Mark Cantley

Commission of the European Economic Community

Charles R. Cantor

College of Physicians and Surgeons of

Columbia University

C. Thomas Caskey

Baylor College of Medicine

James Cassatt

National Institute of General Medical Sciences

James W. Chamberlain

U.S. Embassy, Brazil

Andrew T. L. Chen

Centers for Disease Control

James F. Childress

University of Virginia

George M. Church

Harvard University Medical School

Mary Clutter

National Science Foundation

Stanley Cohen

Stanford Medical School

Francis Collins

University of Michigan

P. Michael Conneally

Indiana University Medical Center

Cheryl Corsaro

National Institutes of Health

Alan Coulson

MRC Molecular Biology Laboratory

Cambridge, United Kingdom
197

Charles L. Coulter

Division of Research Resources

National Institutes of Health

David Cox

University of California at San Francisco

James F. Crow

University of Wisconsin

Terry Curtin

U.S. Senate

Kay E. Davies

Oxford University

Bernard D. Davis

Harvard University Medical School

Ronald Davis

Stanford University

Michael Dean

National Cancer Institute

Larry L. Deaven

Los Alamos National Laboratory

Albert de la Chapelle

University of Helsinki

Enrique Martin de] Campo

Organization of American States

Charles DeLisi

Mount Sinai School of Medicine

Vincent DeVita

National Cancer Institute

Denis Dewez

Embassy of Belgium

Russell F. Doolittle

University of California, San Diego

Janet Dorigan

Office of Science and Technolo~ Policy

Renato Dulbecco

The Salk Institute

Irene Eckstrand

National Institute of General Medical Sciences

Peter Farnham

American Society for Biochemistry and

Molecular Biology

James Fickett

Los Alamos National Laboratory

John C. Fletcher

University of Virginia

Donald S. Fredrickson

National Institutes of Health

Jean Frezal

Hospital for Sick Children, Paris

F. Edwin Froehlich

U.S. Senate

Robert Fujimura

Oak Ridge National Laboratory

David George

National Biomedical Research Foundation

Frank Gibson

The Australian National University

Paul Gilman

U.S. Senate

Alan Goldhammer

Industrial Biotechnology Association

George M. Gould

Hoffmann-La Roche, Inc.

Denise Greenlaw

U.S. Senate

Santiago Grisolia

University of Kansas Medical Center

Ralph Hardy

Boyce Thompson Institute

Wendy Harris

Johns Hopkins University Press

Nemat Hashem

Ain Shams University

Cairo, Egypt

Cyril G. Hide

South African Embassy

C. Edgar Hildebrand

Los Alamos National Laboratory

Joseph R. Hlubucek

Embassy of Australia

Sverker Hogberg

Swedish Embassy

Michael Hunkapiller

Applied Biosystems, Inc.

Thomas Isenhour

Utah State University

Trefor Jenkins

University of the Witwatersrand

Johannesburg, South Africa

Chalmers Johnson

University of California, Berkeley

Irving S. Johnson

Eli Lilly & Co.

Eric T. Juengst

The Pennsylvania State University

Robert F. Karnei

Armed Forces Institute of Pathology
198

Steven Keith

US. Senate

Michael J. Kelly

Intelligenetics, Inc.

Kenneth Kemphues

Cornell University

Thomas Koetzle

Protein Data Bank, Brookhaven National Laboratory

George S. Kopp

U.S. House of Representatives

Arthur Kornberg

Stanford University

David Kristofferson

BIONET/Intelligenetics

Louis Kunkel

Howard Hughes Medical Institute, Boston

Alphonse Lafontaine

Ministerie van Volksgezondheid en van het Gezin

Brussels, Belgium

Roe Laird

Ministry of State/Science and Technology

Canada

Eric Lander

Whitehead Institute

Norman Latker

U.S. Department of Commerce

Eileen Lee

U.S. House of Representatives

Hans Lehrach

Imperial Cancer Research Fund

Rachel Levinson

National Institutes of Health

Jack G. Lewis

University of Southern California

Jiayao Li

The Embassy of the People’s Republic of China

Washington, D.C.

Donald A.B. Lindberg

National Library of Medicine

John Logsdon

George Washington University

Jeffrey T. Lutz

U.S. Embassy, Indonesia

Jerold R. Mande

U.S. Senate

Emmanuele Mannarino

U.S. Embassy, Italy

Daniel R. Masys

National Library of Medicine

Kenichi Matsubara

Osaka University

Japan

Sunil Maulik

BIONET/Intelligenetics

George Mazuzan

National Science Foundation

Jack McConnell

Johnson & Johnson

Victor A. McKusick

The Johns Hopkins University

Mortimer L. Mendelssohn

Lawrence Livermore National Laboratory

Bruce Merrifield

U.S. Department of Commerce

Bradie Metheny

Tricom, Inc.

Jerome P. Miksche

U.S. Department of Agriculture

Sankar Mitra

Oak Ridge National Laboratory

Jan Mohr

Institute of Clinical Genetics, University of Copenhagen

Robert G. Morris

U.S. Embassy, Argentina

Diane Morton

Cornell University

Jay Moskowitz

National Institutes of Health

Tom Murray

Case Western Reserve University

DeLill Nasser

National Science Foundation

Dorothy Nelkin

New York University

Norrine Noonan

Office of Management and Budget

Stephen O’Brien

National Cancer Institute

Maynard V. Olson

Washington University School of Medicine

Gilbert S. Omenn

University of Washington

Stuart Orkin

Howard Hughes Medical Institute, Boston

Joseph Osterman

U.S. Army Medical Research and Development

Command
199

Joseph Palca

Nature

M. Iqbal Parker

University of Cape Town

Jane Peterson

National Institute of General Medical Sciences

Ulf Petterson

University of Uppsala, Sweden

Kate Phillips

Council on Governmental Relations

Betty Pickett

Division of Research Resources

National Institutes of Health

Maya Pines

Howard Hughes Medical Institute

George Poste

Smith Kline & French Laboratories

Michael Probert

Medical Research Council

United Kingdom

Theodore T. puck

Eleanor Roosevelt Institute for Cancer Research

Robert Rabin

National Science Foundation

Alan S. Rabson

National Cancer Institute

Lisa J. Raines

Industrial Biotechnology Association

William F. Raub

National Institutes of Health

Jeremy Rifkin

Foundation for Economic Trends

Jerry H. Roberts

National Institutes of Health

Leslie Roberts

Science

Richard Roberts

Cold Spring Harbor Laboratories

Thomas Rollins

U.S. Senate

Leon E. Rosenberg

Yale University

Luigi Rossi-Bernardo

Consiglio Nazionale della Ricerche, Italy

John Roth

University of Utah

Lesley Russell

U.S. House of Representatives

Joseph Sambrook

University of Texas Health Science Center

Mona Sarfaty

U.S. Senate

D. Schmitz

U.S. Embassy, Federal Republic of Germany

David Schwartz

Carnegie Institution of Washington

Charles Scriver

McGill University and

Science Council of Canada

Gerald Seizer

National Science Foundation

Leroy C. Simpkins

US. Embassy, Mexico

Michael Simpson

Library of Congress

Robert Sinsheimer

California Institute of

Mark Skolnick

University of Utah

Bent Skou

Technology

Royal Danish Embassy

David A. Smith

U.S. Department of Energy

Lloyd Smith

University of Wisconsin

Robert Smith

The Johns Hopkins University

Temple Smith

Dana Farber Cancer Institute

Rand Snell

U.S. Senate

M. Anne Spence

University of California, Los Angeles

J. Claiborne Stephens

Human Gene Mapping Library

Robert E. Stevenson

American Type Culture Collection

Irene Stith-Coleman

Library of Congress

J. Thomas Stocker

U.S. Department of Defense

Gary Stormo

University of Colorado

William Szkrybalo

Pharmaceutical Manufacturers’

Association
200

Bruna Tesso

Organization for Economic Cooperation and

Development

Ignacio Tinoco

University of California, Berkeley

Kevin M. Ulmer

SeQ, Ltd.

Victor L. Urquidi

EIColegio de Mexico, A.C.

Paul Van Belkom

National Health and Medical Research Council

 Commonweakh of Australia

Dorle Vawter

University of Minnesota Health Center

Robert Walgate

The Panes Institute

Bertil Wennergren

Swedish Commission on Genetic

Engineering

Norman Whiteley

Applied Biosystems, Inc.

Robert Williamson

Saint Mary’s Hospital, London

JoAnn Wise

University of Illinois

Carl Woese

University of Illinois

John Wooley

National Science Foundation

James B. Wyngaarden

National Institutes of Health

Douglas J. Yarrow

Embassy of the United Kingdom

Philip Youderian

University of Southern California

Debbie Zucker

U.S. Senate
Appendix G

Glossary

Alleles: Alternative forms of a genetic locus; alleles

are inherited separately from each parent (e.g., at

a locus for eye color there might be alleles resulting

in blue or brown eyes).

Amino acid: Any of a group of 20 molecules that combine to form proteins in living things. The sequence

of amino acids in a protein is determined by the

genetic code.

Autoradiography: A technique that uses X-ray film

to visualize radioactively labeled molecules or fragments of molecules; used in analyzing length and

number of DNA fragments after they are separated

by gel electrophoresis.

Autosome: A chromosome not involved in sex determination. The diploid human genome consists of 46

chromosomes, 22 pairs of autosomes and 1 pair of

sex chromosomes.

Base pak Two nucleotides (adenosine and thymidine

or guanosine and cytidine) held together by weak

bonds. Two strands of DNA are held together in the

shape of a double helix by the bonds between base

pairs.

Centimorgam A unit of measure of recombination frequency. One centimorgan is equal to a 1 percent

chance that a genetic locus will be separated from

a marker due to recombination in a single generation. In human beings, 1 centimorgan is equivalent,

on average, to 1 million base pairs.

Cloning: The process of asexually producing a group

of cells (clones), all genetically identical to the original ancestor. In recombinant DNA technology, the

process of using a variety of DNA manipulation procedures to produce multiple copies of a single gene

or segment of DNA,

Complementary DNA, cDNA DNA that is synthesized

from a messenger RNA template; the single-strand

form is often used as a probe in physical mapping.

Contigs: Groups of clones representing overlapping,

or contiguous, regions of a genome.

Crossing over The breaking during meiosis of one

maternal and one paternal chromosome, the exchanging of corresponding sections of DNA, and the

rejoining of the chromosomes.

Gvalue paradox: The lack of correlation between the

amount of DNA in a haploid genome and the biological complexity of the organism. (C-value refers

to haploid genome size,)

Determinisnx The theory that for every action taken

there are causal mechanisms such that no other action was possible.

Diploid: A full set of genetic material (two paired sets

of chromosomes), one from each parental set. All

cells except sperm and egg cells have a diploid set

of chromosomes. The diploid human genome has

46 chromosomes. Compare haploid.

DNA, deoxyribonucleic acid: The molecule that encodes genetic information. DNA is a double-stranded

molecule held together by weak bonds between base

pairs of nucleotides. There are four nucleotides in

DNA: adenosine (A), guanosine (G), cytidine (C), and

thymidine (T). In nature, base pairs form only between A and T and between G and C, thus the sequence of each single strand can be deduced from

that of its partner.

DNA probes: Segments of single-strand DNA that are

labeled with a radioactive or other chemical marker

and used to identify complementary sequences of

DNA by hybridizing with them. See hybridization.

DNA sequence: The relative order of base pairs,

whether in a stretch of DNA, a gene, a chromosome,

or an entire genome.

Domain: A discrete portion of a protein with its own

function. The combination of domains in a single

protein determines its unique overall function.

Double helix: The shape in which two linear strands

of DNA are bonded together.

Electrophoresis: A method of separating large

molecules (such as DNA fragments or proteins) from

a mixture of similar molecules. An electric current

is passed through a medium containing the mixture,

and each kind of molecule travels through the

medium at a different rate, depending on its electrical charge and size. Separation is based on these

differences.

Enzyme: A protein that acts as a catalyst, speeding

the rate at which a biochemical reaction proceeds

but not altering its direction or nature.

Eukaryote: Cell or organism with membrane-bound,

structurally discrete nucleus and other welldeveloped subcellular compartments. Eukaryotes include all organisms except viruses, bacteria, and

blue-green algae. Compare prokaryote.

Eugenics: Attempts to improve hereditary qualities

through selective breeding. See posititive eugenics,

negative eugenics, eugenics of normalcy.

Eugenics of normalcy: Policies and programs intended to ensure that each individual has at least

a minimum number of normal genes.

Exons: The protein-coding DNA sequences of a gene.

Compare introns.

201
202

Gamete Mature male or female reproductive cell with

a haploid set of chromosomes (23); that is, a sperm

or ovum.

Gene The fundamental physical and functional unit

of heredity. A gene is an ordered sequence of nucleotides located in a particular position on a particular

chromosome. See gene expression.

Gene expression The process by which a gene’s blueprint is converted into the structures present and

operating in the cell. Expressed genes include those

that are transcribed into mRNA and then translated

into protein and those that are transcribed into RNA

but not translated into protein (e.g., transfer and

ribosomal RNAs).

Gene families: Groups of closely related genes that

make similar products.

Gene product: The biochemical material, either RNA

or protein, made by a gene. The amount of gene

product is used to measure how active a gene is;

abnormal amounts can be correlated with diseasecausing genes.

Genetic code: The sequence of nucleotides, coded in

triplets along the mRNA, that determines the sequence of amino acids in protein synthesis. The DNA

sequence of a gene can be used to predict the mRNA

sequence, and the genetic code can in turn be used

to predict the amino acid sequence.

Genetic engineering technologies: See recombinant

DNA technologies.

Genetic linkage map: A map of the relative positions

of genetic loci on a chromosome, determined on the

basis of how often the loci are inherited together.

Distance is measured in centimorgans.

Genetics: The study of the patterns of inheritance of

specific traits.

Genomtx All the genetic material in the chromosomes

of a particular organism; its size is generally given

as its total number of base pairs.

Genome projects: Research and technology development efforts aimed at mapping and sequencing some

or all of the genome of human beings and other

organisms.

Genomic library: A collection of clones made from

a set of overlapping DNA fragments representing

the entire genome of an organism. Compare library.

Haploid: A single set of chromosomes (half the full

set of genetic material), present in the egg and sperm

cells of animals and in the pollen cells of plants. Human beings have 23 chromosomes in their reproductive cells. Compare diploid.

Homeo box: A short stretch of nucleotides whose sequence is virtually identical in all the genes that contain it. It has been found in many organisms, from

fruit flies to human beings. It appears to determine

when particular groups of genes are expressed in

the development of the fruit fly.

Human gene therapy: Insertion of normal DNA

directly into cells to correct a genetic defect.

Human Genome Initiative: Collective name for several projects begun in 1986 by DOE to 1) create an

ordered set of DNA segments from known chromosomal locations, 2) develop new computational methods for analyzing genetic map and DNA sequence

data, and 3) develop new techniques and instruments for detecting and analyzing DNA,

Hybridization The process of joining two complementary strands of DNA, or of DNA and RNA, together

to form a double-stranded molecule.

Informatic: The study of the application of computer

and statistical techniques to the management of information. In genome projects, informatics includes

the development of methods to search databases

quickly, to analyze DNA sequence information, and

to predict protein sequence and structure from DNA

sequence data.

International technology transfer: Movement of inventions and technical know-how across national

borders.

Introns: The DNA sequences interrupting the proteincoding sequences of a gene that are transcribed into

mRNA but are cut out of the message before it is

translated into protein. Compare exons.

Karyotypcx A photomicrograph of an individual’s chromosomes arranged in a standard format showing

the number, size, and shape of each chromosome;

used in low-resolution physical mapping to correlate gross chromosomal abnormalities with the characteristics of specific diseases.

Library: A collection of clones in no obvious order

whose relationship can be established by physical

mapping. Compare genomic library.

Linkage The proximity of two or more markers (e.g.,

genes, RFLP markers) on a chromosome; the closer

together the markers are, the lower the probability

that they will be separated during meiosis and hence

the greater the probability that they will be inherited

together.

Locus: The position on a chromosome of a gene or

other chromosome marker; also, the DNA at that

position. Some restrict use of locus to regions of DNA

that are expressed. See gene expression.

Marker An identifiable physical location on a chromosome (e.g., restriction enzyme cutting site, gene,

RFLP marker) whose inheritance can be monitored.

Markers can be expressed regions of DNA (genes)

or some segment of DNA with no known coding

function but whose pattern of inheritance can be

determined.
203

Meiosis: The process of two consecutive cell divisions

in the diploid progenitors of sex cells. Meiosis results in four rather than two daughter cells, each

with a haploid set of chromosomes.

Messenger RNA, mRNA: A class of RNA produced by

transcribing the DNA sequence of a gene. The mRNA

molecule carries messages specific to each of the

20 amino acids. Its role in protein synthesis is to

transmit instructions from DNA sequences (in the

nucleus of the cell) to the ribosomes (in the cytoplasm

of the cell).

Multifactorial or multigenic disorders See polygenic

disorders.

Mutation: Any change in DNA sequence that results

in a new characteristic that can be inherited. Compare polymorphism.

Negative eugenics: Policies and programs intended

to reduce the occurrence of genetically determined

disease.

Nucleotide: A subunit of DNA or RNA consisting of

a nitrogenous base (adenine, guanine, thymine, or

cytosine in DNA; adenine, guanine, uracil, or cytosine in RNA), a phosphate molecule, and a sugar molecule (deoxyribose in DNA and ribose in RNA). Thousands of nucleotides are linked to form the DNA or

RNA molecule. See DNA, base pair, RNA.

Oncogene A gene, one or more forms of which is associated with cancer. Many oncogenes are involved,

directly or indirectly, in controlling the rate of cell

growth.

Physical map: A map of the locations of identifiable

landmarks on DNA (e.g., restriction enzyme cutting

sites, genes, RFLP markers), regardless of inheritance. Distance is measured in base pairs. For

the human genome, the lowest-resolution physical

map is the banding patterns of the 24 different chromosomes; the highest-resolution map would be the

complete nucleotide sequence of the chromosomes.

Polygenic disorderw Genetic disorders resulting from

the combined action of alleles of more than one gene

(e.g., heart disease, diabetes, and some cancers). Although such disorders are inherited, they depend

on the simultaneous presence of several alleles, thus

the hereditary patterns are usually more complex

than those of single-gene disorders. Compare singlegene disorders.

polymorphism: Difference in DNA sequence among

individuals. Genetic variations occurring in more

than 1 percent of a population would be considered

useful polymorphisms for genetic linkage analysis,

Compare mutation.

Positive eugenics: The achievement of systematic or

planned genetic changes to improve individuals or

their offspring.

Prokaryote: Cell or organism lacking membranebound, structurally discrete nucleus and subcellular compartments. Bacteria are examples. Compare

eukaryote.

Protein: A large molecule composed of chains of

smaller molecules (amino acids) in a specific sequence; the sequence is determined by the sequence

of nucleotides in the gene coding for the protein.

Proteins are required for the structure, function,

and regulation of the body’s cells, tissues, and organs, and each protein has a unique function. Examples are hormones, enzymes, and antibodies.

Recombinant DNA technologies: Procedures used to

join together DNA segments in a cell-free system (an

environment outside of a cell or organism). A recombinant DNA molecule can enter a cell and replicate there, either autonomously or after it has become integrated into a cellular chromosome.

Replication: The synthesis of new DNA strands from

existing DNA. In human beings and other eukary -

otes, replication occurs in the nucleus of the cell.

Resolution: Degree of molecular detail on a physical

map of DNA, ranging from low to high.

Restriction enzyme, endonuclease: A protein that

recognizes specific, short nucleotide sequences and

cuts DNA at those sites. There are over 400 such

enzymes in bacteria that recognize over 100 different DNA sequences. See restriction enzyme cutting

site.

Restriction enzyme cutting site: A specific nucleotide sequence of DNA at which a restriction enzyme

cuts the DNA. Some sites occur frequently in DNA

(e.g., every several hundred base pairs), others much

less frequently (e.g., every 10,000 base pairs).

RFLP, restriction fragment length polymorphism:

Variation in DNA fragment sizes cut by restriction

enzymes; polymorphic sequences that are responsible for RFLPs are used as markers on genetic linkage maps.

Ribosomal RNA, rRNA: A class of RNA found in the

ribosomes of cells.

RNA, ribonucleic acid: A chemical found in the nucleus and cytoplasm of cells; it plays an important

role in protein synthesis and other chemical activities of the cell. The structure of RNA is similar to

that of DNA. There are several classes of RNA

molecules, including messenger RNA, transfer RNA,

ribosomal RNA, and other small RNAs, each serving

a different purpose.

Sex chromosomes: The X and Y chromosomes in human beings that determine the sex of an individual.

Females have two X chromosomes in diploid cells;

males have an X and a Y chromosome.

Single-gene disorders: Hereditary disorders caused
204

by a single gene (e.g., Duchenne muscular dystrophy,

retinoblastoma, sickle cell disease). Compare poly -

genic disorders.

Somatic cells: Any cells in the body except reproductive cells and their precursors.

Technology transfen The process of converting scientific knowledge into useful products.

Transcription: The synthesis of mRNA from a sequence of DNA (a gene); the first step in gene expression. Compare translation,

Transfer RNA tRNA: A class of RNA having structures

with triplet nucleotide sequences that are complementary to the triplet nucleotide coding sequences of mRNA. The role of tRNAs in protein synthesis is to bond with amino acids and tranfer them

to the ribosomes, where proteins are synthesized

according to the instructions carried by mRNA.

Translation: The process in which the genetic code

carried by mRNA directs the synthesis of proteins

from amino acids. Compare transcription,

Vector: DNA molecule originating from a virus, a bacterium, or the cell of a higher organism used to carry

additional DNA base pairs; vectors introduce foreign DNA into host cells, where it can be reproduced

in large quantities. Examples are plasmids, cosmids,

and yeast artificial chromosomes.
—. .—.

Inde x
Index

Acid Precipitation Task Force, 120

acquired immune deficiency syndrome, 64, 72, 96, 117

adenosine, 21-22

adenosine deaminase, 61

agriculture, genome mapping implications for, 73

alanine, codon, 23

Alberts, Bruce, 107

albinism, 149

albumin, 61

alcoholism, 86

aldolase, chromosome assignment of, 33

Alexander, Duane, 94 n.1

alleles, 27, 28, 58

alpha globin, 61

alpha interferon, 64

.Alzheimer’s disease, 65, 95, 146

American Society for Biochemistry and ,Molecular Biology, 127

American Type Culture Collection, 101, 141, 190, 192

amino acids

codon, 23

databases, 97, 98, 190-191

generation of, 22-23

anemias, 64, 136

antibodies, 21

apo]iproprotein E, 61

Applied Biosystems, Inc., automated DNA sequencer, 47,

108, 138

applied research, government controls on, 87

arginine, codon, 23

Argonne National Laboratory, 122

Armed Forces Institute of Pathology, 103

arthritis, 64

Ashburner, Michael, 42

Asian nations, interest in genome projects, 8

asparagine, codon, 23

aspartic acid, codon, 23

atria] natiuretic factor, 64

Australia, genome research, 8, 133, 148, 195

automation of DNA sequencing

DOE initiative for, 7-8

by Japan, 9, 47-48, 137-138

new technologies, 46-48

robotic devices, 48, 137-138

standard setting for equipment for, 103

autoradiography/autoradiographs

automated scanning of, 48

use in DNA sequencing, 46

use in physical mapping, 32, 40, 45

use in RFLP mapping, 29

autosomes

karyotyping of, 32

mapping of genetic loci on, 27, 30, 33-34

bacteria

DNA sequencing of, 45

E. co/i, 41, 45, 47, 100

genome mapping, 4, 40, 41

haploid DNA content, 25

mitochondria similarities to, 71

S. typhimuriurn, 45

bacteriophage T4, genomic map of, 40

Baltimore, David, 124

basic research

government restriction of, 87

value of, 81

Baylor College of Medicine, 97

bears, 36, 69

behavior, human, genetic factors in, 85-86

Berg, Paul, 126

beta globin, 61, 65, 70

beta interferon, 64

Billings, John Shaw, 97

Bio-Rad Laboratories, automated DNA sequencer, 47-48

biomedical research

HHMI support for, 8

NIH funding, 6, 95

Bimolecular Engineering Programme, 140

BIONET

TM, 193

biotechnology

databases, 97

European research programs in, 140-141

international competitiveness in, 11

NBS support for, 103

Biotechnology Action Program, 140-141

Biotechnology Research and Innovation for Detrelopnlent

and Growth in Europe, 140-141

bison, 72

blood pressure disorders, 64

Brenner, Sydney, 147

burn treatment, 64

Botstein, David, 126

Bush, Vannevar, 102

C-value paradox, 24-25

Caenorhabditis elegans

amount sequenced, 47

genome mapping, 42

genome size, 47

California Biotechnology, probe development, 58

California Institute of Technology, automated DNA sequencer, 47, 102

Cambridge University, genome mapping project, 42

Canada, genome research, 8, 133, 148, 195

cancer

mutation-induced, 25

polygenic nature, 62

treatment, therapeutic agents, 64

catalase, 61

cataract surgery, 64

cDNA

clones, 59-63, 67

libraries, 59

mapping, 30, 32, 44, 63

restriction enzyme cutting, 35

cell culture, see somatic cell hybridization

207
208

Cell Line Two-Dimensional Gel Electrophoresis Database, automation of, 47, 48

97

cell receptors, 21-22

Center for the Study of Human Polymorphism

collaborative efforts of, 8, 106, 143-144, 146, 149

family pedigree data set, 58, 143, 146

funding for, 106

mission, 145

Centers for Disease Control, 103

chicken, haploid DNA content, 25

Chiles, Lawton, 97

cholesterol, lowdensity lipoprotein, 58

chromosome markers

for single-gene diseases, 57

funding for research on, 6

mapping through family inheritance patterns, 27

maps, low-resolution, 4

use for genetic linkage studies, 6, 27, 28, 44

chromosomes

banding patterns, 30, 33, 34-35, 40, 42, 45, 56

crossing over (recombination), 26, 27

deletion of, 25, 31, 32

diploid number, 21

Drosophila melanogasfer salivary gland, 30, 32

duplication, 25

E. Coli, 41

gene assignment to, 31

haploid number, 21

hybrids, single, 31

inversion, 26

isolation techniques, 31-32, 43

of clinical significance, 44

phage lambda, 36, 39, 42, 56, 100

polytene, 42

sorting, 31-32, 37, 47, 56, 97, 100

species similarities in, 34-35, 36

translocation, 25-26, 31, 32

yeast artificial, 36-37, 39, 43, 56

chromosomes, human

1, 27

4, 28

6, 148

7, 31, 44, 62

9, 33, 148

10, 32, 33

11, 32

13, 34

16, 31, 44, 100, 148

17/ 31, 33

19, 31, 44, 100

21, 35, 44, 95, 100, 145-146

22, 44, 145

average size, 37

number, 3

resemblance to primate chromosomes, 34-35

X, 24, 27, 30, 31, 44, 63, 100, 148

Y, 24, 30, 31, 145

chronic granulomatous disease, 57, 59, 62

Church, George, 44-45

cloning/clones

access to and ownership of, 147

banding patterns, 40

cDNA, 59-63

disease-associated genes, 57, 59, 60

of DNA fragments, 39, 72

drug development through, 62-63

E. coli, 41

fingerprinting method for ordering, 42

fruit fly chromosomes, 42

gene isolation by, 31, 59

libraries of, 39, 42, 59, 62-63; see also contig maps

microdissection, 42

NIH grants for, 94

ordering of, 38-40, 41, 42

overlapping, 39, 42, 62, 100

phage lambda chromosomes, 36, 39, 42, 56, 100

repositories, 97, 101, 115

S. cerevisiae, 42

vectors, 35-37, 38-39, 42, 56, 67, 100

yeast artificial, 36-37, 39, 43, 56, 157

Cold Spring Harbor Laboratories Conference, 6

collaboration on genome research

by Australia, 148

by Center for the Study of Human Polymorphism, 8,

106, 143, 146, 149, 157

center-based vs. networking, 156

databases and repositories, 8, 139, 158-159

DOE, 157

existing frameworks, 155-157

European, 142, 150

International Human Gene Mapping Workshops, 29,

157

international] journals, 157-158

organizational options, 152-155

precedents for international scientific programs,

150-152

views on, 152-153

Washington University -RIKEN, 157

Collaborative Research, Inc.

DNA probe development, 58, 108

RFLP linkage map, 6, 30

collagen, 61, 67

color-blindness, 21

Columbia University

mapping of E. coli genome, 41

mapping of human chromosome 21, 44, 100

Compton, Arthur Holly, 99

computers, computational methods, and software

artificial intelligence, 96

costs, 180-181

for DNA sequencing, 65, 97

gene mapping applications to, 57, 146

networking, 156

NIH funding for improvements in, 95, 96

see also databases; informatics

Concertation Unit for Biotechnology in Europe, 140

consortia

of Federal/private interests, authority for, 16, 121

funding, 122

goals, 121

intellectual property rights, 122
209

Midwest Plant Biotechnology Consortium, 122

national, to administer genome projects, 14-15, 121-123

peer review, 122

two-tiered system, 122

contig mapping/maps

construction, 39, 40

correlation with large-fragment restriction maps, 42

forward genetics applications, 61

nematode, 42, 43

reverse genetics applications, 62

strategies, 43-44

yeast, 42

controversial issues

Big Science vs. small science, 125-128

DNA sequencing, extent of, 4, 6, 44, 57, 79, 81

feasibility of genome mapping, 4

quotes on, 126

resolution of genome mapping, 3, 79, 81, 88

see also ethical issues

corn, haploid DNA content, 25

Coulson, Alan, 44-45, 147-148

Crick, Francis H.C., 3, 21

cysteine, codon, 23

cystic fibrosis, 57, 58, 62, 149

cytidine, 21-22

Dana Farber Cancer Institute, 97

databases

access, to and ownership of, 12, 82, 102, 128, 134, 139,

146; see also technology transfer

Cell Line Two-Dimensional Gel Electrophoresis, 97

CODATA Hybridoma Databank, 141

DNA Data Bank of Japan, 139, 158

DNA fingerprints, 80

European support of, 141

funding for, 7, 12, 96-97, 141, 190

Genatlas, 157

GenBank”, 46, 96, 98, 109, 115, 139, 142, 154, 158,

190

genetic maps, 24, 98, 106, 189-190

government protection of, 87

HHMI, 7, 8, 98, 106

Human Gene Mapping Library, 106, 189-190

importance, 4, 9

international collaboration on, 8, 139, 158-159

Japan Protein Information Database, 159

linking of, 98

management of, 12

Martinsreid Institute for Protein Sequence data, 159

MEDLARSiMEDLINE, 97

mouse genetics, 106

National Library of Medicine, 7, 8, 12, 96, 97

needs for, 191-192

nucleotide sequence data, 46, 96, 98, 141, 158, 190

On-Line Mendelian Inheritance in Man, 24, 98, 106,

189-190

Protein Data Bank, 190-191

Protein Identification Resource, 97, 98, 158-159,

190-191

Dausset, Jean, 145-146

DeLisi, Charles, 100, 153

Denmark, national genome research efforts, 133, 143,

195

deoxyribonucleic acid, see DNA listings

Department of Defense, biomedical research resources,

104

Department of Energy

funding for genome projects, 7, 96, 100

Health and Environmental Research Advisory Committee report, 101-102

interest in massive sequencing, 9

international research collaboration, 157

as lead agency for genome projects, 12, 14, 116, 117

mission, 7, 99-100

Office of Health and Environmental Research, 99-101

organization, 99, 117-118

peer review, 101, 118

recommendations for genome projects, 4, 11, 100

research supported by, 100, 117

workshops sponsored by, 6, 100

see also Human Genome Initiative

determinism, effect of genome mapping on, 86

development, see human physiology and development

diabetes, 62

diseases

infectious, 64

linking mapping and sequencing data to, 104

see also genetic diseases; and specific diseases

DNA

amount relative to organism complexity, 24-25

C-value paradox, 24-25

cloning in plasmids, 36-37, 39

complementary, see cDNA

discovery, 3

electrophoretic separation of, 37-39

expendable fraction, 25, 57

fingerprints, 89; see also genetic screening

fragmentation of, 37-39

mitochondrial, 71

oldest human samples, 72

polymerase, 45

recombinant technology, see recombinant DNA technology

replication process, 21-22

structure, 3, 21-22

transcription to mRNA, 23-24

see also chromosomes

DNA markers, see chromosome markers

DNA probes

automated synthesis of, 47, 48

cDNA, 28-29, 32, 33, 59-61, 63

companies developing, 58

fluorescently labeled, 46-48

for genetic disease diagnosis, 58-59

in in situ hybridization, 33

number needed to complete human linkage map, 29

oligonucleotides, 48

radioactively labeled, 28-29, 32-33, 40, 44-46, 58

reliability, 58

for RFLP markers, 28-29, 56, 58, 61-62
—. . . —

210

synthetic, 48, 59-60

use to clone genes, 60

DNA Segment Library, 97

DNA sequence/sequencing

automation of, 47-48

commercialization, 82-83, 133, 138-139

computer-assisted, 65

controversies, 4, 6, 44, 79; see also ethical issues

costs, 6, 182-183

database, 46, 96, 98, 190

definition, 3, 21

directly from genomic DNA, 45

E. coli, 41, 100

enhanced fluorescence detection method, 46, 47

exons, 59, 61, 63, 65, 69

expenditures, federal, 8

facilities for, 13

government role in, 87

homeo box, 67-68

importance, 9

introns, 25, 30, 61, 65, 69-70

longest stretch determined, 46

of mitochondria, 71

mukiplex, 44-46

mutation detection applications, 56

NIH funding for, 8

rate, 46

repeated, 25, 28, 43, 57

RFLP mapping required for, 37-39

scanning tunneling microscopy for, 46

selective amplification without prior cloning, 45-46

species comparisons, 68-70

steps, 47

strategies, 44-45

technologies, 44-47

variations, 28, 29

VNTR, 29

Domestic Policy Council, 8, 105, 109, 119

Donis-Keller, Helen, 30

Down’s syndrome, 32, 35, 58, 95, 146

Drosophila melanogaster

amount sequenced, 47

genome mapping, 42-43

genome size, 47

salivary gland chromosomes, 30, 33

drugs and pharmaceuticals, development, 62-63

Duchenne muscular dystrophy, 57-59, 61-63

Duffy blood group, 27

Dulbecco, Renatto, 100, 126, 145

dwarfism, 64

dystrophin, 63

EG&.G Bimolecular) automated DNA sequencer, 47

E.I. du Pent de Nemours & Co., automated DNA sequencer, 47

electrophoresis, see gel electrophoresis

England, see United Kingdom

enzymes

functions, 22

see also specific enzymes

epidermal growth factor, 64

Epstein-Barr virus, 46

erythropoietin, 64

Escherichia coli

amount sequenced, 47

genome mapping, 41, 43, 100

genome size, 47

ethical issues

academic freedom, 87

access to and ownership of databases and repositories,

16, 82, 88

access to and use of genetic information, 79-80

attitudes and perceptions of ourselves and others,

85-86

commercialization, 16, 82-83, 133

diagnostic/therapeutic gap, 83

eugenics, 81, 84-85, 88, 143-144

genetic fingerprinting, 80

government role in mapping and sequencing, 87, 88

international competitiveness, 87-88, 133

physician practice, 83

reproductive choices, 83-84, 88

responsibility for considering, 123-124

eugenics

negative, 85, 143-144

of normalcy, 85

positive, 84-85

eukaryotes, 70-71

Europe, Eastern, interest in genome projects, 8, 133,

143, 195

Europe, Western, genome sequencing and mapping

activities, 139-148; see also specific countries and

organizations

European Economic Community, genome research, 139-

141, 153

European Molecular Biology Laboratory, 8, 139, 141-142,

158

European Molecular Biology Organization, 8, 141

European Research Coordination Agency, 142, 145-146

European Science Foundation, 142, 156

evolution, see molecular evolution

facilities for genome research

bioprocess engineering, 102

data handling, European needs, 142

DOE funding for, 100

flow cytometry, 32, 97; see also specific national laboratories

need for, 10, 128

NSF biology centers, 8, 102-103, 109

factor IX, 61

factor VII, 61

factor VIII:C, 64

familial hypercholesterolemia, 56, 58, 149

family pedigree projects

CEPH data set on, 58, 136, 146

Danish, 143

Egyptian, 134, 136

on mental illness, 156

South African, 149
211

use in genetic linkage mapping, 27, 33, 58, 61

Venezuelan, Huntington’s disease, 63-64, 134-136, 143,

146

fatalism, 86

Federal Advisory Committee Act, 124

Federal Republic of Germany, genetics research, 8, 133,

143-144, 195

fibroblast growth factor, 64

Finland, national genome research effort, 133, 144

flow cytometry

enhanced fluorescence detection in, for DNA sequencing, 46

extraction of whole chromosomes by, 37

facility, 32

France

Center for the Study of Human Polymorphism, 33, 58,

144-146

genome projects, 8, 144-145

published genome research, 133, 195

fruit fly

developmental regulation in, 67

Drosophila melanogaster, 30, 33, 42-43, 47

genome mapping, 42-43

haploid DNA content, 25

human DNA sequences compared with, 68

lethal mutations in larval stage, 42

funding for genome projects

advisory body for determining, 124

of consortia, 122

databases, 7, 12, 96-97, 190

determinants, 98

determinants of congressional appropriations, 11-12

DNA marker studies, 6

DOE, 7, 96, 100, 118, 190

European Economic Community, 139-143

HHMI, 7, 190

international, 8

NIH, 6, 7, 94-98, 117, 155, 190

NSF, 7, 8, 96, 190

pluralism in, 13, 15, 119

priority setting, 10

private vs. federal, 79, 83

recommendations, 4, 11-12, 107

through a lead agency, effects of, 12-13

through a national consortium, 14

USDA, 190

West German, 144

Gall, Joseph, 126

Galton, Francis, 84

gamma interferon, 64

gel electrophoresis

database, 97

DNA separation for phvsical mapping, 37, 39, 45

polyacrylamide, 45 “

pulsed-field, 37, 44, 56

in RFLP mapping, 28, 37, 58

GenBank”, 46, 96, 98, 109, 115, 139, 142, 154, 158, 190

gene expression

control of, 57

steps in, 23-24

study centers, 144

gene products

functions of, 67

with potential as therapeutic agents, 62, 64

gene therapy, 64, 141

genes

biochemical identification, 62

in a chromosome band, number, 33

color-blindness, 21

definition, 3, 21, 24

dosage mapping, 34

encoding ribosomal RNAs, detection, 33

expressed, 24, 30

families of, 25, 70

functions, approaches to understanding, 66-67, 73

homeotic, 68

isolation techniques, 31, 33, 59-62

largest, 63

linked, 26, 34; see also genetic linkage mapping/maps

mapping, see genetic linkage maps

species similarities in, 34

structure/function relationships, study of, 144

see also human genes

genes, human

aldolase, 33

chromosomal locations known, 4

number of loci identified, 24, 30

number per haploid genome, 24

sizes, 61

genetic code

definition, 21--24

for amino acids, 23

genetic diseases

chromosomal locations of genes for, 4

clinical services for, 100

companies developing DNA probes for diagnosis of, 58

correlating gross chromosomal abnormalities with, 32

diagnostic information, physician handling of, 83

family pedigree studies, 61, 63

HHMI support of research on, 8

isolation of genes associated with, 59-62

mechanisms, 4

not associated with biochemical defects, 61

polygenic, 62

RFLP markers for, 28, 56, 58

single-gene, 57, 88

see also specific diseases

genetic information

access to and use of, 79-80, 82, 84

causes of changes in, 25-26

insurer use of, 81, 83

organization and function, 21-26

genetic linkage mapping/maps

autoradiography use in, 29

autosomes, 27

costs, 181-182

databases, 24, 98, 106, 189-190

disease diagnosis applications, 56, 58, 62

distance measurements on, 27
212

early attempts, 4, 6, 21

electrophoretic technology in, 28

family pedigree data in, 27, 33, 58, 61

HHMI funding for, 7

medical applications, 56, 58, 62-64

number of markers needed to complete, 29-30

projects to link physical maps with, 181-182

purpose, 26-27

recombinant DNA technology use in, 28

resolution, 62

reverse genetics applications, 62

of RFLP, 28-30, 62

somatic cell hybridization for, 27

X chromosome, 27

genetic locus, see chromosome marker

genetic screening

ethical questions about, 80, 88

for missing children, 80

for proof of paternity, 80

genetic selection, see eugenics

genetics

definition, 21

forward, 59-61, 62-63

HHMI funding for, 7

molecular, NIH research resources activities related to,

97

NIH funding for, 95

population, 72-73

reverse, 59, 61-62

Genetics Institute, robotic devices for DNA sequencing,

48, 108

Genome Corp., physical mapping project, 108

genome mapping

agricultural applications, 73

application in developmental studies, 42, 65

automation, 47

determinism and, 86

distance measurements in, 40

evolutionary applications, 68-72

facilities, 13

importance, 9

international efforts and cooperation, 8, 9, 150-159;

see also specific countries

resolution levels in, 56, 79

see also genetic linkage mapping/maps; physical

mapping

genome mapping, human

commercialization, 82-83, 138-139

controversies, 3, 4, 6, 9, 44, 55, 57, 102

government role in, 87

priorities for, 88

scale of efforts, 5, 24

strategies, 43-46

genome mapping, nonhuman

bacteria, 4, 40, 41, 44

fruit fly, 42-43, 44

importance, 9, 44, 107

international efforts, 8, 42

nematodes, 4, 42, 44

plants, 73, 136, 149

yeast, 4, 41-42, 44

genome projects

accountability to Congress, 13, 14, 124

administration of, 12-15, 115-123, 184

advisory board structure for, 123-124

appropriations for, see funding

benefits, 11, 55, 56, 133, 172-174

Big Science v. small science approach, 120, 125,

127-128

center-based vs. networking, 156

collaboration on, 150-159, see also collaboration on genome research

commercialization potential, 82-83, 133, 138-139, 151,

165

common features, 7

component nature, 4, 6, 10

congressional oversight, 15-17

congressional role in, 11-17

consortium structure for, 14-15, 121-122

cooperation among agencies, 9, 15, 118-119

costs, 11-12, 4, 47, 180-185

definition, 4

displacement of other research by, 102, 125

duplication of efforts, 13, 82, 105

early estimates of costs for, 184-186

economic impacts, 165, 172

ethical considerations, 79-88

expenditures, Federal, 8

facilities, 10, 13

focus, 7-9

funding, see funding for genome projects

interagency coordination and communications, 8, 11,

123

interagency task force oversight of, 14, 119-121

international efforts on, 133-159; see also specific

countries

lead agency concept, 12-14, 115, 116-118

legislation, 12, 14, 123

manpower availability, 10

medical applications, 56-64; see also disease; medicine

military applications, 174

misconceptions about, 9-10

national prestige associated with, 174

objectives, 7, 9, 55

organization of, 12-15

organizations involved in, 6, 7

policy development for, 134

political interference with, 127-128

quality control and reference standards, 103, 127, 183

resource allocation for, 10; see also funding for genome projects

scope of, 10, 134

training of personnel, 183-184

U.S. competitiveness and, 11, 133

see also genome mapping; DNA sequenceshequencing;

Human Genome Initiative; pilot projects

genome, human

amount sequenced, 46-47
213

bibliometric analysis of research on, 133, 157-158,

size, 24, 43, 46-47

genomes

bacteriophage T4, 40

definition, 3, 21

Epstein-Barr virus, 46

mitochondrial, 71

organization, 21

regeneration, 21

size, 21, 24-25, 43

smallest, 148

genomic library, 35

Germany, see Federal Republic of Germany

Gilbert, Walter, 44-46, 126, 153, 156

glutamic acid, codon, 23

glutamine, codon, 23

glycine, codon, 23

granulocyte colony stimulating factor, 64

guanosine, 21-22

Gusella, James, 136

47

Harvard University, DNA sequencing, 44, 100

heart disease, 58, 62, 64

hemophilia, 56, 57, 58, 64

high-mobility group COA reductase, 61

Hill, Lister, 97

histidine, codon, 23

Hitachi, Ltd., automated DNA sequencer,

Hood, Leroy, 47, 126

hormones, 21

Howard Hughes Medical Institute

as lead agency for genome projects, 13

budget, 8

collaboration with CEPH, 146

databases, 7, 8, 98, 106

expenditures, 102, 106

funding, 7, 105, 109

genome initiatives, 8, 105-106, 109

mission, 7

RFLP mapping project, 6, 29

university centers, 106

Hpa 1, 28

Human Gene Mapping Library, 106, 189-190

Human Gene Mapping Workshop, 29, 106, 144, 157

Human Genetic Mutant Cell Repository, 31, 96, 190,

192-193

Human Genome Initiative

budget, 7-8, 101

expenditures, 7-8

justification for, 102

management, 6

objectives, 6, 7, 14

recommendations on, 101

stages, 101

workshops, 6

human growth hormone, 59, 62, 64

human physiology and development

genome mapping applications to, 65

NICHD-supported research, 95

195 Huntington’s disease, 28, 57, 58, 64, 83, 134-136, 146,

149

hybridization, see in situ hybridization; somatic cell

hybridization

hypercholesterolemia, 56, 58, 149

hypertension, 64

Imperial Cancer Research Fund, 148

in situ hybridization

cDNA mapping by, 30, 33-34

in mapping genes to whole chromosomes, 56

localization of fruit fly clones by, 42, 43

Index Medicus, 97

Industrial Biotechnology Association, opinions on Federal

initiatives in mapping and sequencing, 108

informatics

Advanced Informatics in Medicine, 141

Bioinformatics: Collaborative European Programs and

Strategy, 141

BIONETTM, 193

Contextual Measures for R&D in Biotechnology,

140-141

National Biotechnology Information Center, 193

infrastructure for genome projects

European, 141

Federal support, 8, 102

resource allocation, 10

Institute for Medical Research, somatic cell hybrid line

repository, 31

insulin, 21, 59, 61, 62, 64

Integrated Genetics, DNA probe development, 58, 108

intellectual property, protection of, see patent and copyright policies

IntelliGenetics Corp., 96

interleukin-2, 62, 64

International efforts on genome projects

collaboration and cooperation, 150-159; see also collaboration on genome research

see also specific countries

International Geophysical Year, 150-151

isoleucine, codon, 23

Italy, human genome research, 8, 133, 145-147, 195

Japan

automation of DNA sequencing equipment, 47-48, 137

basic science expertise, 137

collaboration on research, 157

commercialization of mapping and sequencing technologies, 133, 138

competitiveness with U. S., 133, 137-139

cooperation with U.S., 139

databases and repositories, 139

expenditures on genome projects, 8-9, 138

funding for genome research, 137

grants program in genetics, 9

Human Frontiers Science Program, 9, 137-138

mapping and sequencing research, 136-138

Ministry of Education, Science, and Culture, 9, 136-137

Ministry of International Trade and Industry, 137-138
—

214

peer review, 136

physical mapping of E. coli genome, 41

policy development on genome research, 136-137

published genome research, 133, 195

robotics technology, 137

Science and Technology Agency, 8-9, 137

workshop on DNA sequencing technologies, 47

karyotypes, human female, 34

karyotyping, 32-33, 56

Kennedy, John, 97

kidney diseases, 57, 58, 64

Kirschstein, Ruth, 94 n.1, 117

Koshland, Daniel, 126

Lalouel, Jean-Marc, 146

Latin America, genome research, 149

Lawrence Livermore National Laboratory

chromosome sorting, 100

mapping of chromosome 19, 44, 100

ordering of DNA clones, 100, 108

Lederberg, Joshua, 126

Ieucine, codon, 23

leukemia, 64

Levinson, Rachel, 94 n.1

libraries

of DNA fragments, construction of, 39

of overlapping clones, 38-39

see also repositories

life sciences

DOE funding for, 7

HHMI funding for, 7

NIH funding for, 7

NSF funding for, 7, 8

Lifecodes, DNA probe development, 58

ligase, 39

lily, haploid DNA content, 25

Lindberg, Donald A. B., 94 n.1

Los Alamos National Laboratory

chromosome sorting at, 32, 100-101

mapping of chromosome 16, 44, 100

ordering of DNA clones, 100

see also GenBank ”

Lovell, Joseph, 97

lowdensity lipoprotein receptor, 58, 61

lysine, codon, 23

microphage colony stimulating factor, 64

Massachusetts Institute of Technology, bioprocess engineering center, 102

Maxam, Alan, 44-46

Max Planck Society, 144

McKusick, Victor, 24, 98

medicine

diagnostic tool development, 56, 58-59

drug development, 62-63

human gene therapy prospects, 64

isolation of genes associated with diseases, 59-62

see also genetic diseases

meiosis, 26-27

Mendel, Gregor, 3, 73

Mendelian Inheritance in Man, 24, 98, 106, 189

Merriam, John, 42

messenger RNA

function, 23

size of human genes, 61

translation into protein, 23, 30

methionine

codon, 23

mitochondrial genome, human origin clues from, 71

molecular anthropology, 72

molecular biology

Big Science vs. small science, 125, 126-127

of human development, 65, 95

manpower in, 10

plant, genome mapping applications to, 73

molecular evolution

genome mapping and DNA sequencing applications to,

57, 68-72

human origins, 71

primate, 70

unanswered questions in, 69-70

monoamine oxidase, 86

Moskowitz, Jay, 94 n.1

Mount Sinai Medical Center Institute of Human Genomic

Studies, 100

mouse

beta globin gene, 65

cell hybridization, see somatic cell hybridization

genetic similarities to humans, 34, 67

genetics database, 106

haploid DNA content, 25

Mus musculus, amount sequenced and genome size,

47

muscular dystrophy

Becker’s, 63

Duchenne, 57-59, 61-63

mutations

artificially induced, 25

cancer from, 25

chromosome structural changes involved in, 25-26

deletion, 25, 31

detection of, 42, 56, 58, 59

duplication, 25

in fruit flies, 42, 68

Human Genetic Mutant Cell Repository, 31, 96, 190,

192-193

human rates, 72

inversion, 26

lethal, 42

in nucleotide sequence, 23

saturating screen technique for, 42

in sex cells, 25

in somatic cells, 25, 31

translocation, 25-26, 31

National Academy of Sciences

recommendations on genome projects, 107

role in genome project oversight, 14, 15, 124

views on international cooperation, 153

see also National Research Council
—

National Aeronautics and Space Administration, 150-151

National Biotechnology Information Center, 193

National Bureau of Standards, 103

National Cancer Institute, 93-94, 96, 98, 117

National Center for Biotechnology Information Act of

1986, 97

National Flow Cytometry Resource, 32, 97

INational Institute of Allergy and Infectious Diseases,

93-94

National Institute of Child Health and Human Development, 93-94, 95,

National Institute of General Medical Sciences, 93, 95, 94

National Institute of Neurological and Communicative

Disorders and Stroke, 93-94, 95

National Institute on Aging, 95

National Institute on Mental Health, 95

National Institutes of Health

budgets for genome projects, 8, 93

databases, see National Library of Medicine

expenditures for genome projects, 8, 93, 109

funding for genome projects, 6, 7, 14, 93-94, 95-97,

109, 155

genome project objectives, 8, 93-95

as lead agency for genome projects, 12, 13-14, 116-117

mission, 7, 93

organization, 93-94, 99, 116

origin, 93

peer review, 98-99, 109

research infrastructure, 96-98

research resources activities related to molecular

genetics, 97

see also specific institutes

working group on human genome, 94

national laboratories, see specific laboratories

National Library of Medicine, 7, 8, 12, 97-98, 117

National Research Council

physical mapping strategies, 44

recommendations for genome projects, 4, 11, 107, 116

sequencing strategies, 44

National Science Foundation

as lead agency for genome projects, 14

funding for genome-related research, 7, 8, 96, 102-103,

109

mission, 7, 102

role on genome projects, 116

nematodes

Caenorhabditis elegans, 42, 47, 147-148

genome mapping, 4, 42, 147-148

haploid DNA content, 25

human DNA sequences compared with, 68

mutant, 67

neurofibromatosis, 149

nucleotides

base order, 3, 21-22; see also DNA sequence/sequencing

bonding between base pairs, 21

dideoxynucleotide, 45

mutations in sequence of, 23

number of base pairs in human cells, 5

substitution and recombination rates, 70

total sequenced, 46

Office of Science and Technology Policy

Biotechnology Science Coordination Committee, 104

Committee on Life Sciences, 15, 104

interagency coordination of genome projects under, 8,

104, 109, 124

mission, 104

Office of Management and Budget, role in genome

projects, 105

Office of Technology Assessment

cost estimates for human genome projects, 180-185

workshop on genome projects, 4

oncogenes, 67

Organization of American States, 149

Oudtshoorn skin disease, 134, 149

Palade, George, 94 n.1

pandas, 36, 69

parasites, 64

parathJroid, 61

Pardue, Mary Lou, 33

Pasteur Institute, 145, 157

patent and copyright policies, 16-17, 82, 88, 166-170

Patent and Trademark Amendments of 1980, 16, 187

peer review

at DOE, 101, 109, 118

by Japan, 136

in a national consortium, 122

at NIH, 98-99, 109, 118

Pepper, Claude, 97

Perkin-Elmer Cetus Instruments

DNA sequencing technology, 45-46, 47

probe development, 58

phenylalanine, codon, 23

phenylalanine hydroxylase, 61

phenylketonuria, 57

Philipson, Lennart, 142, 152

physical mapping/maps

automation of, 47

bacterial genome, 41

bottom-up, 43

chromosome sorting for, 31-32, 56

comparative mapping of species, 34

construction of libraries of DNA fragments for, 38-39

contig, 30, 39, 40, 41, 43-44, 61

costs, 181-182

detail possible on, 37

distance measurements, 27, 40

forward genetics applications, 61

fragmentation of DNA for, 37-39

fruit fly, 42-43

gene dosage technique, 34

high-resolution, 30, 35-46, 56

human genome, 35--41, 43-46

in situ hybridization in, 33-34, 56

karyotyping in, 32-33, 56

linking of genetic maps with, 181-182

low-resolution, 30-35, 41, 43, 56

medical applications, 64

nematode genome, 42

NIH grants for, 84

nonhuman genomes, 41--43
216

ordering of clones for, 39, 40

private enterprises, 108

purification of chromosomal DNA for, 37

rapid, mass-analysis approach, 41

of restriction enzyme sites, 37-41

size determinants, 43, 81

somatic cell hybridization in, 27, 30-32, 33, 56

strategies, 43-44

time required for, 40-41

topdown, 43

yeast genome, 41-42

physicians’ attitudes and practice, effects of genetic information on, 83

physiology, see human physiology and development

Pickett, Betty, 94 n.1

pilot programs

DNA sequencing, 44

European, 140, 145, 147

importance, 4

NRC recommendations for, 107

yeast chromosome sequencing, 140

plants, genome mapping of, 73

polycystic kidney disease, 57, 58

polymerase, 45

population biology, genome mapping applications in, 72-

73, 134

President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral

Research, 85

private sector

foundation support, 109, 137, 147, 148

funding of genome projects, 14-15, 108, 109

genome mapping efforts, 9

government formation of consortia with, 14-15

role in genome projects, 107-108

technology development, 108; see also automation; robotics

see also specific companies

prokaryotes, lack of introns in, 69-70

proline, codon, 23

protein

classification by period of invention, 68-69

coding sequences, identification of, 65, 67

databases, 97, 98, 158-159, 190-191

engineering, 63, 142, 148

folding, 66

functions, 21-24, 67

kinase C, 61

life cycle regu]ator, 67

for single-gene diseases, identification of, 57, 59

structure/function relationship, 63, 65

synthesis, 23-24, 30

see also amino acids; enzymes; and other specific

proteins

publications

international, 157-158, 195

quagga, 72

recombinant DNA technology

cloning vector development through, 36, 38

definition, 24

use to create genetic linkage maps, 3, 24, 28

repositories for research materials

access to, 58, 134

American Type Culture Collection, 101, 141, 190, 192

Armed Forces Institute of Pathology, 104

Center for the Study of Human Polymorphism, 33, 58

clones, 97, 101, 115

costs, 182

DNA Segment Library, 97

family pedigrees, 58-59

Federal support, 8, 12, 96

Human DNA Probes and Libraries, 96

Human Genetic Mutant Cell Library, 31, 96, 190,

192-193

importance, 4, 9

international collaboration on, 158

tissue, 104

reproductive choices, ethical considerations in, 83-84, 85

restriction enzyme cutting

automation of, 47

infrequent, 41

partial, 39

restriction enzyme cutting sites

on bacteriophage T4 genomic map, 40

high-resolution physical mapping with, 35, 37-41

polymorphisms, see restriction fragment length polymorphisms

restriction enzymes

cDNA cutting with, 35

Hpa I, 28

Not I, 41

restriction fragment length polymorphisms (RFLP)

allelic forms, 28

diagnostic uses, 58, 59, 62

DNA probe detection of, 28-29, 61-62

linkage maps of, 28-30, 62

mapping of, 28-29, 62, 73

markers for genetic diseases, 28, 58, 62

retinoblastoma, 57, 59, 62

ribonucleic acid, see RNA

ribosomes

functions, 23

RIKEN-Washington University collaboration, 157

RNA

functions, 23-24

ribosomal, 23, 30, 33

see also messenger RNA; transfer RNA

structure, 22

robotics

devices for DNA sequencing, 48, 137

DNA extraction devices, 108

DOE initiative in, 7-8

microchemical, 48, 137

Saccharomyces cerevisiae

amount sequenced, 47

genome mapping, 41-42

genome size, 47

salamander, haploid DNA content, 24-25

Salmonella typhimurium, 45
217

Sanger, Fred, 44-45, 47

scanning tunneling microscopy, for DNA sequencing, 46

scleroderma, 64

Seiko, automation of DNA sequencing, 48, 138

Sendai virus, 31

SeQ, Ltd., physical mapping project, 108

serine, codon, 23

sex cells

mutations, 25

progenitors, 26

sickle cell disease, 4, 28, 56, 57, 58, 88

Singer, Maxine, 126

Sinsheimer, Robert, 100, 126

Smith, Cassandra, 41

Smith, Lloyd, 126

somatic cell hybrid lines, 31 n.2, 37

somatic cell hybridization

cDNA mapping by, 30

genome mapping applications, 27, 30-31, 33, 56

of single copies of chromosomes, 31

somatic cells

definition, 21

mutations in, 25, 31 n.2

South Africa, genome research, 133, 149, 195

Soviet Union, genome research, 133, 149, 195

Sulston, John, 147-148

superoxide dismutase, 64

Task Force for Biotechnology Information, 141

Tay-Sachs disease, 4

technology development

costs, 183

NIH grants for, 94-95

NRC recommendations for, 107

private sector role in, 108

see also automation; robotics

technology transfer

advantages of national consortium for, 14-15, 121-122

congressional encouragement of, 166

economic implications, 165, 122, 172

ethical issues, 87-88, 173-174

international, 172-174

military applications, 174

national prestige issue, 174

patent/copyright policies, 16-17, 82, 88, 122, 166-170

strategies for improving, 16

trade secrets, 170-172

Technology Transfer Act of 1986, 14, 16, 167

thalassemias, 57, 134

threonine, codon, 23

thymidine, 21-22

thyroglobulin, 61

Tinoco, Ignacio, 101

tissue p]asminogen activator, 64

Trademark Clarification Act of 1984, 167

transcription

of DNA into mRNA, 23-24, 25, 30

of introns, 25, 30

transfer RNA

functions, 23, 30

structure, 23

translation of mRNA into protein, 23-24, 30

Trivelpiece, Alvin, 101

tryptophan, codon, 23

tumor necrosis factor, 62, 64

Turner’s syndrome, 32, 64

tyrosine, codon, 23

United Kingdom

DNA sequencing, 44

equipment development, 48, 147-148

expenditures, 147

Medical Research Council, 42, 44, 147

national genome research effort, 147-148

nonhuman genome mapping, 8, 42, 147

published genome research, 133, 195

University of California at Los Angeles, clone library, 42

University of California at Santa Cruz, workshop, 6, 100

University of Copenhagen Institute of Medical Genetics,

143

University of Helsinki, 144

University of Manchester Institute of Science and Technology, 48, 148

University of Wisconsin at Madison, physical mapping of

E. coli genome, 41

valine, codon, 23

vectors

cloning of, 36, 38-39

cosmid, 36-37, 38, 42, 56, 101

plasmid, 36-37, 38, 47, 56, 67, 101

robotic devices for producing, 47

viral infections, 64

Wada, Akiyoshi, 152, 156

Walsh, James, 126

Washington University

collaboration with RIKEN, 157

physical mapping of yeast genome, 41

Watson, James D., 3, 21, 126, 152

Weinberg, Robert, 126

Wexler, Nancy, 135-136

White, Raymond, 29, 126, 146

Wilson, Allan, 126

workshops

on automation of DNA sequencing, 47

on collaboration for genome projects, 187

on costs of genome projects, 188

DOE-sponsored, 6, 97

European Economic Community, 141

International Human Gene Mapping, 29, 106, 144, 157

information management system applications, 97

on materials repositories and databases, 97

Matrix of Biological Knowledge, 193-194

NIH-supported, 96-97

OTA, 187-188

University of California at Santa Cruz, 6, 100

wound healing, 64

Wyngaarden, James, 93
218

yeast chromosomes lack of introns in, 69

artificial, 36, 39, 43, 56, 157 pilot project on sequencing, 140

electrophoretic separation of, 37 Saccharomyces cerevisiae, 41-42, 47

genome mapping, 4, 41-42, 157 similarities to other organisms, 67

haploid DNA content, 25 use to isolate human gene functions, 67, 68