Neural Grafting: Repairing the Brain and

Spinal Cord

October 1990

OTA-BA-462

NTIS order #PB91-114249
Recommended Citation:

U.S. Congress, Office of Technology Assessment, Neural Grafting: Repairing the Brain and

Spinal Cord, OTA-BA-462 (Washington, DC: U.S. Government Printing Office, September

1990.

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

Extraordinary developments in the neuroscience in recent years have shown promise of

new advances for treating diseases of the nervous system and for increased general

understanding of the human mind. Paralleling these developments has been a growing

congressional interest in their policy implications. The designation of the 1990s by the101st

Congress as the “Decade of the Brain” is one indication of this interest, as was the request

for OTA to undertake a series of reports under an assessment of “New Developments in

Neuroscience.” Requesting committees are the House Committees on Energy and Commerce;

Science, Space, and Technology; Appropriations; Veterans Affairs; and the Senate

Subcommittee on Science, Technology, and Space of the Committee on Commerce, Science,

and Transportation.

This special report, the second of our neuroscience series, discusses the field of neural

grafting into the brain and spinal cord to treat neurological disorders. It describes the

technology of neural grafting, the neurological conditions that it may be used to treat, and the

patient populations that are affected. Also, the legal and ethical issues raised by the

development of neural grafting techniques are discussed. The report includes a range of

options for congressional action related to the Federal funding of transplantation research

using human fetal tissue, the adequacy of existing Federal laws and regulations regarding the

use of human fetal tissue, and the role of the Federal Government in guiding the development

and promoting the safety and efficacy of neural grafting procedures.

The first publication in OTA’s assessment of “New Developments in Neuroscience”

was Neurotoxicity: Identifying and Controlling Poisons of the Nervous System, published in

April 1990. OTA was assisted in preparing the present study by a panel of advisers, a

workshop group, and reviewers selected for their expertise and diverse points of view on the

issues covered by the assessment. OTA gratefully acknowledges the contribution of each of

these individuals. As with all OTA reports, responsibility for the content of the report is OTA’S

alone.

KA.-# Y A .

JOHN H. GIBBONS

u Directo r

. . .

Ill
New Developments in Neuroscience Advisory Panel

Peter S. Spencer, Chair

Center for Research, Occupational, and Environmental Toxicology

Oregon Health Sciences University

Portland, OR

Robert H. Blank

Social Science Research Institute

Northern Illinois University

DeKalb, IL

James F. Childress

Department of Religious Studies

University of Virginia

Charlottesville, VA

Fred H. Gage

Department of Neuroscience

University of California-San Diego

La Jolla, CA

Bernice Grafstein

Department of Physiology

Cornell University

New York, NY

Ronald Kartzinel

Vice President for CNS Development

CIBA-GEIGY Corporation

Summit, NJ

Laurane G. Mendelssohn

Manager of Personnel Research

Lilly Research Laboratories

Indianapolis, IN

Franklin E. Mirer

Director, Health and Safety Department

United Auto Workers

Detroit, MI

Albert S. Moraczewski

Regional Director

Pope John XXIII Medical, Moral, Research,

and Education Center

Houston, TX

Herbert Paroles

Department of Psychiatry

Columbia University

New York NY

Richard M. Restak

Physician

Neurological Associates, P.C.

Washington, DC Alan Kraut

Executive Director

American Psychological Society

Washington, DC

Neural Grafts Study Panel

Roy A. E. Bakay

Section of Neurosurgery

The Emory Clinic

Atlanta, GA

Nancy Buc (ad hoc)

Partner

Weil, Gotshal & Manges

Washington, DC

Mary B. Mahowald

Center for Clinical Medical Ethics

University of Chicago

Chicago, 11

Jerry Silver

Department of Developmental Genetics

Case Western Reserve Univ.

Cleveland, OH

Robert P. Gale John R. Sladek, Jr.

Division of Hematology and Oncology Department of Neurobiology and Anatomy

University of California-Los Angeles University of Rochester

Los Angeles, CA Rochester, NY

Patricia King (ad hoc) H.Fred Voss

Georgetown University Program Director

Law Center Biotrack, Inc.

Washington, DC Mountain View, CA

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

members. The panels do not, however, necessarily approve, disapprove, or endorse this report. OTA assumes full responsibility

for the report and the accuracy of its contents.

i v
OTA Project Staff-Neural Grafting: Repairing the Brain and Spinal Cord

Roger C. Herdman, Assistant Director, OTA, Health and Life Sciences Division

Gretchen S. Kolsrud, Biological Applications Program Managerl

OTA Project Staff

David R. Liskowsky, Project Director

Timothy P. Condon, Project Director2

Monica Bhattacharyya, Research Assistant

Joyce Anne Brentley, Legal Analyst

Laura Lee Hall, Analyst

Wendy S. Pachter, Legal Analyst

Claire L. Pouncey, Research Assistant

E. Blair Wardenburg, Research Analyst3

Gladys B. White, Analyst 4

Patricia Anderson, NIH Detailees

Support Staff

Cecile Parker, Office Administrator

Linda Rayford-Journiette, Administrative Secretary

Jene Lewis, Secretary

Sharon Oatman, Administrative Assistant6

Contractors

Blair Burns Potter (editor), Bethesda, MD

Julie Phillips (indexer), Oakton, VA

Lori Andrews, American Bar Foundation

Alan Fine, Dalhousie University

Thomas B. Freeman, University of South Florida

Karen Gervais, University of Minnesota Center for Biomedical Ethics

William F. Hickey, Washington University

Ronald D. McKay, Massachusetts Institute of Technology

Rosa Lynn Pinkus, University of Pittsburgh

Ali H. Rajput, University of Saskatchewan

Imou@ September 1989

2mou@ August 1989.

3~ou@ August 1989.

4 Through June 1989.

5 Through October 1989.

6 Through February 1989.
Contents

Page

Chapter 1: Summary, Policy Issues, and Options for Congressional Action . . . . . . . . . . 3

Chapter 2: Introduction ... ... ... ... ... ... ... ... .*. ... .*. ... .$. .*. .$. . **@"$"""""""" 19

Chapter 3: Neuroscience Primer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .29

Chapter 4: General Features of Neural Grafting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39

Chapter 5: Applications of Neural Grafting Into the Brain and Spinal Cord . . . . . . . . . . 61

Chapter 6: Relevant Neurological Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93

Chapter 7: Legal and Regulatory Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113

Chapter 8: Ethical Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149

Appendix A: DHHS Moratorium on Human Fetal Tissue Transplantation Research . . 171

Appendix B: Participants in the Workshop on New Developments in Spinal Cord

Injury: Acute Interventions and Neural Grafts . . . . . . . . . . . . . . . . . . . . . . . . 174

Appendix C: Decade of the Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175

Appendix D: Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177

Appendix E: List of Contractor Documents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180

Appendix F: Acronyms and Glossary of Terms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .187
Chapter 1

Summary, Policy Issues, and

Issues for Congressional Action
CONTENTS

Page

GENERAL FEATURES OF THE NERVOUS SYSTEM AND

GRAFTING . . . .’. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

NEURAL

. . . . . . . . . . . . . . . . . . . . . . . . . 4

Therapeutic Strategies ... ... ... ... ... ... ..*. . o..........*..*....***.*.*+..******* 4

Materials for Neural Grafting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

Determinants of Successful Neural Grafting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

Potential Risks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

APPLICATIONS OF NEURAL GRAFTING INTO THE BRAIN AND

SPINAL CORD . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

RELEVANT NEUROLOGICAL DISORDERS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

LEGAL AND REGULATORY ISSUES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

Protection of Neural Graft Recipients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

Protection of Donors of Fetal Tissue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

Government Oversight . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

ETHICAL ISSUES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

POLICY ISSUES AND OPTIONS FOR CONGRESSIONAL ACTION . . . . . . . . . . . . . . . 11

Figure Page

1-1. Components of the Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

Figures

1-2. Methods Used To Graft Genetically Modified Cells . ......,..........*.**,..*,,. 6

1-3. National Institutes of Health 1989 Estimates of Costs of Neurological Disorders . . 7

Tables

Table Page

1-1. Prevalence of Neurological Disorders in the United States . . . . . . . . . . . . . . . . . . . . . . 3

1-2. Federal Funding of Neural Grafting Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
Chapter 1

Summary, Policy Issues, and Options for Congressional Action

Tens of millions of Americans suffer from some

form of neurological disorder. Some of these

disorders are minor and are easily treated with

medication or rest. Others are marked by severe,

debilitating symptoms and result in pain, suffering,

and sometimes death. Some neurological disorders

may be treatable by neural grafting—i.e., the

transplantation of tissue into the brain and spinal

cord (table l-l). Although few neural grafting

procedures have been carried out to date, the number

could increase in the future.

Neural grafting has long been used in basic

research to study the nervous system. In fact, much

neural grafting continues to be used as a tool for

understanding the development of the nervous

system and its response to injury. In addition to its

use as a research tool, however, neural grafting is

being examined as a possible therapy for neurological disorders. In the clinical arena, neural grafting

consists of the surgical transfer of tissue from

various sources into specific areas of the nervous

system that have been affected by a disease or injury.

This report focuses on the field of neural grafting

into the brain and spinal cord to treat neurological disease and injury.

Current treatments for neurological disorders

include drugs, surgery, physical therapy, and behavioral interventions. These treatments may improve

significantly as advances in the field of neuroscience

provide a better understanding of the causes and

Table l-l—Prevalence of Neurological Disorders

in the United States

Neurological disorder Prevalence

Alzheimer’s disease . . . . . . . . . . . . . . . . 1 to 5 million

Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.8 million

Epilepsy . . . . . . . . . . . . . . . . . . . . . . . . . . 1.5 million

Parkinson’s disease . . . . . . . . . . . . . . . . 500,000 to 650,000

Multiple sclerosis . . . . . . . . . . . . . . . . . . . 250,000

Spinal cord injury. . . . . . . . . . . . . . . . . . . 180,000

Brain injury. . . . . . . . . . . . . . . . . . . . . . . . 70,000 to 90,000’

Huntington’s disease . . . . . . . . . . . . . . . . 25,000

Amyotrophic lateral sclerosis . . . . . . . . . 15,000

a Estimate of persons permanently disabled from head injury.

NOTE: Prevalence is defined as the total number of cases of a disease

estimated to be in existence in the United States at any given time.

SOURCE: Office of Technology Assessment, 1990.

mechanisms of neurological injury and disease. For

most neurological disorders, current treatments do

not provide a cure, but rather relief of symptoms. It

is possible that neural grafting could provide a cure

in some cases where current treatments cannot (e.g.,

injury) or could bring about sustained relief from

symptoms where existing therapies either fail or lose

their effectiveness (e.g., certain diseases, such as

Parkinson’s). Because of this potential, transplantation of tissue into the central nervous system (CNS)

may become a significant therapeutic alternative in

the future.

Currently, grafting of tissue into the CNS to

treat neurological disorders is highly experimental. Neural grafting has advanced to clinical human

research only for the treatment of Parkinson’s

disease; for other applications, basic research is

continuing. (Federal funding of neural grafting

research is presented in table 1-2.) While several

strategies for the use of neural grafting have

emerged, much additional basic research is needed

to determine in what ways and to what extent neural

grafting may be beneficial. It has the potential for

treating damage to the brain and spinal cord, thereby

benefiting millions of Americans with impaired

neurological functions. Realizing the benefits of

neural grafting will depend on a better understanding of both the potential uses of neural

grafts and the mechanisms underlying neurological disorders.

This report is about the technology of neural

grafting, the neurological disorders that it may be

used to treat, the patient populations that might be

affected, and the issues raised by the development of

this technology. Two considerations related to the

development of neural grafting are:

. sources of materials for transplantation, and

● protection of human subjects in research.

In particular, concerns have been raised about

whether or under what circumstances to use human

fetal tissue as a graft material and when to move

from the laboratory to clinical research.

–3–
4 ● Neural Grafting: Repairing the Brain and Spinal Cord

Table 1-2—Federal Funding of Neural Grafting Research (in millions of dollars)

Agency 1987 1988 1989 1990a

National institutes of Health:

National institute of Neurological Disorders

and Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1 6.5 7.3 7.5

National Eye institute . . . . . . . . . . . . . . . . . . . . . . . . 1.2 1.4 1.6 1.6

National institute on Aging . . . . . . . . . . . . . . . . . . . . . 1.1 1.1 1.6 2.1

National institute of Child Health and

Human Development . . . . . . . . . . . . . . . . . . . . . . . — 0.2 0.4 0.4

Alcohol, Drug Abuse, and Mental Health

Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0.3 0.3 0.5 0.4

Department of Veterans Affairs. . . . . . . . . . . . . . . . . . . 0.4 0.5 0.5 0.5

National Science Foundationa . . . . . . . . . . . . . . . . . . . . 0.2 0.2 0.2 0.2

a Estimated.

SOURCE: Office of Technology Assessment, 1990.

GENERAL FEATURES OF

THE NERVOUS SYSTEM

AND NEURAL GRAFTING

The fundamentals of neural grafting are based

on an understanding of how the nervous system

grows and develops, how it responds to injury

and disease, and the mechanisms underlying

neurological disorders. The nervous system is

divided into the CNS and the peripheral nervous

system (PNS) (figure l-l). The brain and spinal

cord, which make up the CNS, are complex structures that control and regulate all of the activities and

functions of the body. Cells of the brain and spinal

cord are much more flexible in their ability to grow

and form interconnections during development than

in the fully formed CNS. Also, PNS elements can

regrow following an injury, even in an adult,

whereas regrowth in the CNS is extremely limited.

Neural grafting takes what is known about these

phenomena and the mechanisms underlying neurological disorders and tries to harness them to repair

the injured or diseased nervous system.

Neural grafting differs from organ transplantation, wherein an entire diseased or injured organ,

such as the heart or kidney, is replaced with a healthy

one. Although neural grafting may entail replacing

a diseased portion of the brain, animal experiments

suggest that it may also serve a number of other

functions and may use tissues from a variety of

sources. Thus, neural grafting is a generic term

that includes many different treatment goals and

materials.

Therapeutic Strategies

How a neural graft improves CNS function within

the graft recipient is not completely understood. In

fact, neural grafts display a wide range of potential

capabilities. These diverse functions lead researchers to predict that neural grafts may be employed

to accomplish different treatment goals in different neuropathological disorders. Continued research is necessary to determine precisely how

neural grafts function and how those functions can

benefit a graft recipient. Three possible functions of

neural grafts have been identified:

●

●

●

They may provide a continuous supply of

chemical substances that have been depleted by

injury or disease in affected regions of the brain

or spinal cord.

They may introduce new substances or cells

that promote neuron survival, neuron regrowth,

or both.

They may replace nerve cells in the CNS that

were lost to injury or disease.

Materials for Neural Grafting

Several types of biological materials maybe used

for neural grafting, each of which raises unique

technical issues. The most important determinant of

a particular material’s usefulness is its ability to

improve CNS function with minimal risk to the

recipient.

Tissue from the fetal CNS, because of its ability

to develop and integrate readily within a host

organism, has been extensively studied. Many

scientists consider fetal CNS tissue to be the most

effective material currently available for neural

grafting. However, ethical, social, and political
Chapter 1--Summary, Policy Issues, and Options for Congressional Action ● 5

Photo credit: C. Freed, Department of Medicine and Pharmacology,

University of Colorado

A portion of the dissected human fetal central

nervous system.

issues surrounding its use have been raised in the

United States and propel the search for alternative

materials. Other materials that are being examined

include PNS tissue; peripheral autonomic neurons;

tissue from outside the nervous system; and isolated,

cultured, or genetically engineered cells (figure 1-2).

Determinants of Successful Neural Grafting

To survive grafting, cells must endure mechanical

and metabolic disruption during preparation for

grafting, and they must incorporate into the foreign,

and potentially hostile, environment of the host. The

surgical technique and specific material used for

neural grafting are important determinants of success. Immature tissue can survive grafting more

readily than its mature counterpart. The ability of

grafted materials to avoid immunological rejection

by the host and to obtain ready access to nutritional

support and a supply of oxygen by becoming

incorporated with the host blood supply are major

determinants of graft survival.

Potential Risks

As with any surgical intervention, neural grafting presents risks to the recipient. Unfortunately,

many of the risks attributed to neural grafting are

either poorly understood or simply speculative.

Before neural grafting can become routine in humans, the risks must be carefully delineated, minimized, and measured against expected benefits.

Problems may result from complications associated

with the neurosurgery itself or immunological rejection of the graft. Concerns that grafts could induce

unwanted psychological effects, be a means for

Figure l-l-Components of the Nervous System

Z@R%. brain

PNS Y/y ~ ,7,

\*/

< :.

. . -:.. x....: . .. .. .

. .

., .:

. . . .

. . . .

. . .

. . . . . . *.>? ,. .

. . .-,. . . . .

1

..: . -.. +..,

.: ‘~,,,. *=—

@ii

t:

. . i~.> ‘ ““’ spinal

. -. . .. .

. . . . . <,

. . . . . cord . . . : “..,

. . 6 - .. . spi

ner

‘ W4W? spine

The nervous system is composed of the central (CNS) and

peripheral nervous systems (PNS).

SOURCE: C. Romero-Sierra, fVeuroanatorny, A Conceptual Approach

(New York, NY: Churchill Livingstone, 1986).

transmitting bacterial and viral infections, or grow

excessively once implanted have also been raised.

APPLICATIONS OF NEURAL

GRAFTING INTO THE BRAIN AND

SPINAL CORD

The technology of grafting into the brain and

spinal cord to restore functions lost through

disease or injury is still very much in the initial

stages of development. Research in animals has

indicated that neural grafting may provide beneficial

therapeutic effects in some neurological conditions,

notably Parkinson’s disease. But in every case,

including Parkinson’s disease, there is still much

information that needs to be collected before neural

grafting can be adapted for general use in humans.

Research currently being conducted in this field is
6. Neural Grafting: Repairing the Brain and Spinal Cord

Figure 1-2—Methods Used To Graft Genetically

Modified Cells

/

/

Grow cells

t

1° cells \

Culture cells

-

J~\EE/ $ Biochemical Genetic characterization

Select modified cells modification

SOURCE: F. Gage, Department of Neuroscience, School of Medicine,

University of California, San Diego.

aimed at learning more about basic mechanisms

involved in grafting tissues into the CNS and the

actions and effects neural grafts can exert there.

Scientists use many different kinds of experiments with animals to obtain this information. The

need for animal models that mimic a given neurological disorder in humans is as important in the field of

neural grafting as it is in most other areas of clinical

research. The closer an animal model is to the human

condition of interest (in terms of the neurological

damage induced and the behavioral effects that

damage produces), the easier it is to extend observations from the model to a human disorder. Virtually

all scientists in the field of neural grafting believe it

is essential to develop good animal models for use

in neural grafting experiments.

Neural grafting has been used to treat some

patients with Parkinson’s disease; however, this

clinical use of neural grafting, begun in the early

1980s, has generated controversy in the scientific

and medical communities. The tissue used has

come from two sources: the recipient’s adrenal gland

and the fetal CNS. In both cases, there is some

concern that the treatment has been used prematurely. In the case of adrenal grafting, many observers believe that there has been a rush to proceed with

human trials without having first collected adequate

data from animal experiments. In the case of fetal

tissue grafts, while there is a larger base of animal

data to draw on, there is still concern that widespread

implementation of human fetal tissue grafting could

Photo credit: J.R. Slade~ Jr.

A picture of a graft of monkey fetal tissue implanted into the

brain of an adult monkey.

proceed before adequate information has been derived from experimental studies.

As of 1990, between 300 and 400 persons with

Parkinson’s disease had received neural grafts

worldwide, with about 100 of them having received

fetal tissue grafts. In the United States, approximately 130 patients have been treated with adrenal

tissue, while fewer than 10 have had fetal tissue

implants. The use of fetal tissue for implantation is

limited in the United States to privately funded

ventures because the Secretary of Health and Human

Services has imposed a moratorium on Federal

funding of research involving the transplantation of

human fetal tissue obtained from induced abortions

into human subjects.

The question of whether clinical experiments

using grafting procedures to treat Parkinson’s disease patients should continue before additional data

are gathered from animal experiments is unan-
Chapter 1--Summary, Policy Issues, and Options for Congressional Action ● 7

swered. In the case of adrenal grafts, many persons

in the medical and scientific communities have

retreated from the rush of enthusiasm that accompanied their initial use. In the case of fetal tissue grafts,

many believe that questions can best be answered

with additional animal research, coupled with limited human experimentation.

The use of neural grafts for other neurological

disorders is still at the stage of animal experimentation. Much basic research is being conducted to

examine what role grafts might play in a variety of

neurological conditions. For neurodegenerative diseases (e.g., Huntington’s disease, Alzheimer’s disease, and motor neuron disease), the ability of grafts

to provide lost neurotransmitters, replace lost cells,

and stimulate growth in the diseased brain is being

studied. Neural grafts are being used in animal

models of brain and spinal cord injury in hopes of

reversing functional deficits by inducing regrowth or

replacing damaged areas. In conditions such as

epilepsy, neuroendocrine defects, and demyelinating diseases (i.e., multiple sclerosis), the ability

of grafts to supply specific chemicals to control or

reverse the effects of these disorders is being

examined.

Neural grafting holds the promise of new

treatments for neurological disorders, but a final

determination of its usefulness must await more

information about the mechanisms underlying

neurological disorders, graft functions, and how

those functions relate to various neurological

disorders.

RELEVANT NEUROLOGICAL

DISORDERS

Since neural grafting is in the very early stages of

development, predicting its ultimate utility is speculative at best. However, since current animal research intimates that neural grafting may be applied

to the study and treatment of diverse neurological

disorders, this technology may have a significant

impact on medicine and society.

Neurological disorders are a significant cause of

illness, disability, and death in the United States.

They cost, by conservative estimates from the

National Institutes of Health, more than $100 billion

per year in medical expenses and lost income (figure

1-3). Not all neurological disorders are amenable to

treatment by neural grafting. The Office of

Figure 1-3-National Institutes of Health 1989

Estimates of Costs of Neurological Disorders

Alzheimer’s disease

Stroke

CNS injury

Epilepsy

Movement disorders”

Multiple sclerosis

Amyotrophlc lateral

sclerosis t 1 1 1 1

0 10 20 30 40 50 60

Billions of dollars

● Parkinson’s and Huntington’s diseases.

NOTE: Costs are per year, including medical care, lost income, etc.

SOURCE: National institutes of Health.

Technology Assessment identifies those disorders

that may one day be treatable with grafting

technology. A disorder was considered treatable

if current understanding of its nature and cause

suggests that neural grafting may be a beneficial

treatment approach or if results from animal

experiments offer support for this possibility.

These neurological disorders afflict persons of all

ages. Adolescents and young adults are most likely

to suffer from epilepsy, head or spinal cord injury, or

multiple sclerosis; Huntington’s disease and

amyotrophic lateral sclerosis first appear in middle

age; stroke, Alzheimer’s disease, and Parkinson’s

disease afflict primarily the elderly.

Preventive measures can reduce the incidence of

CNS injury, but the causes of the other diseases are

unknown. While in every case the pathological

hallmarks of the disorder can be described, there is

no cure for the nerve cell death and abnormal

functioning that cause mortality and morbidity.

Research involving genetic analysis, molecular biology, and new drug development, as well as neural

grafting, continues to advance our understanding of

the various disorders and possible treatments for

them.

LEGAL AND REGULATORY

ISSUES

To the extent that Federal funds are used to

support research involving neural grafts or to pay for
8 ● Neural Grafting: Repairing the Brain and Spinal Cord

the clinical use of such procedures, Federal regulations govern the conduct of that research. Even if

Federal funds are not used, the Federal Government

has powers under the interstate commerce clause to

regulate neural grafting research. This power is the

basis for the establishment of the Food and Drug

Administration (FDA), the prohibition on payment

to organ donors for transplantation, and the regulation of medical laboratories engaged in interstate

commerce. The Federal Government may, under the

Public Health Service Act, regulate intrastate activities as necessary to prevent transmission or spread of

communicable diseases. However, questions have

been raised about the extent to which these mechanisms address neural grafting procedures. Some

existing Federal policies governing experimentation

and organ transplantation could affect tissue transplants, but they were developed before the recent

extensive debate on fetal tissue transplantation.

Protection of Neural Graft Recipients

Department of Health and Human Services

(DHHS) regulations apply to all research with

human subjects that is conducted or funded by

DHHS [45 CFR 46.101]; in addition, DHHS

regulations are used widely as guidelines by other

institutions, regardless of whether they receive

Federal funding. These regulations specific that

research protocols be reviewed and approved by an

Institutional Review Board (IRB), that selection of

subjects be equitable, and that informed consent be

obtained from each subject. IRB review is also

necessary for any product for which marketing

approval is sought from the FDA. Informed consent

is defined by Federal regulations which specify what

information must be provided to the research subject. Other Federal regulations pertain to research on

particularly vulnerable groups, including the mentally disabled, and provide guidelines for IRB

approval and informed consent related to research

involving these subjects. Such regulations may also

pertain to those experimental neural transplant

subjects who are mentally impaired. In research

programs where there is no Federal involvement

or influence, government oversight will depend

on whether there are State statutes, although few

States have statutes that address human experimentation in any detail.

Decisions regarding the safety and efficacy of

neural grafting materials are likely to come within

FDA jurisdiction. However, FDA’s role in regulating neural grafting materials is complicated by

the fact that there are several different types of

materials, each of which raises slightly different

questions. In addition, neural grafting materials

represent developing technologies that have not yet

been directly addressed by the FDA. The FDA has

jurisdiction over the manufacture and distribution of

materials that meet statutory definitions of drugs,

devices, or biologics. Safety considerations and the

FDA’s current regulation of similar products make

it likely that the agency will seek to regulate most

neural grafting materials. Questionable jurisdiction

under the Public Health Service Act could limit

FDA’s ability to regulate these materials, since it is

unclear whether neural tissue grafts, cell lines, and

products of biotechnology to be used as neural grafts

are analogous to the articles listed as biologics in the

statute. Other legal issues include questions of FDA

jurisdiction when a neural graft is produced and

performed intrastate and jurisdiction in relation to

the practice of medicine.

Unlike the intricate system of regulation to ensure

the safety and efficacy of articles intended for use in

the diagnosis, treatment, or prevention of disease in

humans, there is no direct Federal regulation of new

surgical procedures developed for the same purposes. New surgical procedures are usually subject

to IRB review and are regulated indirectly by

third-party payers, including Federal insurers such

as the Health Care Financing Administration, the

Department of Veterans Affairs, and the Department

of Defense, which decide whether or not to reimburse. Other forms of indirect regulation include

hospital standards set by the Joint Commission on

Accreditation of Healthcare Organizations, professional standards of practice, State licensing laws,

and medical malpractice cases. This system of

indirect regulation will preside over the development and introduction of neural grafting procedures using materials that fall outside the jurisdiction of the other Federal regulatory mechanisms.

Protection of Donors of Fetal Tissue

Since fetal tissue is one of the possible sources of

neural grafts, Federal regulations and State laws

governing the donation and use of embryos and fetal

tissue in research may apply. Federal regulations

[45 CFR 46.201-211] lay out specific guidelines

for research conducted on living fetuses. Under

these regulations, certain types of fetal research are
Chapter I-Summary, Policy Issues, and Options for Congressional Action ● 9

allowed, with constraints based on obtaining parental consent and minimizing risk to the pregnant

woman and the fetus. They defer to State laws on

the subject of research on fetal cadavers.

The overwhelming majority of State legislatures

have yet to address the issues associated with

experimental neural grafting using fetal tissue. Only

Missouri and Pennsylvania have enacted legislation

directed specifically toward fetal tissue transplants.

Although other States have not specifically addressed the question of neural tissue grafts from

fetuses, the general fetal research laws pertaining to

research on living fetuses, in effect in 25 States, may

come to bear on it. Of these 25 States, 14 have

provisions regulating research with fetal cadavers.

In addition, 16 of the State fetal research statutes

prohibit the sale of fetal tissue, 7 of them for any

purpose and 9 for research purposes. The most

significant factor in regulating research on dead or

live fetuses and in determiningg the extent of

restriction imposed appears to be whether the

research concerns a fetus that has been or is to be

intentionally aborted. Most of the State fetal research statutes were passed as part of abortion

legislation.

Government Oversight

Issues and questions raised by the introduction

and development of neural grafting procedures

could make other government regulatory mechanisms relevant. For example, issues and legal

questions regarding restrictions imposed on research

could be raised. Not all regulations on research are

constitutional. Laws restricting research may be

struck down as too vague or as violating the equal

protection clause of the Constitution. Laws applying

to experimentation on fetuses or in the context of

abortion may violate the constitutional right to

privacy. Some legal commentators posit that there is

a constitutional right to undertake or participate in

research; however, even if undertaking and participating in research were constitutionally protected,

certain restrictions to further health and safety could

be permissible.

Regulations regarding the disposition of cadavers, particular fetal remains, may be of

relevance. Most State statutes specify when fetal

deaths must be registered and how fetal remains are

to be disposed of. These statutes are important not

only because they provide penalties for unauthorized uses of dead bodies, but also because they

determine what must be done with fetal remains

once their research or clinical value has been

exhausted and what reports must be filed.

The Uniform Anatomical Gift Act (UAGA) is

of special significance because it is the only

uniform body of law that might be used to

regulate fetal tissue implants. Adopted in all 50

States, the UAGA regulates the donation and

distribution of cadaveric organs. While it includes

fetuses and their tissues, some States exclude these

provisions from their version of the UAGA. Because this Act was drafted before neural grafting

technology became known, it was not designed to

address the specific and unique problems that

fetal grafts raise, and some of its provisions may

not be appropriate for this use.

The possibility that women might be paid for fetal

tissue for transplants has raised particular concern

within some groups. The National Organ Transplant Act (NOTA) bans the sale of certain listed

organs (including certain fetal organs and their

subparts) [42 U.S.C. 274(e)] and provides that the

Secretary of Health and Human Services may list

additional organs. Since the brain, spinal cord,

and other components of the nervous system are

not listed as organs, payment for use of fetal

nervous system tissue for transplantation will not

be banned until the Secretary so designates. Apart

from NOTA, the procurement of fetal tissue is

regulated by State statutes.

ETHICAL ISSUES

Neural grafting technology is a complex subject

for ethical discussion because of the scope of the

issues it raises. Some ethical issues raised by neural

grafting are not unique to this technology, as they

concern the allocation of limited resources and the

tension between the Federal Government’s commitment to promote the public health by funding

biomedical research and its responsibility to respond

to public concern about certain research and its

possible applications.

Public funding of biomedical technology involves

broad analyses of economic benefits and costs, as

well as possible social benefits and ethical consequences of the new technology. Knowledge of

economic consequences is necessary for financial

planning, but it is also integral to ethical decisionmaking, since the allocation of public funds raises
10 ● Neural Grafting: Repairing the Brain and Spinal Cord

questions about justice and equity. Some people

believe that justice requires the expenditure of funds

in areas where they can benefit the greatest number

of persons. To resolve some of these questions, it

might be helpful to evaluate neural grafting in

relation to treatments for other diseases, keeping in

mind the priorities set and the amount of research

funded. In order to make decisions about funding

neural grafting research, it will be necessary to

estimate the efficacy of the technology, the number

of people now affected by the neurological disorder,

and the number likely to be affected in the future.

The use of various grafting materials and the risks

of surgery to recipients of grafts also raise ethical

issues. The most ethically problematic issue is the

use of fetal tissue. Fetal tissue from spontaneous

abortion or ectopic pregnancy has been suggested as

an acceptable source of graft material since this

tissue is free of association with elective abortion.

There is some question as to whether the physiological anomaly that caused the pregnancy to end would

also cause increased risk to the graft recipient after

implantation. While using fetal tissue from therapeutic or spontaneous abortions may avoid association of neural grafting with elective abortion, it may

not be a practical source of graft material.

Tissue obtained from electively aborted fetuses is

currently believed to be the most promising neural

graft material, but it is also the most controversial.

The primary impediment to resolving this ethical

issue has been the lack of consensus about the moral

relevance of elective abortion to any subsequent use

of the tissue. The positions taken on the morality of

fetal tissue grafting, however, do not necessarily

reflect a person’s beliefs about the morality of

abortion. Both supporters and opponents of

abortion rights have articulated reasons for

supporting fetal tissue grafting research, and

both have identified reasons for not doing so.

Although personal opinions on fetal tissue transplantation tend to be consistent with personal

opinions on elective abortion.

Arguments for and against the use of electively

aborted fetal tissue for neural grafting stem from

issues raised by current research and issues that may

be raised if neural grafting is accepted as standard

medical practice in the future. These include questions of whether the grafting procedure denies

respect for fetal life by using the fetus as a means to

an end. There has also been discussion of whether

groups besides fetuses, such as women and society

at large, maybe adversely affected by a policy that

endorses fetal tissue grafting. Some claims have

been made about the consequences of neural grafting

in the future, such as the effect this research may

have on the number of elective abortions performed

in the United States. Currently, there is no evidence

to support or refute the contention that fetal tissue

grafting research would cause an increase in the

number of abortions performed.

The use of small amounts of fetal tissue to start

cell lines that can be propagated in a laboratory may

allay some concerns about the consequences of

using electively aborted fetal tissue for neural

grafting. Such use complicates the issue of consent,

however, because questions are raised about

whether the tissue donor has property rights. For

example, although it maybe deemed appropriate for

a woman who aborts to consent to the use of fetal

tissue in a cell line, it may not be considered

appropriate for her to profit financially from it.

While questions regarding the ownership of tissues

used for commercially profitable cell lines are being

addressed by the courts, discussion has been limited

to the ownership of adult tissues. Questions pertaining to ownership of fetal tissue remain unanswered.

Controversy also exists about whether the woman

who elects to have the abortion is the appropriate

person to give consent for fetal tissue donation and,

if so, when consent should be solicited. Both the

regulations for the protection of research subjects

and those for the donation of body parts have been

suggested as models for fetal tissue donation, but

these regulations do not explicitly cover the donation of fetal tissue for transplantation research.

The ethical issues related to neural graft recipients

rekindle discussions about the treatment of research

subjects and the meaning of informed consent.

While these issues are not unique to neural grafting,

they may warrant special attention for this technology. Existing regulations may not adequately protect recipients from the risks unique to this surgery.

The possibility of doing a sufficient risk-benefit

analysis has been challenged on the grounds that not

enough research has been done to know what the

benefits of neural grafting are likely to be. Obtaining

informed consent may be difficult, both because the

risks and benefits cannot be realistically estimated at

this time and because persons with neurological

disorders may also have cognitive limitations.
Chapter I-Summary, Policy Issues, and Options for Congressional Action ● 11

POLICY ISSUES AND OPTIONS

FOR CONGRESSIONAL ACTION

Three policy issues related to neural grafting were

identified during the course of this assessment:

Federal funding of human fetal tissue transplantation research,

the adequacy of existing Federal laws and

regulations regarding the use of human fetal

tissue, and

the role of the Federal Government in guiding

the development and promoting the safety and

efficacy of neural grafting procedures.

Associated with each policy issue are several

options for congressional action, ranging from

taking no action to making substantial changes.

Some of the options involve direct legislative action.

Others involve the executive branch, but with

congressional oversight or direction. The order in

which the options are presented do not imply any

priority. Moreover, the options are not, for the most

part, mutually exclusive; adopting one does not

necessarily disqualify others within the same category or in any other category. A careful combination

of options might produce the most desirable effects.

It is also important to keep in mind that changes in

one area may have repercussions in other areas.

ISSUE 1: Should the Federal Government fund

human fetal tissue transplantation research?

A number of grafting materials are being studied

for their usefulness in ameliorating the symptoms of

neurological disorders. Neural tissue from human

fetuses is a promising source of neural grafting

material; however, the Department of Health and

Human Services (DHHS) has imposed a moratorium

on the use of Federal funds to support research

involving the implantation of human fetal tissue

from induced abortions into human patients. First

imposed in March 1988, the moratorium was extended indefinitely in November 1989.

Option 1: Take no action.

If Congress takes no action, it appears that the

moratorium will stand indefinitely, resulting in a

lack of Federal funds for both neural grafting and

other areas of research using human fetal tissue and

a consequent lack of Federal involvement in the

conduct of such research.

Photo 

As a result of the moratorium, research involving

the implantation of human fetal tissue from induced

abortions into human patients can only be funded by

private sources. Since the inception of the moratorium, a few privately funded efforts to examine fetal

neural grafts for the treatment of Parkinson’s disease

have been undertaken in the United States. The lack

of Federal support for these neural grafting studies

has limited the scope of Parkinson’s disease research

in the United States.

As basic research continues, neural grafting

techniques using human fetal tissue may be developed to treat other neurological disorders. The

transition from animal to human studies may be

difficult without Federal funding. Lack of Federal

funds for clinical studies could retard the development of these techniques in the United States,

leaving progress to be made by other countries,

where this research is continuing. Some observers

suggest that the moratorium has had the secondary

effect of discouraging basic research in neural

grafting, resulting in the channeling of investigators

into other areas of biomedical research.
12 ● Neural Grafting: Repairing the Brain and Spinal Cord

Privately funded clinical research is regulated

under applicable State laws. Although Federal

regulations, including review of research protocols

by a local Institutional Review Board (IRB), are

often voluntarily used to guide privately funded

research, there is no requirement that they be used.

Thus, in the absence of Federal funding, fetal tissue

transplantation research can proceed without the

oversight required for federally funded biomedical

research. This oversight includes the peer review

process established by funding agencies such as the

National Institutes of Health (NIH) or the Alcohol,

Drug Abuse, and Mental Health Administration

(ADAMHA), and without the steering function of

these agencies to ensure efficient, standardized

collection of data.

Option 2: Commission a study to assess the impact

on society of the lack of Federal funding for

human fetal tissue transplantation research.

Congress could commission a study by a governmental or nongovernmental agency, such as the

National Academy of Sciences, to assess the implications for society of the lack of support by the

Federal Government of fetal tissue transplantation

research. Public debate has highlighted a number of

areas that could be affected by Federal support of

this research, including the manner and timing of the

procurement of fetal tissue; the possible commercialization of fetal tissue; the conditions for informed consent for donation of the tissue; the effect

that the use of fetal tissue could have on the

incidence of abortion; and the implications that the

lack of Federal funding could have for the acquisition of new biomedical information and the development of new treatments for some neurological

disorders. To date, there has been no comprehensive

study of what effects Federal funding might have on

these areas. The results of such a study could be used

to guide policy decisions and develop guidelines for

Federal funding of fetal tissue transplantation research.

Option 3: Enact legislation to permit Federal

funding of human fetal tissue transplantation

research.

Congress could reinstate Federal funding of

human fetal tissue transplantation research and

introduce guidelines for its implementation through

direct legislative mandate. Guidelines could be

based on the recommendations of the NIH’s Human

Fetal Tissue Transplantation Research Panel, which

was convened under the direction of the Assistant

Secretary for Health in 1988. The DHHS Ethics

Advisory Board, which was disbanded in 1980,

could also be reconvened to propose guidelines.

Such legislation would most likely result in

increased research in neural grafting in the United

States. Increased research could clarify the role that

neural grafts might play in some neurological

disorders and could result in the development of new

therapies for those disorders.

On the other hand, some observers have expressed

the concern that if Congress takes this action and

research in this area were to increase, a number of

detrimental effects could ensue. Arguments made by

supporters of the moratorium include concerns that

Federal funding of human fetal tissue transplantation research might encourage induced abortion; that

the number of induced abortions in the United States

might increase; and that, in the absence of carefully

crafted guidelines, negative effects related to the

donation, procurement, distribution, and transplantation of fetal tissue could occur.

ISSUE 2: Do existing Federal laws and regulations governing organ transplantation adequately address concerns raised by human

fetal tissue transplantation?

Concerns over the possible commercialization of

fetal tissue and the lack of regulation of its use have

been raised in public debates about human fetal

tissue transplantation. Neither DHHS regulations for

the protection of human subjects [45 CFR 46] nor

the National Organ Transplant Act (NOTA) explicitly addresses the use of cadaveric fetal tissue in

neural grafting, although either could be amended to

do SO.

The DHHS regulations for the protection of

human subjects apply to research supported or

conducted by DHHS, although they are often

voluntarily followed for privately funded research.

These regulations impose specific conditions on

research involving living fetuses or their tissues.

With respect to research involving fetal cadavers or

the use of cadaveric fetal tissue, the regulations state

that research must be conducted according to State

and local laws. The extent to which other provisions

of the DHHS regulations apply to research using

tissue obtained from a fetal cadaver is unclear.

NOTA bans the sale of certain organs (including

fetal organs and their subparts) and provides that the
Chapter 1--Summary, Policy Issues, and Options for Congressional Action ● 13

Secretary of Health and Human Services may list

other organs. The brain, spinal cord, and other

components of the nervous system are not listed as

organs covered by NOTA.

The Uniform Anatomical Gift Act (UAGA),

which was drafted by the Commissioners on Uniform State Laws and adopted in all 50 States, is the

only other body of law that might be used to regulate

the use of cadaveric fetal tissue for neural grafts. It

provides guidelines for the donation and receipt of

cadavers for research, education, therapy, and

transplantation. The UAGA specifically includes

stillborn infants and fetal cadavers, although some

States have excluded fetuses from their provisions of

the law. However, some observers feel that there are

provisions of the UAGA that do not take into

account concerns raised by fetal tissue donation. The

UAGA allows the next of kin, starting with either

parent and following a fixed order of priority, to

donate fetal tissue and allows the donor of the tissue

to designate a recipient. It also allows consent for

donation to be sought immediately before death. If

this last provision were applied in the case of fetal

tissue, it might allow consent to be obtained from a

pregnant woman before an abortion. The ethics of

designating a recipient and obtaining consent for

donation before an abortion are controversial. The

question of who has the right to donate tissue from

an elective abortion has also been raised. Thus the

appropriateness of some of the provisions of the

UAGA for the regulation of the donation of fetal

tissue for transplantation is in question.

Option 1: Take no action.

In the absence of congressional action, no direct

Federal regulatory framework pertaining to the use

of cadaveric fetal tissue for transplantation would

exist. While some aspects of fetal tissue transplantation would continue to be covered under the UAGA

and other State laws, such regulations differ from

State to State. No specific regulations would pertain

to the use of cadaveric fetal tissue for transplantation

research supported by DHHS, and payment for fetal

brain, spinal cord, or other components of the

nervous system will not be banned by Federal law,

although it might be banned by State laws.

Option 2: Establish a congressional commission to

recommend Federal policy on human fetal tissue

transplants.

Congress could establish a commission to examine the comprehensiveness of existing legislation

and regulations surrounding the use of human fetal

tissue for transplantation. Such a commission could

suggest guidelines for regulating the donation,

procurement, distribution, and use of fetal tissue for

transplantation. Findings could be used to direct

further Federal regulatory and legislative action or to

amend the UAGA.

Option 3: Encourage the National Conference of

Commissioners on Uniform State Laws to amend

the Uniform Anatomical Gift Act.

Congress could encourage the Conference,

through a letter of request by a Committee or through

legislation, to amend the UAGA to take into account

the issues raised by the donation of cadaveric fetal

tissue. While the Conference is under no obligation

to respond to congressional initiatives, taking this

action would indicate Congress’ concern about the

appropriateness of some of the provisions of the

UAGA for dealing with fetal tissue donation.

Option 4: Direct the Secretary of Health and

Human Services to amend the current Department of Health and Human Services regulations

regarding the protection of human subjects.

Congress could direct the Secretary of Health and

Human Services to amend existing regulations to

address specifically the use of cadaveric human fetal

tissue for transplantation research. Such regulations

could guide the procurement, distribution, and use of

fetal tissue. If Congress takes this action, it would

result in the establishment of uniform, specific

regulations for the use of tissue from fetal cadavers

in federally funded research.

Option 5: Mandate that the brain and nervous

system tissue be added to the list of organs

covered by the National Organ Transplant Act.

NOTA lists certain organs (including those from

a fetus) that cannot be bought or sold and provides

that the Secretary of Health and Human Services

may add other organs to the list. The brain, spinal

cord, and other components of the nervous system

are not now on that list. Congress could add them,

either by amending NOTA directly or by directing

the Secretary of Health and Human Services to do

so. Taking this action would result in a Federal

injunction against the buying or selling of tissue

from the fetal nervous system and would thus ban
14 ● Neural Grafting: Repairing the Brain and Spinal Cord

the commercialization of fetal nervous tissue for use

in neural grafting procedures.

ISSUE 3: Should the Federal Government take

further action to guide the development and

promote the safety and efficacy of neural

grafting procedures?

The development of new medical and surgical

procedures, such as neural grafting, generally proceeds through a series of stages. First, basic research

is conducted using animal models and other experimental designs. Based on the results of these studies,

researchers may proceed to clinical research, prior to

introduction of the procedure as standard therapy.

However, unlike the elaborate Federal regulatory

framework that guides the development and introduction of new drugs and medical devices to ensure

their safety and efficacy, there is little direct Federal

oversight of the development and introduction of

new medical and surgical procedures.

Because of the diverse nature of neural grafting

materials, it is unclear where in the Federal regulatory framework neural grafting procedures will fall.

In addition, concerns have been raised about the

criteria that have been used to move neural grafting

from the laboratory to clinical research.

Option I: Take no action.

If Congress takes no action, the Food and Drug

Administration (FDA) could seek to regulate the

development of those neural grafting procedures that

use materials which fall under its jurisdiction. There

will be little or no Federal regulation of neural

grafting materials that do not come under FDA

oversight. In such cases, and in the absence of

congressional action, decisions concerning when the

transition from animal to human studies should

occur, how human research should be carried out,

and when a neural grafting procedure ceases to be

experimental will be made through traditional mechanisms for the development of new surgical procedures.

The decision to move from animal to human

studies, as was made for the use of neural grafts for

the treatment of Parkinson’s disease, is generally

made by individual researchers or institutions. For

federally supported studies, research protocols are

subject to the peer review process conducted by

Federal funding agencies and to DHHS regulations

for the protection of human subjects. These regulations require that research proposals be approved by

the local IRB; however, IRBs have no specific

criteria for moving from animal studies to human

trials. While nonfederally funded studies may be

submitted to local IRB scrutiny and may undergo a

peer review process, there is no requirement that

they do so. If Congress takes no action, the decision

of when a neural grafting procedure is ready to

proceed from animal to human experimentation will

be made in this way. Some observers believe that

this framework did not provide adequate guidance in

the case of neural grafting for the treatment of

Parkinson’s disease, resulting in a premature move

to clinical trials. Others believe that additional

oversight would be unduly burdensome and could

stifle scientific progress.

In clinical research, the designs of the studies and

the protocols followed are determined by the researchers involved. Coordination of efforts, to enhance the efficient collection and analysis of data (as

has been attempted in some trials of neural grafting

for the treatment of Parkinson’s disease), is sometimes undertaken voluntarily by professional societies, private organizations, or agreements between

research groups. Federal funding agencies can impose criteria for the conduct of research and thus

ensure more efficient data collection and analysis. In

the absence of congressional action, the development of neural grafting procedures in humans may

proceed in a fashion that does not optimize the

coordination of research efforts, which could result

in an inefficient collection of the data necessary to

make a determination about the safety and efficacy

of procedures.

Data collected during clinical trials guide the

transition from research to standard therapy. Neural

grafting procedures have not yet reached this stage,

but it is possible that they may. Clinical use and

availability of a procedure are indirectly regulated

by third-party payers, professional societies, State

licensing laws, and medical malpractice claims.

There is no direct Federal oversight of this process;

however, the Federal Government regulates it indirectly in its role as an insurer of medical care. The

Health Care Financing Administration (HCFA)

determines when sufficient information is available

to warrant Medicare or Medicaid coverage; HCFA

may also establish criteria that must be met by

facilities providing the procedure. The Department

of Defense, through the CHAMPUS insurance

program, and the Department of Veterans Affairs are
Chapter 1--Summary, Policy Issues, and Options for Congressional Action . 15

also third-party payers. The decisions of these

Federal agencies often influence private third-party

payers’ decisions to reimburse for a new medical or

surgical procedure and the medical community’s

decision to provide it.

The Agency for Health Care Policy and Research

(AHCPR), established within DHHS to promote

research on selected surgical and medical procedures in order to assess their appropriateness,

necessity, and effectiveness, could also play a role in

this process. If directed to do so, the AHCPR could

serve as a Federal mechanism for assessing neural

grafting procedures. In the absence of congressional

action, AHCPR may or may not choose to study

neural grafting procedures.

Option 2: Direct that the National Institutes of

Health establish guidelines for neural grafting

research protocols with humans.

Congress could direct the Secretary of Health and

Human Services, through NIH, to provide IRBs and

peer review boards with guidelines concerning

proposed grafting research projects using human

subjects. Such guidelines could provide information

about the status of the procedure, what animal

research has been conducted, and whether sufficient

data have been collected to warrant the transition

from animal to human studies. These guidelines

could be used to direct decisions regarding federally

funded research proposals and provide guidance for

decisions about nonfederally funded studies.

Option 3: Direct the Secretary of Health and

Human Services to coordinate federally funded

human neural grafting trials in order to optimize

the collection of data.

Congress could direct the Secretary of Health and

Human Services, through NIH and ADAMHA, to

coordinate federally funded human neural grafting

trials. Such coordination could take a number of

forms, such as designating specific centers to carry

out experimental trials using uniform protocols and

procedures or requiring federally funded studies to

follow specified guidelines concerning experimental design and the collection of data. By taking this

action, Congress could ensure that federally funded

experimental trials to determine the safety and

efficacy of neural grafting procedures would proceed in the most efficient manner.

Option 4: Mandate that the Agency for Health Care

Policy and Research monitor the development of

neural grafting procedures.

The AHCPR, through the Medical Treatment

Effectiveness Program, assesses the medical effectiveness and patient outcomes associated with selected medical and surgical procedures. Congress

could direct AHCPR to assess the development of

neural grafting procedures and develop guidelines

for the use of these procedures.
Chapter 2

Introduction
CONTENTS

Page

NATURE OF NEUROLOGICAL DISORDERS . .......,?*..........*..*,*,.....,.* 20

Injury ... .*. ... ... ... ... ... ... ... ... ... ... ... ..*. ... .*. ... **+ ** c**+**a.**G****. 20

Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . *.***..........*....,*. 20

APPROACHES TO TREATMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .21

HISTORICAL PERSPECTIVE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

FEDERAL INTERESTS . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

THE OTA STUDY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

CHAPTER 2 REFERENCES ... ..*. ..*. ... ... ... ... ... ..*. +

.. ..*** e.**. ..*** .. t**** 24

Figure

Figure Page

2-1. Annual publications on Grafting Into the Nervous System . . . . . . . . . . . . . . . . . . . . . . 22

Tables

Table Page

2-1. Tissue and Organ Transplants in the United States, 1989 . . . . . . . . . . . . . . . . . . . . . . . 19

2-2. Landmarks for Neural Grafting in Mammalian Central Nervous Systems 23

2-3. Federal Funding of Neural Grafting Research

. . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
Chapter 2

Introduction

Tens of millions of Americans suffer from some

form of neurological disorder. Some of these

disorders are minor and are easily treated with

medication or rest. Others are marked by severe,

debilitating symptoms and result in pain, suffering,

and sometimes death. These conditions include

dementias, such as Alzheimer’s disease; movement

disorders, such as Parkinson’s disease; damage

caused by stroke or injuries to the brain or spinal

cord; and epilepsy. Some of these neurological

disorders may be treatable by neural grafting—

i.e., the transplantation of tissue into the brain

and spinal cord.

In 1989, over 500,000 Americans received tissue

or organ transplants. The vast majority of these

operations involved transplantation of bone, cornea,

kidney, liver, heart, pancreas, lung, and bone marrow (table 2-l). A small number of procedures,

however, involved neural grafts. Although few

neural grafting procedures have been carried out to

date, the number could increase in the future.

The use of neural grafting in the laboratory is

not new. It has long been used in basic research to

study the nervous system. In fact, much neural

grafting continues to be used as a tool for understanding the development of the nervous system and

its response to injury. In addition to its use as a

research tool, however, neural grafting is being

examined as a possible therapy for neurological

disorders.

In the clinical arena, neural grafting consists of the

surgical transfer of tissue from various sources into

specific areas of the nervous system that have been

affected by disease or injury. The ability of neural

grafts to repair injured nerves in the peripheral

nervous system has been studied fairly extensively.

Examination of the potential therapeutic effects of

neural grafts within the central nervous system

(CNS) (i.e., the brain and spinal cord) is a more

recent field of study. This report focuses on the

field of neural grafting into the brain and spinal

Table 2-l—Tissue and Organ Transplants in

the United States, 1989

Material transplanted Number

Bone or bone fragment . . . . . . . . 450,000 (approximate)a

Cornea . . . . . . . . . . . . . . . . . . . . . 36,900’

Kidney . . . . . . . . . . . . . . . . . . . . . . 8,886

Bone marrow . . . . . . . . . . . . . . . . 2,500 (approximate)

Liver . . . . . . . . . . . . . . . . . . . . . . . . 2,160

Heart . . . . . . . . . . . . . . . . . . . . . . . 1,673

Pancreas . . . . . . . . . . . . . . . . . . . 412

Lung . . . . . . . . . . . . . . . . . . . . . . . 89

Heart and lung . . . . . . . . . . . . . . . 70

Neural . . . . . . . . . . . . . . . . . . . . . . <30

a 1998~

SOURCE: United Network for Organ Sharing; American Association of

~ssue Banks; Eye Bank Association of America; North American Autologous Transplant Registry; International Bone Marrow

Transplant Registry; Office of Technology Assessment, 1990.

cord to treat neurological disorders. It is about

the technology of neural grafting, the neurological disorders that neural grafts may be used to

treat, the patient populations that might be

affected, and the legal and ethical issues raised by

the development of this technology.

Although therapeutic neural grafting into the CNS

of humans is relatively new, several strategies for its

use have emerged. These strategies can be grouped

as follows:

● grafts to replace lost chemicals of the nervous

system;

● grafts to stimulate growth and promote survival

of cells in the nervous system; and

. grafts to replace lost structures in the nervous

system.

Much additional basic research is needed to

determine in what ways and to what extent neural

grafting may be beneficial. It has the potential for

treating damage to the brain and spinal cord, thereby

benefiting millions of Americans with impaired

neurological functions. Realizing the benefits of

neural grafting will depend on a better understanding of both the potential uses of neural grafts and the

mechanisms underlying neurological disorders.

–19-
20 ● Neural Grafting: Repairing the Brain and Spinal Cord

NATURE OF NEUROLOGICAL

DISORDERS

Injury

Injury to the CNS can result from mechanical

damage to the brain or spinal cord (e.g., skull

fracture, concussion, wounds from projectiles,

broken backs) or a disruption in the normal flow

of blood to the brain (e.g., stroke). It can result in

short- or long-term impairment. Blunt injury to the

head, for example, can result in immediate but

short-term unconsciousness that has no lasting

effect. Blunt injury to the head can also cause severe

trauma to the brain (swelling, decreased blood flow,

lack of oxygen, and massive cell death), resulting in

permanent paralysis, loss of the sense of touch or

ability to feel pain, loss of cognitive function, or

death. Severe trauma, such as that which can occur

in automobile collisions or sports injuries, can cause

profound and often permanent damage to the spinal

cord. Such damage usually results in paralysis and

severe physical disability. The ability of grafted

material to replace tissue lost through injury and to

promote recovery following an injury is a major area

of investigation.

Disease

The brain and spinal cord are complex and fragile

organs susceptible to a number of diseases. Among

them are neurodegenerative disorders, demyelinating disorders, and epilepsy.

Neurodegenerative Disorders

Neurodegenerative disorders are a class of

neurological diseases marked by the loss of

specific nerve cell population(s) in the brain or

spinal cord. In most cases, the cell loss is a gradual

progression that continues indefinitely. Neurodegenerative disorders include Parkinson’s disease,

Huntington’s disease, Alzheimer’s disease, and

amyotrophic lateral sclerosis (Lou Gehrig’s disease). The nature of the functional loss or impairment associated with a neurodegenerative disorder

is directly related to the population of neurons

affected. In Parkinson’s disease, for example, the

loss of dopamine-producing cells in the substantial

nigra results in such motor symptoms as tremors and

rigiditv. while in Alzheimer’s disease loss of acetylcholine-producing cells in the forebrain results in

cognitive deficits such as memory loss and confusion. Although the cause of the selective loss of cell

populations in neurodegenerative disorders remains

unknown, it is possible that multiple factors are

responsible. It is also possible that the ultimate

mechanism of cell death in these disorders may be

similar, although the stimuli that trigger the mechanism could be quite different in each.

Neural grafting might play a number of roles in

treating neurodegenerative disorders or their symptoms. Neural grafts could replenish chemicals that

have been depleted by cell loss, replace the lost cells

with new ones that could reestablish contacts with

other brain cells, or furnish growth factors that could

protect threatened cells or stimulate new growth

from other cells. All of these potential applications

are being studied in animal models and other

experimental paradigms to determine their feasibility.

Photo credit: National Institutes of Health

A patient undergoing a brain scan.
Chapter Introduction ● 2 1

Demyelinating Disorders

Demyelinating disorders are marked by loss of

the fatty material (myelin) that surrounds many

axons in the brain and spinal cord. When a cell

loses this myelin sheath, its ability to send messages

is impaired. Myelin loss can be caused by certain

types of injuries and by disease. One of the most

common demyelinating diseases is multiple sclerosis. The ability of grafted myelin-producing cells to

replace myelin lost as a result of disease or injury is

currently being explored.

Epilepsy

Epilepsy is a disruption of the normal electrical

activity of the brain. It can occur in a specific,

confined area of the brain, or it can involve the entire

brain. The seizures normally associated with epilepsy result from an episode of abnormal electrical

activity in the brain. Epilepsy can occur spontaneously or as a result of disease or injury to the brain.

Neural grafts are being examined in animal research

for their ability to curtail the number and severity of

epileptic seizures.

APPROACHES TO TREATMENT

Current treatments for neurological disorders

include drugs, surgery, physical therapy, and behavioral interventions. For most disorders, current

treatments do not provide a cure, but rather relief of

symptoms. Nevertheless, treatments are likely to

improve significantly as advances in the field of

neuroscience provide a better understanding of the

causes and mechanisms of neurological injury and

disease. It is possible that neural grafting could

provide a cure in some cases where current treatments cannot (e.g., injury) or could bring about

sustained relief from symptoms where existing

therapies either fail or lose their effectiveness (e.g.,

certain diseases, such as Parkinson’s disease).

Currently, grafting of tissue into the nervous

system to treat neurological disorders is highly

experimental. It is just beginning to emerge into the

clinical arena, and there is a great need for basic

research to determine the scope of its effectiveness

in a variety of disorders. To date, neural grafting has

only been used to treat a relatively small number of

patients. However, because of its potential to

replace damaged nerve cells, restore chemicals

lost through injury to nerve cells, and stimulate

nerve cell growth and regeneration, grafting of

tissue into the CNS may become a significant

therapeutic alternative in the future.

HISTORICAL PERSPECTIVE

The first report of attempted tissue transplantation

into the brain is attributed to W.G. Thompson, an

American scientist. Thompson published a brief

account of his animal experiments in 1890 (3). A

number of reports followed over the next 20 years,

but it was not until 1917 that E. Dunn frost

demonstrated that CNS tissue transplanted from

newborn rodents into adult rodents could survive

over an extended period of time, provided the

transplanted tissue was in an immature, developing

state. During the following 50 years, only occasional

reports on transplantation into the CNS appeared. In

the last 20 years, however, there has been an

explosion of experimental work in this area

(figure 2-l). Some historical landmarks in neural

grafting into the mammalian CNS are presented in

table 2-2.

The vast majority of neural grafting experiments to date have been conducted on animal

models (e.g., rodents and nonhuman primates).

The first grafting experiments on humans were

undertaken in 1982 in Sweden in an attempt to

treat Parkinson’s disease (2). The Swedish group

implanted dopamine-producing cells into the brains

of Parkinson’s disease patients whose medication

was no longer effective. The cells came from each

patient’s own adrenal gland in order to minimize the

chances of rejection by the body’s immune system.

It was theorized that replacing the lost dopamine in

the brain would ameliorate some of the characteristic

symptoms of Parkinson’s disease. From 1982 to

1984, neural transplants were performed on four

patients. The patients, however, did not show any

significant, long-term improvement (7).

In 1986, a neurosurgical team from Mexico City

announced substantial amelioration of most of the

clinical signs of Parkinson’s disease after transplanting adrenal tissue to the patient’s brain (10). Based

on the success reported by this group, many other

groups attempted the procedure, and by mid-1989

over 300 patients in at least six countries (Sweden, Mexico, United States, Cuba, Spain, and

China) had received adrenal cell transplants,

with mixed results.

Since many researchers failed to achieve the level

of success reported by the Mexican group, a number
22 ● Neural Grafting: Repairing the Brain and Spinal Cord

Figure 2-l—Annual Publications on Grafting Into the Nervous System

200

150

100

50

U.J.AuA

1890 1900 1910 1920 1930 1940 1950 1960 1970 1980 1988

Year

SOURCE: Adapted from J.R. Sladek, Jr., and D.M. Gash (eds.h Neura/ Tramdants: fkdomnent and/%nction (New .

Yo~, NY: Plenum Press, 1984).

.,

of the transplant groups in the United States

suspended neural grafting with adrenal cells. Some

groups raised questions about the efficacy of this

approach in humans, the amount of animal experimentation done prior to use of the procedure on

Parkinson’s patients, and the magnitude of effect

seen in these animal studies (12). However, reports

of limited success in treating Parkinson’s patients

with neural grafting of adrenal cells continue to

appear in the scientific literature (1,5,6).

In 1988, grafting of human fetal CNS tissue

into the brain was announced by the same

Mexican and Swedish research groups that had

previously performed adrenal cell transplants in

Parkinson’s patients (9,11). Subsequently, several

centers around the world—in the People’s Republic

of China, Cuba, Spain, Great Britain, and the United

States-began performing these procedures. Fetal

CNS tissue was chosen for grafting because developing tissue is more likely to become integrated in

the brain and restore lost or damaged nervous system

functions than mature CNS tissue. Despite the more

extensive animal research preceding this move to

human experiments, concerns were still raised about

the efficacy and experimental nature of this treatment for Parkinson’s disease. The use of human

fetal tissue from elective abortions has also raised

ethical questions. Recently, some beneficial effects

from human fetal tissue grafts have been reported in

a limited number of Parkinson’s disease patients

(4,8).

In a few instances, neural grafting has been

attempted inpatients suffering from other neurological disorders. (See ch. 5 for a complete description

of the history of neural grafting in Parkinson’s

disease and its use to date in other disorders.)

FEDERAL INTERESTS

As is often the case in the biomedical sciences, the

development of neural grafting has raised scientific,

legal, and ethical issues, including:

● protection of human subjects in research, and

● sources of tissue for transplantation.

The role of the Federal Government in the

research, development, and regulation of neural

grafting is questioned by some parties.

A continuing question in biomedical research

is when to move from the laboratory to the

clinical arena. How much animal experimentation

should be conducted before performing new or

innovative procedures on humans? What kind of

animal experimentation should be conducted? How

should the results be assessed? What mechanisms

and safeguards exist to guide the development of
Chapter Introduction ● 2 3

Table 2-2—Landmarks for Neural Grafting in Mammalian Central Nervous Systems

Year Researcher Accomplishment

1890

1898

1907

1909

1911

1917

1921

1924

1940

1957

1979

1982

1985,

1986

1987

W.G. Thompson (U. S.A.) . . . . . . . . . . . . . . . . . .

J. Forssman (Sweden) . . . .’.. . . . . . . . . . . . . . .

G. Del Conte (Italy) . . . . . . . . . . . . . . . . . . . . . . .

W. Ranson (U. S.A.) . . . . . . . . . . . . . . . . . . . . . .

F. Tello (Spain) . . . . . . . . . . . . . . . . . . . . . . . . . .

E. Dunn (U.S.A.) . . . . . . . . . . . . . . . . . . . . . . . . .

Y. Shirai (Japan) . . . . . . . . . . . . . . . . . . . . . . . . .

G. Faldino (ltaly) . . . . . . . . . . . . . . . . . . . . . . . . .

W.E. LeGros Clark (U.K.) . . . . . . . . . . . . . . . . . .

B. Flerko and J. Szentagothai (Hungary) . . . . .

A. Bjorklund and U. Stenevi (Sweden)

M.J. Perlow et al. (U.S.A.) . . . . . . . . . . . . . . . . . .

E.O. Backlund et al. (Sweden) . . . . . . . . . . . . . .

R.A.E. Bakay et al. (U.S.A.)

D.E. Redmond et aL (U.S.A.) . . . . . . . . . . . . . . .

O. Lindvall et al. (Sweden)

l. Madrazo et al. (Mexico); . . . . . . . . . . . . . . . . .

Attempt to graft adult CNS tissue into brain

Neurotrophic effects of grafted CNS tissue

Attempt to graft embryonic tissues into brain

Successful grafting of spinal ganglia into brain

Successful grafting of peripheral nerve into brain

Successful grafting of neonatal CNS tissue into adult brain

Demonstration of brain as an immunologically privileged site

Successful grafting of fetal CNS tissue into anterior eye chamber

Successful grafting of fetal CNS tissue into neonatal brain

Successful intraventricular grafting of endocrine tissue

Functional recovery after grafting dopamine-producing cells into the brain

Human neural graft with adrenal chromaffin cells (autograft)

Reversal of experimentally induced Parkinson’s disease in nonhuman

primates

Human fetal tissue graft (allograft)

NOTE: All experimental work performed in animals unless otherwise indicated.

SOURCE: Ada@ed from A. Bi&klund and U. Stenevi (eds.), “lntracerebral Grafting: A Historical Pers@ctive,” Neural Grafting in the Mamm~ian CNS

(Amsterdam: Elsev~er Science Publishers, 1985).’

new treatments from conception and evolution in the

clinical research environment to accepted medical

practice?

In its efforts to protect the public health, the

Federal Government regulates one important aspect

of medical care, namely, the development, testing,

and marketing of drugs, biologics, and medical

devices. Are similar regulatory schemes necessary

or desirable to protect patients’ welfare in clinical

trials of medical and surgical procedures? Is the

present system of Institutional Review Boards,

under the auspices of the Department of Health and

Human Services, adequate to safeguard patients in

cases of experimental surgical procedures? When

does an experimental surgical or medical procedure,

such as neural grafting, become standard therapy?

Related to these questions is the issue of the type

and function of the material to be grafted. There are

many possible sources of material for neural

grafts. One is cultured and genetically manipulated

cells. Because of the nature and possible functions of

these materials (e.g., as drug delivery systems),

regulation would probably fall under the jurisdiction

of the Food and Drug Administration (FDA).

Another possible source of material is unmanipulated tissue from other organs or fetal tissue. These

substances may not be regulated by the FDA, since

they do not fall under its jurisdiction and their use as

neural grafting material may be considered the

practice of medicine. Thus, depending on what

material is used, there may or may not be direct

Federal oversight of neural grafting technologies.

An issue of particular concern is the procurement and use of human fetal tissue for neural

grafting procedures. Because of its unique characteristics, human fetal tissue is a widely used source

of neural grafting material. Although many scientists believe that it may ultimately be superseded in

some proposed applications by other sources of

material (e.g., cell lines, genetically manipulated

cells), they also believe that this is not likely to occur

in the near future. Most scientists feel that, at

present, continued study of fetal tissue is needed

to discern the mechanisms that underlie the

ability of the nervous system to heal and to

evaluate what role fetal tissue grafts can play in

that process.

Many of the same concerns that have been voiced

about organ transplantation in general pertain to the

use of human fetal tissue for neural grafting. These

include:
24 ● Neural Grafting: Repairing the Brain and Spinal Cord

Table 2-3-Federal Funding of Neural Grafting Research (in millions of dollars)

Agency 1987 1988 1989 1990’

National Institutes of Health:

National Institute of Neurological Disorders

and Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1 6.5 7.3 7.5

National Eye Institute . . . . . . . . . . . . . . . . . . . . . . . . 1.2 1.4 1.6 1.6

National Institute on Aging . . . . . . . . . . . . . . . . . . . . . 1.1 1.1 1.6 2.1

National Institute of Child Health and

Human Development . . . . . . . . . . . . . . . . . . . . . . . — 0.2 0.4 0.4

Alcohol, Drug Abuse, and Mental Health

Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0.3 0.3 0.5 0.4

Department of Veterans Affairs . . . . . . . . . . . . . . . . . . . 0.4 0.5 0.5 0.5

National Science Foundationa . . . . . . . . . . . . . . . . . . . . 0.2 0.2 0.2 0.2

aEstimated.

SOURCE: Office of Technology Assessment, 1990.

buying and selling of organs for transplantation, and

legal authority for consent to donate organs or

tissues.

Use of fetal tissue raises some additional sensitive

and controversial questions. Are the issues surrounding abortion relevant to the use of fetal remains

for research and medical therapy? Should the

moratorium on Federal funding of abortion have any

bearing on Federal funding of research employing

fetal tissue for transplantation? Should cadaveric

fetal tissue (i.e., tissue from dead fetuses) be

discarded when this material could provide a therapy

for neurological disorders? Are there potential

abuses in the acquisition and use of fetal tissue for

which safeguards should be developed?

In 1988, the Assistant Secretary for Health placed

a moratorium on all federally funded therapeutic

transplantation research that used human fetal tissue

from induced abortions. This moratorium was extended indefinitely in 1989. As a result of this

action, no Federal funds can be used to support

the transplantation of human fetal tissue obtained from an induced abortion into a patient.

Of continuing interest to Congress is the level of

funding for both basic and clinical research and the

development of new technologies (table 2-3). It has

been suggested that neural grafting has the potential

to treat millions of Americans with certain neurological disorders. However, questions about the precise benefits of this technology, the particular

disorders that may be affected, and the time

frame for applying these technologies as human

therapies remain to be answered.

THE OTA STUDY

This report to Congress examines the development of neural grafting into the central nervous

system, i.e., the procedures and materials involved

in the transplantation of tissue to the brain and spinal

cord for the treatment of neurological disorders.

Although other advances in neuroscience have great

potential in treating neurological disorders, those

advances are beyond the scope of this report.

In the six chapters that follow, OTA examines the

impact neural grafting is likely to have on the

treatment of neurological disorders and the legal,

regulatory, and ethical issues these new procedures

raise. In addition, OTA examines the role of

Congress and the Federal Government in addressing

these public policy issues.

Chapters 3,4, and 5 describe basic principles of

neuroscience, general principles and concepts of

neural grafting, and the research that has been

conducted thus far on neural grafting as a treatment

for neurological disorders. Chapter 6 identities some

of the disorders that may be amenable to treatment

by neural grafting procedures, and chapters 7 and 8

discuss the legal, regulatory, and ethical issues

associated with neural grafting.

1.

2.

CHAPTER 2 REFERENCES

Apuzzo, M. L.J., Neal, J.H., Waters, C.H., et al.,

“Utilization of Unilateral and Bilateral Stereotactically Placed AdrenomedWary-Striata.l Autografts in

Parki.nsonian Humans: Rationale, Techniques, and

Observations,” Neurosurgery 26:746-757, 1990.

Baclclund, E. O., Granberg, P. O., Hamberger, B., et

al., “Transplantation of Adrenal Medulkuy Tissue to

Striatum in Parkinsonisrn, First Clinical Trials,”

Journal of Neurosurgery 62:169-173, 1985.
Chapter 2--Introduction ● 25

3.

4.

5.

6.

7,

Bjorklund, A., and Stenevi, U. (eds.), “Intracerebral

Neural Grafting: A Historical Perspective,” Neural

Grafting in the Mammalian CNS (Amsterdam:

Elsevier Science Publishers, 1985).

Freed, C.R,, Breeze, R.E., Rosenberg, N.L., et al.,

“Transplantation of Human Fetal Dopamine Cells

for Parkinson’s Disease, Results at 1 Year,” Archives

of Neurology 47:505-512, 1990.

Goetz, C.G., Tanner, C.M., Pem, M.D., et al.,

“Adrenal Medullary Transplant to the Striatum of

Patients With Advanced Parkinson’s Disease: l-Year

Motor and Psychomotor Data,” Neurology 4Q273-

276, 1990.

Lieberman, A., Ransohoff, J., Berczeller, P., et al.,

“Adrenal Medullary Transplants as a Treatment for

Advanced Parkinson’s Disease,” Acta Neurological

Scandinavia 126:189-1%, 1989.

Lindvall, O., “Transplantation Into the Human

Brain: Present Status and Future Possibilities,”

Journal ofNeurology, Neurosurgery, and Psychiatry

special supp.:39-54, 1989.

8.

9.

10.

11.

12.

Lindvall, O., Brundin, P., Widner, H., et al., “Grafts

of Fetal Dopamine Neurons Survive and Improve

Motor Function in Parkinson’s Disease,” Science

247:574-577, 1990.

Lindvall, O., Rehncrona, S., Gustavii, B., et al.,

“Fetal Doparnine-Rich Mesencephalic Grafts in

Parkinson’s Disease” [letter], Lancet 2:1483-1484,

1988.

Madrazo, I., Drucker-Colin, R., Diaz, V., et al.,

“open Microsurgical Autograft of Adrenal Medulla

to the Right Caudate Nucleus in Two Patients With

Intractable Parkinson’s Disease,” New England

Journal of Medicine 316:831-834, 1987.

Madrazo, I., km, V., Torres, C., et al., “Transplantation of Fetal Substantial Nigra and Adrenal Medulla

to the Caudate Nucleus in Two Patients With

Parkinson’s Disease” [letter], New England JournuZ

of Medicine 318:51, 1988.

Sladek, J.R., Jr., and Gash, D.M., “Nerve-Cell

Grafting in Parkinson’s Disease,’ Journal of Neurosurgery 68:337-351, 1988.
Chapter 3

Neuroscience Primer
CONTENTS

Page

ORGANIZATION OF THE NERVOUS SYSTEM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Cellular Components . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Central Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Peripheral Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Autonomic Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ●

NEURAL COMMUNICATION . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

GROWTH AND DEVELOPMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .*

RESPONSE TO INJURY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .*.

CHAPTER 3 REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

29

29

30

32

32

32

33

34

36

Box

Box Page

3-A. Neurotrophic and Neurotropic Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36

Figures

Figure Page

3-1. Components of the Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3-2. The Neuron . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3-3. Glial Cells . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3-4. The Central Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3-5. The Spinal Cord . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3-6. The Synapse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3-7 A Neuron and Its Synapses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3-8. The Development of the Human Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3-9. The Response of a Neuron in the Peripheral Nervous System to Injury . . . . . . . . . .

29

30

30

31

32

32

33

34

35
Chapter 3

Neuroscience Primer

This chapter describes the major anatomical

components of the nervous system, some of the basic

processes underlying neural growth, development,

and communication, and the response of the nervous

system to injury. A grasp of these basic concepts of

neuroscience is helpful to understanding neural

grafting. Additional information is available from a

number of sources (1,3,4).

ORGANIZATION OF THE

NERVOUS SYSTEM

The nervous system can be divided into two

parts: the central nervous system (CNS) and the

peripheral nervous system (PNS) (figure 3-l). The

CNS is made up of the brain and spinal cord. The

PNS is composed of all the nerves, nerve cells, and

specialized sensory receptors that lie outside the

CNS. Sensory information about the outside world

is brought into the CNS via the nerves and sensory

receptors in the PNS; activation and regulation of

activity in muscles, glands, and organs are conveyed

by the motor, or outflow, component of the PNS.

Most information processing, decisionmaking, and

coordination of activities is under the control of the

CNS.

Cellular Components

There are two major classes of cells in the

nervous system: neurons, or nerve cells, and glia,

or glial cells.

Neurons

All information processing in the nervous system

is done by networks of neurons that communicate

with each other. Neurons consist of a cell body with

long extensions, much like branches of a tree, called

dendrites. Also projecting out of the cell body is a

single fiber called the axon, which can extend for

great distances (figure 3-2). All nerves in the body

are actually the bundled axons of many neurons

conveying information to and from the CNS. The

end of the axon is also branched.

Glial Cells

Glial cells support neurons by carrying on important chemical and physiological reactions and producing a variety of substances that are needed for

normal neurological functioning. There are a number of different types of glial cells in the PNS and

CNS--astrocytes, microglia, Schwann cells, and

oligodendrocytes (figure 3-3). Schwann cells (in the

PNS) and oligodendrocytes (in the CNS) produce

myelin, a fatty insulating material that forms a

sheath around axons and speeds the conduction of

electrical impulses. Both of these types of cells play

a crucial role in nerve cell regeneration: Schwann

cells support regrowth of peripheral nerves, while

recent evidence suggests that oligodendrocytes inhibit the regrowth of damaged axons in the CNS.

The other glial cells help regulate the biochemical

environment within the nervous system, provide

Figure 3-l-Components of the Nervous System

cranial

nerves

/

\

PNS ‘–

nerves ‘Pina’ m“

CNS

/

spinal

cord

The nervous system is composed of the central (CNS) and

peripheral nervous systems (PNS).

SOURCE: C. Romero-Sierra, A/euroanatorny, A Conoeptua/ Approach

(New York, NY: Churchill Livingstone, 1986).

–29–
30 ● Neural Grafting: Repairing the Brain and Spinal Cord

Figure 3-2—The Neuron

Two neurons in synaptic contact.

SOURCE: R. Restak, The Brain (New York, NY: Bantam Books, 1984).

structural support for the neurons, and supply certain

substances that are essential for the nervous system

to work properly.

Central Nervous System

The Brain

One useful way of visualizing the brain is as a

mushroom. The cap of the mushroom is the cerebral

cortex, and the stem of the mushroom is the rest of

the brain, which is made up of hundreds of nuclei

(figure 3-4). A nucleus is a group of cells that share

the same anatomical region and, to varying degrees,

the same function. Information is conveyed throughout the brain and spinal cord along the axons

extending from nuclei. For any given function, such

as vision, a number of nuclei and areas of the

cerebral cortex must act together in a coordinated

and synchronized reamer so that information can be

accurately analyzed.

The anatomy of the brain and the intricacy of the

connections among nuclei are exceedingly complex.

Information from every area of the nervous system

about many different functions is constantly being

combined, compared, contrasted, and coordinated.

The brain determines the relevance of each bit of

information, fits it in with all other information

available, and decides what actions should or should

not be taken to regulate bodily functions and to

Figure 3-3-Glial Cells

B.

u.

Types of glial cells include: A) astrocytes, B) microglia, C)

oliogdendrocytes, D) Schwann cells (surrounding an axon).

SOURCE: Adapted from J.A. Kiernan, Introduction to Human Neuroscience (Philadelphia, PA: J.B. Lippincott, 1987).

permit successful interaction with the external

environment. The result is everything that makes up

life and existence as human beings perceive it—

from the maintenance of heart rate to falling in love;

from finding food to contemplating the nature of the

universe. All of these arise from the biological

events that make up the activity of the human brain.
Chapter 3-Neuroscience Primer ● 31

Figure 3-4—The Central Nervous System

cortex

- - l

,

1

. .. . . ,:...,7.---- I

Spinal cord

1

1

I

The brain (cerebral cortex, upper brain, brain stem) and the spinal

cord.

SOURCE: Adapted from R. Restak, The Mind (New York, NY: Bantam

BOOkS, 1988).

The bottom of the stem of the mushroom is the

brain stem, which regulates essential bodily functions. Heart rate, blood pressure, and respiratory

activity are all controlled by nuclei in the brain stem.

Higher up the stem of the mushroom is the upper

brain, containing other structures, such as the

hypothalamus and the thalamus. Each of these is a

collection of nuclei with specific functions. The

thalamic nuclei are primarily involved in analyzing

and relaying sensory and motor information. Some

hypothalamic nuclei control behaviors such as

eating, “ drinking, and sexual activity; others help

with regulating the activity of the endocrine system.

Still further up the stem of the mushroom are the

basal ganglia, nuclei that help mediate movement.

Also in this area are some of the nuclei of the limbic

system, which is involved in emotional behaviors,

and the hippocampus, a limbic nucleus that is also

one of the nuclei crucial to learning and memory.

These are only a sampling of the many nuclei located

in the stem of the mushroom.

Overlying the stem is the cerebral cortex, the

evolutionary newest part of the brain and its most

advanced decisionmaking portion. The cerebral

cortex consists of layers of neurons and their axons,

which communicate with each other and with other

regions of the brain. Roughly divided into four lobes

on each side, the cerebral cortex receives sensory

information and analyzes, deciphers, and puts it into

context based on previous experience. Combining

new input with experience, the cerebral cortex

decides what actions should be taken and institutes

those actions by activating the proper motor and

endocrine networks. It is at the level of the cerebral

cortex that differences among species become most

notable. Warm-blooded animals have a more highly

developed cerebral cortex than cold-blooded animals. The cortex is most fully developed in humans,

with highly developed frontal lobes and specialized

areas to subserve the development and use of

language. The frontal lobes are thought to be the seat

of higher order thinking, which gives humans the

ability to engage in abstract thought and to develop

philosophical concepts of morality, self, and place in

the universe.

The Spinal Cord

Extending downward ii-em the base of the stem of

the mushroom is the spinal cord. The spinal cord is

composed of a central core of cells surrounded by

pathways of axons. Leaving and entering the spinal

cord are the nerves that bring sensory information

into the CNS and convey motor and other activating

information out into the periphery (figure 3-5). The

spinal cord is divided into 31 segments that are

demarcated by collections of nerves called nerve

roots. The spinal segments and their nerve roots

serve the organs of the body and corresponding

regions of muscles and skin in the limbs and along
32 ● Neural Grafting: Repairing the Brain and Spinal Cord

Figure 3-5-The Spinal Cord

Axons

Cell

Ventral root \.’<~ Nerve root

The spinal cord is made up of a central core of cell bodies,

surrounded by axons. The nerve roots convey information into

(dorsal root) and out of (ventral root) the spinal cord.

SOURCE: Adapted from A.C. Guyton, Basic Neuroscience: Anatomy and

Physio/ogy(Philadelphia, PA: W.B. Saunders, 1987).

the trunk of the body. There is communication

among segments and between the segments and the

brain. Some basic functions, such as motor reflexes,

are organized and directed from within the spinal

cord. The spinal cord also contains a column of

specialized cells that help control the autonomic

functions of the body (see later discussion of the

autonomic nervous system). All the areas within the

spinal cord that control bodily activities are modulated by the brain.

Peripheral Nervous System

The PNS is made up of all the sensory nerves

coming into, and motor nerves leaving, the spinal

cord via the nerve roots. These include the nerves of

the autonomic nervous system. In addition, the PNS

includes some sensory and motor nerves that enter

and exit from the brain stem.

Autonomic Nervous System

The autonomic nervous system is made up of the

portions of the CNS and PNS that are concerned with

the control of visceral functions. These functions

include heart rate, blood pressure, digestion, and

reflexive sexual activities. Within the CNS, the

neurons of the autonomic nervous system are in the

brain stem and the spinal cord; in the PNS, the

neurons occur in specialized groups, known as

ganglia. The ganglia are found in columns on either

Figure 3-6-The Synapse

0

0

00 ~o

Axon 0 0 000

terminal

‘“’’” Body of neuron

The anatomy of a synapse.

SOURCE: Adapted from A.C. Guyton, Basic Neuroscience; Anatomy and

Physiology (Philadelphia, PA: W.B. Saunders, 1987).

side of the spinal cord or in close association with the

organs they serve (2).

NEURAL COMMUNICATION

Information in the nervous system is conveyed by

chains of neurons. It usually travels through a neuron

in one direction-horn the dendrites, through the

cell body, and along the axon. The end of the axon

of one neuron interacts with the next neuron in the

chain. Information in the nervous system is coded

as an electrical-chemical message that is sent

from one neuron to the next. The point where the

axon of one neuron connects with a dendrite or cell

body of another neuron is called a synapse (figure

3-6). The two neurons never actually touch each

other; instead, there is a small space between them

called the synaptic space. Because the end of the

axon and the dendrites of a neuron are branched, the

axon of any one neuron can form synapses with

thousands of other neurons and thus can send

messages to and receive messages from thousands of

other neurons (figure 3-7).

When a neuron generates a nerve impulse, or

‘‘ fires,’ an electrical message is sent along the axon

toward the synapse. When the electrical message

gets to the synapse, it causes the release of a

chemical, called a neurotransmitter, from the axon

into the synaptic space. The neurotransmitter acts as

a messenger, moving across the synaptic space and

binding to the membrane of the next neuron. The
Chapter 3--Neuroscience Primer ● 33

Figure 3-7-A Neuron and Its Synapses

The terminals of many axons can make synapses with the

dendrites or cell body of one neuron.

SOURCE: R. Restak, The Mind(New York, NY: Bantam Books, 1988).

binding of the neurotransmitter to the membrane

then initiates, facilitates, or hinders an electrical

message in that neuron. The time it takes for this

process to occur, from the initiation of a message in

one neuron to the release and binding of the

neurotransmitter and the initiation of a message in

the next neuron, is measured in thousandths of a

second.

There are many different kinds of neurotransmitters. Whether and when a neuron will release a

neurotransmitter is determined by the combined

action of all its synapses, with their excitatory and

inhibitory neurotransmitters, at any one time.

GROWTH AND DEVELOPMENT

In humans, the first signs of the developing

nervous system appear in the third week of embryonic development (figure 3-8). The cells destined to

form the brain and other parts of the nervous system

then go through a period of proliferation, during

which time they multiply. At the same time, the cells

migrate to their proper positions in the developing

brain. Following this period of proliferation and

migration, the cells stop dividing and differentiate

into the various types of neurons and glial cells that

make up the nervous system. At this time, the

number of neurons becomes fixed; for the rest of the

person’s life, no new neurons are thought to be

produced. Most glial cells, on the other hand,

maintain the capacity to replicate.

The mechanisms by which neurons migrate to the

proper location and axons find their way to the

proper target site and form synapses are not fully

understood. The process of axonal growth is thought

to include an initial, genetically predetermined map

of axonal pathways. The growing axons are guided

to their final destinations by chemicals called

neurotrophic (nourishing) and neurotropic (guiding) factors (see box 3-A). Neurotrophic factors

promote axonal growth and neuronal survival, and

neurotropic factors provide a surface, or substrate,

for the axon to grow along to its target. These factors

act as signposts to guide the growing axons and

provide chemical addresses for them to reach. Which

chemical address, or target site, an axon will search

for is believed to be genetically programmed within

each neuron.

Once the cells are in position, differentiation

occurs: the dendrites and axons of the neurons begin

to grow and establish the proper synaptic contacts.

In the case of some axons this can mean elongation

over considerable distances, while in other cases all

of the synaptic contacts of a neuron can occur within

a few millimeters of the cell. The ultimate wiring

of the brain, made up of billions of synapses and

connections, is extremely complex. Although in

humans most axons reach their target sites before

birth, the final configuration of the synaptic contacts

is not completed until well after birth.

There are many more neurons in the developing

nervous system than there are in the mature nervous

system. It has been estimated that about half of the

cells initially generated die. Death is caused by

competition between the growing neurons for available synaptic sites and a matching of the number of

neurons to the needs of the developing nervous

system. This process results in the survival of those

neurons that have grown properly. There are about

200 billion neurons in the mature human brain.

Although the general pattern of synapses established once an axon reaches its target is both

genetically predetermined and under the control of

chemical factors, the final, precise synaptic pattern

of an axon can also be shaped by other factors. These

include the amount and kind of activity that occur in

the pathway in response to outside stimulation. This

flexibility in synapse formation in response to
34 ● Neural Grafting: Repairing the Brain and Spinal Cord

Figure 3-8-The Development of the Human Brain

6R&@@

25 days 35 days 40 days 50 days 100 days

Q

. .’, ’

....., ..., , -# . . . . . .

. . . .!.

. . ... ,.,

. . . :.. ,. :., .,,. ,, ..:

,.,

..,,” .

: . . . . . . . . .

. . . . . ‘.’. ,, : ..;.”:’ .”:

.,’., , ,.. ,: ;, -;2;:..:!”

-.. ;?::./” : ,, -

, . ..;:”..”.””: . . ,

x ““””””’” ‘K’.. ?“”:”

Five months

L’

Eight months

\

L

\

Six months Seven months

The human brain shown in its developmental sequence, starting at 25 days and progressing through birth.

SOURCE: R. Restak, The Brain (New York, NY: Bantarn Books, 1984).

environmental stimuli is maintained throughout life

and may play a role in learning and memory.

RESPONSE TO INJURY

The CNS and PNS respond differently to injury.

When a peripheral nerve is damaged, the axons

of the damaged neurons can regrow; but when

damage occurs in the CNS, axonal regrowth is

limited. Research on animals has shown that this

difference is due not to differences in peripheral and

central neurons (in fact, many peripheral nerves arise

from cell bodies in the CNS), but to variations in the

environment surrounding the axons in the CNS and

PNS.

The key element in axon regrowth in the PNS is

the presence of Schwann cells and the growth factors

they secrete. Schwann cells normally surround each

axon, supplying its fatty myelin sheath. When a

peripheral nerve is damaged and dies, the bundled

axons die and leave behind the Schwann cells that
Chapter 3--Neuroscience Primer ● 35

Figure 3-9—The Response of a Neuron in the Peripheral Nervous System to Injury

A) The normal neuron and part of the axon; B) the axon is injured and the section away from the cell body dies; C) the end of the injured

axon begins to grow into the remaining Schwann cells.

SOURCE: RerXinted bv ~ermission from “Reactions of Neuronsto ldw,” Pri~@/= of~euro=ief=, pd ~.. E-R. Kandel and J.H. *hwartz (*.).(N’SWyOkJ . NY: Elsevie~ !3cience Publishers, 1985), p. 191. - -

had surrounded them. When the nerve regenerates,

its axons grow within the column of remaining

Schwann cells to the sense organ or muscle to which

they were originally connected (figure 3-9).

Schwann cells release neurotrophic and neurotropic

factors that promote elongation and provide a

pathway for the regenerating axons.

When the CNS is damaged, there is some

regrowth that is limited to a small area around the

wound. A process called synaptic sprouting occurs,

whereby fibers from nearby, undamaged axons form

new branches and make new synapses to replace

some of the lost ones. However, unlike Schwann

cells, the myelin-producing oligodendrocytes of the

CNS do not promote regrowth of the damaged

axons. In fact, recent studies have shown that

oligodendrocytes actively block regeneration. Furthermore, following an injury, another type of glial

cell, the astrocyte, forms a scar at the site of the

wound and blocks regrowth. Why there are mechanisms in the CNS that actively block healing is not

known. It is thought that once all the wiring of the

brain is established, the growth-promoting mechanisms that were present during development are no

longer needed, and these inhibitory mechanisms

take over to prevent any further growth that could

short-circuit the completed brain. By learning more

about the differences in the environments that

allow regeneration in the PNS and block it in the

CNS, scientists may ultimately be able to control

the processes involved and enable CNS damage

to be repaired.
36 ● Neural Grafting: Repairing the Brain and Spinal Cord

Box 3-A—Neurotrophic and Neurotropic Factors

During the last few years, neuroscientist have learned that the development, maintenance of function, and

response to injury of neurons are influenced by chemicals called neurotrophic and neurotropic factors. These

substances are produced by some neurons and glial cells and can affect the nervous system in two ways. Some are

secreted by a cell into the spaces between cells in the nervous system; they can then be absorbed by neurons to initiate

an intracellular process, such as growth of an axon. Other factors can act externally to guide the growing axon along

a particular path to its region of synaptic contact. A chemical that stimulates growth or development is called a

neurotrophic agent, while one that helps guide a growing neuron is called a neurotropic agent.

Only a few substances have been positively identified as neurotrophic or neurotropic factors. Of them, nerve

growth factor (NGF) has been the most extensively studied NGF is a protein that is known to promote growth in

specific areas of the peripheral nervous system and to play a role in the development of vertebrate sensory systems.

What role NGF plays in the central nervous system (CNS) is not well understood. It seems that NGF has a selective

effect on certain populations of cells in the brain that use acetylcholine as their neurotransmitter. NGF promotes

growth and development of these cells in the fetal brain and, when extra amounts are administered in experimental

conditions, can promote growth and prevent cell death following an injury in the adult brain. It has also been shown

that NGF can facilitate the incorporation of some neural grafts. The observation that NGF seems to exert this effect

only on certain cells in the brain suggests that there maybe different neurotrophic factors for different groups of brain

cells. Thus far, other substances that have been identified as having possible neurotrophic or neurotropic effects

include ciliary neurotrophic factor, brain-derived neurotrophic factor, neurotrophin-3, glia-derived nexin, fibroblast

growth factors, insulin and insulin-like growth factors, epidermal growth factor, S100 protein, and laminin. What role

these play in CNS regeneration is unclear at this point.

Neurotrophic and neurotropic factors are known to be present in the developing CNS and to play an important

role in the formation of neuronal circuitry. Much less is known about their role in the mature CNS. When an injury

occurs in the brain, there is an increase in neurotrophic activity at the site of the wound. This activity seems to promote

the limited amount of healing and cell survival that is seen following some injuries. It is also thought that some of

these factors are important for maintaining normal function and structural integrity in the adult brain. It has been

observed that some neurons die in the absence of neurotrophic factors. It is possible that some of the factors associated

with growth and development are either no longer present or are somehow inactivated within the adult CNS.

Introducing missing factors or stimulating deactivated ones in the CNS by implanting tissues that produce

neurotrophic and neurotropic factors may reestablish the environment needed for growth.

SOURCE: Office of Technology Assessment, 1990.

CHAPTER 3 REFERENCES tion, Apr. 25, 1990.

1. Adelman, G. (cd.), Encyclopedia of Neuroscience, 3. Ferry, G., “Getting Wired Up," New Scientist, Mar. 4,

1989, pp. 1-4. vols. I and II (Cambridge, MA: Birkhauser Boston,

1987). 4. Kandel, E. R., and Schwartz, J. H., Principles of Neu2. Coquelin, A., professor, Texas Tech University Health roscience (New York, NY: Elsevier Science PublishSciences Center, Lubbock, TX, personal communica- ing, 1985).
Chapter 4

General Features of

Neural Grafting
CONTENTS

Page

THERAPEUTIC STRATEGIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39

Source of Depleted Chemical Substances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39

Promotion of Neuron Growth and Survival . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40

Replacement of Lost Structures in the Brain and Spinal Cord . . . . . . . . . . . . . . . . . . . . . . . 41

MATERIALS FOR NEURAL GRAFTING . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .42

Fetal Central Nervous System Tissue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .42

Peripheral Nerve Tissue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43

Peripheral Autonomic Tissue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

Tissue From Outside the Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45

Isolated, Cultured, or Genetically Engineered Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46

DETERMINANTS OF SUCCESSFUL NEURAL GRAFTING . . . . . . . . . . . . . . . . . . . . ...49

Developmental State of the Graft Material . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49

Immune System Response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49

Blood Vessel Formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51

The Age of the Host . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52

POTENTIAL RISKS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52

Immune System Reaction or Suppression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52

Unwanted Psychological Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52

Effects of the Surgical Procedure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52

Excessive Growth of Graft Material . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52

Infection and Other Effects on the Host CNS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53

SUMMARY AND CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53

CHAPTER 4 REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53

Box

4-A. The Deep Freeze: Cryopreservation

Box

Page

of Fetal CNS Tissue . . . . . . . . . . . . . . . . . . . . . . . 46

Figures

Figure Page

4-1. Injured Nerve Cells With and Without Growth Factor Treatment . . . . . . . . . . . . . . . 41

4-2. Fetal Central Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

4-3. Transplanted Fetal Nerve Cell . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45

4-4. Peripheral Nerve Graft . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45

4-5. Genetic Engineering of Graft Tissue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48

4-6. Blood-Brain Barrier in Transplanted Tissue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50

4-7. Blood Vessel Growth in Transplant . . . . . . . . . . . “ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
Chapter 4

General Features of Neural Grafting

Neural grafting has been hailed as.. one of the

most promising approaches to have come from

experimental neurobiology as a potential therapy for

a variety of disorders involving damage to the

central nervous system” (41). It has also triggered a

debate among physicians and medical researchers

about when a medical procedure should be advanced

from a research tool in animals to a treatment in

humans. The use of neural grafting to treat patients

suffering from Parkinson’s disease has led to both

dramatic claims of success and more cautious

statements of results. A proposal for neural grafting

research prompted the Executive Branch of the U.S.

Government to forbid Federal support of transplantation procedures employing human fetal tissue

from induced abortions. All of this controversy begs

a clear answer to the question, What is neural

grafting?

The term neural grafting, as used in this

report, refers to the transplantation of tissue into

the brain or spinal cord. Neural grafting differs

from organ transplantation, wherein an entire diseased or injured organ, such as the heart or kidney,

is replaced with a healthy one. Although neural

grafting may entail replacing a diseased portion of

the brain, animal experiments suggest that it may

also serve as a drug delivery system, providing

chemical substances to the central nervous system

(CNS) of the graft recipient, or that it may be used

to promote recovery of the host’s injured brain or

spinal cord. In addition, a neural graft may be

derived from various types of tissues, including fetal

CNS tissue, peripheral nervous tissue, cells from

other organs, or cell lines sustained in the laboratory.

Thus, neural grafting is a generic term that

embraces many different treatment goals and

materials.

This chapter focuses on the salient features of

neural grafting and issues related to its potential use

to treat the diseased or injured CNS. Unless otherwise specified, data discussed in this chapter are

derived from animal studies. Despite the publicity

that has recently attended neural grafting attempts in

patients suffering from Parkinson’s disease, the

clinical usefulness of this approach is not certain. In

the case of Parkinson’s disease, optimal methods for

using neural grafting are still under investigation. In

general, the development of innovative techniques,

including the use of genetically engineered cells,

relies on extensive basic research. Furthermore,

many questions concerning the functional effects of

neural grafts, as well as the problems presented by

their use, are unanswered. Neural grafting may,

however, lead to promising treatments for neurological disorders, which often resist therapeutic intervention. Issues addressed in this chapter include:

What therapeutic strategies are possible

through neural grafting?

What tissues and cells can be used for neural

grafting?

What factors influence the successful survival

and function of neural grafts?

What potential risks are presented by neural

grafting?

THERAPEUTIC STRATEGIES

How a neural graft improves CNS function within

the recipient is not completely understood. A neural

graft may simply provide a depleted chemical

substance to the brain or it may permit other

therapeutic strategies as well (5,33,61). In fact,

neural grafts display a wide range of capabilities.

These diverse functions lead researchers to predict that neural grafts will be employed to

accomplish different treatment goals in different

neuropathological disorders. Continued research

is necessary to determine precisely how neural grafts

function and how those functions can benefit a graft

recipient (37). In this section, potential therapeutic

strategies are discussed. Neural grafts may:

● provide a source of depleted chemical substances,

● stimulate neuron growth and promote survival

of neurons, and

● replace lost structures in the brain and spinal

cord.

Source of Depleted Chemical Substances

Neural grafts may supply chemical substances

that have been depleted in the CNS by injury or

disease.

The loss of neurons within the brain or spinal cord

can severely impair memory, the control of muscle

-39-
40 ● Neural Grafting: Repairing the Brain and Spinal Cord

movement, and other functions performed by the

nervous system. Impaired CNS function may result

from a depletion of the chemical substances normally produced by the degenerating or missing

neurons. Conventional drug therapy can be employed to replenish the supply of a depleted chemical in the brain. However, several factors can make

drug therapy problematic. For example, some

administered substances are prevented from entering

the CNS by the blood-brain barrier, which excludes

many cells and molecules in the blood from the CNS

(11,74).

The current limited success in treating CNS

disorders via drug therapy may be circumvented by

the use of neural grafts. Cells that synthesize and

secrete a neurotransmitter (a messenger molecule

used by neurons in communication) or other chemical substance may be implanted in the CNS; it is

thought such implants may provide a continuous

supply of chemicals directly to the depleted region

of the brain or spinal cord.

It is postulated that neural grafts supply chemical

substances in one of two ways (5). If the graft is

composed of cells that do not form connections

(synapses) with the host neurons, it may simply

synthesize and release a steady and diffuse supply of

chemical substances to adjacent regions of the CNS,

acting as a localized pump, or drug delivery system.

If synapses are forged between graft and host

neurons, integrating the graft into a neuron network,

the release of chemicals may be more carefully

regulated by the host neurons. In this case, rather

than indiscriminately spewing chemicals near the

graft site, the grafted neurons may discharge the

chemicals in a more controlled fashion at synapses

abutting host neurons.

Promotion of Neuron Growth and Survival

Neural grafts may introduce new substances or

cells that promote and guide host neuron regrowth, prevent host neuron death, or both.

The complex network of nerve fibers within the

mature brain and spinal cord attests to the tremendous neuron outgrowth and synapse formation that

occurs during development. Developing neurons

may form long fibers and establish contact with as

many as 1,000 other neurons. While mature neurons

do enjoy some regenerative potential, the ability to

extend long fibers appears to be masked or inhibited

in the mature CNS. Anything more than modest

Photo credit: Laura Lee Hall

Injured nerve ceils.

injury of mature neurons often proves fatal to them.

In general, glial cells inhibit neuron regrowth

following injury (20,76,84). Injured neurons may be

permanently disconnected from their targets within

the CNS, they may degenerate and die, or both.

Furthermore, neurons that die are not replaced, since

they lack the ability to reproduce themselves.

Experimental evidence suggests that the degenerative consequences of neuronal injury in the mature

brain and spinal cord can be prevented, or at least

ameliorated, if a growth-promoting environment,

such as that found in the developing brain, is

provided. In other words, recovery of injured neurons within the mature CNS may be enhanced by

cells or chemical factors that promote neuron

regrowth, neuron survival, or both (figure 4-l). It is
Chapter 4-General Features of Neural Grafting ● 41

speculated that neural grafts may be used in this

capacity, stimulating neuron functions such as nerve

fiber and synapse growth or preventing neuron death

(21).

A neural graft may lead to the recovery of injured

neurons in several ways. Grafted cells may synthesize and release growth-promoting factors near the

injured neurons, preventing neuron death and promoting neuron regrowth. Neural grafts may also be

used to form a bridge between a group of neurons

and their target within the CNS, bypassing the

unfavorable environment of the mature CNS. These

graft materials may enhance neuron outgrowth and

provide a terrain over which it is directed. Neural

grafts may also serve to reduce scar formation within

the injured CNS or neutralize the growth-inhibiting

effect of the mature CNS (85,90). Other graft

activities, such as the removal of toxic substances,

may also be possible (34).

A neural graft used to promote regrowth and

recovery of the host’s own brain or spinal cord tissue

may be required only temporarily, thus making

long-term graft survival, which may be difficult to

achieve, unnecessary.

Replacement of Lost Structures in

the Brain and Spinal Cord

A neural graft may be used to replace nerve

cells in the CNS that were lost to injury or disease.

Normal aging, injury, disease, or lack of oxygen

can precipitate the death of nerve cells within the

CNS. Since neurons generally are not replaced

within the brain and spinal cord of adult mammals,

their death leads to a permanent decrease in the

number of neurons in the brain and creates a missing

link in neuronal networks. This loss of neurons and

disruption of neuronal networks may result in the

Figure 4-1—injured Nerve Cells With and Without Growth Factor Treatment

N(5F +NGF

r

A f

v, ‘b

s

?

‘ J!@” --””’

* .-. ~ %4 .

5

#

,*,-

Photograph of brain section; nerve cells are darkly stained. Injured nerve cells on side D received nerve growth factor (NGF) and therefore

survived injury. Injured nerve cells on side B, in the absence of NGF, degenerated.

SOURCE: S. Varon, “Neuronal Growth Factors,” Neura/Fbgeneratkm and Transpkmtation, Frontiers of C/inica/Neuroscience, vol. 6, F.J. Seil (cd.) (New York,

NY: Alan R. Lies, 1989).
42 ● Neural Grafting: Repairing the Brain and Spinal Cord

permanent impairment of a CNS function. Another

therapeutic use for neural grafts may be the replacement of degenerated neurons.

Replacement of neurons and the reconstitution of

neuronal networks within the adult CNS seem a

remote possibility, considering the intricate interactions that occur between neurons within the nervous

system. A single neuron may receive thousands of

contacts from different regions of the brain. Despite

this complexity, grafted fetal neurons demonstrate a

remarkable ability to integrate into the mature CNS

of a recipient. Grafts of fetal neurons can send nerve

fibers into the host CNS and form synapses with host

neurons, often in an appropriate and recognizable

pattern. Grafted fetal neurons may also receive

synaptic input from the host.

Complete and literal replacement of a group of

neurons is probably impossible. For example, when

neurons that normally project long distances within

the CNS degenerate, replacement neural grafts are

generally implanted near the target in the host CNS

rather than in the original site of nerve cell degeneration. In this situation, juxtaposition of graft and host

CNS target can be important for their interaction

(41). Although the graft will probably not receive the

full range of normal inputs from other CNS regions,

it may be sufficiently integrated into host neuronal

networks to restore a useful degree of function.

MATERIALS FOR

NEURAL GRAFTING

Several types of biological materials may be

used for neural grafting. The first and perhaps

most important determinant of a particular material’s usefulness is its ability to improve CNS

function with minimal risk to the recipient. The

availability and source of the graft material will also

significantly influence its application in humans.

Currently, several sources of tissue for neural

grafting in humans seem possible, including human

fetuses, cells maintained in cultures, or tissue from

graft recipients themselves. Nonhuman species also

represent a potential source of neural grafting

material, although they may present serious functional and immunological problems (30,52,67,70).

Each of these sources presents unique technical

issues and questions about availability. In addition,

the type and source of material used are central to the

ethical and legal questions surrounding neural grafting (see chs. 7 and 8). In this section, general features

of the following potential neural grafting materials

are discussed:

●

●

●

●

●

tissue from the fetal central nervous system;

tissue from the peripheral nervous system;

peripheral autonomic neurons;

tissue from outside the nervous system; and

isolated, cultured, or genetically engineered

cells.

Fetal Central Nervous System Tissue

Animal experiments have shown that fetal tissue,l

unlike mature CNS tissue, readily develops and

integrates within a host organism following grafting.

A majority of neural grafting research in animals has

made use of tissue from the fetal brain and spinal

cord. In pioneering experiments, fetal CNS tissue

often displayed a considerable capacity for survival

within the CNS of the graft recipient (for reviews see

7,35,89). During the 1960s and 1970s, technological

advances heralded a new era of neural grafting with

fetal CNS tissue. Reliable methods for distinguishing surviving graft tissue within the host were

developed, as were improved surgical methods for

inserting the graft material. When fetal CNS tissue

was transplanted into the CNS of young animals, it

matured and interacted with the host brain for a

substantial period of time. Subsequent studies revealed that fetal CNS tissue could also be successfully grafted into the mature brain. In fact, the

grafted fetal CNS tissue was shown not only to

survive and develop in the host, but to integrate into

the host brain in a predictable manner.

Research further established that grafted fetal

nervous tissue often produced functional improvements in animals with neurological deficits.

For example, in several studies grafted neurons were

seen to increase brain hormone production in

animals that demonstrated a deficiency of hormones

(38,40,58). The absence of the hormones impaired

the brain’s regulation of kidney or reproductive

organ function. When the appropriate fetal nerve

cells from the same species were introduced into the

CNS of the impaired animals, they produced the

deficient hormones and restored control of kidney or

reproductive function. More recent studies, directed

toward the analysis of biological rhythms, have

lh thi5 c~pter, when referring to hums, the fetal stage is considered the period from the end of the eighth week after fertilization UIW Mh.
Chapter 4--General Features of Neural Grafting ● 43

shown that fetal tissue from a region of the brain

called the suprachiasmatic nucleus could be grafted

and subsequently control daily cycles of behavior in

hamsters (73).

Animal models for parkinsonism were employed

to evaluate the effectiveness of grafted fetal nervous

tissue (6,72). In rodents and nonhuman primates,

chemicals were used to destroy the nerve cells that

degenerate in humans suffering from Parkinson’s

disease. The chemically induced nerve cell death is

manifested as abnormal rotatory movement in rodents and as abnormal body movements (similar to

those seen in humans with Parkinson’s disease) in

nonhuman primates. When fetal neurons are grafted

to replace the destroyed cells, the movement disorder is partially reversed. The success of this technique led to its adaptation for studies in humans

suffering from Parkinson’s disease. Ongoing clinical trials are examining the effectiveness of neural

grafting with human fetal tissue for the treatment of

persons with Parkinson’s disease (see ch. 5).

Many different animal models of neurological

deficits are being used to study the effects of

grafted fetal CNS tissue. Results suggest that

neural grafting with fetal neurons may one day be

developed to treat several neurological disorders

(see ch. 6).

The number of fetal nerve cells needed for

neural grafting may be of critical importance,

especially when the graft recipient’s brain is

relatively large, as is the adult human ’s. While too

many grafted fetal neurons pose the threat of

excessive growth and overenlargement within the

CNS of the host, too few cells (a more common

occurrence) may fail to improve CNS function

significantly. For example, the amelioration of

symptoms of Parkinson’s disease reported in a

single patient following neural grafting required

CNS tissue from four human fetuses (62). Invariably, some neurons are lost while collecting the fetal

tissue. In addition, identification of the region of the

fetal brain required for grafting is difficult; the

desired fetal brain region transplanted into humans

with Parkinson’s disease is approximately 1 millimeter long (less than 4/100 of an inch) (figure 4-2).

Human fetal CNS tissue for neural grafting is

derived from first-trimester elective abortions,

which are commonly performed via vacuum aspiration; this results in fragmented fetal tissue, the

transplantable components of which maybe difficult

to identify (18). Some researchers have estimated

that human fetal tissue for neural grafting in

Parkinson’s disease is correctly identified in only 10

to 50 percent of aborted tissue analyzed (27,61).

Furthermore, only 5 to 10 percent of the transplanted

neurons may survive the grafting procedure. Improving graft retrieval and survival could diminish

the amount of fetal tissue necessary for transplantation.

Like other tissue used for neural grafting, fetal

CNS tissue presents some risks (see discussion of

risks later in this chapter). However, many scientists consider fetal CNS tissue to be the most

effective material currently available for neural

grafting (46,93). Fetal CNS cells appear to be less

vulnerable than adult cells to damage from, for

example, lack of oxygen, which is encountered

during the transplantation process. Also, cells within

fetal CNS tissue can readily mature and integrate

within the host; mature CNS tissue has lost these

capabilities. Of all the graft materials available at the

present time, fetal CNS tissue is most capable of

reconstituting nerve cell structure and function

within the host CNS. In addition, fetal CNS tissue

may enjoy at least a temporary immunological

advantage (see later discussion) and, like other

potential graft materials, is amenable to long-term

storage via cryopreservation (figure 4-3) (box 4-A).

Despite the usefulness of fetal tissue for neural

grafting, ethical, social, and political issues have

created a barrier to its use in the United States

and propel the search for alternative neural

grafting materials.

Peripheral Nerve Tissue

The permanent deficit in function that frequently

results from injury to the mature CNS reflects, in

part, the stymied regrowth of neurons within the

CNS. In contrast, axons in the peripheral nervous

system (PNS), which lies outside the brain and

spinal cord, can regrow following injury. Components of the PNS, including Schwann cells, a type of

glial cell that produces the insulating myelin sheath

around axons, promote axon growth (19).

Investigators have attempted to harness the

growth-promoting capacity of peripheral nerves

by grafting segments of peripheral nerve into the

CNS. Early animal experiments showed that a piece

of peripheral nerve placed into a lesion in the CNS

would bridge the lesion, allowing host nerve fibers
44 ● Neural Grafting: Repairing the Brain and Spinal Cord

Figure 4-2—Fetal Central Nervous System

A portion of the dissected human fetal central nervous system.

SOURCE: Curt Freed, Department of Medicine and Pharmacology, University of Colorado,

to penetrate and completely traverse the graft (22)

(figure 4-4). Nerve fibers that regenerate through a

grafted peripheral nerve penetrate only a short

distance on reentry into the host CNS. However,

even this shallow penetration back into the host

brain permits some reconnection with target neurons. Thus, some recovery of function may be

obtained by using this approach (55). This approach

may be limited to certain regions of the CNS due to

geometric constraints on nerve graft placement. For

example, it may be impossible to interconnect

deeply embedded regions of the brain with a nerve

graft without damaging the surrounding brain tissue.

Most of these animal experiments have involved

autografts; that is, the graft material has come from

the animal itself. An autograft provides two advantages: rejection of the graft by the host immune

system is avoided, and the graft recipient serves as

a readily available source of material.

Peripheral Autonomic Tissue

Some neurons are located outside the brain and

spinal cord and interact directly with various organs,

regulating body temperature, metabolism, and the

body’s response to stress. These peripheral neurons

are part of the autonomic nervous system, and they

synthesize neurotransmitters and other chemical

substances that are similar to those found in the

CNS. In addition, mature peripheral autonomic

neurons can survive injury and redevelop nerve

fibers. Because this class of neurons is easily

accessible and exhibits a great potential for regrowth, several investigators have examined the

usefulness of peripheral autonomic neurons for

neural grafting. Autonomic neurons have been
Chapter 4--General Features of Neural Grafting ● 45

Figure 4-3-Transplanted Fetal Nerve Cell

Photograph of a fetal nerve cell following cryopreservation and

transplantation.

SOURCE: D.E. Redmond, Jr., F. Naftolin, T.J. Collier et al., “Culture and

Transplantation of Human Fetal Mesencephalic Tissue Into

Monkeys,” &“errce 242:788-771, 1988.

grafted into the mature brain in a few animal

experiments, and in some cases these grafted neurons survived and led to improvement in function

within the injured CNS (54, 83).

Tissue From Outside the Nervous System

Some nonneuronal cells located outside the central and peripheral nervous systems share a common

heritage with nervous tissue; i.e., they develop from

the same type of embryonic precursor cell as nervous

system cells. These cells (sometimes referred to as

paraneurons) produce neurotransmitters and can be

stimulated to extend nerve fibers. Included in this

category are some cells in the adrenal gland, as well

as other, smaller collections of cells in the body (e.g.,

carotid body cells, which monitor the concentration

of oxygen in the blood). Because such cells resemble

neurons, they have been considered potential candidates for neural grafting. Cells from the adrenal

gland have been studied extensively.

The adrenal glands are located above each kidney,

and they produce various hormones. The innermost

region of the adrenal gland is the adrenal medulla.

One type of adrenal medullary cell, the chromaffin

cell, is derived from precursor cells that also

generate neurons in the autonomic nervous system.

Figure 4-4—Peripheral Nerve Graft

Diagram of graft from the PNS, permitting CNS nerve fiber

regrowth to target.

SOURCE: A.J. Aguayo, “Regeneration of Axons From the Injured Central

Nervous System of Adult Mammals,” Encyclopedia of fVeuroscience, vol. 11, G. Adelman (cd.) (Boston, MA: Birkhi?mser,

1987).

Chromaffin cells produce neurotransmitters chemically related to those made in the nervous system.

One of the neurotransmitters produced by- chromaffin cells is dopamine, the chemical that is

deficient in the brain of persons with Parkinson’s

disease.

The finding that fetal neurons which produce

dopamine could reverse parkinsonian symptoms in

animals suggested the use of adrenal medulla cells

for neural grafting (6,72). In the latter case, animals

could provide their own chromaffin cells for grafting, thus eliminating concerns about a source of

tissue and possible rejection of the graft. The

adrenal medulla grafts were shown to reverse

some of the abnormal body movements in animal

models of parkinsonism (see ch. 5).

A few recent experiments have employed another

nonneuronal tissue, human amnion membrane matrix (HAMM), taken directly from the discarded

human placenta, as a neural graft material (23,32).

When positioned in an animal’s brain, HAMM

appears to serve as a bridge that supports neuron

outgrowth. HAMM does not contain cells; rather, it

contains a chemical substance that promotes and

guides neuron regrowth. It does not seem to provoke

rejection of the graft by the host immune system, and

it is available in abundance. Although more research

is necessary to evaluate the usefulness of HAMM in

neural grafting, these experiments suggest that

manmade materials, coated with a growthpromoting chemical, may ultimately be developed and used in neural grafting.
46 ● Neural Grafiing: Repairing the Brain and spinal Cord

Box 4-A—The Deep Freeze: Cryopreservation of Fetal CNS Tissue

Neural grafting with fetal CNS tissue is constrained by the need for rapid implantation of freshly collected

tissue into the graft recipient. The viability of fetal CNS tissue diminishes within hours of procurement. Extending

the interval between tissue collection and implantation would greatly ease the logistics of neural grafting and allow

assessment of tissue contamination, vitality, and genetic compatibility with the intended recipient. Cryopreservation, or freezing of cells and tissue at very low temperatures, can be used to extend the time between tissue collection

and neural grafting. This technique is routinely used for the storage of continuous cell lines and other types of cells.

In fact, cryopreservation of fetal CNS tissue has a long history.

Prior to cryopreservation, cells or tissue are typically treated with a cryoprotectant, a chemical that limits tissue

damage during the freezing process. The cryoprotected material is then either abruptly or more gradually lowered

to -l%” C, the temperature of liquid nitrogen. Once at this temperature, cells or tissue can be stored for a long time;

frozen cells can also be transported readily between clinical centers.

Fetal CNS tissue from several species, including humans, has been examined following cryopreservation. In

general, cryopreserved fetal CNS tissue demonstrated a significant reduction in viability when thawed. Recently,

however, improved cryopreservation of human fetal tissue has been reported, resulting ’in 95 percent viability of

thawed fetal neurons. Furthermore, cryopreserved human fetal tissue has been shown to survive following grafting

into monkeys and humans.

SOURCES: T.J. Collier, D.E. Redmond, Jr., CD. Sladek et al., “Intracerebral Grafting and Culture of Cryopreserved Primate Dopamine

Neurons,” Brain Research 436:363-366, 1987; T.J. Collier, C.D. Sladek, M. J. Gallagher et al., “Cryopreservation of Fetal Rat and

Non-human Primate Mesencephalic Neurons: Viability in Culture and Neural Transplantation,” Progress in Brain Research, vol.

78, Transplantation Info the Mammlian CNS, D.M. Gash and J.R. Sladek, Jr. (eds.) (Amsterdam.: Elsevier Science Publishers,

1988); D.E. Redmond, Jr., “Fetal Tissue Transplantation: Animal and Human Studies,’ paper presented at the American

Association for the Advancement of Science annual meeting, New Orleans, LA, 1990, D.E. Redmond, Jr., F. Naftolin, T.J. Collier

et al., “Culture and Transplantation of Human Fetal Mesencephalic Tissue Into Monkey s,” Science 242:768-771, 1988; D.E.

Redmond, Jr., D. Spencer, F. Naftolin et al., “Cryopreserved Human Fetal Neural Tissue Remains Viable 4 Months After

Transplantation Into Human Caudate Nucleus,’ paper presented at the Society for Neuroscience 19th annual meeting, Phoenix,

Arizona, 1989; V. Silani, A. Pizzuti, O. Strada et al., ‘‘Human Neuronal Cell Viability Demonstrated in Culture After

Cryopreservation,” Brain Research 473:169-174, 1988; T. Sorensen, S. Jensen, A. Moller et al., “Intracephalic Transplants of

Freeze-stored Rat Hippocampal Tissue, ’ Journal of Comparative Neurology 252:468-482, 1986.

Isolated, Cultured, or Genetically Cell Suspensions

Engineered Cells

The graft materials discussed thus far have been

distinct types of tissue harvested directly from a

donor organism. Technical developments that permit the separation of individual cells from a solid

block of tissue, the maintenance of living cells in the

laboratory, and the manipulation of genes within

cells may expand the types and forms of materials

available for neural grafting. The methods described

in this section can be applied to many cell types. In

this report, however, the cells derived from each

tissue source via the methods described are treated

as a separate neural grafting material because each

gives rise to unique technological issues. The forms

of neural graft materials presented in this section

Neural grafting can involve the placement of

small, solid pieces of tissue into the brain (8,61);

however, solid pieces of tissue cannot be implanted

and sustained in all locations within the CNS. In

order to overcome this limitation, procedures have

been developed in which solid tissue is dispersed

into individual cells or, more often, aggregates of

cells prior to grafting (8,16). Dispersed cells in a

supporting fluid are known as a cell suspension. Use

of cell suspensions for grafting involves: 1) removal

of the required tissue from a donor organism, 2)

dissociation of the tissue into individual cells or

small aggregates of cells, 3) suspension of the

individual cells or aggregates in a supporting fluid,

and 4) injection of the suspension into the host CNS.

include: Cell suspensions from several types of tissue have

been used for neural grafting in animals (71).

● cell suspensions,

Experiments have shown that fetal neurons

● cells in culture, and grafted in the form of a cell suspension are

● genetically engineered cells. capable of long-term survival and interaction
Chapter 4--General Features of Neural Grafting ● 47

with the host CNS and can restore function in a

damaged region of the brain (8). In fact, neuron

suspension grafts may provide more rapid and

complete integration into the host brain than solid

grafts. Another advantage of using cells in suspension rather than solid tissue for neural grafting is the

ease with which suspensions can be manipulated. A

solid piece of tissue contains a heterogeneous

population of cells, the number and viability of

which cannot be determined. In contrast, cell number and viability can be monitored more accurately

in suspensions, and it may be possible to isolate a

single type of cell for transplantation (16,63). Also,

neural grafting with a cell suspension may provoke

a less severe immune system response than solid

tissue grafts.

Cells in Culture

Once solid tissue is dissociated into a suspension

of cells, the living cells can be maintained in the

laboratory for several weeks or months in culture.

For primary culture, cells are taken directly from an

organism and grown in vitro (literally, in glass).

Culturing cells prior to grafting them increases

the opportunity for manipulating the cells and

thus may increase the versatility of neural grafting.

A vast amount of information concerning the in

vitro culturing of different groups of nerve cells,

each with its specific requirements, has emerged

from basic neuroscience research (9), including a

recent report of successful culturing of human

neurons (78). Primary cultures of nerve cells, which

are generally derived from embryonic or fetal tissue,

have demonstrated the ability to survive implantation in the host CNS, to integrate into the host brain,

and to promote recovery following an induced injury

(15,39,51). In general, culturing fetal neurons diminishes their survival in the host following grafting.

The use of primary cultures of glial cells for neural

grafting has also been studied. For example, neural

grafts of astrocytes from the developing brain can

reduce scar formation following CNS injury in

animal experiments (90) and promote recovery of

brain function (56). Schwann cells and oligodendrocytes, both myelin-producing glial cells, have also

been grown in primary cultures and used for neural

grafting. Cultured Schwann cells and oligodendrocytes have been implanted into the CNS of myelindeficient rats, resulting in the formation of myelin

within the host CNS (31,45).

Photo credit: National Institute of Neurological Disorders and

Sfroke, Bethesda, MD, 1990

Nerve cells in culture.

Most cells survive for only a limited period in

primary culture, either replicating a freed number of

times or not at all. However, some cells can continue

to replicate and thus can potentially survive indefinitely. These continually self-propagating cells may

arise spontaneously, may be derived from tumors, or

may be created via genetic engineering. Sustained,

self-propagating cells in culture are known as

continuous cell lines (CCLs). Because CCLs can

produce a large number of cells and are in a sense

immortal, they have been extremely useful in a

number of areas of research.

Several CCLs have been studied extensively as

model systems for neuron development and function, including PC12 and neuroblastoma cells. These

neuronal CCLs, originally derived from tumors, can

be induced to stop replicating and to develop

features of adult neurons (e.g., formation of long

nerve fibers and secretion of neurotransmitters).

Experiments have shown that neuronal CCLs
48 ● Neural Grafting: Repairing the Brain and Spinal Cord

can be successfully grafted into the CNS and may

attenuate functional problems produced by lesions in the CNS (29,36,48,57).

Because CCLs are capable of continuous selfreplication, they could provide an inexhaustible

source of donor tissue for neural grafting; however, this very trait presents a critical obstacle to

their use. As is true of all replicating cells, their

potential for uncontrolled growth in the host CNS

may lead to tumor formation. Tumor formation

has been observed in some, but not all, animal

experiments using CCLs for neural grafting

(29,53,57). In order to eliminate the threat of tumor

formation, strategies for chemically controlling the

occurrence and arrest of cell replication are being

evaluated (2,57). Although CCLs may offer an

attractive option for neural grafting in the future,

more research is necessary to characterize and

control cell replication in tissue culture and in the

graft recipient.

Genetically Engineered Cells

Research is demonstrating that cells may be

designed to synthesize a specific chemical substance or to perform a specific function before

being implanted into a recipient. This customized

approach to neural grafting is made possible by the

use of genetic engineering techniques. Genetic

engineering permits the insertion of new genes into

a cell. Genes code for proteins, which carry out many

cell functions, and different genes direct the synthesis, or expression, of different sets of proteins. Cells

derived from fetal CNS tissue, the prospective host,

primary cell cultures, or a CCL can be genetically

engineered.

Genetic engineering techniques have been applied to tissue from the CNS. In one approach,

immature precursor cells from the developing CNS

of rats, which are capable of developing into mature

brain cells, were isolated and maintained in primary

cell culture (42,66). There they replicated for a finite

period and then matured. Genetic engineering methods were designed to permit the immature precursor

cells to replicate indefinitely in the laboratory, but

then subsequently to mature and to stop replicating

when transplanted into a host brain or spinal cord.

Using this approach, specific CCLs from the brain

and spinal cord may be developed for use in neural

grafting (10). The hope is that specific ‘‘immortal”

precursors for each type of cell within the brain and

spinal cord can be isolated and made available to

Figure 4-5-Genetic Engineering of Graft Tissue

/

1° cells \

Grow cells Culture ceils

4

s

!’,IL==J, Biochemical @iiiiia@&iiiia Genetic

characterization

Select modified cells modification

Diagram of methods used to graft genetically modified cells.

SOURCE: Fred H. Gage, Department of Neuroscience, School of Medicine, University of California, San Diego.

replace diseased or injured cells through neural

grafting.

Two types of nonneuronal cells have been used

for genetic engineering and neural grafting: astrocytes and fibroblasts (cells found in connective

tissue) (figure 4-5). Early research demonstrated that

genetically engineered cells can survive and function within the host CNS (34). In more recent

experiments, fibroblasts have been genetically engineered to synthesize: 1) an enzyme important for the

production of the brain chemical L-dopa, which is a

precursor of the brain chemical dopamine; and 2 )

nerve growth factor (NGF) (25,79,97). When used

for neural grafting, these genetically engineered

cells enhanced survival and growth of neurons,

improved CNS function, or both.

The use of genetically engineered fibroblasts,

which are easily derived from the skin, as neural

graft material has all the advantages of autografts: a

ready source of tissue and no worry about immune

system rejection of the graft. Although the use of

nonneuronal cells precludes the graft from forming

synapses with host neurons, genetically engineered

nonneuronal cells may be able to function as a drug

delivery system in the host. Fibroblasts, like other

replicating cells, do present some risk of excessive

replication within the host. However, since fibroblasts are primary cells, not derived from a CCL,

their multiplication is inhibited by contact with other

cells, minimizing the threat of tumor formation.
Chapter 4--General Features of Neural Grafting ● 49

Many important questions remain concerning

the grafting of genetically modified cells into the

human brain. Perhaps most important, the genes

controlling various cell functions within the CNS

(e.g., neurotransmitter synthesis and growth factor

production) must be identified. Once the genes

controlling CNS function and disease are identified,

they must be isolated and made available for genetic

engineering. Providing multiple genes to cells for

neural grafting and controlling their expression are

long-term goals requiring extensive research. Nevertheless, current research represents an encouraging

start toward many of these revolutionary therapeutic

strategies.

DETERMINANTS OF

SUCCESSFUL NEURAL

GRAFTING

To survive grafting, cells must endure mechanical

and metabolic disruption during their preparation for

grafting, and they must incorporate into the foreign,

and potentially hostile, environment of the host. The

surgical technique and tissue used for neural grafting

are important determinants of success. Several

additional characteristics may figure prominently in

the survival of a neural graft, including:

. the developmental state of the graft material,

● the host’s immune system response,

. blood vessel formation into the graft, and

. the age of the host.

Developmental State of the Graft Material

In general, immature tissue can survive grafting more readily than its mature counterpart.

Several characteristics of immature tissue, especially fetal tissue, make it well-suited for grafting

(l). In general, cells from fetal tissue replicate

rapidly and can differentiate into functioning mature

cells. Nutritional support provided by blood vessels

from the host is easily accepted and probably

promoted by fetal tissue. Fetal tissue is amenable to

cell culture and storage techniques, thereby expanding its flexibility for use in grafting. These features,

which make fetal tissue especially suitable for

grafting, are diminished or lost with maturity.

Early experiments in neural grafting of tissue

from the adult brain and spinal cord indicated that

this tissue survives poorly in the host CNS (7,35,89).

In contrast, tissue from the CNS of a fetus or

newborn exhibits great potential for survival and

development following neural grafting. Neural

grafting experiments in which cell suspensions are

used demonstrate an even greater reliance on the use

of fetal nervous tissue (8).

Although CNS tissue in later stages of development has been used with some success for neural

grafting in rodents and nonhuman primates, survival

is greatest when fetal CNS tissue is used (17,86).

Apparently, immature neurons, which have not yet

grown long and elaborate fiber-like extensions, are

less vulnerable to the mechanical disruption associated with tissue collection. In addition, immature

cells may be more resistant to other stresses’ associated with the grafting procedure, such as a temporary

reduction in oxygen supply. Because neurons

throughout the CNS develop and mature asynchronously, different groups of neurons reach the optimal developmental stage for neural grafting at

different fetal ages. The developmental stage of the

CNS tissue used for grafting may present immunological considerations. Grafts of fetal CNS tissue fail

to provoke an immediate immune response, probably because the cells and molecules that trigger

graft rejection by the host immune system have not

yet developed within fetal tissue. Fetal CNS tissue

does possess the capability of expressing immunoreactive molecules on maturity, hence it could

provoke a delayed immune system response.

The optimum donor age of non-CNS tissues for

neural grafting has not been as extensively evaluated. Adrenal medulla transplants in rats demonstrate greater functional effects when derived from

younger rather than older animals (28). Thus,

optimal success in adrenal grafting maybe obtained

by using young, and perhaps even fetal, adrenal

medulla tissue. Grafted nerve cells from the autonomic nervous system do not survive well when

derived from the fetus; however, mature autonomic

nerve cells regenerate briskly when transplanted

(82).

Immune System Response

Mammals have evolved an immune system to

protect them from disease-causing agents encountered in the environment. This system is a finely

tuned collection of tissues, organs, cells, and molecules that seek out, identify, destroy, and remember

foreign cells and molecules. An individual’s immune system vigilance against cells and mole-
50 ● Neural Grafting: Repairing the Brain and Spinal Cord

cules that do not originate within itself presents a

major obstacle for organ or tissue transplantation. In order for a graft to survive for an extended

period of time in the host, the host’s immune system

must be contravened or suppressed.

Rejection of a graft can be prevented by using

tissue from the host’s own body. As noted earlier,

such a graft is called an autograft. Graft material

from an identical twin-an isograft--should behave

immunologically like an autograft. After these two

types of grafts, compatibility is increasingly rare.

Either an allograft--tissue transferred between different members of the same species--or a xenograft--tissue transferred between individuals of

different species-can lead to graft rejection. Host

rejection of grafted tissue may be prevented by

reducing the genetic disparity between the donor

and the host and by using drugs that suppress the

action of the immune system.

It has long been thought that the CNS enjoys

relative isolation from the immune system because

it permits the entry of few cells from the immune

system that recognize foreign cells or molecules (for

review, see 69,94). This isolation has given rise to

the concept of immunological privilege; i.e., the

CNS is not subjected to the same degree of scrutiny

by immune system components as the rest of the

body. However, although allografts within the CNS

seem to survive frequently without inducing rejection, xenografts in the CNS do provoke graft

rejection (69). These data and others demonstrate

that the immune system can penetrate the CNS and

lead to graft rejection, thus casting doubt on the

degree to which immunological privilege operates in

the CNS.

Many immune system components are excluded

from the CNS by the blood-brain barrier, an important agent of immunological privilege (figure 4-6).

Injury, surgery, or infection can disturb the bloodbrain barrier, allowing cells and molecules from the

immune system to enter the CNS and cells from the

CNS to enter the bloodstream. While there is debate

about whether the blood-brain barrier is permanently

disrupted by the implantation of tissue in the CNS

(12,81), it is undoubtedly disrupted for at least a few

days (13). The type of grafting material used also

appears to affect the development of the blood-brain

barrier within the graft (13,83).

Figure 4-6—Blood-Brain Barrier in

Transplanted Tissue

Blood vessel surrounded by brain tissue shown in photograph.

Inset B displays the source of the blood-brain barrier, i.e., the tight

adhesion of endothelial cells, which line blood vessels.

SOURCE: Richard D. Broadwell, Division of Neurological Surgery, University of Maryland School of Medicine.

A second feature of the CNS which was believed

to isolate grafts and hinder graft rejection is the lack

of extensive lymphatic drainage. Lymphatic drainage returns fluids, molecules, foreign particles, and

cells from various tissues in the body through the

lymphatic system back to the immune and circulatory systems. It is through this drainage that grafted

cells capable of triggering rejection reach the host’s

immune system. The CNS had been thought not to

experience lymphatic drainage; however, some

studies have suggested that molecules and cells can

leave the CNS and enter the lymphatic system. Thus

the CNS may indeed experience some lymphatic

drainage and therefore be capable of provoking

rejection (96).

The use of CNS tissue as a grafting material often

fails to provoke rejection by the immune system, at

least in the short term. Cells within the CNS

normally lack, or express very few, immunoreactive

molecules, i.e., molecules that trigger rejection by
Chapter 4-General Features of Neural Grafting .51

the host’s immune system (88,98).2 Also, tissue

from ‘the CNS was thought not to contain cells that

enter the immune system and trigger an immune

response (47). Unfortunately, recent experiments

suggest that the CNS can be provoked to produce

immunoreactive molecules and that the CNS does

possess cells which may reach the immune system

and initiate graft rejection (3,50,92,98).

Another cell type that can provoke an immune

response is endothelial cells (49,65), which form the

inner walls of blood vessels and are commonly

found in grafts of solid pieces of tissue. This cause

of graft rejection can be eliminated by using neural

grafts composed of a single type of cell, as in cell

cultures or purified suspensions of cells, which do

not contain blood vessels or endothelial cells.

The fact that many types of neural grafts

survive in the host CNS suggests that the brain

and spinal cord do enjoy some immunological

privilege. However, research indicates that some

grafts can be identified and destroyed by the

host’s immune system. Further experiments and

analyses are required to delineate the precise relationship between the immune system and the CNS,

as well as the immune system’s response to neural

grafts.

Blood Vessel Formation

The neural graft’s ability to obtain ready

access to nutritional support and a supply of

oxygen from the host is critical for its survival.

The failure of many early neural grafts may reflect

inadequate incorporation of the grafted tissue into

the host blood supply (8). Solid tissue grafts into the

CNS may not receive an adequate blood supply for

more than 1 week (13).

Several approaches to neural grafting have been

developed to accelerate the provision of nutritional

support to the graft. One entails placing the graft

near a CNS surface that is naturally rich in blood

vessels. The brain ventricles were a favored site for

graft placement in animal experiments for this

reason (82). Ventricles are cavities within the brain

that contain cerebrospinal fluid (CSF). CSF may

provide immediate nutritional support to the solid

graft, and regions rich in blood vessels within the

ventricles provide long-term support. Another apFigure 4-7—Blood Vessel Growth in Transplant

t

‘. .% i $

*%

%4

Darkly stained blood vessels invading neural graft tissue in brain.

SOURCE: Richard D. Broadwell, Division of Neurological Surgery, University of Maryland School of Medicine.

preach is to create a rich vascular surface within the

brain (91). Under normal conditions, new blood

vessels are very rarely formed in the brain. However,

when a cavity is produced surgically in the CNS,

new blood vessel growth is stimulated and the cavity

walls become heavily invested with blood vessels.

Placing a graft within the cavity often results in a

good supply of blood vessels to the grafted tissue.

Greater blood vessel growth is produced by graft

placement than by a wound alone (59). The choice

of grafting material may also influence blood vessel

formation: blood vessels can grow into suspensions

of cells more readily than into solid pieces of tissue,

and fetal tissue seems to stimulate blood vessel

development better than adult tissue (figure 4-7)

(77). Finally, certain drugs may be used to enhance

blood vessel development within a graft (26).

It has been debated whether blood vessels within

a neural graft are derived from the donor or the host.

The relative contribution of each may depend on the

type of tissue transplanted, whether it is transplanted

as a solid piece or in a cell suspension, and the

amount of tissue damage sustained by the recipient

during placement of the graft (13,24,60,69,83).

Blood vessels within the graft may or may not fully

develop a blood-brain barrier, depending on the type

of tissue utilized (13,14,68,80,95). Both of these

observations, the presence of donor cells in the graft

blood vessels and the formation of the blood-brain

barrier, have important implications for graft rejec-

~e presence of specific molecules, including the major histocompatibility complex, or MHC antigens, is an important determinant of a tissue’s

imrnunogenicity. Detection and measurement of these molecules can be diffkult (71).
52 ● Neural Grafting: Repairing the Brain and Spinal Cord

tion. (See the earlier discussion of immune system

response.)

The Age of the Host

In general, the younger the graft recipient, the

more likely the graft is to survive and integrate

within the host brain. A younger host animal,

especially a newborn, maybe better able to support

grafted material because it can more vigorously form

blood vessels (8). Furthermore, an adult recipient

rejects neural grafts more rapidly than an immature

recipient (64). The age of the host, however, is less

critical to graft survival than the age of the donor,

immunological response, and extent of blood vessel

formation.

POTENTIAL RISKS

A major goal of neural grafting is to improve CNS

function following disease or trauma. As with any

surgical intervention, however, neural grafting presents risks to the recipient. Problems may result

from:

● immune system reaction or suppression,

. unwanted psychological effects,

. the surgical procedure itself,

● excessive growth of graft material, or

● infection or other effects on the host CNS.

Unfortunately, many of the risks attributed to neural

grafting are either poorly understood or simply

speculative. Before any routine application of

neural grafting in humans, the risks must be

carefully delineated, minimized, and measured

against expected benefits.

Immune System Reaction or Suppression

The transplantation of tissue from one individual to another presents the risk of graft rejection.

The foreign tissue triggers a cascade of events in the

graft recipient, culminating in destruction of the

graft. In general, allografts implanted in the CNS do

not appear to suffer immediate rejection by the

host’s immune system, although rejection in the

long term may be possible.

When tissue transplantation is performed outside

the CNS, drugs that suppress the immune system are

employed to prevent rejection and promote survival

of the graft. Immunosuppression poses serious risks

to the graft recipient, including increased susceptibility to infection and the development of some

forms of cancer (87). Uncertainty about immune

system reactions in the CNS complicates attempts to

balance the risks of immunosuppression against

those of neural graft rejection. Studies of fetal CNS

tissue grafting in humans with Parkinson’s disease

have both applied and abstained from applying

immunosuppression therapy (27,62,75).

Unwanted Psychological Effects

Implantation of tissue into the human brain

raises the possibility of unwanted psychological

effects. Assessment of adrenal medulla grafts in

humans with Parkinson’s disease indicates that

some psychological changes consistently accompany this procedure, including hallucinations, confusion, and somnolence (43,44). These psychological responses proved, in general, to be transient.

How such changes are produced is unknown, but

they may reflect either trauma to the brain from the

surgical procedure itself or the effects of chemical

substances released by the grafted adrenal tissue.

Similar effects have not been reported in the few

Parkinson’s patients who have received fetal CNS

tissue grafts.

Effects of the Surgical Procedure

Aside from its suspected role in producing temporary psychological changes in the recipient, the

surgical procedure used to insert a neural graft

presents other serious risks. Graft placement in the

brain, especially the more invasive surgical procedures (see ch. 5), can cause serious damage, such

as excessive bleeding or injury to brain tissue.

Injury may result in the loss of CNS function or

exacerbate the recipient’s immune response to the

grafted tissue (41). In addition, surgery disrupts the

blood-brain barrier for at least a week; even the less

invasive method of graft insertion probably disrupts

the blood-brain barrier for 1 to 3 days (14,94). The

CNS’s protected environment may thus be lost

temporarily near the graft site, posing a risk to the

graft recipient.

Excessive Growth of Graft Material

Fetal CNS tissue, some nonneuronal tissues,

and continuous cell lines can continue to replicate

in the CNS of the graft recipient, presenting the

risk of excessive graft enlargement. Brain tissue

can be compressed and permanently damaged by an

expanding mass of tissue. In addition, an enlarging

neural graft placed in the brain ventricles can
Chapter 4--General Features of Neural Grafting ● 53

obstruct the flow of CSF, which can dangerously

increase pressure in the brain. The number of cells

used for neural grafting is thus an important consideration; the number chosen must reflect a balance

between the risk of overenlargement and the more

common problem of inadequate cell survival. As

discussed earlier, some replicating cells pose the

added threat of tumor formation.

Infection and Other Effects on the Host CNS

Transplanted cells can transmit bacterial and

viral infections, placing the graft recipient at risk for

such diseases as hepatitis, AIDS, or herpes simplex

encephalitis. Several actions can reduce this risk.

The likelihood of a potential donor carrying an

infectious agent can be assessed. The potential donor

or graft material can be screened for infectious

agents. In addition, graft material can be treated with

drugs, such as antibiotics, to destroy susceptible

infectious agents prior to implantation.

Materials used for neural grafting may disrupt

or alter CNS function in the recipient. For

example, non-CNS tissue, such as cells from the

adrenal medulla or fibroblasts, may prevent the

reestablishment of the blood-brain barrier near the

graft (13,59,83). The implantation of certain fetal

CNS tissue has been shown to produce seizures in

some experimental animals (33). In addition, injection of brain tissue into the abdomen of animals has

led to experimental allergic encephalomyelitis

(EAE) (4), a potentially fatal inflammatory disease

of the CNS in which immune cells attack components of nerves. Although EAE has not been

reported in neural grafting experiments in animals,

it represents a serious risk, especially in the case of

xenografts. Finally, the graft may be susceptible to

the pathological processes that underlie the neurological disorder being treated. Since many neurological disorders are of unknown etiology, it is difficult

to assess the likelihood of this risk factor.

SUMMARY AND CONCLUSIONS

Neural grafting involves many therapeutic goals,

materials, and procedures. Tissue or cells may be

transplanted to the brain and spinal cord in order to

deliver chemical substances, to promote neuronal

growth and survival following injury, or to replace

lost nerve cells. Numerous materials have been used

for neural grafts, including fetal CNS tissue, peripheral nerve tissue, and tissue from outside the nervous

system. In addition, several types of tissue have been

manipulated, using cell culture and molecular biological techniques, in preparation for neural grafting.

While genetically engineered cells present an exciting possibility for the future of neural grafting, at

present fetal CNS tissue is demonstrably the most

effective graft material available. The developmental stage of the grafted material, the host’s immune

response, vascular support within the host, and the

age of the host also influence graft survival and

function. Depending on the material chosen and the

surgical procedures employed, neural grafting technology does present some risk to the host.

The potential use of neural grafting for the routine

treatment of the diseased or injured CNS requires

much more research, even for Parkinson’s disease,

where the technology is most highly developed at

present. Research is necessary to evaluate and

optimize transplant procedures. Other neural grafting approaches, including the use of genetically

engineered cells, will require even more extensive

basic research. Factors that determine the long-term

survival and function of a neural graft, especially the

immune system reactions, must be probed more

deeply. The influence of the disease process on the

grafted material must also be addressed. Perhaps

most important, a more complete understanding of

the basis of disease and malfunction within the CNS

is required for the development of treatments such as

neural grafting.

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Chapter 5

Applications of Neural Grafting Into

the Brain and Spinal Cord
CONTENTS

Page

NEURODEGENERATIVE DISORDERS . . . . . . .

A.

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Parkinson’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Huntington’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Alzheimer’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Motor Neuron Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

CENTRAL NERVOUS SYSTEM INJURY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Spinal Cord Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Brain Injury and Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

EPILEPSY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

NEUROENDOCRINE DEFICITS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

DEMYELINATING DISORDERS: MULTIPLE SCLEROSIS . . . . . . . . . . . . . . . . . . . . . . . .

SUMMARY AND CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

CHAPTER 5 REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

61

61

73

74

75

75

75

81

82

82

83

84

84

Page

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64

Box

5-A. MPTP, a Key to Parkinson’s

5-B. The Use of Registries To Collect Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70

Figures

Figure .

5-1. The Substantial Nigra and the Striatum . . . . . .

5-2. Monkey Brain Exposed to MPTP . . . . . . . . . . .

5-3. Adrenal Medulla Neural Graft for Parkinson’s

5-4. Grafting Genetically Modified Fibroblasts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67

5-5. Stereotactic Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68

5-6. Brain Activity in an Alzheimer’s Disease and a Normal Brain . . . . . . . . . . . . . . . . . . 74

5-7. Possible Actions of Neural Grafts in Spinal Cord Injury . . . . . . . . . . . . . . . . . . . . . . . . 77

Page

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63

Disease . . . . . . . . . . . . . . . . . . . . . . . . . 65
Chapter 5

Applications of Neural Grafting Into the Brain and Spinal Cord

The technology of grafting into the brain and

spinal cord to restore functions lost through disease

or injury is still in the initial stages of development.

Research in animals has indicated that neural

grafting may provide beneficial therapeutic effects

in some neurological disorders, notably Parkinson’s

disease. But in every case, including Parkinson’s

disease, there is still much information that needs to

be collected before neural grafting can be adapted

for general use in humans. The research currently

being conducted in this field is aimed at learning

more about basic mechanisms involved in grafting

tissues into the central nervous system (CNS) and

the actions and effects neural grafts can exert there.

Information is being sought in three broad areas:

the conditions necessary for graft survival and

incorporation into the host,

the functional role grafted material can play in

alleviating deficits caused by disease or injury,

and

the mechanisms by which grafts produce any

functional recovery that is observed..

Scientists use many different kinds of experiments with animals to obtain this information. Some

experiments are designed to gain information about

basic mechanisms related to brain development, the

brain’s response to injury, and the regenerative

capabilities of nervous tissue. Others examine the

ability of grafts to ameliorate or reverse experimentally induced deficits. Still others use animal models

that either replicate or share features of human

disorders in order to determine whether grafting

could result in improved function. Thus, experimental work in the field of neural grafting

provides information about basic brain mechanisms as well as the role grafts can play in

neurological disorders.

The need for animal models that mimic a given

neurological disorder in humans is as important in

the field of neural grafting as it is in most other areas

of clinical research. Animal models of a disease or

injury can be either homologous (sharing a common

origin with the human condition) or analogous

(sharing similar organ damage, though not necessarily via the same disease mechanism). Currently,

there are very few homologous models of human

neurological disease. The closer an animal model is

to the human condition under study (in terms of the

neurological damage induced and the resulting

behavioral effects), the easier it is to extend observations from the model to a human disorder. Virtually

all scientists in the field of neural grafting believe it

is essential to develop good animal models for use

in grafting experiments.

Theoretically, the applications of neural grafting

technologies into the brain and spinal cord could

encompass many types of neurological disorders.

The possible therapeutic applications of neural

grafting range from the highly speculative to the

actually implemented. This chapter provides an

overview of some of the possible applications of

neural grafting into the brain and spinal cord, the

research that has been conducted so far, and the

current status of each. In addition, the possible

mechanism of therapeutic action of neural grafts for

each condition is discussed. The neurological disorders are presented according to type, with an

emphasis on those that have been studied most

extensively.

NEURODEGENERATIVE

DISORDERS

Parkinson’s Disease

The clinical use of neural grafting in the treatment

of Parkinson’s disease, begun in the early 1980s, has

generated controversy in the scientific and medical

communities. While more is known about neural

grafting in Parkinson's disease than in any other

neurological disorder, the efficacy of grafting in

humans is unclear, and ethical concerns are

unresolved. The concern about the discrepancy

between the base level of knowledge and the actual

clinical use of these procedures, even under experimental conditions, has increased public awareness

of this controversy. This section provides a summary

of the animal research and clinical use of neural

grafting in persons with Parkinson’s disease.

Parkinson’s disease is well suited to the application of neural transplantation because the disease

results from the degeneration of a discrete population of neurons located in an area of the brain called

-61-
62 ● Neural Grafting: Repairing the Brain and Spinal Cord

Figure 5-l—The Substantial Nigra and the Striatum

“’’’’””’X———W

Substantial

The cells of the substantial nigra send their axons to the striatum.

This pathway degenerates in Parkinson’s disease.

SOURCE: R. Restak, The Brain (New York, NY: Bantarn Books, 1984).

the substantial nigra. These neurons produce dopamine, a neurotransmitter, and form synapses with

neurons in another area of the brain, the striatum

(figure 5-l). The neurons in the striatum are not

destroyed in Parkinson’s disease (67); however, the

depletion of dopamine in the striatum, caused by the

loss of cells in the substantial nigra, is associated with

the symptoms of tremor, rigidity, difficulty in

standing, and slowness of movement that are characteristic of Parkinson’s disease. Neural grafting in

Parkinson’s disease has been aimed at correcting the

loss of the dopamine-producing pathway between

the substantial nigra and the striatum by either

replacing the dying cells or supplying additional

dopamine . To do this, neural grafting materials

from two main sources have been used: 1) tissue

from the adrenal gland and 2) tissue from the

fetal CNS. A graft that would survive indefinitely

could produce continuous relief from symptoms, but

evidence suggests that the degeneration of the

dopamine -producing neurons in the substantial nigra

would continue. All research to date has been

aimed at the ability of grafts to provide relief

from symptoms and reduced disability, not cessation or reversal of the degenerative process.

The most obvious site for transplantation of

dopamine -producing cells in Parkinson’s disease

would seem to be the locus of the degenerating cells,

i.e., the substantial nigra. While cells placed in this

site might receive some inputs from neurons in other

areas of the brain that normally send fibers to the

substantial nigra, axons from the grafted cells would

have to grow several centimeters through the brain

to connect with their targets in the striatum. Unfortunately, nerve fibers do not readily grow over such

distances in the adult brain, and it has been shown

that dopamine-producing grafts implanted into the

experimentally damaged substantial nigra of rodents

have no effect on the parkinsonian symptoms such

damage causes (40).

Instead, dopamine-producing cells have been

grafted (either as a cell suspension or as solid pieces)

to sites close to their targets in the striatum, in order

to facilitate formation of synapses. In fact, it is

unclear whether the formation of synapses is actually necessary to produce an effect—it is possible

that some of the effects of dopamine produced in the

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Photo credit: J.R. Sladek, Jr., University of Rochester Medical Center

Picture of a graft of monkey fetal tissue implanted into an

adult monkey.
Chapter 5--Applications of Neural Grafting Into the Brain and Spinal Cord ● 63

striatum by grafts may result simply from the diffuse

release of chemicals in the area and thus do not

require specific, point-to-point synaptic connections

and precisely timed release.

Animal Research

Fetal Tissue—The first indication that grafts

might be effective in the treatment of Parkinson’s

disease was observed in experiments conducted in

1979 (19,1 19). These experiments used rats in which

the pathway between the substantial nigra and the

striatum had been destroyed by the neurotoxin

6-OHDA, l thus chemically affecting the same site

that is thought to be central to the clinical signs of

Parkinson’s disease. Grafts of dopamine-producing

neural tissue from rat fetuses, implanted into the

striatum, were able to reduce some deficits caused

by the wound (40,41); however, the extent and type

of function that was restored depended on where in

the striatum the graft was placed (40,41).

Since these initial experiments, many others using

the same animal model have shown that implanted

fetal tissue sends out fibers and makes contact with

the host tissue, receives inputs from the host tissue,

and performs typical neuronal functions within the

host (3,20,54,55,103,131,139,141, 153).

Although some of the functional recovery produced by neural grafting may be due to the

nonspecific release of dopamine into the host brain,

studies have shown that much of the observed

recovery is related to the extent to which the

implanted tissue becomes incorporated within the

host brain--i.e., the degree to which the graft sends

connections to, and receives connections from, the

host brain. This finding indicates that more than just

a diffuse release of dopamine into the striatum is

involved. In fact, when the graft is removed, the

corrective effects disappear, suggesting that they are

due to a direct action of the graft and not to an effect

unrelated to it (17,42).

Dopamine-producing fetal tissue has also been

studied in the MPTP model of parkinsonism (figure

5-2).2 While it takes only days for MPTP to produce

the symptoms of parkinsonism in laboratory aniFigure 5-2—Monkey Brain Exposed to MPTP

The brain of a monkey that was exposed to MPTP on one side.

‘The substantial nigra on the unexposed side (right) is normal

(black band). On the MPTP exposed side (left) the cells of the

substantial nigra are destroyed.

SOURCE: R.A.E. Bakay, Section of Neurological Surgery, The Emory

Clinic.

reals, as compared to years for the disease itself in

humans, most scientists still regard this as the best

animal model of the disease (see box 5-A). Also,

since MPTP is particularly effective in monkeys, it

has provided scientists with an important primate

model of parkinsonism. (Data derived from experiments using monkeys are more easily extrapolated

to humans than are data from nonprimate animal

models.) As with the 6-OHDA experiments, it was

shown that grafted dopamine-producing fetal neural

tissue can become incorporated into the striatum of

treated monkeys and result in significant, long-

-lasting reductions in movement abnormalities, including tremor, rigidity, and slowness of movement

(7,8,31,49,124,135). Recently, this effect of fetal

tissue grafts in monkeys has been linked to the

ability of the grafts to stimulate new growth from

undamaged neurons (10).

In Summary, a number of different studies have

demonstrated that dopamine-producing fetal tissue can counteract some of the effects produced

in the 6-OHDA and MPTP animal models of

parkinsonism. In particular, some of the results seen

following grafting in nonhuman primates treated

with MPTP have been promising. However, in

l~s tiogoWanim~ model is produced by the neurotoxin 6-hydroxydop amine (6-OHDA), which selectively destroys doparni.m+producing

neurons. In this model the 6-OHDA is injected directly into the substantial nigra. While the lesion produced by this injection destroys the same neurons

that are lost in Parldnson’s disease, the action of the chemical and the temporal course of the neuron destruction do not mimic what occurs in the disease.

Also, the functional deficits produced, while in some respects simiku to those produced by Parkinson’s disease, are not exactly the same.

2- (1-Me~yl.~phenyl.l-z.3-6-te&~y&opfi~e) is a chemical that, when administered, causes a syndrome ShikU tO pMhSOn’S dis-.

Thus, the drug is said to result in parkinsonism rather than Parkinson’s disease (see box 5-A).
64 ● Neural Grafting: Repairing the Brain and Spinal Cord

Box 5-A—MPTP, a Key to Parkinson’s Disease

On a July morning in 1982, a patient was brought into the emergency room of a hospital in Santa Cruz,

California. He was stooped over and displayed the symptoms of rigidity and inability to initiate movement typically

seen in persons in their sixties or seventies who have been suffering from Parkinson’s disease for many years. The

clinical picture was that of classic, late-stage Parkinson’s disease. However, this patient was 24 years 014 and his

symptoms had developed virtually overnight. With this startling patient began one of the most interesting and

important chapters in the history of Parkinson’s disease research and treatment.

A closer examination of this patient and five others who came to hospital emergency rooms in the northern

California area at about the same time revealed that they were all heroin addicts who had injected some homemade

narcotics that contained an impurity. The impurity was determined to be the chemical 1-methy1-4-phenyl-1,2,3,6-

tetrahydropyridine, or MPTP. It was thought that the MPTP might have caused brain damage that mimicked

Parkinson’s disease, resulting in identical symptoms, This hypothesis was lent further credence by an autopsy report

on another individual who had been exposed to MPTP. The report noted that the man’s brain looked like that of

someone who had suffered from Parkinson’s disease for years: The dopamine-containing neurons in the substantial

nigra, which are lost in Parkinson’s disease, were destroyed. It was also found that when given L-dopa, the most

common medicine for treating Parkinson’s disease, the patients exposed to MPTP improved dramatically. However,

the effectiveness of the L-dopa began to wear off after 2 to 3 years, just as it does in most Parkinson’s patients after

5 to 10 years.

Immediately after the identification of MPTP as the agent responsible, scientists began to study the compound

to find out how it causes this model of parkinsonism. They found that MPTP can enter the bloodstream through

direct injection, inhalation, or contact with the skin. Inside the brain, an enzyme called monoamine oxidase B

(MAO-B) breaks down MPTP into other chemicals, including an electrically charged molecule called

methylpyridine (MPP+). The MPP+ molecules are taken up selectively by dopamine-producing neurons. It is

thought that, once inside these dopamine neurons, the MPP+ may cause another chemical reaction to take place.

This reaction produces toxic substances, such as peroxides, and other charged particles, called free radicals. The

production of these substances destroys the cell. It was also found that if the breakdown of MPTP to MPP+ is

prevented by blocking the activity of MAO-B, MPTP has no effect.

This understanding of the chemistry of MPTP has led to a new understanding of what might be occurring in

persons with Parkinson’s disease. It is possible that the same sorts of toxin-producing chemical reactions that MPTP

causes in the brain occur in Parkinson’s patients, What causes the chemical reactions to take place in the disease

is unclear, but it may be some disruption in the normal biochemical activity of the dopamine-producing neurons.

Indeed, it has been known for some time that MAO-B is also involved with the normal breakdown of dopamine

in these cells. It is possible that this normal process gets disrupted somehow and that when the dopamine is broken

down, peroxides and free radicals are produced. Based on these new MPTP data, a drug called deprenyl, which is

known to block the action of MAO-B, was studied. It has been shown, at least in one study, that deprenyl appears

to have a retarding effect on the progression of the disease. While this finding needs to be confirmed, it indicates

how the information gained from the MPTP model of parkinsonism is giving scientists and doctors valuable new

information about the disease,

Another theory that has been proposed as a result of the discovery of MPTP is that Parkinson’s disease might

be caused by environmental exposure to MPTP or a chemical like it. While this is a possibility, no strong evidence

of any link between the incidence of Parkinson’s disease and exposure to MPTP in the environment has been found

to date.

Interestingly, it has been found that MPTP does not affect all species. While it produces symptoms of

parkinsonism in humans, nonhuman primates, and mice, it has little or no effect in rats, cats, rabbits, and a number

of other species. The reason for this is not clear, but it is thought to be due to differences in the blood-brain barrier.

The discovery of MPTP has greatly advanced the understanding of Parkinson’s disease. Not only has it

provided important new insights into the possible mechanism that causes the disease, but it has given scientists an

important and extremely useful new tool to study Parkinson’s disease. The nonhuman primate MPTP model has

been and will continue to be one of the best experimental tools for dete

grafting to treat Parkinson’s disease.

rmining the efficacy of the use of neural

SOURCE: Office of Technology Assesstment, 1990.
Chapter 5-applications of Neural Grafting Into the Brain and Spinal Cord ● 65

Figure 5-3—Adrenal Medulla Neural Graft for Parkinson’s Disease

Tissue from a patient’s adrenal gland, which lies atop the kidney(1), is implanted into the striatum (2).

SOURCE: Newsweek Apr. 14, 19S6, I.B. Ohls.son.

addition to the need to replicate and expand these

findings, there is a need to answer the following

questions by means of additional animal studies:

. Where in the striatum should material be

grafted to achieve maximum effect?

● How long do the effects of the graft last?

Adrenal Medullary Tissue—There is considerable interest in finding alternative sources of dopamine-producing grafting material, for two reasons.

First, there are ethical, legal, and technical obstacles

to procurement of human fetal tissue for transplantation. Second, the use of autografts (tissue from the

person’s own body) eliminates possible immunological rejection of the graft. While other types of

tissue for autografts have been studied [sympathetic

ganglia, carotid body glomus cells, (15,83)], tissue

from the medulla of the adrenal gland has attracted

the greatest interest. In animal experiments, the

adrenal tissue is collected from donor animals; in

humans with Parkinson’s disease, the patient’s own

adrenal tissue can be used for the graft (figure 5-3).

The efficacy of adrenal tissue is more uncertain

than that of fetal CNS tissue. Questions have been

raised about how effective adrenal tissue is in

producing fictional recovery, what mechanism

induces functional effects, and whether any observed functional effect is actually due to a direct

effect of the graft or to some other factor.

Implantation of adrenal medullary tissue can

ameliorate some of the deficits created in the

6-OHDA model in rodents; however, the range of

functions recovered is narrower than when fetal

tissue is used (52,96). The beneficial effects are

thought to result from either a nonspecific, diffuse

release of dopamine by the adrenal cells (53) or an

increase in the number of new dopamine fibers near

the graft site (112). The latter presumably reflects

the degree to which the grafted adrenal medulla cells

are converted into neuron-like cells that produce

dopamine.

The number of adrenal cells that survive implantation is very low in both rodents (15) and monkeys

(1 1,75,108). If the cells do not survive, the chance of

functional recovery is small and any long-term
66 ● Neural Grafting: Repairing the Brain and Spinal Cord

Photo credit: R.A.E. Bakay, The Emory Clinid

Section of a monkey brain showing a surviving graft of

adrenal medulla tissue that was implanted along with other

tissues that produce neurotrophic substances.

recovery that does occur is probably due to some

effect unrelated to continued graft function. Adrenal

cell survival is enhanced when neurotrophic factors,

including nerve growth factor (NGF), are added to

the graft site (16,88,140). In monkeys, increased

fictional recovery is observed when adrenal cells

are grafted along with cells that produce neurotrophic factors (88), although it has been observed in

rats that the same level of functional recovery occurs

when NGF is given in conjunction with either

adrenal grafts or grafts of nondopamine-producing

material (121). This suggests that the functional

recovery observed in the latter case resulted, in part,

from activation of the brain’s injury response

mechanisms due to surgical injury (including release

of growth factors) and the nonspecific action of NGF

to promote axon growth.

Another issue surrounding adrenal tissue grafts is

the influence of donor age on graft efficacy. Grafts

from younger rats are more effective than those from

older rats in promoting functional recovery following destruction of dopamine-producing cells with

6-OHDA (51). Also, older tissue is less likely to

undergo the conversion from adrenal medulla cells

to dopamine-producing neurons (9). This may be

due to a lack of growth-promoting factors, perhaps

NGF, in the older tissue. When NGF is administered

to rats in conjunction with grafts of older adrenal

tissue, more conversion of cells to dopamineproducing neurons is seen and a greater improvement in movement occurs (140). Since many Parkinson’s disease patients are elderly, donor age may be

one reason for the limited effect of adrenal autografts

used in these patients (see later discussion).

The data collected on adrenal grafts in the MPTP

nonhuman primate model of parkinsonism agree

with the data obtained in 6-OHDA experiments with

rats. As noted previously, only limited survival of

grafted tissue following implantation has been

observed (11,75). This raises the question of what is

responsible for the functional recovery that has been

seen. New dopamine fibers growing in the host brain

(47) and functional improvement (11) have been

observed in both grafted animals and animals that

had the surgery performed without tissue implantation. This suggests that the surgical procedure itself

has some effect. As was true of the rats, the degree

of functional recovery in nonhuman primates is less

with adrenal medullary tissue than with fetal CNS

tissue (100).

In summary, the ability of adrenal medullary

tissue to ameliorate the deficits caused in animal

models of parkinsonism is unclear. Questions that

need to be answered include:

●

●

●

Are the functional improvements that have

been observed the result of the adrenal graft or

the surgical procedure?

If adrenal grafts do have a beneficial effect,

what is the range of deficits that can be

improved?

What role can concomitant application of

growth-promoting factors play in the survival

and efficacy of adrenal grafts?

Genetically Engineered Cells-Genetically engineered cells have been shown to survive grafting

into the CNS (58). The ability of genetically

manipulated cells to decrease the abnormal behavior

caused by administration of 6-OHDA to rats has

recently been investigated (151). Certain skin cells,

called fibroblasts, were taken from rats and genetically modified to produce the enzyme tyrosine

hydroxylase (TH), which is required for the production of dopamine (figure 5-4). It was hoped that

inserting these cells into the 6-OHDA rats would

cause the animals to produce dopamine and thus

reduce their abnormal behavior. The grafts of the

genetically engineered cells did reduce abnormal

behavior, by about 40 percent.

Although this important study indicates that

genetically altered cells might be an effective

grafting material, it was noted that the extent of
Chapter 5--Applications of Neural Grafting Into the Brain and Spinal Cord ● 67

Figure 5-4-Grafting Genetically Modified

Fibroblasts

/’” + u

1° cells or

;:j cell line

~ Graft

Behavioral 4

b

testing Culture cells

Biochemical

mk==>f - -

Genetic

characterization

Select modified cells

modification

The process of grafting genetically engineered fibroblasts consists of: 1) culturing the fibroblasts, 2) genetically modifying them,

3) selecting which cells to use, 4) testing them, 5) grafting into the

brain, and 6) behavioral testing of the animal to determine the

effect of the graft.

SOURCE: F. Gage, Department of Neuroscience, University of California,

San Diego.

recovery was less than that which has been observed

when fetal CNS tissue is used. One possible reason

for this difference is that the manipulated cells do not

produce as much dopamine as normal fetal brain

cells. Nonetheless, since the use of genetically

manipulated cells lines would circumvent the problems associated with fetal tissue and the immunological considerations connected with other sources,

continued exploration of their use is an important

area of research.

Human Application

Human trials of neural grafting in persons with

Parkinson’s disease have used both adrenal and fetal

CNS tissue. In both cases, some observers have held

that the trials were premature (137). In the case of

adrenal grafting, many observers believe that there

has been a rush to proceed with human trials without

having first collected adequate data from animal

experiments; in the case of fetal tissue grafts, while

there is a larger base of animal data to draw on, there

is still concern that widespread implementation of

human fetal tissue grafting could proceed before

adequate information has been derived from animal

experiments. This question may place scientists who

are doing the research at odds with patients and

doctors, who must deal with the realities of devastating illness on a daily basis. The participants in this

debate include scientists performing basic research,

desperately ill patients who are willing to undergo

virtually anything that might help them, and clinicians, who are motivated by the altruistic desire to

help their patients and, perhaps, by the ambition to

be on the cutting edge of a new and exciting field.

As of 1990, between 300 and 400 persons with

Parkinson's disease had received neural grafts

worldwide. About 100 of them have been implanted

with fetal CNS tissue, the remainder with adrenal

tissue. In the United States, approximately 130

patients have been treated with adrenal tissue, while

fewer than 10 have had fetal tissue implants. The use

of fetal tissue for implantation in this country is

limited to privately funded ventures because of the

moratorium on Federal funding for such research

(see app. A).

Surgical Procedures--Implantation of adrenal or

fetal tissue into the brain can be done using either a

stereotactic or an open surgical approach. In a

stereotactic procedure, the tissue is implanted by

means of a long needle inserted into the brain

through a small hole made in the skull; this

procedure is guided by various computer-assisted

imaging procedures and brain scans (figure 5-5). In

an open surgical procedure, the area where the graft

is to be placed is exposed so it can be seen by the

neurosurgeon. This procedure, therefore, is more

invasive than the stereotactic procedure. In addition,

a patient undergoing an adrenal transplant must also

undergo surgery to remove one of his or her adrenal

glands for implantation.

Most stereotactic procedures are performed under

local anesthesia, although general anesthesia is

sometimes used. Implantation of tissue using a

stereotactic procedure usually takes 1 to 1 1/2 hours.

Following surgery, patients are often observed in a

neurological intensive care unit overnight in case

surgical complications develop. Provided there are

no complications, the patient could recover from the

operation within 24 to 48 hours and be fit for

discharge a few days after that. In the case of

experimental procedures, however, it is likely that

the patient would be kept in the hospital longer, for

observation and for comprehensive testing.

While an open approach is more invasive, it

provides more flexibility in the way graft tissue can

be implanted. A general anesthetic is given, and a

portion of the skull is removed. For grafting in

Parkinson’s disease patients, the surface of the

striatum is exposed by incising the overlying brain
68 ● Neural Grafting: Repairing the Brain and Spinal Cord

Figure 5-5-Stereotactic Surgery

Photo credit: The Emory Clinic

Adrenal medulla graft surgery.

tion may make it possible to retrieve the adrenal

tissue, preserve it, and then wait until the patient has

recovered from the abdominal surgery before performing the grafting procedure.

An X-ray of a patient in a streotactic apparatus.

SOURCE: Spiegel, Encyclopedia of Neuroscience, vol. G. 

(cd.) (New York, NY: Boston, 1987).

tissue; a cavity is made on the surface of the striatum,

and the graft tissue is placed into that cavity.

Sometimes the graft is held in place by surgical

staples or by a covering of a specially treated

material. The piece of bone that was removed from

the skull is replaced, and the scalp wound is closed.

This operation generally takes 3 to 4 hours. The

patient is usually returned to the neurological

intensive care unit for observation. In general,

recovery from the operation takes several weeks.

When adrenal medullary tissue is used for grafting, one of the patients two adrenal glands has to be

removed. This procedure is called an adrenalectomy.

Since the adrenal gland lies atop the kidney, its

removal requires abdominal surgery. Access to the

adrenal gland is obtained through an incision in

either the abdomen or the side of the patient.

Normally, an adrenalectomy is performed by a

surgeon working in tandem with a neurosurgeon,

who is simultaneously preparing for the implantation. In the future, techniques such as cryopreservaThus far, the majority of patients who have

received adrenal grafts have had both the adrenalectomy and the brain surgery done at the same time.

The procedure is quite debilitating, and recovery

takes a long time, often weeks. Patients may also

experience the surgical complications that can

accompany abdominal surgery and neurosurgery.

Based on the results presented by different groups in

the United States that have done adrenal grafts, the

mortality rate and the rate of complications have

each been estimated at 5 to 10 percent (100).

Adrenal Medulla Grafts—Based on the early

success obtained in rodent experiments using adrenal tissue, the first grafts of adrenal medullary tissue

in humans were performed on two Parkinson’s

patients in Sweden in 1982; both patients had been

experiencing severe fluctuations in the management

of their disease by medications (the so-called on-off

phenomenon ) (5). In a subsequent study, two

additional patients were operated on (97). In all four

patients, a stereotactic technique was used to transplant medullary tissue from the patient’s own

adrenal gland into the striatum on one side of the

brain. These patients showed minor improvements

in motor function that lasted for about 2 months. By

 to and unpredictable shifts between periods in which the symptoms of Parkinson’s waler 

(on), they (off). This occurs regardless of when patients aregiven.It is thought

that the phenomenon results from the continued progression of the disease. Most patients will eventually experience dose-related fluctuations in their

symptoms, but the on-off phenomenon is more rare.
Chapter 5-applications of Neural Grafting Into the Brain and Spinal Cord . 69

6 months, no positive effects remained. No adverse

effects of the procedure were reported. Long-term

followup of these patients has not shown any

influence of the transplant on the course of the

disease (96). In the face of these modest effects and

the simultaneous development of the MPTP primate

model of parkinsonism, it was widely considered

that further animal research was needed before

attempting additional grafts in patients.

In 1986, however, a group in Mexico conducted

similar grafting experiments on patients with Parkinson’s disease. These experiments differed from

those done by the Swedish group in that the adrenal

grafts were performed using an open surgical

procedure and the tissue was placed into the brain in

a slightly different fashion. Furthermore, the patients were generally younger and in a less advanced

stage of the disease. In 1987, the Mexican group

reported dramatic and persistent improvements in

the first two patients (102). The surgeons placed

several fragments of adrenal tissue into a single

cavity on the surface of the striatum on one side of

the brain and anchored them with miniature staples.

Improvements in muscle movements were seen

almost immediately after recovery from surgery,

with continued improvement over the next 10

months. In a second report, in 1988, the outcomes for

the Mexican group’s first 11 grafting patients were

described (38). All patients (ages 35 to 65) were said

to have improved in gait and writing capability;

tremor and rigidity were lessened and movement

was improved in most cases; and medication could

be reduced in all. The Mexican group has now

performed the operation on more than 40 Parkinson’s disease patients. Four of the patients have

subsequently died (the relation of death to the

surgery is not clear); no postmortem confirmation of

surviving adrenal cells has been reported.

Despite the discrepancies between the Mexican

and Swedish results, the 1987 Mexican report led to

a torrent of adrenal medullary operations on Parkinson’s patients around the world. Approximately 300

operations using adrenal medulla autografts have

been carried out worldwide. In many of these

operations, the neurosurgeons attempted to follow

the procedure of the Mexican group, with only minor

modifications. A detailed observation of 19 patients

over a period of 6 months in Chicago, Tampa, and

Kansas City has been published (69,1 18). A modest

reduction in these patients’ off periods (when

symptoms are most severe) was found, but the

patients were still disabled by the disease. Also, the

grafting procedure did not permit dosages of their

medications to be decreased. Frequent medical

complications were associated with the procedure. A

followup study of 7 of the 19 original patients

reported that, 12 months after their operations, the

overall amount of on time was increased and the

severity of symptoms during off time was decreased

(71).

Other studies, including one involving a group of

18 patients treated in Nashville (1) and several

involving smaller groups of patients (2,94,95,

117,148), have been published or presented in

abstract form at scientific meetings. They have

reported variable results with the use of adrenal

grafts. In an effort to establish a centralized repository for the data collected from these procedures,

two registries have been established (see box 5-B).

The results collected by each of these registries have

been published (6,70), with the data from some

centers included in both reports. One registry

indicated that there was “a rather diffuse response

with a general trend for improvement, but mostly

modest improvement” (6) 1 year following surgery,

and the other reported a statistically significant

decrease in disability, as indicated by an increase in

on time and less severe symptoms during off periods

1 year after surgery (70). Neither registry found that

it was possible to decrease the medication patients

received, and both reported a number of postoperative complications. The complications, which in

some cases were transitory (lasting less than 3

months) but in others persisted for as long as a year,

included respiratory problems, pneumonia, urinary

tract infections, and a number of transitory psychiatric problems, including hallucinations or delusions,

sleepiness, and confusion.

Data from both registries clearly show that there

are fewer complications associated with removal of

the adrenal gland through the patient’s side as

opposed to the abdominal cavity and by stereotactic

placement of the tissue into the brain versus an open

neurosurgical approach. Older, more severely affected patients were more likely to have adverse

effects and less likely to benefit from the procedure,

leading to the conclusion that, based on the data

collected thus far, the ideal patient ‘‘. . . would be

less than 55 years of age and only moderately

disabled” (6). The mortality rate according to the

data collected by one of the registries was 10

percent, though not all the deaths were thought to
70 ● Neural Grafting: Repairing the Brain and Spinal Cord

Box 5-B—The Use of Registries To Collect Data

In 1987, in an attempt to docum ent the activity occurring in the field of adrenal-neural grafting, the American

Association of Neurological Surgeons (AANS), in collaboration with the National Institute of Neurological

Disorders and Stroke (NINDS), established the General Registry of Adrenal-Fetal Transplantation (GRAFT’). Like

the National Heart Transplant Registry established in the early 1980s to track the work being done in heart

transplantation, the idea behind GRAFT is to provide a central clearinghouse where researchers in the field can send

their data so that sufficient information can be collected to evaluate the various methodologies being used.

Following the report from Mexico of successful adrenal grafting in persons with Parkinson’s disease, a number of

centers began trying to replicate the results. These studies usually involved small numbers of patients and used

various modifications in the surgical technique. It was thought that, by pooling data from the various sources, an

ongoing analysis could be performed . . of the evolving transplantation experience to document the potential risk

factors and to guide future studies” (Bakay et al., in press).

At about the same time that GRAFT was established, the United Parkinson Foundation (UPF) announced

formation of its own registry. In order to avoid duplication and competition between the two groups, it was decided

that the focus of the two registries would be different. GRAFT would focus on safety, efficacy, and surgical issues

by collecting data from as many centers as were willing to participate. The UPF registry would collect data from

a smaller, more uniform group of investigators. Due to different methods of data acquisition, the UPF would be able

to make a more quantitative evaluation of efficacy, as opposed to GRAFT, which would have to rely on qualitative

measures of efficacy. As a result of this arrangement, some research teams have contributed data to both registries.

As of mid-1990, the GRAFT registry had collected data on 135 patients from 24 centers. Most are from the

United States, with two centers each from Canada and South America and one from Europe and Mexico. The

database includes preoperative information on demography, medical history, and prior treatment of parkinsonism,

as well as qualitative evaluation of patients’ responses to the procedure and complications at 3, 6, and 12 months

after the operation. Followup information more than 1 year later is currently being collected.

The UPF registry has collected information on 61 patients from 13 centers in the United States and Canada.

The same kind of demographic information was collected, but the pre- and post-operative data were collected in

a more uniform manner: All the centers were asked to analyze the patients and their responses to the surgical

procedure using the same rating scale. This made it possible to compare and evaluate the data from all the centers

more easily. These data were collected 12 months tier the operation,

The l-year data from both registries have been published and both registries are continuing to collect

information. Registries are an effective way of collecting and comparing information derived from a variety of

sources in order to evaluate progress in the development of a surgical procedure. Their success depends on the

willingness of investigators to supply their data and in some cases to comply with requests to collect data using

standardized methods. When these criteria are met, data from registries are invaluable guides for future

investigations.

SOURCES: R.A.E. Balmy, G.S. Allen, M.L.J. Apuzzo et al., “Preliminary Report on Adrenal Medullary Grafting From the American

Association of Neurological Surgeons GRAFT Project,” Progress in Brain Research, in press; C.G. Goetz, G.T. Stebbins, H.L.

Klawans et al., “United Parkinson Foundation Neurotransplantation Registry Multicenter United States and Canada Database

Presurgical and 12-Month Followup,” Proceedings of the Third International Congress of Neurotransplantaion: Cambridge

(Amsterdam: Elsevier Science Publishers, 1989).

have been due to the surgical procedure (70). The beginning in 1986. The Chinese group used a

overall level of improvement and number of complications observed led to this summary of the data

collected by both groups:

This strongly suggests that there is an effect from

the transplantation, although the effect inmost cases

is not very dramatic. The mild-to-moderate improvement would be more enthusiastically received if the

surgical morbidity were less (6).

The original Swedish results also inspired a series

of adrenal medullary autografts in Beijing, China,

stereotactic technique similar to that of the Swedish

group, but it used a larger total mass of implanted

tissue and administered antiparkinson drugs after the

operation. Substantial improvements in movement

and lessening of rigidity and tremor were observed

in the first four patients for at least 6 months after

surgery. To date, this group has operated on at least

10 patients, with claims of varying degrees of

improvement in all cases (84). However, some

scientists believe that it is difficult to interpret and

compare the results of this study and others (60,143)
Chapter Applications of Neural Grafting Into the Brain and Spinal Cord ● 71

due to differences in the methods used for assessing

benefit to patients and in the medical treatment they

received pre- and post-operatively.

Adrenal medullary autografts have also been

performed in the United States in a small number of

patients with progressive supranuclear palsy (PSP),

a neurodegenerative disorder marked by loss of

neurons at various locations in the brain, including

the substantial nigra. PSP, though much less common

than Parkinson’s disease, has many of the same

symptoms, including difficulty in moving and standing up. The disease is invariably fatal and there are

no satisfactory pharmacological therapies. One report (87) described three patients with PSP who had

tissue from one of their adrenal glands grafted into

the striatum. Only one of the three patients showed

a small degree of improvement, mostly in his ability

to stand. The authors conclude from these data that

‘‘adrenal medullary transplantation has only limited

efficacy in progressive supranuclear palsy.’

To date, the success reported by the Mexican

group in 1987 has been difficult to replicate. The

reason for this is unclear. Questions about diagnostic

and other criteria used for inclusion of patients, the

methods used to measure the severity of the disease

preoperatively, the handling of the patients’ medications, and the methods used to quantify the improvements in movement that were observed have been

raised about the Mexican study.

Based on the available data, the efficacy of

adrenal medulla autografts is unclear. The relative effectiveness of the various open and stereotactic procedures used, their modes of action, and the

existence of surviving, functional adrenal medullary

cells have not yet been conclusively established. The

efficacy of adrenal grafts has yet to be demonstrated

in experiments using nonhuman primates, and the

human clinical data are inconsistent, with several

studies suggesting that there may be only minimal,

perhaps transitory, improvement. Judging from animal experiments and the small amount of postmortem human data available, the ability of adrenal

tissue to survive in the brain seems to be limited

(80,120). Survival may be improved by concurrent

administration of growth-promoting factors, but this

needs to be explored further in the laboratory. If

adrenal tissue does not survive, it is unclear whether

any observed improvement is the result of the graft

or of nonspecific effects. The observation made in

many of the clinical trials that improvement was

Photo credit: The Emory 

Dissecting tissue to be used as a graft.

seen on both sides of the body when the graft was

placed in only one side of the brain also suggests a

general effect, perhaps circulation of graft-related

factors in the cerebrospinal fluid, rather than a direct

action of the graft. Additional animal experimentation can provide more information and help answer

these questions. Regarding the use of the procedure

in humans, the adrenalectomy and open neurosurgical procedures most widely used are associated with

risk of severe complications in older, more profoundly afflicted patients. Also, the best age for

donor tissue and a clarification of which Parkinson’s

patients are most likely to benefit fromthe procedure

needs to be delineated.

Fetal Neural Tissue-Only about 100 persons

worldwide have received grafts of fetal CNS tissue

for the treatment of Parkinson’s disease. Clinical

trials with such tissue are going on in Sweden,

England, Mexico, the People’s Republic of China,

Czechoslovakia, Spain, and Cuba. Approximately

10 patients have undergone the procedure in the

United States. While the results of some of these

procedures have been reported at various scientific

and medical meetings, there are very few published
72 ● Neural Grafting: Repairing the Brain and Spinal Cord

Some of the most thoroughly documented research has been conducted in Sweden, where two

patients underwent this procedure in 1987 (100).

Dopamine-producing tissue from four human fetuses, 7 to 9 weeks (postconception) of age, was

implanted as a cell suspension, stereotactically, on

one side of the brain in each patient. Both patients

received drugs to keep the graft from being rejected.

Up to 6 months after the operation, although both

patients showed some minor improvement in how

quickly they could move and how well they responded to a single dose of antiparkinson drugs, the

scientists reported that “. . . no major therapeutic

effect from the operation was observed” (96). This

same research group reported a greater degree of

improvement in another patient, for whom they used

different methods of handling and implanting the

fetal tissue and thus may have increased the ability

of the graft to survive (99). This patient exhibited a

lessening of his symptoms and an increased response to his medications for the 6 months he was

observed after the surgery.

Other positive results have been reported from

groups in Mexico and England, but these reports

have not been in the form of published papers in

scientific journals providing information on how the

procedure was performed, what criteria were used

for assessing patients pre- and post-operatively, and

giving all the details necessary to analyze the results.

In the United States, observations of a patient who

was operated on in Colorado in November 1988

were reported 15 months after the operation (50). In

this case, drugs to prevent graft rejection were not

used. Some improvement in movement and motor

coordination was observed in this patient, and the

patient has reported increased ease in doing daily

tasks (cutting food, brushing teeth, and so on). Also,

the patient’s medication could be decreased without

any adverse effects. While the investigators involved state that the patient is not cured, they believe

that the implants can reduce disability, smooth out

medication-related fluctuations in symptoms, and

increase mobility.

The limited data collected to date suggest that

fetal CNS grafts may have a beneficial effect in

controlling some of the symptoms of Parkinson’s

disease. However, more information must be derived before an ultimate determination of the efficacy of this procedure can be made. How long the

grafted tissue survives, the optimal placement of

tissue in the striatum, and the time course for seeing

an improvement are unknown. Additional animal

research can answer these questions. Then the

details of how much tissue is needed to achieve a

worthwhile therapeutic effect and the susceptibility

of the grafted tissue to immunological rejection and

to the underlying destructive mechanism of Parkinson’s disease can be derived from human experimentation. As stated by the Swedish research group:

Although our findings support the idea that neural

grafting can be developed into an effective therapy

in Parkinson’s disease, further work is necessary to

optimize the transplantation procedure. . . (99).

What Is the Next Step?

Whether clinical neural grafting experiments

should continue before additional data are gathered

from animal experiments is still a subject of

scientific debate (93). In the case of adrenal tissue

grafts, the lack of replication of successes and the

lack of a solid basis in animal experimentation have

made many persons in the medical and scientific

communities retreat from the rush of enthusiasm that

accompanied the initial reports.

The effectiveness of fetal tissue grafting in animal

models and the initial reports of some success with

its use in humans indicate that fetal tissue grafting

may have a more solid scientific basis than adrenal

grafting. The question that now arises is how to

proceed from here. Many persons in the scientific

and medical communities feel that the questions

concerning fetal CNS tissue grafting can best be

answered with additional basic animal research,

coupled with limited human experimentation. Then

expanded human trials could proceed to determine

whether fetal CNS grafts area genuinely efficacious

treatment for persons with Parkinson’s disease. This

evaluation has been expressed in the following

statement by two prominent scientists:

. . . too many questions remain unanswered about

the use of embryonic nerve cells to propose anything

more than limited fetal grafting in humans as a

requisite next step. Although scientifically it seems

logical to proceed, considerable information is

needed before therapeutic success might be predicted . . . . We are still at a stage at which basic

scientific studies are needed to elucidate important

details. . . (60).
Chapter 5-Applications of Neural Grafting Into the Brain and Spinal Cord ● 73

When clinical experiments do proceed, it will be

necessary to standardize their designs, the criteria

used for assessing pre- and post-operative levels of

disability, and the methods of reporting results. For

the most part, this has not been done in the clinical

experiments carried out so far, making it difficult to

interpret and compare studies.

Beyond the scientific issues, the legal and ethical

controversies that surround the use of fetal tissue

could impede the initiation of clinical trials. In the

United States, the Federal ban on funding of

transplants using human fetal tissue from induced

abortions will limit clinical research (see app. A).

Huntington’s Disease

Huntington’s disease is a genetic disorder, the

major pathological hallmark of which is a loss of

neurons in the striatum. Symptoms of the disease

include abnormal movements, especially of the face

and extremities, and a progressive deterioration in

mental ability. Unlike Parkinson’s disease, where

only one population of cells dies, Huntington’s

disease involves the destruction of several populations of neurons, generally located in the striatum,

that contain different neurotransmitters. An animal

model in which chemicals known as excitotoxins are

used to destroy the cells in the striatum4 has been

employed to see whether implantation of fetal

striatal tissue could reverse some of the deficits

caused by the injury. This animal model exhibits

some of the same characteristics as persons suffering

from Huntington’s disease (e.g., abnormal movements, inability to respond to sensory stimuli, and

deficits in learning and memory). In most of these

experiments, grafts have been inserted in hopes

of replacing the lost striatal neurons rather than

supplying a single neurotransmitter, as in the

Parkinson’s disease research.

Studies have shown that rat fetal striatal tissue can

survive following implantation into the striatum of

adult rats that have been injected with excitotoxins

(114). These grafts have also been shown to decrease

some of the abnormal movement (36,66,81,129) and

learning and memory deficits (35) produced in this

model; however it has been reported that the

animals’ behavior is not returned to normal (114).

The mechanism by which the fetal tissue grafts act

is not entirely clear. There are two possibilities.

First, the grafted tissue may grow into the host brain,

forming synapses and thus directly and actively play

a role in the function of the striatum. Experimental

evidence to support this includes the need for an

intact, undamaged graft (66) at a specific region of

the striatum in order to achieve a functional effect

(82) (indicating the importance of graft integration

into the host), coupled with the observation of an

interaction between host and grafted tissues

(128,147). The second possibility is that the grafted

tissue could be exerting a growth-promoting effect

that causes the undamaged parts of the host striatum

to grow and assume some of the fictional activity

of the damaged parts. Experimental evidence supporting this idea includes the conflicting observations that integration does not occur (101,146) but a

functional effect may nevertheless take place (113)

and that fetal grafts may be able to protect against

excitotoxins (145) [although this has not been

conclusively proven (11 l)]. Although the majority

of the evidence indicates that grafts do integrate into

the host, the data preclude an unequivocal statement.

The possible role of fetal striatal tissue in the

treatment of Huntington’s disease must await

further elucidation of both the graft’s mechanism

of action and the underlying mechanism of the

disease itself.

There has been one report, not published in a

research journal, that grafting of rat adrenal medulla

tissue into the rat striatum can protect neurons

against the destructive action of excitotoxins (132).

Since one theory holds that excitotoxins may be

involved in Huntington’s disease, adrenal tissue

could possibly play a role in treating this disorder.

Despite the lack of conclusive evidence to support

this hypothesis, a patient with Huntington’s disease

has received an adrenal medulla autograft (132). It

was reported that the patient received no beneficial

effect from the procedure. At this time, there is no

evidence to support the idea that adrenal tissue can

ameliorate any of the symptoms associated with

Huntington’s disease: the role of excitotoxins in the

disorder has yet to be clarified, and the effect of

adrenal tissue on the action of excitotoxins has yet

to be proven.

4~ this model, ~xcitoto~ -Caci~ ibotefic a@ qfio~c acid) ~ ~j~ted &EC~y tito the s~m. These toxhls SdIdilte Sites 011 LleWOIIS

that are normally activated by certain neurotransmitters; however, these acids activate the cells so much (hence the name “exCitO”) that they kill tie

cells. Whether these excitotoxins are actually involved in Huntington’s disease in humans is unclear.
74 ● Neural Grafting: Repairing the Brain and Spinal Cord

Figure 5-6-Brain Activity in an Alzheimer’s Disease

and a Normal Brain

Brain scans showing the activity (white areas) in a normal brain

(control) and the brain of an Alzheimer’s disease patient (AD). The

scan of the Alzheimer’s disease patient shows that many areas in

the brain are not functioning properly.

SOURCE: R. York, NY: Bantam Books, 19S8).

Alzheimer’s Disease

Unlike Parkinson’s or Huntington’s diseases, in

which there is either a loss of a specific population

of neurons or localization of cell destruction in one

region of the brain, Alzheimer’s disease involves a

much more diffuse loss of neurons and affects a

number of different groups of cells (figure 5-6).

Cells in the front of the brain that contain the

neurotransmitter acetylcholine and cells in the

middle of the brain that contain norepinephrine are

particularly affected in Alzheimer’s disease. The

acetylcholine-containing areas are involved with

memory and learning, while the norepinephrinecontaining regions are thought to be associated with

controlling moods. Destruction of these areas results

in the dementia and depression that are characteristic

of Alzheimer’s disease. Due to the diffuse nature

of the damage in Alzheimer’s disease, it is

thought that if neural grafts have a role, it maybe

to supply growth-promoting substances or to

supply lost neurotransmitters rather than to

replace lost structures.

At present there is no fully satisfactory animal

model of the symptoms of Alzheimer’s disease. The

closest is aged monkeys, which can exhibit some of

the memory and cognitive deficits or abnormal

changes in brain cells, or both, seen in persons with

Alzheimer’s disease (122). To date no neural grafting experiments have been conducted on such

monkeys; however, experimentation has been conducted on aged rats and rats that have had injuries

made in the same areas of the brain that are destroyed

in Alzheimer’s disease. These animals exhibit some

of the same types of memory and learning problems

seen in humans with the disease, even though they

do not truly mimic Alzheimer’s disease.

To create animal models, wounds are made in

some of the same areas of the front or middle part of

the brain that are destroyed in Alzheimer’s disease

or in the pathways that connect these areas to other

parts of the brain.s The result is that the animals have

difficulty learning and remembering certain tasks,

such as running through a maze. When rat fetal

tissue is grafted into wounded adult rats near the

areas to which the acetylcholine fibers project, the

grafts take hold and there is a partial improvement in

the rats’ ability to learn and remember specific tasks

(42,43,48,86,150). This occurs if the fetal tissue

implanted is taken from areas in the fetal brain that

correspond to the wounded areas in the adults.

Similar results have been observed in adult rats

when either grafts of fetal tissue from mice (32) or

cultured cells that naturally produce acetylcholine

(89) were implanted.

The ability of acetylcholine-producing grafts to

reverse memory deficits caused by the ingestion of

alcohol has also been examined(4). Large quantities

of alcohol cause brain damage in rats, as in humans,

especially in the regions of the cortex and hippocampus containing acetylcholine; this damage causes

memory and learning deficits. When acetylcholineproducing tissue from the front part of the brain is

implanted into either the cortex or the hippocampus

of rats given alcohol, the deficits decreased. This

does not occur when other tissue, not containing

acetylcholine, is grafted. It is postulated that the

positive effects are due to the increased supply of

acetylcholine into the cortex and hippocampus.

 in front part of the brain send their fibers to the and specific 

the and these cortical areas are very important in mediating learning and memory. The neurons in the middle

of the brain also connect to cortical areas. The wounds result in the loss of these or pathways and the cells giving rise to

them.
Chapter 5--Applications of Neural Grafting Into the Brain and Spinal Cord ● 75

Aged rats are also known to have more difficulty

learning certain types of tasks than younger animals.

Implantation of acetylcholine-producing fetal tissue

into the hippocampus (56,57) or norepinephrinecontaining fetal tissue into ‘the middle of the brain

(30) improves the performance of some aged rats on

certain learning and memory tests.

It is thought that the grafts in these studies exerted

their effect by releasing acetylcholine or norepinephrine into the brain. While the research conducted to date has provided invaluable information

about the ability of neural grafts to decrease experimentally induced deficits in cognitive performance

and deficits in learning and memory in aged rats, the

extrapolation of that information to patients with

Alzheimer’s disease is problematic. These models

share, at best, only a few characteristics of the

disease. In addition, when injuries are produced in

experiments, they are very specific to the area that is

damaged, whereas in Alzheimer’s disease the damage is not restricted to a single group of neurons.

Since acetylcholine-producing cells are one of the

major populations of cells affected in Alzheimer’s

disease and nerve growth factor (NGF) is known to

act on acetylcholine neurons, investigators have

studied the ability of NGF to protect these cells. The

implantation of cells that have been genetically

engineered to produce NGF has been shown to

prevent the acetylcholine neurons in the front part of

the brain from dying following destruction of the

pathway that connects them to the hippocampus

(127) and other areas of the brain (45). In addition,

the protected cells apparently started to grow new

fibers in the direction of the implanted NGFproducing cells. Whether NGF can affect the progression of Alzheimer’s disease is a question being

investigated extensively.

A number of important points must be addressed before the potential value of grafting

therapy in Alzheimer’s disease can be determined. A better understanding of the mechanisms

underlying the disease is needed in order to determine the types of graft tissue likely to have the

broadest possible effect on the disease. Also, development of a valid animal model of the disease or its

symptoms is necessary.

Motor Neuron Disease

Motor neuron disease (MND) is a family of

disorders marked by degeneration of neurons located in the spinal cord and brain that are involved

with regulating movement. Probably the best known

MND is amyotrophic lateral sclerosis (LOU Gehrig’s

disease).

As in some other neurodegenerative disorders,

such as Parkinson’s and Huntington’s diseases, the

hallmark of MND is a selective loss of certain

populations of cells. Since Parkinson’s and Huntington’s diseases are thought to be candidates for

symptom amelioration by neural grafting, it can be

speculated that persons with MND may also benefit

from this procedure. The same strategy of replacing

the lost cell populations with grafts may be applicable. The ability of fetal spinal motor neurons to

become incorporated into the spinal cord of an adult

has been demonstrated in rats (134) and mice (37).

To date, no research on the ability of neural grafts to

restore functional deficits caused by induced injuries

to these cell populations has been conducted.

Whether MND would be at all amenable to this

therapeutic strategy is purely conjectural. The fact

that the populations of cells lost in MND are

distributed throughout the spinal cord and the brain

may be a hindrance to the effective use of implants.

It is also possible that the mechanisms involved in

the development and progression of MND are such

that graft technologies would not be suitable.

CENTRAL NERVOUS SYSTEM

INJURY

Spinal Cord Injury

Injury to the spinal cord occurs most often when

the bones of the spinal column (vertebrae) are

pushed into the soft neural tissue of the spinal cord,

bruising or tearing it. This ensues when a strong,

rapid, mechanical force is applied to the back or

neck, as can occur in automobile collisions or

sporting injuries. Incidents such as these are the

leading cause of spinal cord injury. Damage to the

spinal cord can also be caused by a projectile or knife

wound. In such cases the amount of tissue damaged

is directly related to the strength of the force applied.

A third cause of damage to the spinal cord is

disruption of its blood supply or gradual compression (caused by various types of intruding bodies,

such as tumors or blood clots).
76 ● Neural Grafting: Repairing the Brain and Spinal Cord

Photo credit: University of Florida

A cross-section through a normal(1) and an injured (2) rat

spinal cord.

The spinal cord is made up of a central core of

neuronal cell bodies surrounded by collections of

axons. These axons make up the long pathways that

connect the spinal cord and brain and the shorter

pathways that connect areas within the spinal cord.

Injury to the spinal cord, whatever the cause, can

destroy both axons and neurons located in the

damaged region. In addition, neurons that are

located away from the injury site, whether higher up

in the spinal cord or in the brain, and that contribute

to the damaged pathways can die as a result of the

injury (retrograde cell death). The functional deficits

associated with spinal cord injury range from

paralysis (loss of the power of voluntary movement

in the extremities) and loss of sensation to the loss

of reflex activities coordinated from within the

spinal cord (motor reflexes and reflexes associated

with sexual activity and bladder control). In most

cases, these functional deficits are permanent.

Unlike the case in neurodegenerative diseases,

in spinal cord injury the original neurons are

mostly present, but damaged. Repair of the long

ascending and descending nerve fibers that convey

movement and sensory information between the

brain and spinal cord would require regrowth of

these fibers to reconnect with their original targets.

Repair of the short pathways within the spinal cord

would involve providing a means by which the

intrinsic spinal cord connections could be reestablished.

The goal of neural grafting in spinal cord

injury is to repair or substitute for the damaged

neuronal pathways to induce recovery of function. The aim is to achieve fictional recovery by

reestablishing original synaptic contacts by the

damaged axons; stimulating new outgrowth from

uninjured neurons; or introducing new circuitries

that would transmit functional information through

the site of injury (figure 5-7). If growth of damaged

neurons were to be stimulated, the grafts would

serve as a substrate to induce the severed axons to

reestablish their lost connections, thus regenerating

the original anatomical structures. If undamaged

neurons were to be stimulated, then the grafts would

induce new growth from them to create alternative

pathways, which would assume the role of the

damaged pathways and restore functional activity

without necessarily replicating the original anatomical connections (13). The third possibility is to

construct a functional relay between separated

regions of the spinal cord. ,

The questions to be addressed in determiningg the

ultimate therapeutic role of neural grafts in spinal

cord injury include:

● What grafting material will best integrate with

the host spinal cord and create the environment

most conducive for growth?

. Is there functional recovery following grafting?

To date, most research in this area has provided

information regarding the first question; more basic

research is needed to answer the second question.

Scientists use a number of different types of

experiments to study the mechanisms of regrowth in

the damaged spinal cord. Some of the experiments

closely approximate conditions that would be encountered in a human spinal cord injury. However,
Chapter 5--Applications of Neural Grafting Into the Brain and Spinal Cord ● 77

Figure 5-7-Possible Actions of Neural Grafts in Spinal Cord Injury

A.

o

0 <

0 —— —..— < —— —.. 4

—————— –<

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Graft

c.

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v

---- —. \ .

‘ - -< - .

L

I

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Graft

D.

o <() < – –

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o

– – –– — 

– – – – – 

‘–

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Theoretically, neural grafts could repair the damage caused by an injury to the spinal cord (A) in three ways: B) stimulate regrowth from

damaged axons; C) stimulate new growth from uninjured axons; D) provide a relay that would transmit information through the site of injury.

SOURCE: Office of Technology Assessment, 1990.
78 ● Neural Grafting: Repairing the Brain and Spinal Cord

since different types of injuries can result in a wide

range of insults to the spinal cord (the damage done

in an automobile collision may be quite different

from what occurs in a diving injury), no single model

can be used to study spinal cord injury. The

development of analogous animal models is a

crucial step in exploring the usefulness of neural

grafts in spinal cord injury.

What Makes a Good Graft?

Several sources of grafting materials have been

examined in animal experiments. These include

adult peripheral nerve and fetal CNS tissue, either in

pieces or as cell suspensions. In general, autografts

and allografts have been used in these experiments.

The use of tissue from other species has not been

widely examined; however, there is some evidence

suggesting that such tissue is not as suitable as the

others (142).

Peripheral Nerves—Nerves from the peripheral

nervous system (PNS) are used to bridge a wound.

They enable axons to cross the wound, reenter the far

side of the spinal cord, and reinnervate their original

targets. Over the past decade, some success has been

achieved in implanting segments of peripheral

nerves into the spinal cords of animals with experimentally induced injuries; these grafts have survived

and become incorporated into the host spinal cord

(126,130). The grafts support growth from the

damaged tissue, but the extent to which the elongating axons can emerge from the graft and extend back

into the host tissue is extremely limited (34,126).

While the ability of peripheral nerve grafts to

induce growth in the injured spinal cord of experimental animals has been confined, the ability of

these grafts to restore function has yet to be

demonstrated.

Fetal Spinal Cord Tissue—Another major source

of grafting material in many animal experiments has

been fetal spinal cord tissue, usually from the same

species. Given its ability to support growth, fetal

tissue could act as a bridge across a wound or as a

relay station between the severed axons and their

target sites on the other side of the wound by

providing a system of intervening neurons. Research

into the use of this tissue does not have as long a

history as that into peripheral nerve grafts. Experiments have shown that fetal tissue can create an

environment that supports limited growth in the

damaged adult spinal cord. Also fetal tissue can

sometimes limit the scarring that occurs following

an injury (and that can act as a barrier to growth) (77)

and prevent retrograde cell death (26).

One interesting model has demonstrated the

effectiveness of fetal spinal cord grafts in promoting

growth at the boundary of the central and peripheral

nervous systems. The fibers conveying sensory

information from the body (e.g., sensing when the

bladder is full) into the spinal cord are called dorsal

roots. These fibers travel in both the peripheral and

central nervous systems and traverse the boundary

between the CNS and PNS when they enter the

spinal cord (see figure 3-5). In spinal cord injuries

the dorsal roots are sometimes torn. When damaged,

these fibers will regenerate in the periphery until

they reach the PNS-CNS boundary at the spinal cord

and then stop growing. This phenomenon clearly

demonstrates the ability of fibers to regrow in the

peripheral but not in the central nervous system.

Animal experiments have shown that if fetal spinal

cord tissue is placed where the dorsal root enters the

spinal cord, the severed root will continue to grow

into the implant (133,144) and in some cases, to a

limited extent, through it and into the host spinal

cord (78). Fetal grafts, then, can support regeneration of these specialized peripheral-central fibers

within the CNS and, to a certain degree, overcome

the barriers present at the PNS-CNS boundary.

Fetal spinal cord implants can also support growth

of CNS axons in an animal that is still growing and

developing (24,25). In the newborn rat, axons from

the brainstem are still growing into the spinal cord.

If the spinal cord of a newborn rat is cut, the growing

axons cannot reach their targets, and in many cases

the neurons in the brain that send fibers into the

spinal cord die. When fetal spinal cord tissue is

placed into wounds made in the spinal cords of

newborn rats, the tissue supports the continued

development of the growing spinal cord and prevents neuron death in the brain. Although these

studies clearly show that fetal spinal cord grafts can

facilitate survival and regrowth of CNS axons in the

immature, growing spinal cord, they do not indicate

whether fetal spinal cord grafts would have any

effect in the fully formed, adult spinal cord.

The ability of fetal spinal cord grafts to become

integrated into the adult spinal cord in rats has been

demonstrated (77,125). Fibers from the host spinal

cord can grow into the grafts; however, the outgrowth from fetal grafts, whether by spinal axons
Chapter 5--Applications of Neural Grafting Into the Brain and Spinal Cord . 79

Photo credit: B. Georgetown University

A cross-section through a rat spinal cord with a neural graft

of rat fetal tissue.

transversing the graft or by neurons from within the

graft sending their axons into the host spinal cord, is

very limited. This again demonstrates the inability

of axons to grow in the environment provided by the

mature CNS.

Neurotrophic and Neurotropic Factors—The

mechanism by which peripheral nerves or fetal

tissue induces growth of damaged axons in the

spinal cord is thought to involve certain chemical

factors (see box 3-A). Neural grafting into the spinal

cord may owe its success thus far to the insertion of

tissues that contain the correct mix of these chemicals at the injury site, establishing the proper

biochemical environment to support regrowth of the

damaged axons and to allow reestablishment of lost

synaptic contacts. Providing the proper chemical

messengers to turn the various components of the

regeneration system on and off may be a crucial

element in the repair process. As more is learned

about neurotrophic and neurotropic factors and the

processes by which these substances regulate

growth in the nervous system, abetter understanding

of exactly what is necessary to produce healing can

be determined.

Fetal Brain Tissue—Another grafting strategy

that is being investigated involves the use of tissue

from areas in the fetal brain that are known to

regulate activity in the spinal cord. When the spinal

cord is injured, descending fibers (originating in the

brain and containing a specific class of neurotransmitters called catecholamines) are damaged. It is

known that these fibers modulate the activity of local

centers in the spinal cord which control certain

Photo credit: B. Georgetown University

A rat being tested for the effects of a spinal cord injury. The

rat has difficulty walking across the grid (arrow).

patterns of movement. There has been some investigation of whether these grafts could replace the lost

catecholamines and regulate activity in the affected

regions of the spinal cord. Grafts of fetal tissue from

the relevant areas of the brain, implanted either as

solid pieces (115,1 16) or in a cell suspension

(18,123), become integrated into the host spinal cord

and send fibers containing the catecholamines into

the surrounding tissue.

Is There Functional Recovery?

The most important question regarding these

techniques as they relate to possible clinical applications is whether there is any functional recovery

from an injury after grafting. None of the studies

previously discussed examined whether the grafts

restored functions that were lost as a result of the

injury. Most research to date has been aimed at

determining and establishing the conditions most

conducive to a successful implant and the degree to

which the graft can integrate with surrounding host

tissue. As a result, information regarding functional

recovery following grafting is meager.

One study showed that grafting fetal rat spinal

cord tissue into a small wound made in the spinal

cords of adult rats decreased the difficulty in

walking that the animals normally would have

shown following such an injury (14). Significantly,
80 . Neural Grafting: Repairing the Brain and Spinal Cord

when the spinal cords of the animals that had

received grafts were examined, it was seen that there

had been very little regrowth of the severed fibers.

The authors of the study concluded that the beneficial effects were probably” due to the growthpromoting factors in the grafts stimulating new

growth from surviving neurons. They speculate that

the surviving neurons assumed control of the lost

functions by establishing new pathways that bypassed the injured area.

Injection of a cell suspension of rat fetal brain

stem cells into the spinal cord can enhance leg

reflexes in rats in which catecholamine-containing

neurons have been destroyed (27). The catecholamine-containing cells in the suspension integrate into

the spinal cord and establish new synaptic contacts

with the spinal cord cells. It was hypothesized that

some of the restoration of the leg reflexes was due to

the development of new catecholamine synapses,

not regeneration of damaged cells.

In neither of these studies was the functional

recovery observed thought to be due to regrowth of

the damaged neuronal pathways at the site of the

wound. In the first study, neurotrophic factors were

thought to be involved, while in the second, the

enhancement of reflexes was due partly to an

increase in catecholamine synapses and partly to

other, unknown factors.

Some investigators have found evidence of recovery of function related to reconstruction of the

neuronal pathways at the siteofawound(91). Grafts

of fetal spinal cord tissue placed into the growing

spinal cords of newborn rats lessen the deficits in

walking that occur when the spinal cords of these

animals are injured. Since neural grafts in newborns

allow the growing spinal cord to assume a nearly

normal circuitry, it has been proposed that the

recovery of function is due to this rewiring of the

spinal cord at the site of the injury by the stillgrowing spinal cord.

Questions That Need To Be Answered

Neural grafts may be able to ameliorate deficits

caused by spinal cord injury; however, it is

difficult to predict if and when these technologies

will enter the clinical research arena. Animal

experimentation in this area is yielding a wealth of

information concerning basic biological mechanisms involved in growth and development of the

nervous system, how it responds to injury, and the

feasibility of grafting tissues into the site of a spinal

cord injury. A number of questions remain to be

answered before it can be known what clinical

application, if any, this research will have.

Can Grafted Biologic Material Exert a Healing

Effect on the Damaged Spinal Cord?—Implicit in

this question is the notion that the spinal cord has no

capacity to heal-once it is damaged, it is damaged

forever. Evidence to date shows that this is false. The

normal response of the spinal cord to injury indicates

that it has some regenerative capacity. If this

capacity, coupled with the mechanisms controlling

growth in the immature spinal cord, can be harnessed and manipulated, then some form of healing

can be achieved.

Can the Healing Effects of a Graft Restore

Function?--The ability of grafted material to become incorporated into the damaged spinal cord

serves no clinical purpose in itself. The ultimate

clinical goal of grafting is to restore function. The

requirements for restoration may differ from function to function. For simple functions, such as

awareness of when the bladder is full, it may be

possible to restore the necessary sensory input by

reconnecting the dorsal root sensory nerves that

convey this information to an intact area of the spinal

cord. The graft would enable the sensory fibers to

cross the PNS-CNS boundary and would allow the

message that the bladder is full to enter the nervous

system. While this may not restore complete motor

control, the patient would be able to tell when it was

time to empty the bladder.

In the case of more complex functions under the

control of the spinal cord circuitry (blood pressure

and temperature regulation, sexual reflex activity,

bladder control, motor reflexes), reestablishment of

function may require bridging the wound to reconnect the spinal cord control centers back into the

reflex pathways or to reinstate the higher level

control of these centers. The small degree of

outgrowth from grafts that has been observed in

many experiments may be sufficient for bridging

spinal cord wounds. If the control centers themselves are damaged, then grafts would have to

provide new cells to reform them. This would

require a more complex interaction than just bridging an injury site. Restoration of the motor and

sensory deficits that result in paralysis would require

an even more comprehensive mending process, one

that would initiate regeneration or generation of
Chapter 5--Applications of Neural Grafting Into the Brain and Spinal Cord ● 81

pathways that could mediate the activity necessary

for these functions.

The more complex and coordinated a function is,

the more complex the type of repair needed to

reinstate it. Exactly how much repair is necessary to

restore a given function is not known. It is known

from animal models that, even if only a small

percentage of fibers is spared at the time of injury,

there can be marked recovery of function. It may be

that reestablishment of only a small proportion of

connections, either by direct reconstruction or by

stimulation of new pathways, may be sufficient for

significant fictional recovery. In order to realize

this recovery, it may be necessary to follow the

reconstructive surgery with extensive rehabilitative

therapy.

What Characteristics of the Graft Are Necessary

for Functional Recovery?—The processes set in

motion by implantation of neural tissue must be

understood before this technology can be used as a

therapeutic tool. At the present time, grafting into

the spinal cord is analogous to inserting a “black

box.’ Very little information is available as to what

causes the observed morphological changes and

functional effects. Is an integrated, solid piece of

tissue necessary to supply the proper mixture of

neurotrophic factors to the right location and in the

right form to induce growth? Or is it sufficient just

to supply the growth-promoting factors alone? Is a

mixture of the two needed? Do these needs differ

depending on what type of functional recovery is

desired? The answers to these questions are still

being sought.

What Are the Possible Unwanted Effects of

Grafting Into the Spinal Cord?—It is possible that

inserting tissue into the spinal cord or stimulating

growth from the damaged host tissue could cause

abnormal pathways and connections to be formed.

This could result in unwanted effects, notably the

development of abnormal motor functions, such as

muscle spasticity and increased reflex actions, or

pain or other discomforting sensations (e.g., burning, tingling).

Brain Injury and Stroke

Since grafts may serve to replace lost or

damaged tissue or to stimulate growth from

damaged areas, it is possible that neural grafts

could restore functional losses caused by injury

to the brain. Animal experiments have demonPhoto credit: R.A.E. Bakay, The Emory Clinic

Preparing a cell suspension for grafting.

strated that fetal tissue can survive and become

incorporated into a wound made in the brain of an

adult (e.g.,33,72,110). This includes tissue damage

caused by inducing a stroke in the experimental

animal (usually rats) (104,109). The stroke is caused

by clamping one of the vessels that supplies blood to

the brain, thus mimicking what happens in humans

suffering a stroke. The area of the brain that loses its

blood supply dies. When rat fetal tissue corresponding to the damaged area is placed in the wound, the

graft integrates into the host brain and becomes

incorporated into the host blood supply. The cells in

the graft send signals like normal neurons, indicating

that the graft is active. The grafts survive best when

they are implanted at least 1 week after the stroke, a

phenomenon that is observed when wounds are

made in either the brain or spinal cord. Neither the

stroke studies nor the others previously mentioned

examined whether the grafts reversed any functional

deficits caused by the wounds.

Studies of other kinds of brain injury in rats have

shown that implantation of rat fetal tissue into

wounds made in the cerebral cortex can help

alleviate the deficits caused by the wounds

(46,92,152). Grafting of fetal tissue into these

models results in functional improvement, but only

if the tissue implanted is from regions of the fetal

brain that correspond to the areas destroyed in the

adult.
82 . Neural Grafting: Repairing the Brain and Spinal Cord

The mechanism by which grafts exert their effects

in these animal models of brain injury is unclear.

Recovery may be due either to integration of the

grafted material into the host brain or to effects not

related to integration or even graft survival. It has

been observed that the beneficial effect occurs for

only a short time after implantation of the tissue (44)

and that the same degree of functional recovery is

seen whether a fetal graft, a suspension of glial cells,

or a piece of sponge that has been sitting in the

wound of another animal is placed into the wound

(85). This indicates that part of the remedial effect

may result from the presence of neurotrophic factors

produced when the wound was made or secreted by

cells other than neurons contained in the graft. These

factors could stimulate growth from the injured host

brain. Thus, both incorporation of the graft into the

host and the effects of growth-promoting factors

could play a role in recovery of function. Some

investigators have stated:

It appears. . . that transplants can facilitate functional recovery by more than one mechanism,

including promotion of survival and reactive synaptogenesis [synapse formation] of host neurons,

stabilization of the damaged environment and replacement of neurons (85).

The ability of grafts to reverse functional deficits

caused by brain injury is still unclear. If a functional

effect can be produced, the underlying mechanism of

that effect is uncertain and the requirements for the

grafted material are unknown. Additional basic

research is needed to answer these questions and

to define the ultimate role of grafts in brain

injury.

EPILEPSY

Some success has been achieved in using neural

grafts to block the occurrence of epileptic seizures in

a very specific animal model of epilepsy called the

“kindled” model. It is thought that the kindled

model of epilepsy is analogous to temporal lobe

epilepsy (68), which is the most frequent form of the

disease in adult humans. In this model, an area of the

brain called the locus ceruleus (LC), which inhibits

the ability to induce seizures, is destroyed in rats.

Investigators can therefore induce seizures in the

hippocampus of these animals more easily than in

normal, intact rats.6 A graft of fetal rat LC tissue

placed in the hippocampus, however, can form

connections with the cells in the hippocampus and

inhibit the induction of seizures (12,98). Thus, the

LC graftS mimic, to a certain degree, the normal

action of the intact LC in this model. LC tissue grafts

have also been shown to inhibit seizures in another

rat model of epilepsy that uses a combination of

surgery and drugs to induce seizures (28).

While these studies show that LC grafts can

inhibit the induction of seizures in these models, the

relationship to naturally occurring seizures in persons with epilepsy is unclear. There is no evidence

to date that LC grafts can inhibitor otherwise affect

naturally occurring seizures.

The ability of grafts of other types of fetal brain

tissue to suppress naturally occurring seizures has

been examined in rats that have a genetic predisposition to seizures. The severity of seizures in these rats

can be decreased if either of the neurotransmitters

noradrenaline or gamma-aminobutyric acid

(GABA) is injected into certain areas of the brain;

however, grafts of tissue rich in these neurotransmitters, implanted into the proper areas of the brain, did

not appreciably reduce the intensity of the rats’

seizures (138).

Experiments conducted to date indicate that

grafts can affect the induction of seizures. However, additional animal research is needed to

determine what role grafts could play in reducing

naturally occurring epileptic seizures.

NEUROENDOCRINE DEFICITS

The ability of grafts to supply chemicals makes

them well suited to reduce deficits caused by a

loss or imbalance of normal hormone levels.

Neurons in an area of the brain called the hypothalamus regulate the release of hormones from the

pituitary gland (which lies under the hypothalamus)

into the bloodstream. In addition, some hormones

are made by neurons in the hypothalamus itself and

are released directly into blood vessels. Once in the

blood vessels, the hormones travel throughout the

body.

GSe~es ~induc~ @ el~~~ly sthnu.lating a portion of the brain called the limbic syste~ which includes the hippocarnpus. The dech’id

stimulation is given in small, progressive steps which make the Limbic system so sensitive tbat even a mild electrical shock will induce a generalized

seizure. Thus, the seizure is said to have been kindled. The locus cen,deus is thought to inhibit the kindling phenomenon by sending noradrenaline fibers

to the hippocarnpus. Kindling takes place more quickly and easily when these fibers are destroyed.
Chapter 5--Applications of Neural Grafting Into the Brain and Spinal Cord ● 83

If the area of the hypothalamus that secretes the

hormone vasopressin (VP) directly into the bloodstream is destroyed in rats, the resulting low levels

of VP cause water loss in the urine and produce

dehydration. The same phenomenon is observed in

a mutant strain of rat that has a congenital absence

of VP-producing neurons. If VP-producing neurons

are grafted into either of these animal models, the

grafts become incorporated into the host and secrete

VP into the circulatory system (59,105,136). Grafts

of VP-producing cells can also ameliorate some of

the deficits in fluid regulation seen in these animals

(61,106). Finally, these grafts can prevent the death

of hypothalamic neurons that normally occurs when

a wound is made, perhaps by the release of

growth-promoting factors (107).

Another model that has been used in this line of

research is a special strain of mice with a genetic

abnormality that keeps them from producing the

hormone GnRH (gonadotrophin-releasing

hormone). GnRH, which is released from cells in the

hypothalamus, causes cells in the pituitary gland to

release hormones that control sexual maturation.

Mice of either sex with this genetic abnormality

have immature reproductive organs and are sterile.

The implantation of fetal grafts of hypothalamic

tissue from normal, GnRH-producing mice into the

hypothalamus of adult mice with this dysfunction

can correct many of the reproductive deficiencies

that occur in these animals (22,29,62-65,90). The

grafts result in increased levels of pituitary

hormones, maturation of sexual organs, and initiation of sexual behavior.

Neural grafts have been shown to restore sexual

potency and sexual behavior in aged, impotent male

rats (79). The sexual behavior of such rats before and

after fetal hypothalamic tissue was implanted into

the hypothalamus was observed. Before the implants, the animals did not engage in sexual behavior

when exposed to receptive females. After the grafts,

the sexual behavior of most of the rats was restored,

resulting in increased sexual activity and impregnation of the females.

The ability of neural grafts to reverse deficits and

imbalances in hormone levels due to neurological

damage or abnormalities has been repeatedly shown

in a number of animal models. Since analogous

clinical conditions in humans are rare, and when

they occur are treated with drugs, the ultimate

 Anatomy in Basic Neuroohemistry,

4th G. Siegel, B. R. and P. (New York,

NY: Raven Press, 29.

A photograph through a microscope showing a Schwann

cell (N) and the it produces (black ring)

surrounding an axon (A).

role of neural grafts in human clinical neuroendocrine conditions is yet to be elucidated.

DEMYELINATING DISORDERS:

MULTIPLE SCLEROSIS

Demyelinating disorders disrupt nervous system

activity by causing a breakdown in the insulating

sheath that surrounds many axons. Loss of the

myelin sheath interferes with the normal transmission of signals between neurons, causing messages

to travel more slowly than normal. Specialized glial

cells (oligodendrocytes in the CNS, Schwann cells

in the PNS) produce the myelin covering of neurons.

Within the CNS, demyelinating diseases attack

either the oligodendrocytes or the myelin they

produce.

A number of disorders can affect myelin in the

CNS. While most are rare, one, multiple sclerosis

(MS), is more common. MS destroys patches of
84 . Neural Grafting: Repairing the Brain and Spinal Cord

myelin in an erratic and random fashion throughout

the CNS. The cause of MS is unknown.

Demyelination can also occur in certain types of

spinal cord injuries. Injuries caused by a compressive force on the spinal cord often result in an area

of demyelinated axons surrounding a core of dead

tissue (149). The ability of grafts to restore the

myelin covering of the appropriate axons could aid

in the recovery of lost functions.

The therapeutic strategy underlying the use of

neural grafts in patients with MS or other

demyelinating conditions would be to provide a

source of myelin that could become incorporated

into the affected area and restore the lost myelin

sheath. Any graft tied at replenishing lost myelin

would have to include either oligodendrocytes or

Schwann cells. Since these cells, when implanted

into the CNS, can migrate some distance from the

site of insertion, it is thought that they may be usable

in treating disorders that result in patchy areas of

demyelinated axons.

Over the past decade, animal experiments have

shown that it is possible to replace lost myelin by

injecting the appropriate cells into regions in which

experimentally induced demyelinating lesions have

been produced. This has been demonstrated using

suspensions of Schwann cells from peripheral

nerves (21,22,39,76), cell suspensions of CNS tissue

(23), and fragments of CNS tissue (73,74). Additional animal experimentation is needed to determine whether these grafting procedures can

restore functional deficits caused by demyelination. Also, it is unknown whether implanted myelinproducing cells would be susceptible to the underlying disease process that caused the original demyelination.

SUMMARY AND CONCLUSIONS

The possible therapeutic uses of neural grafting

into the brain and spinal cord are varied and diverse,

encompassing a wide range of neurological deficits.

Of these, the application of neural grafting in

persons with Parkinson’s disease is the most advanced. But in Parkinson’s disease, as well as all

other applications, no definitive statement about the

actual usefulness of neural grafting as a therapeutic

procedure can be made at this time. The data from

the basic research that has been conducted thus far

provide tantalizing hints of the potential usefulness

of neural grafting procedures, but additional animal

experimentation needs to be conducted to clarify

that potential. To increase the applicability of animal

data to human disorders, animal models of the

various neurological disorders under study need to

be developed. Neural grafting holds the promise of

new therapeutic interventions for neurological disorders, but a final determination of its usefulness must

await the accumulation of more information about

the mechanisms underlying neurological disease

and injury, graft functions, and how those functions

relate to various neurological disorders.

1.

2.

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5.

6.

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Chapter 6

Relevant Neurological Disorders
CONTENTS

Page

NEURODEGENERATIVE DISORDERS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . 94

Parkinson’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94

Huntington’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97

Alzheimer’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ● . . . . . . . . . . . . . . . . . . . . . . . . . . 98

Motor Neuron Disease: Amyotrophic Lateral Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . 99

CENTRAL NERVOUS SYSTEM INJURY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100

Spinal Cord Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100

Brain Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101

Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103

EPILEPSY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104

DEMYELINATING DISORDERS: MULTIPLE SCLEROSIS . . . . . . . . . . . . . . . . . . s . . . 105

SUMMARY AND CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107

CHAPTER 6 REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107

Boxes

Box Page

6-A. Cycads and Amyotrophic Lateral Sclerosis, Parkinson’s Disease,

and Dementia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96

6-B. Neurological Disorders and the Veteran . . . . . . . . . . . * . . . . . . *,, *, . . . + * * .+*,**..* 102

Figures

Figure Page

6-1. National Institutes of Health 1989 Estimates of Costs of

Neurological Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94

6-2. Types of Head Injury Causing Death . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103

6-3. Geographical Differences in Death Rate Due to Multiple Sclerosis . . . . . . . . . . . . . . 106

Tables

Table Page

6-1. Incidence of Neurological Disorders in the United States . . . . . . . . . . . . . . . . . . . . . . 93

6-2. Prevalence of Neurological Disorders in the United States . . . . . . . . . . . . . . . . . . . . . 93

6-3. Drugs Used for the Treatment of Parkinson’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . 97

6-4. Drugs Being Developed for the Treatment of Alzheimer’s Disease . . . . . . . . . . . . . . 99

6-5. Department of Veterans Affairs, Spinal Cord Injury Centers, Fiscal Year 1989 . . 102

6-6. Types of Epileptic Seizures ... **. *,, .*. **. ... .,*. ... ... ... ... ..*. .**. +

. ***,*4 105
Chapter 6

Relevant Neurological Disorders

Reports of neural grafts relieving symptoms of

Parkinson’s disease have captured the attention of

the medical profession and public policymakers.

Much of their excitement derives from the somber

fact that Parkinson’s disease is a progressively

debilitating illness, the symptoms of which can be

only imperfectly controlled. In fact, many central

nervous system (CNS) injuries and diseases are

marked by severe, unrelenting symptoms that defy

cure and exact a great toll in personal suffering and

societal costs. Since current animal research

intimates that neural grafting may be applicable

to the study and treatment of diverse neurological

disorders, this technology may ultimately have a

significant impact on medicine and society.

Exactly how far-reaching a therapeutic intervention is neural grafting likely to become? Its use as a

medical treatment is most advanced in Parkinson’s

disease, but even there its ultimate therapeutic value

is far from established. The study of neural grafting

for the treatment of other neurological disorders is

faced with important barriers, including inadequate

animal models and incomplete knowledge about the

basic mechanisms underlying many CNS diseases

and injuries. (See ch. 5 for details.) Despite these

reasons for caution, it is notable that animal research

employing neural grafting has in many cases improved structural or functional deficits in the CNS.

These results are preliminary and their ultimate

application is unknown, but the amount and diversity of neural grafting research suggests wideranging potential applications.

Neurological disorders are a significant cause of

illness, disability, and death in the United States.

They cost, by conservative estimates from the

National Institutes of Health, more than $100 billion

per year in medical expenses and lost income (tables

6-1 and 6-2; figure 6-l). Not all neurological

disorders are amenable to treatment by neural

grafting. In this chapter, the Office of Technology

Assessment (OTA) identifies those disorders that

may one day be treatable with grafting technology.

The

●

criteria for selection were:

current understanding of the nature and cause of

the condition suggests that neural grafting may

be a beneficial treatment approach, and

Table 6-1—incidence of Neurological Disorders

in the United States

Neurological disorder Incidence

Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 500,000

Brain injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 500,000

Alzheimer’s disease . . . . . . . . . . . . . . . . . . . . . . 130,000

Epilepsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125,000

Parkinson’s disease . . . . . . . . . . . . . . . . . . . . . . 50,000

Spinal cord injury . . . . . . . . . . . . . . . . . . . . . . . . 10,000

Multiple sclerosis . . . . . . . . . . . . . . . . . . . . . . . . 8,800

Amyotrophic lateral sclerosis . . . . . . . . . . . . . . . 5,000

Huntington’s disease . . . . . . . . . . . . . . . . . . . . . 850

NOTE: Incidence is defined as the number of new cases of a disease

estimated to occur each year in the United States. Sources for

estimates are the same as those in the text.

SOURCE: Office of Technology Assessment, 1990.

Table 6-2—Prevalence of Neurological Disorders

in the United States

Neurological disorder Prevalence

Alzheimer’s disease . . . . . . . . . . . . . . . .

Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Epilepsy . . . . . . . . . . . . . . . . . . . . . . . . . .

Parkinson’s disease . . . . . . . . . . . . . . . .

Multiple sclerosis . . . . . . . . . . . . . . . . . . .

Spinal cord injury . . . . . . . . . . . . . . . . . . .

Brain injury. . . . . . . . . . . . . . . . . . . . . . . .

Huntington’s disease . . . . . . . . . . . . . . . .

Amyotrophic lateral sclerosis . . . . . . . . .

1 to 5 million

2.8 million

1.5 million

500,000 to 650,000

250,000

180,000

70,000 to 90,000’

25,000

15,000

a Estimate of persons permanently disabled from head injury.

NOTE: Prevalence is defined as the total number of cases of a disease

estimated to be in existence in the United States at any given time.

Sources for estimates are the same as those in the text.

SOURCE: Office of Technology Assessment, 1990.

● results from animal experiments indicate the

possibility of therapeutic value.

Although it is reasonable to underscore the

potential of neural grafting for the treatment of

patients suffering from the neurological disorders

chosen, neural grafting as a general therapeutic

approach is in the very early stages of development, and predictions of its ultimate utility are

speculative at best. Furthermore, only a subset of

patients suffering from a particular disorder may

benefit from neural grafting. For example, in experiments, grafting with adrenal medulla tissue appears

to be more successful if the tissue is derived from a

younger rather than an older animal (15). A brief

review of the current understanding of, treatment

-93–
94 ● Neural Grafting: Repairing the Brain and Spinal Cord

Figure 8-l-National Institutes of Health 1989

Estimates of Costs of Neurological Disorders

Alzheimer’s disease

Stroke

CNS injury

Epilepsy

Movement disorders.

Multiple sclerosis

Amyotrophic lateral

sclerosis ~ -–– - — ~–- .- .—. -7. – ~

o 10 20 30 40 50 60

Billions of dollars

*Parkinson’s and Huntington’s diseases.

NOTE: Costs are per year, including medical care, lost income, etc.

SOURCE: National Institutes of Health, 1990.

approaches to, and epidemiological data1 on each of

the designated disorders is presented, exemplifying

some of the factors that drive neural grafting

research. (A detailed description of the neural

grafting research related to each of the listed

disorders is presented in ch. 5.)

The epidemiology of the neurological disorders

included in this chapter warrants special discussion.

In some instances, epidemiological data are inadequate, despite the extensive national health and

mortality data collected by the Federal Government

(16). This lack of data may reflect several factors.

Some disorders are difficult to diagnose. Some are

rare and thus elude medical data collection systems.

Epidemiological studies can also be confounded by

ambiguous criteria for diagnosing a disorder or

variations in health care among communities. Many

studies were conducted using populations that are

not necessarily representative of the United States;

for example, information has been derived from

local community studies or surveys in which institutionalized persons were not included. Despite these

concerns and others, the epidemiological data used

in this chapter testify to the significant impact these

neurological disorders have on society.

NEURODEGENERATIVE

DISORDERS

Parkinson’s Disease

In 1817 Dr. James Parkinson described six

patients with marked shaking and impaired mobility

(46). He called this condition “shaking palsy.”

Other physicians noted similar cases and named the

disease after Parkinson. The predominant pathological change observed in persons with Parkinson’s

disease is death of nerve cells in a region of the brain

called the substantial nigra. In the healthy brain,

nerve cells in the substantial nigra communicate with

nerve cells located in the striatum, using the

chemical transmitter dopamine. Death of substantial

nigra nerve cells and the resulting dopamine depletion lead to the symptoms characteristic of the

disease--tremor, slowing of movement, and rigidity.

Parkinsonism represents not just one disease, but

a collection of illnesses. Some manifestations of

parkinsonism are secondary to known causes (e.g.,

drugs and other toxic chemicals, rare brain tumors,

and recurrent head injuries, such as those sustained

by professional boxers) (32). The most common

form of parkinsonism, however, is that marked by a

progressive loss of nerve cells in the substantial nigra

due to unknown causes. This subgroup of parkinsonism is called idiopathic Parkinson’s disease, or just

Parkinson’s disease, and it accounts for 80 to 90

percent of parkinsonism cases. In the following

section, when discussing the scope of parkinsonism,

all forms of the disease will be considered; when

examining potential causes of the disorder, the focus

will be on Parkinson’s disease.

While it is not known what causes the nerve cell

death in Parkinson’s disease, there is now considerable evidence that the disease process begins a

number of years before the clinical features become

visible (33, 39, 41). Nerve cell death in the substantial

nigra proceeds slowly and does not produce any

symptoms until a critical number of cells (80 percent

or more) has died.

The onset of symptoms of Parkinson’s disease is

so imperceptible that patients usually require assisl~pi&fiO1@,~ &b are presented as incidence, the number of new cmes W eurring during a specified period of time (usually 1 year) within a

designated are% incidence rate, incidenee per unit of Population prevalence, the total number of cases in existence at a speci.fkd time in a designated

area; pnwaZence rate, prevalence per unit of populatio~ and mortality rate, the number of deaths attributable to a disorder during a speci.fhxl period of

time within a designated area per unit of population.
Chapter 6--Relevant Neurological Disorders ● 95

Photo credit: B. Pansky, Medical College of Ohio

Right: picture of the brain of a Parkinson’s disease patient showing significant reduction in nerve

cells as compared to the adjacent picture, showing the same region of the brain in a

normal

tance from friends and relatives to recall its first

manifestation. Parkinson’s disease is extremely rare

in persons under age 20, but the incidence and

prevalence rates increase with age. In a study of 806

Parkinson’s patients, the median age of onset was

found to be 63 (i.e., half the patients had symptoms

by their 63rd birthday), and the majority (56 percent)

of patients evidenced symptoms before age 65. The

mean duration of illness (onset to death) varied from

8 to 14 years (40).

The most crucial element in determiningg the cause

of Parkinson’s disease is identifying the source of

the nerve cell damage. Although the disease is more

common among older persons, there is little evidence that it is related to arteriosclerosis, tumor,

brain injury, or nutritional problems often associated

with aging. Other possible causes may be genetic

factors, altered immune system function, or infection. In general, however, there is a lack of evidence

that any of these factors plays a role in Parkinson’s

disease.

Since it is known that certain toxic substances in

the environment can produce parkinsonism, there is

great interest in examining the role of exogenous

toxins in Parkinson’s disease (box 6-A). Because of

individual.

the ubiquitous nature of Parkinson’s disease, many

substances have been suggested as possible causative agents. For example, nine metals-aluminum,

arsenic, calcium, copper, iron, manganese, magnesium, mercury, and zinc-have been correlated with

Parkinson’s disease (10). As yet, however, metal

toxicity as a cause of Parkinson’s disease does not

have a sound scientific basis.

In 1979, it was discovered that a synthetic

narcotic, l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP), can cause parkinsonism in humans (9)

(see box 5-A). Subsequent observations suggested

that Parkinson’s disease may be caused by a toxic

substance related to MPTP (14). Drugs that inhibit

MPTP’s toxic effect are currently under investigation for treating Parkinson’s disease.

The standard treatment for Parkinson’s disease

has been drug therapy aimed at increasing dopamine

in the brain (50). Dopamine is not readily absorbed

into the brain, so administration of dopamine itself

is not efficacious. However, levodopa (L-dopa), the

precursor of dopamine, is a very effective treatment.

When L-dopa is taken, it is absorbed into the brain

from the blood and is converted into dopamine by

the remaining substantial nigra nerve cells, amelio-
96 Neural Grafting: Repairing the Brain and Spinal Cord

Box 6-A--Cycads and Amyotrophic Lateral Sclerosis, Parkinson’s Disease, and Dementia

Amyotrophic lateral sclerosis-Parkinson’s disease-dementia (ALS-P-D) syndrome has been known among the

Chamorro natives of the Mariana Islands in the Pacific Ocean for more than 150 years and came to the attention

of U.S. scientists soon after World War II. It is characterized by parkinsonism and prominent dementia, or

amyotrophic lateral sclerosis (Lou Gehrig’s disease), or a combination of the three. Gradually, the incidence of the

disorder declined, and that decline coincided with a change in lifestyle of the native population, including reduced

ingestion of the seed from the endogenous plant known as Cycas circinalis. The cycad seed is known to contain

highly potent neurotoxic substances. During World War II, cycad seeds were the major source of flour and medicine

in certain parts of the Mariana Islands. The subsequent high incidence of ALS-P-D syndrome has been attributed

to the increased use of cycad for food or medicine.

Monkeys fed the amino acid derived from the cycad seed (known as Beta-N-methyl amino-L-alanine, BMAA)

develop motor neuron and parkinsonian symptoms and behavioral changes. Another neurotoxic syndrome in man,

lathyrism, is known to be caused by an amino acid that is structurally similar to BMAA. These observations are

strong indications that a cycad neurotoxic substance acting like BMAA is the cause of ALS-P-D syndrome,

Although this syndrome is distinct from Parkinson’s disease, studies of ALS-P-D syndrome provide valuable clues

to the etiology of amyotrophic lateral sclerosis, Parkinson’s disease, and Alzheimer’s disease.

SOURCES: P.S. Spencer, P.B. Nunn, and J. Hugon, “Guam Amyotrophic Lateral Sclerosis-Parkinsonism-Dementia Linked to a Plant Excitant

Neurotoxin,” Science 237: 517-522, 1987; J.C. Steele and T. Guzman, “Observations About Amyotrophic Lateral Sclerosis and

the Parkinso nism-Dementia Complex of Guam With Regard to Epidemiology and Etiology, ” Canadian Journal of Neurological

Sciences 14:358-362, 1987.

rating many of the motor symptoms of the disease. delayed the onset of serious disability and treatment,

Usually L-dopa is given in conjunction with another

drug, carbidopa, which increases the amount of

L-dopa that can enter the brain, thus making the drug

even more effective. Unfortunately L-dopa, the

standard therapy for Parkinson’s disease, does

not have any effect on the progression of the

disease, and nerve cell death continues unabated.

As a result, in most patients L-dopa therapy loses

its effectiveness as the disease progresses, and

symptoms become more and more difficult to

control.

Other drugs are used to treat persons with

Parkinson’s disease as well (table 6-3). All of these

work by counteracting the effects of decreased

dopamine in the striatum (50). Like L-dopa, these

drugs lessen the symptoms of Parkinson’s disease

without affecting the underlying mechanism that

causes the nerve cell death. They, too, tend to lose

their effectiveness as the disease progresses. Neural

grafting as a treatment in Parkinson’s disease is

currently under investigation in animals and

humans. Strategies for the use of neural grafting

include the replacement of degenerating neurons

and the provision of dopamine.

Recently, a drug that actually slows the progression of Parkinson’s disease has been developed (47).

In a group of patients with early, untreated Parkinson’s disease, administration of the drug deprenyl

compared to a group of patients who did not receive

the drug. This finding is not only extremely important for the treatment of Parkinson’s disease, it also

represents the first time a drug has been shown to

have a retarding effect on any neurodegenerative

disorder. As more is learned about how deprenyl

works, it may shed new light on the mechanisms that

produce other progressive degenerative disorders

such as Alzheimer’s disease and Huntington’s

disease.

Currently, data on the national prevalence and

incidence of parkinsonism are limited. Available

data are based on community studies and researchers’ estimates. The reported prevalence rates of

parkinsonism vary widely, from 4 to 187 cases per

100,000 persons (40). This vast difference undoubtedly reflects the variability in the completeness of

case findings and the varying standards of health

care indifferent areas, which determine survival and

hence prevalence rate. The number of persons with

parkinsonism in the United States has been

estimated at 500,000 to 650,000 (37).

The reported annual incidence rates of parkinsonism also vary widely, from 5 to 24 cases per 100,000

persons (40). Data collected from a survey conducted in Rochester, Minnesota, indicated that the

annual incidence rate of parkinsonism is 20.5 cases

per 100,000 population (adjusted to the 1970 U.S.
Chapter &Relevant Neurological Disorders ● 97

Table 6-3-Drugs Used for the Treatment of

Parkinson’s Disease

Drug Action

Levodopa (L-dopa) . . . . . Increases dopamine levels

Amantadine . . . . . . . . . . . Increases release of dopamine

Bromocriptine . . . . . . . . . Stimulates dopamine receptors

Trihexyphenidyl . . . . . . . . Decreases acetylcholine activity

Benztropine . . . . . . . . . . . Decreases acetylcholine activity

Deprenyl . . . . . . . . . . . . . . Slows progression of cell deatha

aUnder investigation.

SOURCE: Office of T*nology Assessment, 1990.

population) (51). Study of the same community

indicates that Parkinson’s disease accounts for 85.5

percent of all cases of parkinsonism and that

drug-induced cases (due to antipsychotic drugs used

to treat certain mental disorders, and generally

reversible) are now the second most common form

of parkinsonism (51). The number of persons

diagnosed with parkinsonism before age 50 seems to

be increasing (2).

Huntington's Disease

Huntington's disease (HD) is an incurable,

inherited disorder. Onset is commonly between the

ages of 30 and 50 (7). It is heralded by personality

and behavioral changes and involuntary movements

(12). As HD progresses, the involuntary movements,

consisting of uncontrollable writhing and jerking, or

chorea, become more frequent and exaggerated,

eventually rendering the patient bedridden and

incapable of per-forming everyday activities. Some

patients, especially with the juvenile form of the

disease, also experience slowed movement and

rigidity. As the disease progresses, the patient’s

memory and mental abilities decline. Patients may

become emotionally deranged; all eventually lapse

into dementia. HD leads to a steady decline in health,

and death usually occurs 14 to 19 years after onset

of the disease.

The brains of persons with HD appear shrunken at

autopsy (12). There is extensive nerve cell death in

certain regions of the brain, including the striatum

and the cerebral cortex. The abnormal movement

associated with HD is attributed to loss of nerve cells

in the striatum; dementia is attributed to loss in other

regions. The nerve cell loss associated with HD

results in a profound decrease in certain brain

chemicals, including GABA (gamma-aminobutyric

acid) and acetylcholine. How nerve cell death is

produced in HD remains a mystery.

A single defective gene appears to be responsible

for HD (29). Because HD is an autosomal dominant

condition, any child of a parent with HD has a 50

percent risk of inheriting the gene and succumbing

to the disease. Advances in molecular genetics have

pinpointed the location of the HD gene to chromosome 4 (23, 29). Although the gene itself has not

been identified, knowledge of its location has

important practical implications-a person or fetus

carrying the HD gene may be identified prior to

onset of the disease. Researchers are attempting to

determine the gene’s function and eventually to

develop an effective treatment for HD.

There is at present no cure for HD (12).

Attempts to replace deficient brain chemicals have

been unsuccessful. Treatment is aimed at minimizing the abnormal movements and mental problems

associated with the disease. In their normal state,

nerve cells that degenerate in HD may suppress the

activity of other, dopamine-producing nerve cells.

Destruction of the former may lead to excessive and

uncontrolled dopamine production, causing the involuntary movements typical of HD. Drug therapy

aimed at blocking the action of dopamine is employed to suppress the involuntary movements. This

therapy produces undesirable side-effects, however,

including sedation, depression, and severe limitation

of movement. Drugs are also used to help control the

mental changes associated with HD. None of these

drug therapies is adequate for the treatment of HD,

and none prevents the progression of the disease.

Since the symptoms of HD are produced by the

death of specific groups of nerve cells, the limited

animal research into the treatment of HD by

neural grafting is based on the possibility of

replacing degenerated cells or replenishing certain brain chemicals.

Huntington’s disease is a relatively rare disorder.

Epidemiological assessment is complicated by the

fact that it is extremely rare in many regions but

unusually frequent in others (37). Its worldwide

prevalence rate is estimated to be five cases per

100,000 persons (37). Its incidence rate is estimated

to be 3.4 cases per 1 million persons each year. In

certain regions of the world, notably the Lake

Maracaibo region of Venezuela, the prevalence rate

is extremely high, affecting up to 700 people per

100,000 persons. Between 1968 and 1974, it was

estimated that HD accounted for 1.15 deaths per 1

million persons in the United States per year (37).

Although there are no reliable national data on
9/I ● Neural Grafting: Repairing the Brain and Spinal Cord

the prevalence of HD, it is estimated that 25,000

Americans now suffer from this disorder (7, 29,

52). Another 125,000 Americans are thought to be at

risk of developing the disease.

Alzheimer's Disease

Alzheimer’s disease (AD) is an incurable disorder

that robs its victims of their intellect and eventually

of their physical health. Its onset is insidious.

Typically, its first symptom-loss of memory for

recent events—is ignored or attributed to other

causes, such as stress, a drug side-effect, or the

general forgetfulness of old age. As the disease

progresses, memory loss worsens and can no longer

be ignored or dismissed. A cascade of other behavioral symptoms ensues, including confusion, irritability, combativeness, restlessness, and fearfulness.

Problems with language occur, as do difficulties in

executing purposeful movements. Ultimately, the

AD patient will be completely helpless—

incontinent, bedridden, and unable to speak or eat.

Postmortem examination of the brains of AD

patients reveals a loss of nerve cells in specific

regions, including the basal forebrain, amygdala,

hippocampus, locus ceruleus, and parts of the

cerebral cortex. The nerve cell loss is associated with

reduced quantities of certain brain chemicals, particularly acetylcholine. Reduced noradrenaline and

other chemicals in the brain have also been reported

(8, 19, 24).

At the present time, a definitive diagnosis of AD

is achieved only after the patient’s death; it is based

on the presence of abnormal structures in the brain:

neurofibrillary tangles and neuritic plaques. Neurofibrillary tangles are accumulations of twisted

protein filaments inside nerve cells, and neuritic

plaques are abnormal clusters of degenerating nerve

cell fibers, other brain cells, and amyloid protein (see

later discussion) found in the areas between neurons

(49). More recent developments have linked the

detection of a protein, called Alzheimer’s diseaseassociated protein (ADAP), in postmortem brain

tissue with AD (17). Chemical tests for ADAP may

lead to the development of a diagnostic test for AD.

The cause or causes of Alzheimer’s disease are

not known. Genetic effects, environmental effects,

and disrupted chemical processes in the brain have

all been examined as possible factors in the disease

(30, 62, 69). Recently, attention has been focused on

a protein called beta-amyloid, which is a key

~oto credit: R. Rest&, The Mind (New York NY: Bantam Books, 1988)

Picture of microscopic changes, including neurofibrillary

tangles and neuritic plaques, that occur in the brain when

afflicted with Alzheimer’s disease.

component of neuritic plaques (56). It may be that

some defect in beta-amyloid synthesis leads to the

formation of neuritic plaques and nerve cell degeneration seen in AD (58). Aluminum or aluminum

binding is also under consideration as a possible

cause of AD (69). Growth factors, specifically nerve

growth factor (NGF), may also play a role in the

development of AD. NGF has been shown to protect

acetylcholine-producing nerve cells from experimentally induced damage in laboratory animals (27,

67).

Pharmacological treatment of AD has met with

little success, and there is no cure for AD (table

6-4). As discussed earlier, AD patients suffer from a

deficit of several brain chemicals, particularly acetylcholine. Since acetylcholine has been demonstrated to be involved in learning and memory,

restoration or augmentation of acetylcholine in AD

victims may lead to improvements in their memory

and other cognitive abilities. In addition, drugs that

act on other chemical systems implicated in AD may

also lead to fictional improvements. None of these

drugs would have an effect on the cause of the

disease, and none would halt its progression. As a

result of this fact and the lack of uniform success in

alleviating AD symptoms with such drugs, other

treatments for AD are being explored.

As mentioned earlier, NGF has been shown to

prevent the degeneration of acetylcholine-producing

nerve cells after injury, and it appears to improve

memory in a rat model of cognitive impairment with

age (13). These and other findings have led research-
Chapter 6--Relevant Neurological Disorders ● 99

Table 6-4-Drugs Being Developed for the Treatment

of Alzheimer’s Disease

Drug Action

Velnacrine maleate . . . . .

Physostigmine . . . . . . . . .

Tetrahydroaminoacridine

(THA) . . . . . . . . . . . . . .

Suronacrine maleate. . . .

Milacemide . . . . . . . . . . . .

Captopril . . . . . . . . . . . . . .

Acetyl-L-carnitine . . . . . .

Nimodipine . . . . . . . . . . . .

Idebenone . . . . . . . . . . . .

Inhibits cholinesterase

Inhibits cholinesterase

Inhibits cholinesterase

Amplifies noradrenaline action

Stimulates glycine activity

Inhibits angiotensin activity

Enhances activity of nerve growth

factor

Blocks calcium channel

Enhances cerebral metabolism

SOURCE: J.F. Beary, “Alzheimer’s Medicines: Sixteen Medicines in

Testing,” American Journal of Alzheimer’s Care and Related

Disorders & Research (January/February): 4-6, 1990.

ers to suggest that administration of NGF may slow

the progression of the major symptoms of AD and

could be efficacious in treating persons with the

disease (48). The potential use of neural grafts to

treat AD has been explored mainly in experiments involving rodents and is based largely on

the ability of neural grafts to provide growth

factors, such as NGF.

The collection of accurate statistics on the

incidence and prevalence of AD is hampered by

the inability to diagnose AD definitively during a

patient’s lifetime. AD is given as the clinical

diagnosis when other causes of a progressive dementia have been eliminated (e.g., cardiovascular disease, stroke, head injury, or adverse reaction to

drugs). Although improvements have been made in

the ability to diagnose AD clinically (30), it remains

extremely difficult to diagnose the disease definitively early in its course.

Alzheimer’s disease is the primary cause of

dementia in the United States. Few national statistics

are available on the prevalence and incidence of AD

per se; most available data relate to dementing

disorders as a whole. A 1987 OTA report (62)

estimated that the prevalence of severe dementia

in the United States is 1.5 million persons. Mild or

moderate dementia was estimated to occur in

another 1 to 5 million persons. AD is estimated to

account for about 66 percent of all cases of dementia.

Much of the incidence and prevalence data

available specifically for AD are based on studies

that differ from each other in diagnostic criteria and

procedures and in the populations analyzed. Incidence rates per year have been estimated at 123.3

cases per 100,000 persons over the age 29; the

age-adjusted rate was calculated to be 51.6 persons

per 100,000 persons per year (54). Prevalence rates

of AD have been estimated from recent community

studies; AD was found among 2.0 to 10.3 percent of

those over the age of 65, with an estimated 3 to 5

million persons in the United States afflicted with

AD (11, 31). Estimates of the total yearly costs of

AD range from $30 billion to $80 billion (28, 62).

Motor Neuron Disease: Amyotrophic

Lateral Sclerosis

Motor neuron diseases destroy the nerve cells that

control muscle movement, resulting in impaired

muscle function. The most well-known motor neuron disease is amyotrophic lateral sclerosis (ALS),

or Lou Gehrig’s disease. ALS is an incurable

neurological disease. The average age of patients at

the time of diagnosis is 56 (44). Initial symptoms can

include difficulty in performing fine tasks, weakened leg muscles, or difficulty in speech and

swallowing. There is progressive loss of muscle

control, and ultimately patients are unable to move,

except to blink; they cannot speak, eat, or breathe

without assistance, yet the mind and senses are left

intact. The median survival time following onset of

ALS is 23.8 months (37). Fewer than 20 percent of

ALS patients survive 5 years or more.

Paralysis in ALS is produced by the selective

death of nerve cells in the brain and spinal cord that

control muscle movement (43, 72). No single cause

of ALS has been widely accepted. Five to 10 percent

of ALS is familial, and research is being directed

toward uncovering its genetic underpinnings. Genetic factors were initially thought to be responsible

for the high incidence of ALS observed in Guam.

More recent studies, however, indicate that an

environmental factor may have produced the high

incidence of ALS in Guam (box 6-A) and may be

responsible for the increase in ALS mortality rate in

the United States (38). An infectious cause of ALS

has also been considered (43). Disrupted immune

system function, leading to autoimmunity, is another

suspected cause of ALS, and clinical trials are now

under way to evaluate the effectiveness of immunosuppression in treating the disease.

Early diagnosis of ALS can be difficult, since it is

not associated with any specific chemical marker

(44). Abnormal muscle function is generally detect-
100 Neural Grafting: Repairing the Brain and Spinal Cord

able at the time of diagnosis, however, and concentrations of a chemical associated with muscle

atrophy may be elevated in the blood. At present,

there is no treatment or cure for ALS. Medical

intervention is directed at the management of

symptoms. Drugs may be employed to limit muscle

spasticity and cramping and hypersalivation. Counseling and rehabilitation services are employed to

help ALS patients adapt to their disability. In the

final stages of the disease, a feeding tube or

respirator may be used to maintain the patient.

Neural grafting with motor neurons has been

reported in a few animal experiments, although

many difficulties characterize this approach to

the treatment of ALS.

Difficulty in early diagnosis of ALS and some

disagreement over nomenclature have complicated

epidemiological studies of this disease (37). A recent

study indicates that the mortality rate from motor

neuron disease increased among the elderly between

1962 and 1984 (38). In 1987, 3,381 deaths in the

United States were attributed to motor neuron

disease (64). The number of people suffering from

ALS in the United States can only be estimated,

since there are no national data on the incidence

and prevalence of this disease. The incidence of

ALS is estimated from medical records in Rochester,

Minnesota, between the years of 1925 and 1977; on

average, two cases per 100,000 persons were diagnosed each year (37, 72). Extrapolation from these

data indicates that 5,000 new cases of ALS are

diagnosed in the United States each year. It is

estimated that approximately 15,000 Americans

suffer from ALS at any given time. Since the

incidence of ALS increases with age, the number of

cases is expected to increase as the population ages.

CENTRAL NERVOUS SYSTEM

INJURY

Spinal Cord Injury

Spinal cord injury is any damage to the spinal cord

that results in paralysis or loss of sensation in various

parts of the body, or both. The magnitude of

fictional loss following injury to the spinal cord is

directly related to the extent of the damage and

where in the spinal cord the injury occurs. Damage

to the spinal cord can be caused by a sudden impact

(from a motor vehicle collision or sporting injury),

gradual compression of the spinal cord tissue (from

a tumor, blood clot, or herniated disk), or an

interruption in the blood supply to the spinal cord.

Spinal cord injury caused by sudden impact

usually results from a forceful blow on the bones of

the spine, causing them to strike the soft nervous

system tissue of the spinal cord and injure it. The

victim exhibits loss of movement and sensation

below the level of the injury. This is partly due to the

initial shock of the injury. The injury also sets in

motion a chain of microscopic events that leads to

degenerative changes. This secondary response may

be the most important cause of the permanent

damage associated with spinal cord injury.

Unlike sudden-onset trauma, injury due to gradual

compression is the result of a relatively slow

deformation of the tissue by an intruding body.

While permanent loss of function can result from

spinal cord compression, the functional loss is often

reversed once the compressing body is removed.

Disruption of the blood supply to the spinal cord

for a prolonged period of time can result in cell death

and permanent damage. Any sort of blockage of

blood vessels, such as a blood clot, or damage to the

major arteries supplying the spinal cord can cut off

the blood supply.

Whatever the cause, damage to the spinal cord

disrupts the nerve cell networks and the brain’s

control over body functions. Injuries to the upper

regions of the spinal cord affect most of the body and

are often life-threatening because control of breathing may be disrupted. Patients with an injury to the

upper portion of the spinal cord generally must be

maintained on a respirator for the rest of their lives.

Quadriplegic, or paralysis and loss of sensation from

the shoulders down, results from damage to the

upper spinal cord. Paraplegia, or loss of movement

and sensation from the waist down, results from

damage to the middle or lower portions of the spinal

cord. Other results of injury to the spinal cord

include muscle problems such as spasticity; sensory

conditions where the patient can experience pain

from the slightest touch; abnormal blood pressure

and temperature regulation; disturbances of sexual

function; loss of voluntary bladder control, which

can lead to bladder infections; and loss of voluntary

bowel function.

As many as 30 percent of persons die within 24

hours of a spinal cord injury (36). The nature of the

traumatic event and the amount of force that caused
Chapter 6--Relevant Neurological Disorders . 101

the injury are important factors related to survival

during the first 24 hours. For example, one study

showed that the 24-hour survival rate was 97 percent

for recreational injuries and 60 percent for motor

vehicle crashes (36). If a patient survives the initial

spinal cord trauma, his or her chance of long-term

survival is high. It has been estimated that 86 percent

of patients who survive the first 24 hours following

a spinal cord injury are still alive 10 years later (60).

In the event of an injury to the spinal cord, there

are two phases at which therapeutic interventions

can be directed-the acute phase and the chronic

phase. Interventions during the acute phase are

aimed at prevention of damage, while treatment

during the chronic phase is directed toward improvement of function.

During the acute phase, 8 to 12 hours immediately

following a spinal cord injury, surgical intervention

may be necessary to prevent further damage to the

spinal cord. In addition, attempts may be made to

slow or confine further nerve cell death and degeneration in response to the spinal cord injury. Since it

has been shown in animal experiments that only a

small fraction of nerve cells has to be saved to retain

some degree of function, any tissue spared could

significantly improve subsequent rehabilitation. A

number of drugs are being considered for use in this

situation, including antioxidants, calcium channel

antagonists, naloxone, thyrotropin-releasing

hormone, and corticosteroids. Dramatic results have

been reported when the corticosteroid methylprednisolone was administered shortly after an injury to the

spinal cord (42). This treatment significantly decreases the ultimate extent of injury in patients and

lessens the disability they exhibit following the

injury. The continued development of drugs and

procedures that prevent, or at least contain, this acute

degenerative process is an important and promising

area of research.

The chronic phase of treatment, aimed at rehabilitation and improving function, continues throughout

the life of the patient. Some newer techniques

include electrical stimulation of muscles and various

biofeedback procedures. Advances in microelectronics have paved the way for the development of

neural prosthetic devices to activate and coordinate

activity in the injured spinal cord. All of these

therapies are aimed at maximizing the rehabilitation

process following an injury to the spinal cord: None

is directed at repairing the damaged spinal cord.

Several strategies for the use of neural grafts to

repair spinal cord injury have been proposed and

tested in animal experiments, including the

promotion of regrowth, the bridging of the

injured region, and the replacement of nerve cells

in the spinal cord.

Since the vast majority of spinal cord injuries is

caused by trauma, prevention is an important strategy in reducing incidence. Motor vehicle crashes

have been reported to account for 48 percent of

spinal cord injuries, followed by falls (20 percent),

acts of violence (15 percent), and sports injuries (14

percent) (60). Older adolescents and young adults

have the highest rate of spinal cord injury, both in the

United States and in other countries (34).

The incidence of spinal cord injury may be

underestimated because injuries resulting in immediate death may not be reported. The average

age-adjusted mortality rate for spinal cord injury was

estimated at 2.9 per 100,000 persons in Olmsted

County, Minnesota, from 1935 to 1981 (20). The

incidence rate in that population was 8.34 per

100,000 males, and 2.77 per 100,000 females (21).

The estimated prevalence rate was 47.3 per 100,000

persons (20). A recent survey of a nationwide

sample of institutionalized and noninstitutionalized persons estimated the prevalence rate of

spinal cord injury to be 72.1 cases per 100,000

persons or a prevalence of approximately 180,000

persons in the United States (25) (box 6-B).

Medical intervention, rehabilitation services, and

lost income due to spinal cord injury have been

estimated to cost more than $2 to $8 billion annually.

Brain Injury

Traumatic brain injury has been labeled the silent

epidemic (66); brain injury is the major cause of

death and disability among children and young

adults in the United States (66). Since so many of

the people who sustain brain injury are young, the

cost to society, including medical and rehabilitation

expenses, support services, and lost income, is great,

estimated at nearly $25 billion each year (66).

Motor vehicle collisions, violent assaults, and

falls are the main causes of head trauma and brain

injury. The consequences of head trauma depend

upon the amount and type of damage sustained by

the brain (53). When head injury produces a mild

concussion, there are usually few overt symptoms,

although the brain may sustain structural damage
102 . Neural Grafting: Repairing the Brain and Spinal Cord

Box 6-13-Neurological Disorders and the Veteran

There are approximately 27 million veterans in the United States. Their medical needs are handled through the

172 medical centers and 227 outpatient clinics of the Department of Veterans Affairs (VA). In fiscal year 1989,

71,995 patients were discharged from the medical centers after having been treated for a variety of neurological

disorders. These included cerebrovascular disease (18,850 patients), dementia and organic brain syndrome (13,406),

epilepsy (13,950), neuromuscular diseases (7,&17), diseases of the basal ganglia (3,096), and demyelinating diseases

and diseases of the spinal cord (2,755).

Spinal cord injury (SCI), caused principally by battlefield trauma during wartime and vehicular and diving

injuries during peacetime, is of special concern to the VA, which maintains 20 SCI centers throughout the United

States (table 6-5). The number of veterans with an SCI has been put at 45,000. During fiscal year 1987,18,300 such

patients were treated at VA centers; 64 percent of their injuries were service-related. Among this patient population,

50 percent were over the age of 55, and just about all (98.9 percent) were men. Forty-one percent of the men served

during World War II, veterans from the Korean conflict made up 22 percent of the patient population, and 30 percent

were from the Vietnam and post-Vietnam eras. Within this VA population of SCI patients, 53 percent were

paraplegic and 47 percent were quadriplegic. For fiscal year 1988, $90.8 million was allocated for direct medical

care by these SCI centers.

SOURCES: L. Lehman, acting director, Neurology, Dep artment of Veterans Affairs, Washington, DC, personal communication% April 1990;

T. Stripling, Paralyzed Veterans of America, personal communication, July 1990; Department of Veterans Affairs, Spinal Cord

Injury Service, Washington DC, 1990.

Table 6-5-Department of Veterans Affairs, temporary loss of consciousness, seizures, paralysis,

Spinal Cord Injury Centers, Fiscal Year 1989 loss of memory, permanent loss of responsiveness,

Operating Inpatients Outpatient or death.

beds -treated visits

Augusta, GA. . . . . . . . . 60 546 342 Immediate and expert medical attention may be

Brockton/

West Roxbury, MA .

Bronx, NY. . . . . . . . . . .

Castle Point, NY . . . . .

Cleveland, OH . . . . . . .

East Orange, NJ . . . . .

Hampton, NY . . . . . . . .

Hines, IL . . . . . . . . . . . .

Houston, TX . . . . . . . . .

Long Beach, CA.. . . . .

Memphis, TN . . . . . . . .

Miami, FL . . . . . . . . . . .

Milwaukee, WI . . . . . . .

Palo Alto, CA . . . . . . . .

Richmond, VA . . . . . . .

San Diego, CA. . . . . . .

San Juan, PR . . . . . . .

Seattle, WA . . . . . . . . .

Sepulveda, CAa 

. . . . . .

St. Louis, MO . . . . . . . .

Tampa, FL . . . . . . . . . .

Total . . . . . . . . . . . . . . .

115

80

43

80

25

64

135

26

197

120

36

56

30

120

5

20

37

NA

42

70

548

182

259

271

135

134

522

159

980

690

207

506

277

785

89

197

330

NA

351

448

1,361 7,616

201

1,766

972

338

191

94

1,660

1,327

15,316

3,381

375

2,205

1,378

996

4,195

1,086

1,613

1,096

496

2,588

41,184

able to prevent death and limit complications that

follow serious injury of the brain; rehabilitation may

enhance and foster intact neurological functions.

The death of nerve cells in the brain, however,

cannot be reversed by any medical intervention at

this time. The irreversible nature of brain injury

emphasizes the importance of strategies aimed at

preventing and reducing the severity of traumatic

brain injury. The basis for neural grafting as a

therapeutic approach in brain injury is the

possible replacement of degenerated nerve cells.

This strategy has been examined in animal

experiments.

The system for determining the incidence and

prevalence of brain injury in the United States

has been decried as inadequate (35, 59). Many

Outpatient center.

SOURCE: Department of Veterans Affairs, Spinal Cord Injury Service,

Washington, DC, 1990.

with long-lasting effects. More serious head trauma

can lead to diffuse injury throughout the brain, brain

swelling, extensive bleeding, or direct damage of

nerve cells. The sequelae of such damage depend on

which areas of the brain are injured and may include

factors contribute to the difficulty of tracking such

injuries. There is no single registry of all victims of

brain injuries. Sufferers of brain injury are widely

dispersed throughout the health care system; for

example, 50 percent of the fatal cases of brain injury

never enter the hospital, where many statistics are

collected. And universal nomenclature for defining

head and brain injuries is lacking. The Interagency

Head Injury Task Force (66), convened in response
Chapter 6--Relevant Neurological Disorders ● 103

Figure 6-2-Types of Head Injury Causing Death

1 00

80

60

40

20

l-t

Transport

I

20

0

- Olmsted Co U S San Diego Co Bronx, No Central San Diego Chicago

Minn. California N Y Virginia California area

Graph illustrates regional differences in death rates following

head injury due to transport (vehicle collisions), assault and use

of firearms, falls, and sporting injuries.

SOURCE: J.F. Kraus, “Epidemiology of Head Injury,” Head h’@y, P.R.

Cooper (cd.) (Baltimore, MD: Williams & Wilkins, 1987).

to congressional concerns about the seriousness of

traumatic brain injury, affirmed the need for epidemiologica1 investigation.

Each year in the United States, 75,000 to 100,000

persons die from head injuries (66) (figure 6-2). A

study of deaths associated with brain injury in the

United States between 1979 and 1986, based on data

from the National Center for Health Statistics, found

an annual rate of 16.9 deaths per 100,000 persons, or

approximately 42,250 people each year (59). A

community-based study in Olmsted County, Minnesota, between 1965 and 1974, estimated that brain

injuries are responsible for 32 deaths per 100,000

persons among males and 9 deaths per 100,000

persons among females (3; see also 35). Currently,

there are no national data on the prevalence of brain

injury. Estimates of the incidence rate of brain

injury, mostly derived from community studies,

indicate that 200 persons per 1003000 population

per year, or 500,000 persons per year in all, suffer

from injury to the brain that is serious enough to

require hospital admission (35). There are no data

on how many people sustain permanent loss of

function due to head injuries. It has been calculated

that 70,000 to 90,000 people each year are

permanently disabled as a result of head injury

(35).

Stroke

Most strokes are caused by cerebrovascular disease. They result in a sudden, specific neurological

deficit, the severity of which varies depending on

Photo credit: R. Restak, The Mind (New Yoti, NY: Bantam Books, 1988)

Picture of CAT scan of brain following a stroke.

Arrow indicates region of damage.

where in the brain the lesion occurred. Functional

problems can include coma, paralysis, or inability to

speak. A severe stroke can result in death.

There are two broad categories of conditions

under the heading of stroke. Ischemia, or decreased

blood flow, is most commonly caused by blockage

of a blood vessel in the brain and produces 82

percent of strokes (45, 61). Bleeding into the brain

tissue or spaces around the brain causes 18 percent

of strokes and is largely attributable to rupture of

blood vessels and less often to high blood pressure.

Both ischemic stroke and intracranial hemorrhage

interrupt normal blood flow to brain tissue and cause

a shortage of oxygen and nutrients.

Currently, the brain damage produced by a

stroke cannot be reversed. Therapeutic interventions are aimed at reducing any further damage in the

brain and preventing a reoccurrence (71). Medical
104 . Neural Grafting: Repairing the Brain and Spinal Cord

therapy to reverse and prevent blood vessel blockage

includes aspirin and other drugs that prevent or

disrupt the formation of blood clots. Drugs that

inhibit blood vessel spasm may also be useful. Drugs

or surgery may be necessary to reduce bleeding or

excess fluid in the brain. Rehabilitation therapy is

advised in order to maximize functional recovery

following a stroke. Recovery depends on many

factors, including the site and size of the stroke and

the degree of brain damage incurred.

Recent experimental data suggest that much of the

brain damage induced by strokes may ultimately be

preventable. The immediate nerve cell death produced by an interrupted blood supply appears to be

rather modest; subsequent changes in the brain, such

as changes in the blood vessels and the release of

excess excitatory chemicals, may be more destructive. Experiments in animal models of stroke indicate that blocking the action of excess excitatory

chemicals in the brain can reduce nerve cell death

(45). Since nerve cell death causes the disability

that follows stroke, replacement of the nerve cells

with a neural graft is considered a potential

medical therapy in some cases. Some animal

experimentation has been carried out investigating this possibility.

The nomenclature for stroke has varied considerably during the last century, complicating epidemiological analysis. Furthermore, stroke is sometimes

overdiagnosed (37). Despite these problems, it is

apparent that stroke is the third leading cause of

death in the United States, after heart disease and

cancer. It is estimated that stroke costs $10 billion

each year in direct medical expenses and lost

income. In 1987, approximately 150,000 deaths

nationwide were due to stroke, representing an

age-adjusted mortality rate of 30.0 per 100,000

persons, or 7.1 percent of all deaths (66). With

increasing age, the incidence of stroke, as well as

death due to stroke, increases; however, the nationwide incidence of and mortality rate from stroke are

declining, perhaps due to improved control of

hypertension, diabetes, and cardiac disease, as well

as a reduction in cigarette smoking (61, 71).

Mortality statistics do not present the entire

medical picture of stroke, since strokes are not

always fatal. There are 500,000 new stroke victims

in the United States annually (45). Among persons

under age 54, the yearly incidence rate of stroke is 17

per 100,000 persons (37). Among persons over age

65, the annual incidence of stroke is more than 500

per 100,000 persons.

A national survey conducted by the National

Institutes of Health found that as of 1976,1.7 million

people still living had a history of hospitalization for

stroke (65). The most recent national data available

from the National Health Interview Survey indicated

a prevalence rate in the United States of 1,120 cases

per 100,000 persons (66).

EPILEPSY

An epileptic seizure may suddenly render an

individual unconscious and lead to violent body

movements, or it may simply cause a brief loss of

consciousness or repetitive and sometimes subtle

movements such as chewing. The occurrence of a

seizure does not necessarily lead to a diagnosis of

epilepsy, since seizures may result from infections,

head injury, and tumors. In general, a diagnosis of

epilepsy is made if repeated seizures occur in a

patient due to CNS dysfunction.

Approximately one-half of those who suffer from

epilepsy experience their first seizure before age 20

(18). Seizures are classified as generalized or partial,

depending on the nature of the onset of abnormal

brain function (table 6-6). Electrical recording of

brain activity during a seizure and clinical symptoms

are used to delineate the different classes of seizure.

Generalized seizures involve large regions of the

brain and are often characterized by loss of consciousness and symmetrical involvement of the

muscles of the body. A partial seizure reflects

abnormal activity beginning in a single area of the

brain and usually results in more restricted disturbances.

The electrical impulses that are normally used by

nerve cells to communicate and to send information

throughout the body go awry in epilepsy. Nerve cells

display excessive excitability and dispatch electrical

impulses at a manic rate. At the same time,

metabolism in the brain is profoundly altered. Nerve

cells may be unable to regulate properly the entry of

charged molecules, thus rendering them more excitable. In addition, research indicates that abnormal

input from other nerve cells may lead to enhanced

excitability.

Management of epileptic disorders is complex

(18). The first step involves accurate diagnosis and

determination of the cause of the seizures. A careful
Chapter 6--Relevant Neurological Disorders ● 105

Table 6-6—Types of Epileptic Seizures

. Partial (seizures that begin in a discrete region of the brain)

— simple partial (no loss of consciousness)

— complex partial (impaired consciousness)

— partial seizures that spread throughout the brain

. Generalized (seizures that begin throughout the brain)

● Unclassified

SOURCE: Office of Technology Assessment, 1990.

medical history and sometimes intensive monitoring

are necessary to diagnose the origin of seizures; in

most cases, however, the cause of seizures is not

found. The second step is to design a drug therapy.

Anticonvulsant drugs can completely eliminate or at

least significantly curtail the occurrence of seizures

among 75 percent of persons with epilepsy; however, none of the drugs currently available can cure

epilepsy, and all have side-effects. Anticonvulsant

drugs may act by blocking the entry of charged

molecules into nerve cells or by increasing the action

of the inhibitory brain neurotransmitter GABA.

Constant assessment and monitoring of the dosage

and combination of drugs to control a patient’s

epilepsy are generally necessary. Another treatment

for some cases of epilepsy involves surgical removal

of the hyperexcitable nerve cells. Initial animal

experiments have shown that neural grafting can

inhibit seizures, suggesting that this approach

may one day provide a useful therapy for some

cases of epilepsy (5).

There are a number of sources of epidemiologica1

data about epilepsy. Estimates of the prevalence and

incidence of epilepsy vary with the definition of the

disorder (a single seizure v. chronic seizures). The

source of the data, whether from medical records or

surveys, also adds variability to the estimates. There

is no doubt, however, that epilepsy is a common

disorder. Five to 10 percent of the population will

suffer at least one epileptic seizure (26). The

prevalence rate of epilepsy in 1974 in Rochester,

Minnesota, was 650 cases per 100,000 persons;

when extrapolated nationwide, these data indicate

that there are approximately 1.5 million cases of

epilepsy in the United States (37). Approximately

40 to 60 new cases per 100,000 persons are

diagnosed each year (37).

DEMYELINATING DISORDERS:

MULTIPLE SCLEROSIS

Multiple sclerosis (MS) is a chronic neurological

disease characterized by an array of symptoms,

Photo credit: National Institutes of Health

Picture of measurement of brain activity using an

electroencephalograph, or EEG. Measurement is used to

detect epilepsy.

depending on wherein the CNS lesions occur (57).

Initial symptoms of MS may include muscle weakness; numbness and tingling, especially in the arms

and legs; loss of coordination and balance; dizziness; slurred speech; fatigue; and loss of bowel or

bladder control. Optic neuritis, which can result in

blurred or double vision or disturbances of color

vision, may bean early symptom of the disease. The

onset of MS usually occurs between the ages of 20

and 40 (70). The course of the disease is unpredictable; typically, symptoms emerge, go away completely, and then reemerge. Less frequently, symptoms worsen steadily without remission.

The relapsing-remitting symptoms of MS are

associated with widespread lesions of myelin

sheaths in the CNS. Myelin surrounds many nerve

fibers in the nervous system, insulating them and

thus permitting the rapid conduction of electrical

impulses. When the myelin sheath is destroyed, the

conduction of electrical nerve impulses is retarded,

producing the characteristic symptoms of MS. It is

not known what causes the destruction of myelin in

MS. Some data suggest that an infectious agent,

particularly a virus, acquired between the ages of 5

and 15 maybe involved, although no such agent has

been isolated, despite extensive research (6, 70).

Unequal geographic distribution of MS seems to

support the idea of an infectious or environmental

cause (37). The disease rarely occurs near the

equator, and its incidence increases with latitude in

the Northern and Southern hemispheres (figure 6-3).

Furthermore, migration before the age of 15 to a

geographic area with a different incidence of MS
106 ● Neural Grafting: Repairing the Brain and Spinal Cord

Figure 6-3-Geographical Differences in Death Rate Due to Multiple Sclerosis

Deaths per 100,000 persons, by state of residence at death. Death rates are significantly higher in the

northern versus the southern regions of the United States.

SOURCE: J.F. Kurtzke and L.T. Kurland, “The Epidemiology of Necrologic Disease,” C/inica/ Neurology, R.J. Joynt

(cd.) (Philadelphia, PA: J.B. Lippincott, 1989).

changes an individual’s risk of MS to that of the

native population. While the immediate cause of MS

is likely to be found in the environment, susceptibility is probably genetically determined.

Other data indicate that disrupted immune function may underlie MS. Some genes related to

immune system function are associated with MS

(55). Furthermore, immune system cells that respond to components of myelin have been identified

in individuals with MS (1, 68). It is postulated that

a virus may initiate this immune response in

genetically susceptible individuals.

Diagnosis of MS presents some difficulties; it

rests upon the characteristic symptoms, direct viewing of demyelination within the CNS using MRI

(magnetic resonance imaging), and the absence of

any other explanation. There is no cure for MS at

present. Therapy is directed at shortening the time

during which symptoms are present and alleviating

disabling symptoms such as muscle spasms or pain.

When symptoms of MS flare up, ACTH (adrenocorticotropic hormone) or methylprednisolone is often

administered. Such long-term measures, which inhibit immune system function, have not proven to

prevent new or more disabling bouts with MS, and

they cause serious side-effects. A few animal

experiments have suggested that myelinproducing cells can be introduced into the CNS to

seek out and myelinate nerve fibers; this research

suggests a potential role for neural grafting in MS

(22).

A national survey conducted in the 1970s indicated that approximately 10,000 persons are diagnosed with MS annually (4). According to that

survey, there were 123,000 MS patients in the

United States in 1976, a prevalence rate of 58 cases

per 100,000 persons. More current national prevalence data, from the National Health Interview

Survey, estimate that 151,000 persons suffer from

MS, a prevalence rate of 70 cases per 100,000

persons (63). The incidence and prevalence of MS

were also estimated from medical records in Olmsted County, Minnesota, between 1905 and 1984

(70). The prevalence rate of MS increased during the

last 10 years of the study, averaging 175 cases per

100,000 persons. Extrapolated nationwide and accounting for the geographical gradient of MS, these

data suggest that approximately 250,000 people in

the United States suffer from MS. This observed
Chapter 6--Relevant Neurological Disorders . 107

increase in MS was attributed largely to improved

diagnosis, although an increase in survival or

occurrence of the disease may have also contributed.

Two-thirds of the MS patients were ambulatory and

able to work.

SUMMARY AND CONCLUSIONS

Neurological disorders that may one day prove

amenable to treatment with neural grafting are listed

in this chapter. It is impossible to assert definitively

the future applications of neural grafting at this early

stage in its development. However, the wide array of

animal research currently probing the many different

uses and actions of neural grafting suggests that this

technology may ultimately have several applications. Furthermore, as new discoveries unveil the

chemical and structural alterations associated with

other brain disorders, additional applications of

neural grafting may become apparent.

While precise epidemiological data are often

unavailable, it is clear that the neurological disorders

listed in this chapter area significant cause of illness,

disability, and death in the United States. For many

of these disorders, there is no known cause and no

adequate therapy. For none is there a cure for the

nerve ceil death or other underlying pathology that

causes mortality and morbidity. Research efforts

involving genetic analysis, molecular biology, and

new drugs, as well as neural grafting, continue to

improve investigators’ understanding of the disorders and to suggest treatments.

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Chapter 7

Legal and Regulatory Issues
CONTENTS

Page

PROTECTION OF NEURAL GRAFT RECIPIENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113

Coverage by Department of Health and Human Services Regulations

Governing Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113

Coverage by State Laws and Regulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113

Role of Institutional Review Boards . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116

FDA Regulation of Neural Grafting Materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122

Regulation of New Surgical Procedures ... ..*. ... ... ... *.. ... ... ,++*. *,** *e **o,** 127

PROTECTION OF DONORS OF FETAL TISSUE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129

Development of Federal Policy on Fetal Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130

Federal Regulations Governing Fetal Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131

State Laws Governing Embryonic and Fetal Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132

Payment in Connection With Fetal Experimentation . .....,.....,....,*...*..**.* 136

Interstate Transfer of a Fetus ... ... ,.. ... ... ... ... ..*, ,., .*** ee*, **,   ** + **,$* 137

GOVERNMENT OVERSIGHT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .137

Potential Constitutional Challenges to Restrictions on Research . . . . . . . . . . . . . . . . . . . 137

Fetal Remains Laws ... ... ... ... ... ... ... ..+ +

, ... Q,oe*** *, *e**,*,,****.*,***.*** 138

Uniform Anatomical Gift Act . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .139

Compensation for Fetal Tissue in a Nonresearch Setting . * . . * ., . * . . * . . * . . ..,+*..., 140

SUMMARY AND CONCLUSIONS ... ... ... ... ... ... *.. ... .., .*. ... ... O **O*+,*** 143

CHAPTER 7 REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143

Box

Box Page

7-A. The Genesis of Medical Research Ethics . .........,.*..........*.*.....,**,* 114

Figure

Figure Page

7-1. An Institutional Review Board Approval Process . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118

Tables

Table Page

7-1. State Regulations Pertaining to the Protection of Human Subjects in

Experimentation ... ... ... ... ... ... ... ... ... e

.. ... .ce**m* **** . *m.+.**.*****, 115

7-2. State Regulations Pertaining to the Use and Procurement of Fetal Tissue

for Grafting Research ... ... ... ... ... ... ... ..*. ... ... ..** ... **** *..

v**.***** 133
Chapter 7

Legal and Regulatory Issues

Basic legal tenets govern experimentation and

biomedical research on human beings (see box 7-A).

This chapter addresses the legal issues raised by

neural grafting, including protection of recipients,

protection of donors, informed consent, and Federal

and State regulation.

PROTECTION OF NEURAL

GRAFT RECIPIENTS

Recipients of neural grafts may often be individuals needing special protection. Both the Federal and State Governments have recognized this

need and have sought to provide protection through

statutes and regulations. The relevant Federal and

State legislation is outlined below.

Coverage by Department of Health and

Human Services Regulations Governing

Research

Department of Health and Human Services

(DHHS) regulations apply to all research with

human subjects that is conducted or funded by

DHHS [45 CFR 46.101]. These Federal regulations

have potentially widespread application. The Federal budget for the National Institutes of Health

(NIH) alone represents over one-third of all money

spent on health-related research in the United States

(63). In addition, the reach of these Federal regulations extends well beyond federally funded research,

since the regulations are used widely as guidelines

in institutions that do not receive Federal funding

(19).

The DHHS regulations apply to both therapeutic

and nontherapeutic research and define research as

“a systematic investigation designed to develop or

contribute to generalizable knowledge” [45 CFR

46.101-46.409; 21 CFR 50.1-50.48; 45 CFR 46.102

(e)]. Some types of research are exempt from Federal

regulations under certain conditions, for example

educational research and research involving survey

or interview procedures [45 CFR 46.10 l(b)(l) and

(3)].

All Federally funded human research projects

must be reviewed and approved by an Institutional Review Board (IRB) [45 CFR 46.103(b)].

IRBs are required to conduct continuing review,

which can include third-party observation [45 CFR

46.109(e)]. The intervals of continuing review are

contingent on the degree of risk involved in the

experiment but must not be less than once per year.

The regulations also provide that risks of the

proposed research must be minimized and must

be reasonable in relation to anticipated benefits

[45 CFR 46.ill(a)(l), (2)], and they provide for

expedited review of research that involves minimal

risk [45 CFR 46.1 IO@)]. “Minimal risk” means

that the risks of harm anticipated in the proposed

research are not greater than those encountered

in daily life or during the performance of routine

physical or psychological tests [45 CFR

46.102(g)]. Research activities involving no more

than minimal risk include, for example, collection of

hair and nail clippings, recording of data that do not

involve invasion of the subject’s privacy [46 FR

8392], and minor changes in approved procedures

[45 CFR 46.110(b)].

Federal regulations require that selection of

subjects be equitable [45 CFR 46.ill(a)(3)] and

that informed consent be obtained from each

subject [45 CFR 46.116]. The regulations stipulate

the basic elements that must be included in informed

consent and require that such consent be documented and provided in language the subject can

understand. They further provide that neither the

researcher, the institution, nor the sponsor may be

released from liability through the subject’s oral or

written consent. DHHS regulations specifically

address research involving fetuses, pregnant

women, and human in vitro fertilization [45 CFR

46.201]. Moreover, separate provisions are included

for research with children [45 CFR 46.401 (a)].

Coverage by State Laws and Regulations

In research programs where there is no Federal

involvement or influence, government oversight

will depend on whether there are State statutes.

Where DHHS and Food and Drug Administration

(FDA) regulations overlap State statutes, the Federal

regulations are not intended to preempt applicable

State or local laws [45 CFR 46.10 l(g); 21 CFR

50.25(c)]. Few States have statutes that address

human experimentation specifically. At least six

address human research as part of patients’ rights

–113–
114 ● Neural Grafting: Repairing the Brain and Spinal Cord

Box 7-A—The Genesis of Medical Research Ethics

Many legal principles in the area of medical research ethics have been developed in response to abuses of

research subjects in Nazi Germany. Examples of unethical research in the United States further stimulated public

discussion and policy considerations. The most well-known examples of research abuses in the United States are

the Willowbrook hepatitis study and the Tuskegee syphilis study. In the 1960s, institutionalized mentally disabled

children at Willowbrook Institution were infected with live hepatitis virus in an effort to develop a vaccine. The

scientists justified their procedures by noting that hepatitis ran rampant through the institution and that all of the

children would eventually contract the disease. From 1932 to 1972, scientists conducting a U.S. Public Health

Service study of 400 black men suffering from syphilis deliberately withheld treatment from them in order to study

the effects of allowing the disease to take its course, even though penicillin had been found to be an effective

treatment. At least 28 of perhaps as many as 107 men died as a result of this study.

In the trials of Nazi physicians, the court set forth standards that should be met before and during research. The

Nazi physicians tried to defend themselves by pointing out abuses in research that had occurred elsewhere, including

those in the United States, However, this defense did not succeed, and 15 of the 23 physicians were found guilty

of war crimes and crimes against humanity. Those standards, subsequently adopted by the United Nations General

Assembly, are known as the Nuremberg Code. The tenets of the code significantly influenced subsequent State laws.

For example, the preamble to the California human experimentation law states that the law was necessary since the

Nuremberg Code was not codified and thus is unenforceable [Cal. Health & Safety Code 24171(b)]. Federal

regulations in the United States dealing with research were likewise influenced.

The Nuremberg Code provides guidelines for ensuring that participation in research is voluntary and that the

risks of research are minimized It provides that:

. certain basic research and animal research must be done before human research is undertaken;

. the research must be well designed;

● the research must be undertaken only by scientifically qualified individuals;

. the potential results must justify the risk involved in the performance of the research; and

. those results must not be procurable by other means of study.

The central principle of the Nuremberg Code is that participation in research must be voluntary, informed, and

uncoerced and that subjects have the right to bring the experimentation to an end. The code also requires that risks

be minimized through appropriate design and conduct of the research as well as adequate preparation and facilities

to protect the subjects. Research is forbidden if there is an a priori reason to believe that death or disabling injury

will occur (although the code does allow an exception if the scientists also serve as subjects), and ongoing research

must be stopped if there is reason to believe that its continuation will lead to the injury, disability, or death of the

subjects.

In applying the ethical principles enunciated in the Nuremberg Code to the issue of neural grafting, the question

of whether there has been sufficient animal research may arise. Fetal grafts in rodents and in monkeys have been

studied, but some experts in the field believe that more animal research is necessary. They also believe that certain

additional information is needed about the nervous system. They argue that eventually, however, human subjects

must be involved.

SOURCES: Office of Technology Assessment, 1990; based on L. Andrews, Medical Genetics: A Legal Frontier (Chicago, IL: American Bar

Foundation, 1987); B. Barber, “The Ethcis of Experimentation with Human Subjects,” Scientific American 234(February): 25-31,

1976; A.M. Capron,"Human Experimentation," BioLaw l0:217-229, 1986; T. Gill and R Lund., “Implantation of Tissue into the

Brain: An Immunologic Perspective, ‘‘ Journal of the American Medical Association 261 :2674-2676, 1989; S. GoIby, “Experiments

at the Willowbrook State School,’ Lancet 1:749, 1971; R. Greenwald, M. Ryan, and J. Mulvihill, Human Subjects Research: A

Handbook for Institutional Review Boards (New York, NY: Plenum Press, 1982); J. Jones, Bad Blood: The Tuskegee Syphilis

Experiment (New York, NY: Free Press, 1981).

statutes. Some States have statutes protecting partic- that list the requisite elements of informed consent.

ular groups of research subjects (e.g., the mentally Some statutes simply prohibit human experimentadisabled), while others have a professional ethics tion that involves any significant risk of physical or

statute that mandates obtaining patients’ consent to psychological harm. Often, the statutes use the terms

experimentation. The provisions range from a sim- “human research” and “human experimentation”

ple statement that individuals have the right to refuse interchangeably. Table 7-1 lists State regulations

to participate in experimental research to statutes covering human subjects in experimentation.
Chapter 7-Legal and Regulatory Issues ● 115

Table 7-l-State Regulations Pertaining to the Protection of Human Subjects in Experimentation

Alaska regulates human experimentation with the mentally ill;

limits experiments to those that pose no hazardous risk.

Arizona requires informed consent before a person may participate in a research project as a human subject. Regulates

human experimentation with the developmentally disabled.

Arkansas regulates human experimentation with the mentally ill;

provides that patients have the right to refuse to participate.

California has a comprehensive statute regulating experimentation involving novel therapy and research on human subjects.

Requires Institutional Review Board (IRB) approval and informed consent for any research involving human subjects;

requirements for informed consent include an explanation of

procedures, possible side-effects, information about alternative

therapy, and subject’s right to withdraw consent at any time

during the experiment. Regulates human experimentation with

the mentally ill; informed consent of the patient or guardian is

required, and the research must be intended to benefit the

mentally ill subject. A grievance mechanism is provided should

the experiment go awry.

Colorado requires informed consent before a person may

anticipate in a research project as a human subject. Regulates

human experimentation with residents of facilities for the

developmentally disabled; informed consent of the patient or

guardian is required.

Connecticut provides that prospective subjects in human experimentation have the right to refuse to participate.

District of Columbia requires informed consent before a person

may participate in a research project as a human subject.

FE

mentally retarded; informed consent of the patient or guardian

and review board approval are required.

Delaware regulates human experimentation with the mentally

disabled; informed consent of the patient and IRB approval are

required. The requirement for informed consent may be waived

in cases where an attempt to obtain informed consent from the

patient has failed, no other therapy exists or the patient has not

responded to accepted therapies, the research would be in the

best interests of the patient, and the waiver has been approved

by the IRB and the patient’s legal guardian or next of kin.

Florida requires informed consent before a person may particiate in a research project as a human subject. Regulates

human experimentation with the developmentally disabled;

informed consent of the patient or guardian is required.

Physician may request court approval when unwilling to act on

developmentally disabled patient’s consent and the guardian is

unknown or cannot be located.

Hawaii regulates human experimentation with the mentally

disabled; states that patients have the right to refuse to

participate.

Illinois regulates human experimentation with the mentally ill and

developmentally disabled; informed consent of the patient or

guardian is required.

Kansas requires informed consent for participation in research

Projects. Regulates human experimentation with mentally ill

inpatients; requires informed consent of the patient and his or

her guardian.

Maine requires informed consent before a person may participate

in a research project as a human subject. Regulates human

experimentation with the mentally retarded; informed consent

of the patient or guardian is required.

Massachusetts provides that prospective subjects in human

experimentation have the right to refuse to participate.

Michigan provides that respective subjects in human experimentation have the rig t to refuse to participate. R

Minnesota requires informed consent for participation in research

projects.

Missouri requires IRB approval for research with the mentally

disabled, informed consent of the patient or guardian, and that

the research be intended to benefit the mentally ill subject. f

Montana requires State review board approval and informed

Nevada provides that prospective subjects in human experimentation have the right to refuse to participate. K

New Hampshire requires IRB approval for any research involving

human subjects.

New Jersey regulates experimentation with the mentally ill and

mentally retarded; provides that mentally disabled patients

have the right to refuse to participate and requires that the

research be intended to benefit the mentally ill subject. Court

approval is mandatory if the disabled patient is declared

incompetent.

New Mexico regulates human experimentation with the developmentally disabled and the mentally ill; requires informed

consent of the patient or guardian.

New York has a comprehensive statute regulating experimentation with novel therapy on humans and research on healthy

human subjects. Requires IRB approval of any research with

human subjects; requirements for informed consent include an

explanation of procedures, possible side-effects, alternative

therapies, and subject’s right to withdraw consent at any time

during the experiment. Ma es specific mention of these rights l

with respect to the mentally ill.

North Carolina regulates human experimentation with the mentally ill, the retarded, and substance abusers; requires informed

consent of the patient or guardian.

North Dakota requires informed consent for participation in

research projects. Regulates human experimentation with the

mentally ill and developmentally disabled; requires informed

consent of the patient or guardian and that research be in the

best interests of the patient. A court order is mandatory for

psychosurgery, sterilization, medical/behavioral research, or

pharmaceutical research on resident of a facility for the

developmentally disabled.

Ohio regulates human experimentation with the mentally ill;

requires informed consent of the patient or guardian. A court

or r equired for unusually hazardous treatment procedures ders

if the patient is legally incompetent or involuntarily committed to

a mental institution.

Oregon requires informed consent for participation in research

projects.

Rho e Island requires informed consent for participation in d

research projects.

South Carolina regulates human experimentation with the

mentally ill and the developmentally disabled; states that

mentally disabled patients have the right to refuse to participate.

South Dakota requires State review board and informed consent

of the patient or guardian before the mentally ill may participate

in research.

Texas provides that prospective subjects in human experimentation have the right to refuse to participate. R

Vermont provides that prospective subjects in human experimentation have the right to refuse to participate.

Vlrginia has a comprehensive statute regulating experimentation

with novel therapy on humans and research on healthy

subjects. Requires IRB approval of any research with human

subjects; requirements for informed consent include an explanation of procedures, possible side-effects, alternative therapies, and subject’s right to withdraw consent at any time during

the experiment. Specifically regulates human experimentation

with the mentally ill; experiments are limited to those that pose

no hazardous risk.

Washington requires informed consent for participation in research projects.

Wisconsin regulates human experimentation with the developmentally disabled, mentally ill, and substance abusers; requires

informed consent of the patient and his or her guardian and IRB

approval.

Wyoming requires informed consent for participation in research

Projects. Regulates human experimentation with the mentally

ill; informed consent of the patient or guardian is required.

consent for research with the mentally disabled.

SOURCE: Office of Technology Assessment, 1990.
116 ● Neural Grafting: Repairing the Brain and Spinal Cord

Only three States have enacted comprehensive

legislation that applies specifically to medical research with human subjects-California, New York,

and Virginia [Cal. Health & Safety Code 24170-

24179.5; N.Y. Public Health Law 2440-2446; Va.

Code 37.1-234-37.1-241]. The statutes of both

California and New York affirm that human experimentation is vital for the benefit of humankind but

require that it be undertaken with due respect for the

rights of individuals to determine what is done with

their bodies. The New York and Virginia statutes

provide that researchers conducting experimentation

in compliance with Federal regulations concerning

protection of human subjects are not subject to the

State requirement. California provides that researchers conducting investigations within institutions

receiving Federal funding and who obtain informed

consent as required by Federal regulations are

exempt from all State requirements except the

provisions requiring that the subject receive a list of

subjects’ rights and a list of any penalties that may

attach for violation. The list of subjects’ rights does

not include information beyond that required in the

Federal regulations. As noted earlier, compliance

with Federal regulations does not render State or

local laws inapplicable [45 CFR 46.10 l(g)]. Therefore, in States that do not make provisions for the

overriding applicability of Federal regulations, researchers must observe both Federal regulations and

any State or local statutes or regulations.

All three of the comprehensive State statutes

appear to regulate experimentation involving novel

therapy on patients as well as research on healthy

subjects. Each defines human experimentation (research). Virginia defines “human research” as any

medical research that departs from established

methods using human subjects who might be exposed to possible injury as a consequence of their

participation. This appears to encompass therapeutic

experimentation. California and New York define

“human experimentation” as experiments that are

not necessary for treatment nor of direct benefit to

the subject. Although these statutes appear to be

aimed primarily at experimentation on healthy

subjects, both include as an element of informed

consent a requirement that the individual receive

information concerning appropriate alternative procedures. As this information would not be relevant

to the subject of purely nontherapeutic experimentaion, it could be argued that these statutes also apply

to therapeutic experimentation.

Although Federal regulations and the statutes of

California, New York, and Virginia specifically

address the elements of informed consent, some

States merely provide that informed consent be

obtained. In all, statutes of 24 jurisdictions contain

provisions requiring some kind of informed consent

before a person may participate in a research project

as a human subject. Of these statutes, 11 apply to

research with the mentally disabled. Eleven of the

informed consent statutes do not specify what

information must be provided. Many States have

general medical consent statutes that would apply to

recipients of neural grafts. Of the remaining statutes,

10 provide only that the prospective subject has a

right to refuse to participate in human experimentation. Four of these statutes apply only to research

with the mentally disabled.

The California human experimentation statute

provides fines and terms of imprisonment for anyone

who violates its requirements. Liability extends to

persons who are primarily responsible for conducting medical experiments and representatives or

employees of pharmaceutical companies who are

directly responsible for contracting with the subjects.

Role of Institutional Review Boards

There has been concern that research proposals be

reviewed in advance by groups uninvolved with the

research project itself. This has led to the formation

of IRBs to assess the ethical ramifications of

proposed research. IRB approval is necessary before

a project can receive Federal funding [45 CFR

46. 103(b)]. Federal regulations and some State laws

provide for advance review of research proposals by

IRBs. This mechanism arose out of concern for

the rights of human subjects who participate in

medical research (5,53) and the fear that relying

on the investigator’s sense of professional responsibility was an insufficient safeguard of the

subject’s rights (45). There is an inherent conflict

between the researcher’s goals in undertaking

the experiment (which may lead to acquisition of

knowledge, enhanced professional status, or commercial gain) and the patient’s rights (53). Because of this conflict, it was thought necessary to

ensure that proposed research is reviewed by an

impartial body. When functioning properly, IRBs

prevent premature experimentation with human

subjects (by monitoring whether appropriate

laboratory and animal research has been con-
Chapter 7--Legal and Regulatory Issues . 117

Photo credit: Gregory Robertson, Howard University

An Institutional Review Board voting on approval of a protocol involving human subjects in research.

ducted to support the scientific design and safety

of the study) and ensure that the subject has given

fully informed consent.

Currently, the Federal Government requires that

any product for which marketing approval is sought

from FDA and all research involving human subjects

that is conducted or funded by DHHS be reviewed

and approved by an IRB [45 CFR 46.101-46.409; 21

CFR 56.107, 56.108]. Similarly, four States—

California, New Hampshire, New York, and Virginia-require IRB review of any research involving

human subjects. Seven States and the District of

Columbia provide for IRB approval of any research

with the mentally disabled.

Federal regulations and New York and Virginia

statutes set forth duties of an IRB, which include

evaluating risks and benefits to the prospective

subject and ensuring that risks are outweighed by

potential benefits to the subject or by the importance

of the knowledge to be gained. An IRB must take the

following factors into consideration in deciding

whether or not to authorize human research:

●

●

●

●

●

●

the adequacy of the researcher’s description of

the potential benefits and risks involved;

the adequacy of the methodology of the research;

whether any nontherapeutic research presents a

hazardous risk to human subjects;

whether risks to human subjects are outweighed by potential benefits to the subjects;

the adequacy of the informed consent form; and

whether the informed consent is to be obtained

by adequate and appropriate methods.

IRBs are also charged with deciding whether the

persons proposing to conduct human research are

qualified and competent, and they must periodically

investigate each project to ensure that it is being

carried out according to the original proposal [N.Y.

Public Health Law 2444; Va. Code 37.1-236].

Figure 7-1 illustrates the procedure for obtaining

IRB approval for projects involving human subjects

at one research institution.

In any IRB review, the fundamental ethical

guidelines for determining whether a therapy
118 ● Neural Grafting: Repairing the Brain and Spinal Cord

Figure 7-l—An Institutional Review Board Approval Process

I 1 I I

Principal Investigator/ Department Chairman,

Project Director + > Dean/Director

I

t 1 A

I

Correspondence Applications for review

reflecting

Board action

Correspondence to IRB

v r I

I v

I

Executive Secretary

and

Support Staff of the IRB

(Assistant Dean for Research,

College of Medicine)

Pharmacy and Therapeutics

4

 — — – — — – — – —+ Committee, Howard University

Hospital

1

\ \ \ \

Agenda, \ \

\

Critiques and minutes, \

Hospital Director

recommendations proposals for \

Howard University Hospital

review \

\

E---”‘

Institutional Review Board --———

‘x Medical Director

Howard University Hospital

These interactions shall occur as the need arises, such as projects involving drugs (PTC); inpatients

. . Howard University Hospital (Hospital and Medical Directors); adverse reaction (Medical Director,

Hospital Director, and Vice President for Health Affairs); annual reports (Vice President for Health

Affairs).

Procedure for obtaining Institutional Review Board approval currently in use at one research institution.

SOURCE: Howard University, Institutional Review Board, Washington, DC.

may be experimentally used on humans is to hold

each person fundamentally entitled to respect as

an individual (70) and to proceed only if there is

a favorable ratio of benefits to risks (l). Specifically, this standard requires a thorough assessment

of the probable outcome (in both its helpful and

harmful aspects), which is weighed against the

results of not using the proposed treatment. For

example, if a patient has a fatal disease and there are

no known mitigating treatments, a therapy previously untested in humans that was not likely to cause

serious or lethal harm to the patient might be

approved for experimental use in the patient.

Only the Federal regulations [45 CFR 46.109; 21

CFR 56.108] and the statutes of Delaware, New

York, Missouri, and Virginia set forth the composition of an IRB. Under Federal law each IRB must

include:

. at least five members with varying

grounds (including racial and cultural

grounds);

. a combination of men and women;

backback-

. a member from a nonscientific discipline, such

as a lawyer or an ethicist; and

. a member who is not otherwise affiliated with

the institution [45 CFR 46.107].

Problems may arise if members of the IRB are

associated with the institution. Such individuals may

not be able to be completely objective because of

their identification with the researcher, their loyalty

to the institution, and the fact that any possible

success may accrue indirectly to associated review

board members (45). One way to avoid this problem

would be to require that the IRB include as members

only individuals who have no connection with the

research institution. Some commentators argue that

this proposal may promote unwarranted public

interference with medical research (45) and that

membership on an IRB could become a political

appointment, which might threaten the academic

freedom of researchers (56). However, it has been

suggested that the possibility of political interference should be outweighed by the necessity for

objective input. The principle underlying IRBs is

that protection of the rights of human research

subjects overrides the absolute freedom of the
Chapter 7&gal and Regulatory Issues . 119

researcher to perform unrestricted experimentation (56).

Requirements for Informed Consent

The doctrine of informed consent is based on

the right of every individual to participate in

decisions about his or her own medical care (17).

Informed consent means the ‘knowing” consent of

a person or, if the person is not competent to consent,

his or her legally authorized representative (24). An

individual cannot consent to be an experimental

subject without understanding what that may entail.

Adequate informed consent requires that the researcher transmit to the prospective subject, in

language the subject can understand, any information that might influence the subject’s decision to

participate or not participate (24).

Potential problems with attempting to convey all

updated information to subjects have been noted

(69). Studies are statistically designed to have

sufficient power to acceptor reject a given hypothesis; however, unplanned interim analyses may be

invalid and may not provide sufficient, reliable

information. Early disclosure of benefits (or lack of

benefits) may be unfair to patients recruited early in

the study. Such patients consent to participate

without any preliminary data. Patients acquired after

the study has been under way may be at a distinct

advantage if they are provided with benefits gleaned

from data (or lack of data) derived from the earlier

patients. However, it would be reasonable to update

the informed consent by providing information

concerning new risks or alternative therapies (69).

Some of the likely recipients of experimental

neural grafts, persons with Alzheimer’s disease, for

example, may have impaired mental functioning,

which may or may not affect their ability to give

informed consent. Thus, it is likely that some

subjects in this field may be incapable of giving

consent for themselves (11,64,65). Various guidelines have been suggested for research on subjects

who are incapable of consenting. There is general

agreement that such individuals should be allowed

to participate in therapeutic research the intent of

which is to provide a health benefit to them. With

respect to nontherapeutic research, some commentators suggest that it should not be undertaken on

people who cannot personally give valid, informed

consent (49). Others suggest that it should be

permissible to undertake important, nontherapeutic

research on incompetent individuals, provided there

is proxy consent and there are minimal or no risks

(32).

Discussion of research in the four decades since

adoption of the Nuremberg Code has highlighted

some additional ethical concerns. The concern that

selection of subjects for research be equitable has

been incorporated into the Federal regulations [45

CFR 46.ill(a)(3)]. For example, a particular class

or race of persons should not serve as subjects for

research that primarily benefits persons of another

class or race. Some commentators suggest that this

should be particularly true in the case of subjects

incapable of consenting (e.g., research on an incompetent, elderly subject should benefit other elderly

people).

The adequacy of consent for experimental

therapy raises more questions than that for

proven treatment because less is known about the

efficacy and risks involved in an experimental

procedure. Although no absolute guarantee exists that an established treatment will be effective

and will cause no harm, even fewer and possibly

no guarantees exist when the proposed therapy is

experimental. Therefore, a prospective subject

must be made aware that little is known about the

possible risks and consequences involved in participation in the experiment (15). As the New York

human experimentation law provides, “Every

human being has the right to be protected against the

possible conduct of medical or psychological research on his body without his voluntary informed

consent” [N.Y. Public Health Law 2440].

Federal regulations and laws in California, New

York, and Virginia provide that the information

given for proper informed consent must include the

following:

●

●

●

●

●

an explanation of the procedures, drugs, or

devices to be used in the experiment;

a description of any possible risks and discomforts that might be expected;

an explanation of possible benefits;

a disclosure of appropriate alternative procedures, drugs, or devices;

an offer to answer questions that the prospective subject may have concerning the experiment and its effect; and
120 ● Neural Grafting: Repairing the Brain and Spinal Cord

Photo credit: Gregory Robertson, Howard University

Clinical investigator counsels patient prior to obtaining

informed consent for her participation in human subjects

research protocol.

. an instruction that the individual’s consent to

participate in the experiment maybe withdrawn

at any time, without prejudice [Cal. Health &

Safety Code 24172; N.Y. Public Health Law

2441; Va. Code 37.10234; 45 CFR 46.116].

There is virtually no disagreement concerning the

requirement of these elements for informed consent.

Federal regulations require, in addition, that informed consent include a statement describing the

extent to which the confidentiality of the subject will

be maintained, the expected duration of the subject’s

participation, and an explanation as to whether any

medical treatments or compensation are available in

the event of injury.

When the subject is also a patient, it is important

that a realistic assessment of the expected results of

the therapy be provided. Patients may tend to

overestimate the benefits they will experience with

an experimental treatment. To counter that tendency,

it may be useful to provide information, when

applicable, about the extent of previous research on

the experimental treatment in animals and humans.

Informed consent must also include a statement of

whether any alternative treatments exist. The subject

should be told if the use of the experimental

treatment will foreclose any of those alternatives. An

example of this would be when the subject’s disease

will have advanced too far after he or she has

received experimental therapy to treat it with traditional therapy (30).

The use of aborted fetal tissue for neural

transplantation raises a unique issue about consent. The recipient should be told the source of the

tissue-that it was from an aborted fetus-since that

information may be material to the recipient’s

decision whether or not to consent to the transplant

(57). Another commentator goes further, stating that

disclosure should be made concerning all animals

used in preclinical studies (10).

There are concerns about what should happen if

the human subject is harmed in the study. According

to Federal regulations and California law, the subject

should be given an explanation of the availability of

medical therapy in case of injury incurred as a result

of the experiment [45 CFR 46.116(a)(6); 21 CFR

50.25(a)(6); Cal. Health & Safety Code 24172(f)]. If

compensation for research injuries is not provided

for, the prospective subject should be so informed.

If a subject has not been specifically informed that

he or she bears the financial cost of potential

physical injury, the informed consent is, arguably,

not complete (53).

Research subjects must also be given an assurance

that they are free to refuse to participate or to

withdraw their consent at any time and to discontinue participation in the project without penalty or

loss of benefits to which they are otherwise entitled

[45 CFR 46.116(a)(8); 21 CFR 50.25(a)(8)]. All

ethical codes stipulate that subjects must be able to

withdraw from an experimental project at any time,

without prejudice or penalty (30). The right to

withdraw is derived from the premise that the

subject is doing something for the benefit of others

and that such acts are generally not obligatory (30).

If researchers do not provide adequate information to a subject before the study is undertaken, they

can be sued for damages if harm results (26). In

addition, physician-researchers who do not obtain

informed consent may be disciplined for unprofessional conduct. In the Jewish Chronic Disease

Hospital case, 22 debilitated patients were injected

with live cancer cells without first having given their

informed consent (45). The Attorney General of

New York brought an action against the principal

investigators to the Board of Regents Discipline

Committee, which found the doctors guilty of fraud,

deceit, and unprofessional conduct. The doctors

were punished, not because they performed

experiments that resulted in harm to the patients,

but because they did not obtain informed consent

before proceeding. California law also provides

penalties for violation of the informed consent

provision, including damages up to $1,000 for
Chapter 7--Legal and Regulatory Issues . 121

negligent failure to obtain informed consent, damages up to $5,000 for willful failure to obtain

informed consent, and damages up to $10,000 and

up to 1 year in jail for willful failure to obtain

informed consent that exposes the subject to substantial physical or psychological risk. Additional

protections are provided regarding drug companies.

A representative or employee of a pharmaceutical

company who knows of substantial physical or

psychological risks of an experiment and does not

disclose them can be imprisoned for up to a year and

freed up to $10,000 [Cal. Health & Safety Code

24176(a)].

Handling of Grievances and Nonrelease

From Liability

The California statute provides a grievance mechanism for patients when an experiment goes awry. It

requires that the subject be given the ‘‘name,

address, and phone number of an impartial thirdparty, not associated with the experiment, to whom

the subject may address complaints about the

experiment” [Cal. Health & Safety Code 24173

(c)(lo)].

Like the Federal regulations [45 CFR 46.116; 21

CFR 50.20], the statutes in California, New York,

and Virginia provide that any attempted or purported

waiver of an individual’s legal rights is void. The

New York and Virginia statutes state that it is

impermissible to release any individual, institution,

or agency and any agents thereof from liability for

negligence [Cal. Health & Safety Code 24176; N.Y.

Public Health Code 2442; Va. Code 37.1-235].

Protections for Particularly Vulnerable Subjects

Some statutes and regulations cover research on

particularly vulnerable groups, for example children

or the mentally disabled. Statutes concerning research on the mentally disabled may be relevant to

experimental neural grafts into subjects with disorders that affect their mental functioning. Federal

regulations provide that IRBs shall add appropriate

additional safeguards if the potential subjects suffer

from acute or severe physical or mental illness [45

CFR 46.ill(b)]. Although the regulations do not

describe what these additional protections might be,

NIH has introduced guidelines covering intramural

research (20). The guidelines include a procedure for

obtaining proxy consent as well as additional

oversight for research that involves more than

minimal risk. The guidelines prohibit research of

more than minimal risk if the patient is incapable of

choosing a proxy decisionmaker and has no next of

kin to seek court-appointed guardianship.

Twenty-five States and the District of Columbia

specifically regulate experimentation on the mentally disabled (see table 7-l). Other States regulate

experimentation on residents of nursing homes [Mo.

Ann. Stat. 198.088(l)(b)(c); Or. Rev. Stat. 441.385].

The abundance of State legislation reflects a general

concern that institutionalized persons are frequently

used as experimental subjects because they are

“administratively convenient” to the researcher

(30) and that they are often taken advantage of,

either because of their mental deficiencies or their

guardians’ lack of interest in their welfare (2). That

State laws tend to pay close attention to the issue of

informed consent for mentally ill patients is due to

concerns not only about voluntariness, but also

about the capacity of these persons to comprehend

information (76).

Of the 25 jurisdictions that provide statutory

guidelines for experimentation on the mentally

disabled, 14 States and the District of Columbia

require that informed consent of the patient or

patient’s guardian be obtained. Kansas and Wisconsin require informed consent of both the mentally

disabled person and the guardian [Kan. Stat. Ann.

59-2929(6); Wise. Stat. Ann. 51.61]. Five States

provide only that mentally disabled patients have the

right to refuse to participate in experimentation

projects.

In some States, the permissibility of research on

mentally disabled individuals turns on both its

purpose and its level of risk. At least two States,

Alaska and Virginia, limit experimentation on the

mentally deficient to that which poses no hazardous

risks. These statutes authorize an administrator to

determine what procedures are both experimental

and risky. Four States, California, Missouri, New

Jersey, and North Dakota, require that the research

be intended to benefit the mentally ill subject. A

similar approach, with more stringent provisions, is

taken by the Delaware statute, which prohibits the

participation in experimental research of mentally ill

persons who are incapable of giving voluntary

consent-except under the following circumstances

[Del. Code Ann. Tit. 16,5172, 5175]:

. an attempt to obtain informed consent from the

patient has failed;
122 ● Neural Grafting: Repairing the Brain and Spinal Cord

no other therapy exists or the patient has not

responded to accepted therapies;

the research would be in the best interests of the

patient; and

the waiver has been approved by the IRB and

the patient’s legal guardian or next of kin.

proposed waiver must then be approved by a

court, which may deny approval for any reason it

deems appropriate.

Other statutes specify a particular review mechanism that must be followed. Six States require prior

review and approval of any research projects by an

IRB, while three jurisdictions require review and

approval by State boards before experiments are

conducted on mentally disabled persons. Florida,

New Jersey, North Dakota, and Ohio require some

sort of judicial determination of the necessity of an

experimental procedure before it maybe used on an

incompetent person. Florida, New Jersey, and North

Dakota require that the patient be physically present

at such a judicial hearing, represented by counsel,

and provided the right and opportunity to confront

and cross-examine witnesses. These three States

also place the burden of proof on the party alleging

the necessity of the treatment.

FDA Regulation of Neural Grafting Materials

Neural grafting presents a number of issues for

would-be recipients. A potential patient might be

concerned about what material is to be grafted into

his or her brain and whether that material is safe and

effective. These issues are likely to come within the

jurisdiction of the FDA. Any description of the

FDA’s role in regulating the safety and efficacy of

neural grafting materials is complicated by the fact

that there are several different types of materials,

each of which raises slightly different questions. In

addition, neural grafting materials (and materials

that could potentially be used for neural grafts)

represent developing technologies that have not yet

been directly addressed by the FDA. A final

complicating factor is the developing nature of FDA

policies for the regulation of biological products that

may be analogous to neural grafting materials and

the resulting lack of published regulations or decisions in this area.

The FDA is responsible for regulating the distribution of drugs and devices under the Federal Food,

Drug, and Cosmetic Act (FFDCA) [21 U.S.C. 321 et

seq.] and has been delegated authority to regulate the

commercial distribution of biologics under the

Public Health Service Act (PHSA) [42 U.S.C. 262].

In addition, the Coordinated Framework for the

Regulation of Biotechnology [49 FR 50856; 50 FR

47174; 51 FR 23302] delegated authority for the

regulation of human drugs, medical devices, and

biologics produced by biotechnology to the FDA. As

described in chapter 4, materials used in neural

grafting are varied and may come from various

sources. Neural grafting ranges from implanting

tissue obtained from the patient’s own body to

implanting genetically engineered cells from a cell

line developed and maintained in a laboratory. The

risks inherent in using each type of material have yet

to be assessed by the FDA, but it is possible to

outline the issues that the agency is likely to

consider, based on its statutory mandate, existing

regulations, and decisions with respect to similar

materials.

Neural grafting materials present challenges at the

cutting edge of developing FDA policy because

these materials are sometimes analogous to tissue

transplants and sometimes to products of genetic

engineering. The principal questions regarding neural grafting materials are:

● Is the FDA likely to regulate the manufacture

and distribution of the product?

● If the answer to the first question is yes, will the

product be regulated as a drug, device, or

biologic?

FDA jurisdiction with respect to drugs, devices,

and biologics is described below. Areas in which the

law is unclear as it may apply to neural grafting

materials are described, and issues in the potential

regulation of specific types of neural grafts are

presented.

FDA Jurisdiction

Drug—The FFDCA defines “drug” in part as

“articles intended for use in the diagnosis, cure,

mitigation, treatment, or prevention of disease in

man. . .’ and ‘articles (other than food) intended to

affect the structure or any function of the body of

man . . . but does not include devices or their components, parts, or accessories” [21 U.S.C. 321(g)

(l)]. The classification of a product is thus based in

part on the use intended by the manufacturer. A

product may not be classified as both a drug and a

device, but it maybe regulated as both a drug and a

biologic. The Supreme Court has sustained the
Chapter 7--Legal and Regulatory Issues ● 123

Photo crsdit: Food and Drug Administration

FDA’s authority to interpret the FFDCA’S definitions broadly, in view of the broad public health

objectives of the legislation (60).

Device—The term “device” is defined in the

FFDCA as “an instrument, apparatus, implement,

machine, contrivance, implant, in vitro reagent, or

other similar or related article. . . which is . . . intended for use in the diagnosis of disease or other

conditions, or in the cure, mitigation, treatment, or

prevention of disease” or which is “intended to

affect the structure or any function of the body” and

“which does not achieve any of its principal

intended purposes through chemical actions within

or on the body” and “which is not dependent on

being metabolized for the achievement of any of its

principal intended purposes” [21 U.S.C. 321(h)].

The items listed as devices in the statute imply

that Congress intended the term to refer to manmade products. Aside from implants and in vitro

reagents, the items in the list are synthetic products

that are generally made of materials such as metal or

plastic. The legislative intent underlying the definition of device is probably limited to artificial

implants (66). Some products that may otherwise fit

the definition of drugs or biologics are regulated as

devices because they are considered accessories to

or components of a device. A product may be

classified as both a biologic and a device.

Biologic—The law that authorizes Federal

regulation of biological products for human use was

enacted in 1902 and was revised in 1944 as part of

the recodification of the PHSA, (now codified at 42

U.S.C. 262) (39). The PHSA establishes requirements for ‘‘any virus, therapeutic serum, toxin,

32-801 0 - 90 - 5 : QL 3

antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product . . . applicable to the prevention, treatment, or

cure of diseases or injuries of man” [42 U.S.C. 262].

At present, the scope of the term “analogous

product” is unclear. It has not been extensively

reviewed by the courts (71), nor did Congress clarify

the term in 1970, when, in response to conflicting

positions by the courts on whether blood was an

analogous product, it amended the PHSA to specifically include blood, blood components or derivatives, and allergenic products [Public Law 91-515].

It is therefore unclear whether courts would

uphold FDA regulation of neural grafting materials under the PHSA without the enactment of

specific language to add such materials to the

statute.

The initial question, then, in determiningg whether

the FDA has jurisdiction to regulate neural grafting

materials is whether a particular material meets the

definition of a drug, device, or biologic. All biologics are considered either drugs or devices as well

as biologics (71). However, an article proposed for

use as a neural graft cannot simultaneously be both

a drug and a device. The question of how to

categorize neural grafting materials will be considered further later in this chapter.

FDA Regulation of Safety and Efficacy

The FDA regulates product safety and efficacy

in a number of ways. Under the FFDCA, a drug or

device is deemed to be adulterated if it consists of a

filthy substance or if it has been prepared under

unsanitary conditions such that it may have been

contaminated with filth or rendered injurious to

health. Drugs and devices are considered adulterated

if the methods used in manufacturing, storing, or

packing them do not conform to current good

manufacturing practice or if the container is made of

a substance that may render the contents injurious to

health. Drugs are also adulterated if their strength,

purity, or quality is less than is represented [21

U.S.C. 351].

A drug or device is misbranded [21 U.S.C. 352] if

its labeling is false or misleading or if adequate

directions for use or adequate warnings against

unsafe use are omitted from the label. Any drug or

device is misbranded if it is dangerous to health

when used in the dosage or manner or with the

frequency or duration described in the labeling.
124 . Neural Grafting: Repairing the Brain and Spinal Cord

Owners or operators of establishments for the

manufacture, preparation, propagation, compounding, or processing of drugs or devices must register

all places of business with the FDA [21 U.S.C. 360]

in order to facilitate inspection and enforcement of

FDA regulations. Several types of operations are

exempted from the registration requirement. These

include pharmacies dispensing prescription drugs or

devices on prescriptions of licensed practitioners

prescribing for patients in the course of professional

practice [21 U.S.C. 360(g)(l)], practitioners licensed by law to administer drugs or devices and

who manufacture these items solely for use in their

professional practices [21 U.S.C. 360 (g)(2)], and

persons who make the products solely for use in

research, teaching, or chemical analysis and not for

sale [21 U.S.C. 360 (g)(3)].

Premarket approval of a new drug application

(NDA) is required for new drugs [21 U.S.C. 355]. A

“new drug” is one that is not generally recognized

by qualified experts as safe and effective for use

under the conditions prescribed in the labeling [21

U.S.C. 321(p)(l)]. An application for premarket

approval (PMA) is required for some devices [21

U.S.C. 360(e)], but all manufacturers of devices are

required to at least notify the FDA 90 days before

introducing a device into the market [21 U.S.C. 360

(k)].

An exemption from premarket approval may be

obtained for shipment of products intended solely

for investigational use by filing an investigational

new product application. This submission is either

an investigational new drug application (IND) [21

U.S.C. 355(i); 21 CFR Part 312)] or an investigational device exemption [21 U.S.C. 360(j)(g); 21

CFR Part 812]. The FDA reviews the submission to

protect the safety of investigational subjects and to

ensure that the research design is adequate for the

purpose of testing safety and effectiveness in the

event that an NDA or PMA is filed. The study must

be approved by an IRB in each institution or area in

which the drug or device will be tested.

The FDA requires manufacturers of approved

drugs and devices to make prompt reports of adverse

events and periodic reports on safety and effectiveness [21 CFR 314.80, 314.81, and part 803] after the

products have been distributed for use.

Biologics are subject to all of the FFDCA

requirements listed above except the premarket

approvals. Instead of an NDA or PMA, both

biologics and the establishments that produce them

must be licensed (product and establishment licenses are required prior to marketing). In addition,

biologics are regulated for false labeling under the

PHSA [42 U.S.C. 262(b)].

The FDA can enforce its requirements in a variety

of ways. Administrative mechanisms include

inspections to monitor compliance, revocation of

approved marketing applications (NDA, PMA, or

product licenses), and recalls. Judicial actions that

may be sought by the FDA include seizures of

adulterated, misbranded, or unapproved drugs or

devices (including biologic), injunctions against

shipping, and criminal prosecutions (71).

Possible Limits on the FDA’s

Regulatory Authority

Two legal concepts, interstate commerce and

the practice of medicine, may limit the FDA’s

jurisdiction over some types of neural grafting

materials. Arguments on both sides of each concept

are summarized here, although the courts have

generally allowed the FDA broad authority to carry

out its statutory mandates. The success of the

arguments outlined below will depend, however, on

the facts and circumstances of the cases in which

they may arise.

Interstate Commerce-One argument against

Federal regulation is that if the material is produced

and distributed within a State, the interstate nexus

required for Federal regulation does not exist. For

example, cells obtained from one patient that are

cultured and then grafted into the brain of another

patient within the same hospital do not appear to be

involved in interstate commerce.

The FDA has successfully mounted several arguments that enabled it to regulate products that were

not shipped interstate. First, some of the statutory

requirements for drugs, devices, and biologics do not

require the showing of an explicit interstate nexus.

Examples of these are registration of producers of

drugs and devices [21 U.S.C. 360] and regulation of

false labeling of biologics [42 U.S.C. 262(b)] (61).

In addition, the Medical Device Amendments of

1976 [Public Law 94-295] authorize seizure of

misbranded or adulterated devices without proof of

interstate commerce (39).

A second argument used successfully by the FDA

has been that if a component of the drug travels in

interstate commerce, the interstate nexus has been
Chapter 7--Legal and Regulatory Issues ● 125

satisfied. An analogous argument could be made

about the solutions in which tissues are preserved or

the petri dishes or media in which cells are cultured.

Finally, section 361 of the PHSA [42 U.S.C. 264]

authorizes the Surgeon General, with the approval of

the secretary of DHHS, to make and enforce

regulations to prevent the transmission or spread of

communicable diseases. This authority has been

delegated to the Commissioner of the FDA for

fictions related to FDA-regulated products [21

CFR 5.10 (a)(4)]. The power of the FDA to ban the

intrastate sale of small turtles in order to prevent the

interstate spread of Salmonella was upheld pursuant

to this provision in State of Louisiana v. Mathews

(58). The FDA also relied on section 361 as a

primary source of statutory authority to regulate

blood in intrastate commerce in order to prevent the

spread of syphilis, hepatitis B, and HIV (71).

Practice of Medicine--Traditionally, the FDA

has not interfered with the practice of medicine. The

FDA does not regulate the use by physicians of

approved drugs for unapproved purposes (62,72),

and physicians practicing medicine are specifically

exempted from the registration requirement imposed

by the FFDCA [21 U.S.C. 360(g)(l)(2)]. The new

technologies involved in neural grafting present

difficult questions of what constitutes the practice

of medicine, whether there are circumstances

under which the FDA would decide to regulate

what might be called the practice of medicine,

and the circumstances, if any, under which FDA

jurisdiction to do so would be upheld.

The traditional exemptions serve several purposes. Approved drugs are presumably safe when

reasonable doses are prescribed and contraindications are observed. In fact, the freedom of physicians

to prescribe as they see fit can lead to the discovery

of important new uses for existing products. The

U.S. District Court in United States v. Evers,

concerned about regulation of the intrastate practice

of medicine, stated that restricting the medical

profession (here a licensed physician) from using a

drug for a purpose not contraindicated on the label

would exceed the powers of Congress (62). The

court opined that malpractice claims provide appropriate protection for the patient. Another reason for

the traditional exemption of the practice of medicine

might be the difficulty of trying to regulate the

practices of individuals relative to the ease of

regulating manufacturers, who are likely to be

shipping large quantities of products in interstate

commerce. Finally, the fact that the practice of

medicine usually overlaps the issue of intrastate

commerce (because physicians have generally practiced on patients within their States) may have

influenced the position of the FDA with respect to

individual practitioners.

Neural grafting materials and other tissues or

products of biotechnology raise new questions

about FDA regulation and the boundaries of the

practice of medicine. What is the boundary

between product and process? For example,

should the safety and efficacy of neural grafting

be seen as a function of the quality of the grafting

material, the storage of the material (e.g., tissue

banking), or the grafting process? Is the grafting

process the practice of medicine? If so, will the

FDA regulate the process?

In practice, the decision to regulate will probably

depend on the perceived dangers of the product. For

example, concern about HIV infection through

blood products led to an innovative process for the

regulation of blood banks. At the Federal level,

blood is regulated as a service rather than a product.

This has the effect of decreasing the liability of

blood banks and hospitals from strict liability for a

dangerous material to malpractice liability for negligence. Some persons believe that tissue banks

should be similarly regulated.

Genetically engineered materials present the option of customized biologics, or therapeutics tailored

to each individual patient (34). This is a very

different situation from that of traditional biologics,

such as vaccines, which were produced in large

quantities and distributed to large portions of the

healthy population in order to prevent disease. Cells,

for example, might be genetically engineered in a

laboratory at the same hospital where they will be

grafted into the patient. Is this the practice of

medicine? The label “practice of medicine” does

not necessarily preclude FDA regulation. Rather, it

indicates a gray area in which the FDA may find

enforcement difficult and physicians may protest

regulation. Products of biotechnology such as genetically engineered cells present safety hazards unlike

those of traditional drugs or biologics. Manufacturing problems include difficulty in product characterization and potency, nonreproducible products,

difficulty with product stability, and the presence of

adventitious agents and contaminants (intrinsic and
126 . Neural Grafting: Repairing the Brain and Spinal Cord

acquired). Scientific problems include the absence

of feasible animal models for preclinical testing for

safety, efficacy, or both (38).

The problems outlined above present both a

reason for the FDA to be concerned about the

safety of neural grafting materials derived from

biotechnology and a challenge to its present

regulatory scheme. The development of these

products and their use by physicians may present a

challenge to the traditional exemption of the practice

of medicine from FDA regulation.

Regulation of Neural Grafting Materials

The principal questions with respect to FDA

regulation of materials used in neural grafting are:

● Will FDA regulate the material?

. If so, how will the material be categorized

(drug, device, or biologic)?

The decision as to whether the FDA will

regulate neural grafting materials depends

largely on whether the FDA determines that the

product fits within the statutory definition of

drug, device, or biologic. Another consideration is

whether the FDA has reason to be concerned about

the safety of the material. Finally, the question of

whether or not the product is intended for commercial distribution may be relevant. The terms of the

PHSA are “sale, barter or exchange” [42 U.S.C.

262], which may allow for regulation even where

commerce is not involved. As described earlier, the

Commissioner of the FDA is empowered to promulgate regulations to prevent the transmission or

spread of communicable diseases, without regard to

interstate commerce [21 U.S.C. 264].

The second question is how neural grafting

materials will be categorized. At present, there are

no published regulations to help answer this question. The FDA has issued “Points to Consider” for

manufacturers of exvivo-activated mononuclear leukocytes and for cell lines used to produce biologics.

Points to Consider do not have the force of law, nor

do they represent formal FDA policy, but they do

indicate the current thinkin“ g of scientists at the FDA.

Points to Consider for somatic cell therapy are likely

to be relevant to neural grafting materials, but they

have not yet been approved for distribution by the

FDA. Tissue products and products of biotechnology are regulated on a case-by-case basis in order

to allow flexibility with respect to new technologies.

Decisions about whether a given product is a drug,

device, or biologic and which administrative center

at the FDA will regulate it depend on the intended

use of the product, who in the agency has the

requisite expertise, and what analogous products are

regulated in each center. This means that the

situation will change as similar materials are regulated, making it impossible to predict with confidence how neural grafting materials will be regulated by the time they are actually considered by the

FDA. As more tissue and biotechnology products

are developed and regulated by the FDA, however,

the agency could develop consistent regulations, as

it did for blood products. As mentioned earlier, it is

unclear whether a court would find neural grafting

materials ‘analogous’ to blood products and therefore subject to regulation under the PHSA without

the enactment of more specific statutory language.

There are many different types and sources of

neural grafting materials (see ch. 4). The following

classification scheme will be used here to describe

the issues the FDA is likely to consider in deciding

whether and how to regulate these materials:

●

●

●

●

autografts of tissue,

allografts of tissue or cultured cells,

autografts of genetically engineered cells, and

genetically engineered cells distributed to patients.

The discussion which follows is subject to the

caveat that there are no formal regulations specifically describing the role of the FDA with respect to

these materials. Considerations that are salient today

could become less important by the time the FDA is

actually confronted with the need to regulate neural

grafting materials.

Autografts of Tissue—This refers to tissue obtained from the patient’s own body (e.g., the adrenal

medulla) and grafted into his or her brain. This

material is least likely to be regulated by the FDA

because there is minimal manipulation of the tissue,

there is no increased risk of transmission of communicable disease, and the procedure is within the

traditional practice of medicine. The FDA does not,

for example, currently regulate bone marrow autografts.

Allografts of Tissue or Cultured Cells—The

source of this same-species graft material could be,

for example, fetal tissue or cells from another

person. This category is a gray area in which it is
Chapter 7-Legal and Regulatory Issues ● 127

unclear what the FDA will decide. The FDA is

likely to want to regulate for safety purposes (e.g., to

prevent the spread of communicable diseases such as

HIV infection). The considerations here could be

analogous to those surrounding blood banks, leading

to regulation of tissue banking and distribution.

The FDA has recently decided to regulate implants of dura mater, the tough, outer membrane

covering the brain and spinal cord, because of

concern about the possible transfer of CreutzfeldtJacob disease or human retroviruses. Dura mater is

regulated as a device because it does not achieve any

of its principal intended purposes through chemical

actions within or on the body or through metabolism.

To the extent that tissue grafts for mitigation of

Parkinson’s disease are intended to act by releasing

dopamine, they are more likely to be regulated as

drugs than as devices. Tissue grafts used to patch

injured neural systems may be more analogous to

dura mater and therefore regulated as devices.

Similarly, certain cell lines that are cultured in vitro

and used for skin transplantation and in wound and

burn therapy are regulated as medical devices (74).

This suggests that cell lines used as neural grafting

material for the purpose of mechanically bridging

the traumatized or injured central nervous system

could be regulated as devices. It is most likely,

however, that such cell lines would be considered

biologics, because the neural bridging function is

dependent on the biological activity of the cells (75).

Cells that are cultured, modified, or otherwise

expanded in vitro are regarded by the FDA as

biological drugs and are believed to be subject to

regulation under the PHSA (74). The regulatory

status of in vitro-cultured cells that are not shipped

in interstate commerce is not clear, but in most

instances such cells are administered with investigational biologics, necessitating an IND application

(74). If an investigator were to produce cells without

additional investigational agents, the role of the

FDA in regulating the therapy under the IND

regulations would be less clear (73).

Autografts of Genetically Engineered Cells—

Cells that are prepared by a patient’s personal

physician for infusion back into the same patient

may be considered “practice of medicine” and

therefore may not be subject to FDA regulation (74).

However, safety issues arise in therapies that make

use of genetically engineered cells because of the

unknown effects of the foreign genetic material on

the patient and persons in contact with the patient

(74). In addition, cells may synthesize a drug or

biologic. The FDA might therefore choose to assert

jurisdiction despite the practice of medicine issue. A

clinical trial begun under an IND at NIH recently set

a precedent for FDA regulation of an autograft of

genetically engineered cells. The FDA is concerned

that when using a virus there is a small chance of

recombination with a virus already existing in the

body (25).

Genetically Engineered Cells Distributed to

Patients-This category includes cells from animals

or humans other than the patient which are engineered and then grafted into the patient. Given the

safety considerations and the precedent established for autologous grafts of engineered cells

described above, it is likely that the FDA would

seek to regulate engineered cells in wider distribution.

Regulation of New Surgical Procedures

The previous section described briefly the complex regulatory scheme developed by Congress and

the FDA as it might apply to neural grafting

materials. That intricate system of regulation to

ensure the safety and efficacy of articles intended for

use in the diagnosis, treatment, or prevention of

disease in humans contrasts sharply with the absence

of any direct Federal regulation of new surgical

procedures developed for the same purposes.1

Whether considering biomedical articles or procedures, the problem is whereto draw the line between

safety and efficacy, on the one hand, and encouragement of biomedical innovation, on the other.

This section describes the implications of the

absence of direct Federal oversight for the development of neural grafting procedures. Indirect mechanisms for regulating new surgical procedures are

outlined, and a mechanism for potential Federal

involvement in the assessment of safety and efficacy

of new surgical procedures is described. The intent

is to describe the current situation and ways in which

it could be modified, if that is deemed desirable.

While Congress and the FDA have recognized

the need for careful consideration before moving

from animal studies to controlled clinical trials

l~s swtion is con~rned with new surgical procedures that are not part of federally funded research.
128 ● Neural Grafting: Repairing the Brain and Spinal Cord

involving gradually increasing numbers of patients for assessment of new products, there is no

analogous regulation of the move from animal

studies to human trials for surgical procedures.

An IRB will only approve protocols that demonstrate some hope of benefit to the subject and the

absence of long-term negative effects, but there are

no specific criteria for moving from animal

studies to human research.

Of the neural grafting procedures, only techniques

meant to alleviate the symptoms of Parkinson’s

disease have progressed to human trials. Grafts of

tissue from a patient’s adrenal medulla have been

performed for Parkinson’s disease patients in Sweden, Mexico, China, Canada, England, Spain, Portugal, Cuba, Colombia, Chile, and the United States.

Implants of human fetal tissue have been per-formed

in Sweden, Mexico, England, Spain, Cuba, China,

and the United States (18). A few studies have been

done privately in the United States despite the ban on

federally funded transplantation research that uses

fetal tissue obtained from induced abortions. Although these trials are already under way, debate

continues as to whether the results of animal studies

justify them. Some believe that animal research has

already produced sufficient information to justify

limited human trials. In the words of one scientist,

‘‘animal research is the key to initial understanding

and refining techniques, but never solves all the

problems” (4).

Persons who question the wisdom of advancing to

human neural grafting trials at this stage of research

question whether the animal (and the few human)

trials that have been done provide evidence of the

absence of long-term adverse immunological effects

or the presence of beneficial effects. Others argue

against progressing with human trials on the grounds

that no one has been able to identify the etiology of

Parkinson’s disease and it is therefore not known

whether the same disease processes that caused the

initial neuron degeneration could also produce

degeneration of grafted neurons (23). A neurologist

who has used the procedure and identified adverse

side-effects stated: ‘‘This is an area in which we’ve

done too much too fast” (40). A neurobiologist

advised even greater caution: “I’m not convinced

the procedure is ready for humans. . . if we move

ahead too soon, the results can be overinterpreted”

(40).

While well-controlled human research using

methods such as randomized clinical trials is essential to the development of new drugs, the feasibility

and utility of such methods for evaluating the

efficacy of new surgical procedures is controversial.

Some surgeons argue that surgical procedures differ

from drugs in ways that render the results of

randomized clinical trials of surgical procedures

useless, if not harmful, to the development of

surgical treatments (8, 9, 68). The outcomes of

surgical procedures, according to this view, are so

dependent on the skill and experience of the

individual surgeon and the circumstances of the

individual patient that research which generalizes

across patients and physicians will be meaningless.

Other physicians and surgeons believe that controlled clinical trials are important for determining

whether an innovative surgical therapy is of value (6,

31) and when an accepted surgical procedure of

unproved value should be discontinued (21).

The absence of well-controlled clinical studies

and of standards for deciding when to move from

animal to clinical studies may lead to several

problems. First, physician-investigators may be

encouraged to take large risks in order to be among

the first to perform new surgical procedures. This

encouragement takes the form of publicity, funding,

and professional attention for bold new efforts to

save lives. While the surgeon may risk his or her

professional reputation, the greater risks are to the

patient, who may not be able to give truly informed

consent because of the combination of chronic or

terminal illness and lack of information about

benefits and risks of the new surgical procedure. The

physician and patient may believe that any procedure is better than certain death or prolonged, severe

disability, even if the benefits and risks of the

procedure are unknown. This logic was used to

justify liver transplantation in 1983, before there

were adequate data supporting its efficacy (51). In

the absence of well-controlled clinical trials, procedures may be widely accepted clinically even if they

are not actually effective.

A study of the introduction of four new surgical

procedures found that, with the exception of one

procedure which was evaluated through the FDA

drug approval process, the procedures were introduced without controlled clinical trials or welldesigned observational studies (12). This means that

the procedures which were performed did not

contribute to an overall evaluation of their efficacy
Chapter 7&gal and Regulatory Issues ● 129

and that future patients will not have adequate

information on which to base their decisions about

treatment. In addition, when effectiveness is still in

question, tension is likely to develop about the

extremely high costs of some new surgical procedures (51).

A three-stage procedure for the evaluation of new

surgical procedures has been suggested (12). First,

the physician-investigator should develop the new

procedure and define diagnostic criteria to evaluate

it. The second stage would be collaborative clinical

trials in which formal research protocols are followed and quantitative evidence is collected and

analyzed according to predetermined statistical criteria. Finally, after efficacy is established, the

procedure could be released for more general use.

Indirect Regulation of New Surgical Procedures

New surgical procedures are regulated indirectly by third-party payers, which decide

whether or not to reimburse for them. The number

of patients who undergo a procedure is determined

in part by the extent to which coverage is provided

by insurers. Federal insurers of medical care include

the Health Care Financing Administration, Department of Veterans Affairs, and the Department of

Defense. Safety and efficacy determinations are

sometimes part of the process by which insurers

decide whether a surgical procedure is experimental

or accepted treatment and, ultimately, whether they

will cover the procedure. Discussion of the means by

which each Federal and private insurer assesses

safety and efficacy in the course of deciding the

status and coverage of procedures is beyond the

scope of this report. The very different processes by

which decisions were made about the status of liver,

kidney, and heart transplantation have been described (51).

Other forms of indirect regulation of surgical

practice include hospital standards set by the Joint

Commission on Accreditation of Healthcare Organizations, professional standards of practice from

specialty societies, State licensing laws, and medical

malpractice claims. IRBs exert the most direct

control over research on new surgical procedures.

While research protocols are often submitted to

local IRBs, there is no Federal requirement that

this be done unless the research receives Federal

funding or takes place as part of an FDA

application. In addition, IRBs will have difficulty

evaluating a protocol in the absence of risk-benefit

information.

Potential Federal Role

Concern about rising health-care costs and the

safety and efficacy of new medical procedures has

led to increasing congressional interest in the

evaluation of such procedures. While direct regulation of the practice of medicine may strain the

regulatory authority of the FDA, the Federal

Government could play a role in the evaluation of

new procedures and could promulgate standards

of practice for purposes of consumer information

and decisionmaking by physicians and thirdparty payers.

Neural grafting may eventually be considered as

a treatment for some debilitating neurological disorders that affect large numbers of vulnerable patients

with chronic or terminal illnesses. It is essential,

therefore, that the clinical development and use of

the procedures be based on well-controlled research

on safety and efficacy rather than on desperate hopes

of cures for these patients. The methods of assessing

the safety and efficacy of liver transplants prior to

1984 (51) are a model of what to avoid in assessing

new surgical procedures.

The newly created Agency for Health Care Policy

and Research [Budget Reconciliation Act of 1989,

Public Law 101-239, sec. 6103] is charged with

promoting research on selected surgical procedures

in order to assess their appropriateness, necessity,

and effectiveness. This agency could be charged

with assessing the development of clinical neural

grafting procedures, still in their infancy, to ensure

that the use of these procedures develops in accordance with data from well-controlled studies, rather

than in response to factors external to the actual

efficacy of the procedures.

PROTECTION OF DONORS OF

FETAL TISSUE

Since embryos and fetuses are among the proposed sources of tissue for neural grafts (23), Federal

regulations and State laws governing embryo and

fetal research may apply. Some of these laws appear

to be sufficiently restrictive to forbid experimental

transplants using fetal tissue in certain States.

However, if neural grafting becomes standard medical therapy, current embryo and fetal research laws

would no longer prohibit the procedure. In legal
130 ● Neural Grafting: Repairing the Brain and Spinal Cord

contexts, the term ‘‘embryo’ has been used to refer

to the conceptus from fertilization until the end of

the eighth week, and the term ‘fetus” has been used

to refer to the conceptus in all stages of development.

The use of fetuses as a source of tissue for

neural grafts raises complicated issues. In most

instances, the tissue will come from fetal cadavers,

although the tissue itself may still be living. Abortuses of between 8 and 12 weeks’ gestation are

presently considered appropriate sources of tissue

for grafting. However, there may also be instances in

which physicians intend to remove tissue from live,

nonviable fetuses (fetuses incapable of surviving

outside the womb). Moreover, some experimental

interventions might involve the pregnant woman

and her living, in utero fetus; for example, a woman

might be asked to undergo an alternative abortion

procedure in order to better preserve fetal tissue or

to postpone the abortion until the fetus is more

developed (36). Different laws will apply, depending on whether the fetus is dead, alive ex utero, or

alive in utero and depending on whether the experiment presents risks to the pregnant woman as well.

Photo credit: National Institutes of 

Further issues are raised regarding maternal

consent. These center on whether a pregnant woman

should have the right to prohibit or authorize the use

of her fetus for experimentation. Some laws address

this issue, as well as the role of the father in the

consent process. An additional issue addressed by

fetal research laws is whether women should be

allowed to receive payment for fetal tissue. Some

laws banning compensation would extend to payment of third-party intermediaries as well.

Development of Federal Policy on

Fetal Research

Federal activity with respect to the issue of fetal

research has been extensive. In 1974 Congress

passed the National Research Act [Public Law

93-348]. This legislation established the National

Commission for the Protection of Human Subjects

of Biomedical and Behavioral Research, whose first

charge was to investigate the scientific, legal, and

ethical aspects of fetal research. The statute prohibited all federally funded nontherapeutic research on

fetuses prior or subsequent to an abortion until the
Chapter 7--Legal and Regulatory Issues . 131

Commission made its recommendations and regulations were adopted. In 1975 the Commission made

its recommendations (46), and in 1976 the Department of Health, Education, and Welfare (now the

Department of Health and Human Services) adopted

regulations for the Federal funding of fetal research

[45 CFR 46.201-211]. Under these regulations,

which for the most part comport with the recommendations of the Commission, certain types of fetal

research are allowed, with constraints based on

obtaining parental consent and minimizing risk to

the pregnant woman and the fetus.

In 1985, Congress again acted on the issue of fetal

research. It passed a law forbidding Federal conduct

or finding of research on viable ex utero fetuses [42

U.S.C. 289]; however, there is an exception for

therapeutic research and for research that ‘will pose

no added risk of suffering, injury, or death to the

fetus and the purpose of which is the development of

important biomedical knowledge which cannot be

obtained by other means” [42 U.S.C. 289g(a)]. It

also provides that, for research on living fetuses in

utero, Federal regulations must require the standard

of risk to be the same for fetuses that will be aborted

as for fetuses that will be carried to term. Simultaneously, Congress passed legislation creating a Biomedical Ethics Board, composed of six members of

the Senate and six members of the House of

Representatives, with an outside advisory committee [42 U.S.C. 275]. Fetal research was the first order

of business for the group. Under existing Federal

regulations, the Secretary of DHHS may authorize

research that does not comply with the regulations in

instances of great need and great potential benefit

[45 CFR 46.211]. A recent statute, however, suspends that authority until the Biomedical Ethics

Advisory Committee (BEAC) conducts a study of

the “nature, advisability, and biomedical and ethical

implications of exercising any waiver of the risk

provisions of the existing Federal regulations on

fetal research” [42 U.S.C. 289g(c)]. As of autumn

1989, the activities of the BEAC had been suspended, and it seems that no report on fetal research

will be undertaken.

Federal attention again turned to the issue of fetal

tissue transplantation research in 1988. The Director

of NIH requested permission to fund projects using

fetal tissue for transplantation. On March 22, 1988,

the Assistant Secretary for Health denied the request

on the grounds that the use of fetal grafts raised

ethical and legal issues that should be addressed by

an advisory panel and imposed a moratorium on

Federal funding of human fetal tissue transplantation research using tissue from induced abortions.

Such an advisory panel was convened and subsequently published its recommendations in the Report of the Human Fetal Tissue Transplantation

Research Panel (67). The panel recommended

lifting the moratorium and emphasized that commercialization should be prohibited and that the

abortion procedure should be separated from the

procedure using fetal tissue. (See app. A for a

discussion of the DHHS moratorium on fetal tissue

transplantation research.)

Federal Regulations Governing

Fetal Research

Federal regulations define the term “fetus” as a

conceptus after implantation. They defer to State and

local laws on the subject of research with fetal

cadavers [45 CFR 46.210]; however, there is some

dispute about whether another section of the statute,

which does not specifically apply to dead fetuses,

should be read to apply in the context of research (3).

That section provides that “[n]o inducements,

monetary or otherwise, may be offered to terminate

pregnancy for purposes of the [research] activity”

[45 CFR 46.206(b)]. Even if this section on inducements were read into the Federal law about research

on fetal cadavers, it would not necessarily preclude

experimentation involving neural grafts from abortuses. Although some commentators have alleged

that the possibility of donating fetal tissue for

experimental transplantation might lead women to

undergo abortion (3) and thus is an inducement,

others have suggested that there is little evidence

that women would do so if there were prohibitions

on payment for fetal tissue and on donation of tissue

to a relative (54). These persons have noted that

informing women who are ambivalent concerning

abortion about the chance to donate tissue would not

be an inducement unless it were specifically aimed

at convincing the woman to abort, particularly if no

valuable consideration is offered (54). Moreover,

there is support for the position that the term

“inducement” means valuable consideration and

that the possibility of participating in research,

without compensation, would not be considered

valuable consideration (54).

With respect to research on live fetuses, Federal

regulations provide that appropriate studies must be

done on animal fetuses before human studies are
132 ● Neural Grafting: Repairing the Brain and Spinal Cord

carried out [45 CFR 46.206(a)(2)]. When research

involving live human fetuses is undertaken, the

consent of the pregnant woman and prospective

father are required (unless the prospective father’s

identity or whereabouts are not reasonably ascertainable, he is not reasonably available, or the pregnancy

resulted from rape) [45 CFR 46.208(b), 46.209(d)].

Some persons criticize the requirement that the

prospective father’s consent be obtained (54). To

protect the pregnant woman and the fetus, the

research must not alter a pregnancy termination

procedure in a way that would cause greater than

minimal risk to either [45 CFR 46.206(a)(3) (4)].

To protect the fetus, the researchers must not have

a role in either the determination of what procedure

is used to terminate the pregnancy or the assessment

of whether the fetus is viable [45 CFR 46.206(a)(3)].

In utero fetal research may be undertaken if the

research is designed to be therapeutic to the particular fetus and places the fetus at the minimum risk

necessary to meet its health needs [45 CFR

46.208(a)(l)]. It may also be undertaken if the

research imposes minimal risks and ‘the purpose of

the activity is the development of important knowledge which cannot be obtained by other means” [45

CFR 46.208(a)(2)].

Where it is unclear whether an ex utero fetus is

viable, that fetus may not be the subject of research

unless the purpose of the research is to enhance its

chances of survival or the research subjects the fetus

to no additional risk and its purpose is to develop

important, otherwise unobtainable biomedical

knowledge. Research on a living, nonviable, ex

utero fetus may be undertaken if the vital functions

of the fetus will not be artificially maintained,

experimental activities terminating the heartbeat or

respiration will not be employed, and the purpose of

the research is the development of important,

otherwise unobtainable biomedical knowledge [45

CFR 46.209(b)].

State Laws Governing Embryonic and

Fetal Research

The overwhelming majority of State legislatures

have yet to address the issues associated with

experimental neural grafting using fetal tissue. Only

Missouri and Pennsylvania have enacted legislation

directed specifically at fetal tissue transplants. The

Missouri law makes it a crime for any physician to

perform an abortion knowing that the woman is

seeking it for the purpose of donating the fetal tissue

for implantation, or for anyone to offer consideration

for the conception of a fetus which will be aborted

and used for transplantation. In Pennsylvania no

fetal tissue or organs maybe obtained for transplant

purposes without the written consent of the pregnant

woman. No payment of any kind maybe offered, and

consent is valid only if obtained after the decision to

abort has been made. All persons who participate in

the procurement, use, or transplantation of fetal

tissue or organs, including the recipients, must be

informed of the source of the tissue or organs (e.g.,

stillbirth, miscarriage, ectopic pregnancy, abortion,

or other means). The person giving consent to the

procurement or use of fetal tissue or organs may not

designate the recipient. Violation of these provisions

may result in civil penalties.

A proposed law in California takes a similar

approach (59). While allowing the donation of a

fetus for “medical research or therapeutic application,” this law incorporates many guidelines first

suggested in 1987 in a forum on fetal tissue

transplants convened by Case Western Reserve

University School of Medicine (35) and suggested

by the Human Fetal Tissue Transplantation Research Panel in its report (67). The proposed law

prohibits consideration as an inducement to undergo

an abortion for the purpose of donating the tissue, the

naming of a specific recipient, and doctors “participating in the procedures resulting in the loss of a

fetus” from participating in any research using

tissue from that fetus.

Although other States have not specifically addressed the question of neural tissue grafts from

fetuses, the general fetal research laws in effect in 25

States may bear on it. Table 7-2 lists and describes

State regulations. State laws governing fetal research are not as precise as Federal law. Some

contain no definition of fetus, death, or research.

Indeed, “the uncertainties surrounding the reach of

such State regulatory regimes may both create a

dangerous chilling effect on even peripheral research, and leave the regimes exposed to constitutional attack” (59).

Only one State, New Mexico, has adopted a law

patterned on Federal regulations pertaining to fetal

research. Other States have enacted a variety of

regulatory approaches, with the permissibility of

fetal research depending, in part, on the following

factors:
Chapter 7--Legal and Regulatory Issues ● 133

Table 7-2-State Regulations Pertaining to the Use and Procurement of Fetal Tissue for Grafting Research

Arizona regulates research using fetal cadavers and live ex utero

fetuses; prohibits research with fetal cadavers (except for

pathological examinations and autopsies) obtained through a

planned abortion; prohibits experimentation on live ex utero

fetuses.

Arkansas requires maternal consent for research using fetal

cadavers obtained through planned abortions; bans nontherapeutic research involving live ex utero fetuses. Prohibits the

sale of tissue from fetal cadavers.

California regulates research using live ex utero fetuses and fetal

cadavers obtained through planned abortions; prohibits nontherapeutic research with live ex utero fetuses. Prohibits

contribution of organs for valuable consideration, but excludes

from “valuable consideration” the costs of removing, transporting, inspecting, preserving, and reimplanting the organ or

tissue; prohibits sales and purchases of an organ or tissue when

the organ or tissue is to be removed after the death, as well as

the use of an organ known to have been transferred for valuable

consideration; prohibits the sale of unclaimed bodies.

Connecticut has no regulations directly addressing experimentation with fetal tissue. Prohibits contribution of organs for

valuable consideration, but excludes from “valuable consideration” the costs of removing, transporting, inspecting, preserving, and reimplanting the organ or tissue, as well as the donor’s

expenses of travel, housing, and lost wages; prohibits trafficking in dead bodies.

District of Columbia has no regulations directly addressing use

of fetal tissue. Prohibits offering valuable consideration for

organs; nothing is excluded from definition of valuable consideration.

Delaware has no regulations directly addressing experimentation

with fetal tissue. Prohibits organ donor from receiving compensation for disposition of his or her own body; however, payment

to mother for fetal tissue is not prohibited.

Florida bans nontherapeutic research on live in utero and live ex

utero fetuses when done in connection with a planned abortion.

Bans the selling, purchasing, or transferring of a human embryo

for valuable consideration. Prohibits the offering of valuable

consideration for organs, but excludes from “valuable consideration” the expenses of removal and use of organ (this statute

would require regulatory action to cover brain tissue); prohibits

the purchase and sale of unclaimed bodies.

Georgia has no regulations directly addressing experimentation

with fetal tissue. Prohibits buying or selling a human fetus or

fetal part; this prohibition does not apply to donations under the

Uniform Anatomical Gift Act (UAGA), reimbursement of a living

donor’s actual expenses, or payment of costs associated with

collecting, storing, and implanting a donated part; prohibits the

purchase and sale of bodies.

Hawaii has no regulations directly addressing experimentation

with fetal tissue. Prohibits contribution of organs for valuable

consideration, but excludes from “valuable consideration” the

costs of removing, transporting, inspecting, preserving, and

reimplanting the organ or tissue; prohibits sales and purchases

of an organ or tissue when the organ or tissue is to be removed

after the death; prohibits sale of dead bodies.

Idaho has no regulations directly addressing experimentation

with fetal tissue. Prohibits contribution of organs for valuable

consideration, but excludes from “valuable consideration” the

costs of removing, transporting, inspecting, preserving, and

reimplanting the organ or tissue; prohibits sales and purchases

of an organ or tissue when the organ or tissue is to be removed

after the death.

Illinois prohibits research with fetal cadavers except for autopsies and pathological examinations) obtained through planned A

abortions [the Federal District Court recently ruled that this law

is unconstitutional]; with fetus not obtained from a planned

abortion, research can be undertaken on its tissues or cells with

the consent of one parent. Prohibits sale of fetal tissue for any

purpose; prohibits contribution of organs for valuable consideration, but excludes from “valuable consideration” the costs of

removing, transporting, inspecting, preserving, and reimplanting the organ or tissue.

Indiana regulates research with fetal cadavers and live ex utero

fetuses; prohibits research with fetal cadavers (except for

autopsies and pathological examinations) obtained through a

planned abortion; with fetal cadavers not obtained from a

planned abortion, research can be undertaken on tissues or

cells with the consent of one parent; prohibits research with live

ex utero fetuses.

Kentucky bans research using live ex utero fetuses. Prohibits

donation of live fetus for experimentation; prohibits sale of

tissue from live or viable fetuses for research purposes.

Prohibits sale or purchase of a child for adoption or any other

Louisiana prohibits farming in vitro fertilized fetuses for research

or for any use other than to create a pregnancy. Prohibits sale

of in vitro fertilized embryos prior to implantation; prohibits

purchases and sales of all bodies and parts for valuable

consideration.

Maine prohibits research on live ex utero and live in utero fetuses.

Prohibits sale or donation of fetal tissue from live fetuses for

research.

Massachusetts regulates research using fetal cadavers, live ex

utero fetuses, and live in utero fetuses; requires mother’s

consent for research with fetal cadavers; bans research on live

ex utero fetuses and live in utero fetuses which is nontherapeutic for the fetus when the fetus is to be the subject of a planned

abortion except for diagnostic and remedial measures to

preserve the life or health of the mother) ;when fetus is not to be

the subject of a planned abortion, study of in utero fetuses is

allowed, providing the procedures do not substantially jeopardize the life or health of the fetus. Prohibits donation of a fetus for

experimentation; prohibits the performance of an abortion in

cases where “part or all of the consideration for said performance is that fetal remains may be used for experimentation”;

prohibits sale of fetal tissue for research; prohibits purchase and

sale of bodies.

Michigan regulates research using fetal cadavers, live ex utero

fetuses, and live in utero fetuses; requires mother’s consent for

research with fetal cadavers; bans research on live ex utero

fetuses and live in utero fetuses which is nontherapeutic for the

fetus when the fetus is to be the subject of a planned abortion

(except for diagnostic and remedial measures to protect the life

of the mother); when fetus is not to be the subject of a planned

abortion, study of in utero fetuses is allowed, providing the

procedures do not substantially “jeopardize the life or health of

the fetus. Prohibits donation o a fetus for experimentation; f 

prohibits the performance of an abortion in cases where” art

or ail of the consideration for said performance is that etal f

remains may be used for experimentation”; prohibits contribution of organs for valuable consideration, but excludes from

“valuable consideration” the expenses of removal of the organ,

use of the organ, and donor’s losses and expenses (this statute

would require regulatory action to cover brain tissue).

Minnesota prohibits nontherapeutic research using live ex utero

and live in utero fetuses. Prohibits sale of tissue from live

fetuses for any purpose. Prohibits sale of living conceptuses or

nonrenewable organs, but allows the buying and selling of a cell

culture line from a nonliving conceptus.

Missouri prohibits nontherapeutic research using live ex utero or

live in utero fetuses obtained through a planned abortion.

Prohibits physicians from performing an abortion knowing that

the woman will donate tissue for implantation; prohibits monetary inducement to conceive with the intention of aborting the

pregnancy and using the tissue for experimentation or tissue

implantation; prohibits knowingly offering or receiving valuable

consideration for organs or tissues of an aborted fetus other

than payments for burial, other final dispositions, and pathological examination.

Montana bans nontherapeutic research on live ex utero fetuses.

Nebraska bans research using live ex utero fetuses obtained

through a planned abortion (except for diagnostic and remedial

measures to preserve the health of the mother). Prohibits sale

of tissue from live or viable fetuses for research when fetal

tissue is obtained through a planned abortion.

Continued on next page
134 ● Neural Grafting: Repairing the Brain and Spinal Cord

Table 7-2—State Regulations Pertaining to the Use and Procurement of Fetal Tissue

for Grafting Research-Continued

Nevada prohibits anyone from using or making available the

remains of an aborted embryo or fetus for commercial purposes; prohibits contribution of organs for valuable consideration, but excludes from “valuable consideration” expenses

associated with removal and use of donated organ as well as

expenses incurred by the donor.

New Mexico prohibits nontherapeutic research or research that

poses a greater than minimal risk to the fetus on live ex utero

and live in utero fetuses. Prohibits monetary inducement to

conceive in order to subject fetus or live-born infant to clinical

research activity; prohibits sale of unclaimed bodies.

New York has no regulations directly addressing experimentation

with fetal tissue. Prohibits contribution of organs for valuable

consideration but excludes from “valuable consideration” the

costs of removing, transporting, inspecting, preserving, and

reimplanting the organ or tissue, as well as travel expenses and

lost wages of donor (this statute would require regulatory action

to cover brain tissue).

North Dakota regulates research with fetal cadavers, live ex utero

fetuses, and live in utero fetuses; prohibits research using fetal

cadavers obtained through a planned abortion; fetal cadavers

not obtained through a planned abortion allowed with maternal

consent; bans nontherapeutic research using live ex utero and

live in utero fetuses except to preserve mother’s health.

Prohibits donation of fetus or experimentation; prohibits the f

performance of abortions done to obtain material for

experimentation; prohibits the sale of live fetuses; prohibits the

Sal’e by anyone but the mother of fetal cadavers or research; r

prohibits the contribution of organs for valuable consideration,

but excludes from valuable consideration” the costs of removing, transporting, inspecting, preserving, and reimplanting the

organ or tissue; prohibits sales and purchases of an organ or

tissue when the organ or tissue is to be removed after death.

Ohio regulates research with fetal cadavers and live ex utero

fetuses; prohibits research with fetal cadavers obtained from

abortions except for autopsies and pathological examinations;

bans research on live ex utero fetuses. Prohibits the sale of fetal

tissue.

Oklahoma regulates research with fetal cadavers, live ex utero

fetuses, and live in utero fetuses; prohibits research with fetal

cadavers obtained from abortions except for autopsies and

pathological examinations; bans nontherapeutic research on

live ex utero fetuses and live in utero fetuses. Prohibits the sale

of fetal tissue for any purpose.

Pennsylvania regulates research with fetal cadavers, live ex

utero fetuses, and live in utero fetuses; requires mother’s

consent for research or human transplantation using fetal

cadavers (no payment allowed in return for consent, consent

must be obtained after the decision to abort, and the mother

may not designate the recipient of any transplanted tissue);

bans nontherapeutic research using live ex utero and live in

utero fetuses. Prohibits sale of fetal tissue from fetuses

obtained through an abortion; prohibits contribution of organs

for valuable consideration, but excludes from valuable consideration” the costs of removal and use of organ.

SOURCE: Office of Technology Assessment, 1990.

whether the fetus is dead or alive;

whether the research involves a fetus prior to,

during, or subsequent to an induced abortion;

whether the pregnant woman consented to the

research;

whether the fetus is in the womb or outside the

womb; and

whether the fetus has reached a point or has

acquired characteristics that would warrant

treating it as a person, or has acquired some

characteristic, such as the capability of experiRhode Island regulates research with fetal cadavers, live ex utero

fetuses, and live in utero fetuses; requires mother’s consent for

research with fetal cadavers; bans research on live ex utero

fetuses and live in utero fetuses which is nontherapeutic for the

fetus when the fetus is to be the subject of a planned abortion

(except for diagnostic and remedial measures to preserve the

life or health of the mother); prohibits abortion if main motivation h

is procurement of tissue for research; prohibits donation of fetus

for experimentation. Prohibits sale of fetal tissue for experimentation.

South Carolina has no regulations directly addressing experimentation with fetal tissue. Prohibits purchase and sale of dead

bodies.

South Dakota requires consent for research with fetal cadavers,

live ex utero fetuses, and live in utero fetuses.

Tennessee requires mother’s consent for research with fetal

cadavers obtained through a planned abortion; maternal consent required for research using live ex utero fetuses. Prohibits

sale of tissue from live fetuses for any purpose; prohibits receipt

of compensation for an aborted fetus by anyone except the

mother.

Texas has no regulations directly addressing experimentation

with fetal tissue. Prohibits knowing and intentional transfers of

fetal tissue for valuable consideration, but excludes from

“valuable consideration” fees to physicians, reimbursement to

benefit ultimate receiver, and donor’s travel, housing, and lost

wages; prohibits sale of organs for valuable consideration, but

excludes from “valuable consideration” costs for removing,

transporting, inspecting, preserving, and reimplanting the or an

or tissue and for expenses incurred by the donor; prohibits

purchase and sale of bodies.

Utah prohibits research using live in utero fetuses. Prohibits sales

and

f “

purchases of unborn children.

Virgin a has no regulations directly addressing experimentation

with fetal tissue. Prohibits contribution of organs for valuable

consideration, but excludes from “valuable consideration” the

costs of removing, transporting, inspecting, preserving, and

reimplanting the organ or tissue.

West Virginia has no regulations directly addressing experimentation with fetal tissue, Prohibits contribution of organs for

valuable consideration, but excludes from “valuable consideration” the costs of removing, transporting, inspecting, preserving, and reimplanting the organ or tissue, as well as the donor's

travel expenses and lost wages.

Wisconsin has no regulations directly addressing experimentation with fetal tissue. Prohibits contribution of organs for

valuable consideration, but excludes from “valuable consideration” the costs of removing, transporting, inspecting, preserving, and reimplanting the organ or tissue (this statute would

require regulatory action to cover brain tissue).

Wyoming bans experimentation using live ex utero fetuses;

prohibits donation of live or viable fetus for experimentation.

Prohibits sale of fetal tissue for experimentation from a live or

viable fetus obtained through a planned abortion.

encing pain, that would give it an important

claim to protection (this factor is often expressed in terms of the fetus’ viability or

nonviability).

Many States’ fetal research laws do not apply to

research that is potentially therapeutic to the fetus;

this exception is not applicable in the case of neural

grafting, since the procedure is not being done for

the benefit of the fetus. Nine States underscore their
Chapter 7--Legal and Regulatory Issues ● 135

ban on experimentation on fetuses by prohibiting

anyone from donating a fetus for experimentation.

Research on Fetal Cadavers

Under State law, research involving fetal cadavers

and living tissues from fetal cadavers is regulated

under the Uniform Anatomical Gift Act (47), which

has been adopted by all 50 States and the District of

Columbia. However, some States have excluded

fetuses from their provisions of the law. Research

with fetal cadavers is also regulated in some States

by fetal research statutes. According to the provisions of the UAGA, either parent may donate all or

any part of a fetus “after or immediately before [its]

death,’ provided that the other parent does not

oppose the gift. Under the UAGA, a ‘‘decedent’ is

defined to include “a stillborn infant or fetus.” The

Act covers the donation of all or any portions of the

human body for purposes that include both educational and therapeutic benefits. Thus, if abortion and

organ donation are both legal, this should also cover

tissue donation (55).

Of the 25 States that have more specific laws

governing fetal research, 14 have provisions regulating research with fetal cadavers (table 7-2). These

laws deviate from the provisions of the UAGA either

in their consent requirements or prohibitions they

place on the uses of fetal tissue. Eight of these laws

require the pregnant woman’s consent for research

but make no provision for consent or objection by

the father. The California statute that allows research

with fetal tissue is silent on the issue of parental

consent. The remaining five States diverge from the

UAGA, prohibiting any research with fetal cadavers

except for pathological examinations or autopsies .

The divergences of these 14 laws from the provisions of the UAGA are perhaps attributable to

lawmakers’ interests in regulating abortion and

related practices. Of the 14, eight apply only to

research with abortuses. Of the five statutes that

prohibit any research except for pathological examinations, four apply exclusively to abortuses, and one

puts more restrictions on research with fetal cadavers resulting from an induced abortion (table 7-2).

Research on Live Fetuses

There may be instances in which an experimental

protocol requires that some action be undertaken on

a dying or about-to-be-aborted fetus in order to

better prepare the fetus for use as a donor of tissue.

There are significant questions about whether such

actions should be permitted. For example, some

commentators argue that no research should be

permitted on fetuses that are about to be aborted

which would not be permissible on fetuses that

would be carried to term (46). In addition, there are

State statutory constraints on research on live

fetuses. Federal regulations provide that, even in

cases of federally funded fetal research, the State

laws are applicable [46 CFR 46.201(b)].

State laws governing research on live fetuses

severely constrain research that is not therapeutic to

the fetus itself (thus covering neural grafting research, which is not therapeutic to the fetus). Of the

24 State fetal research laws that regulate research on

live ex utero fetuses (see table 7-2),21 would appear

to prohibit research involving neural grafting, either

because the procedure is not therapeutic to the fetus

or because all experimentation on such fetuses is

prohibited. Of these 21 statutes, 5 permit diagnostic

and remedial measures to preserve the life or health

of the pregnant woman, perhaps leading to the

incongruous result that the pregnant woman may

donate fetal tissue to herself but to no one else. While

it has been argued that an ex utero fetus is not

technically a fetus (36), two of the remaining statutes

would appear to permit research involving a live ex

utero fetus, provided the pregnant woman has

consented. The final statute prohibits only the

farming of in vitro-fertilized embryos for research

purposes and any use of such embryos other than to

create a pregnancy.

Of the 14 States regulating research on live in

utero fetuses, 13 would appear to prohibit neural

grafting research, either because it is not therapeutic

to the fetus itself or because all experimentation on

such fetuses is prohibited. One State, South Dakota,

would apparently permit it, as long as the pregnant

woman consented.

Distinction Based on Whether the Research Is

Done in Connection With an Abortion

The most significant factor in regulating research

on dead or live fetuses and in determining the extent

of restriction imposed appears to be whether the

research concerns a fetus that has been or is to be

obtained through an induced abortion. Most of the

State fetal research statutes were passed as part of

abortion legislation. Twelve of the 25 laws apply to

research only where it concerns a fetus prior to or

subsequent to an induced abortion (see table 7-2). Of

the 13 that apply to fetuses more generally, 5 impose
136 . Neural Grafting: Repairing the Brain and Spinal Cord

more stringent restrictions on fetal research in

conjunction with an abortion.

Another approach that has been used to ensure

that fetal research does not encourage abortion is to

prohibit the performance of an abortion where some

or all of the consideration for the abortion is the

donation of fetal remains for experimental use.

In the past, important scientific gains were made

through experimentation in the context of an induced abortion. For example, prenatal diagnostic

techniques have been developed in pregnant patients

about to undergo abortions (27). The most appropriate tissue for neural grafting will probably come

from elective, rather than spontaneous, abortions.

Tissue from spontaneously aborted fetuses may not

be appropriate for neural grafting since a fetal

pathology may have lead to the miscarriage and

since the fetus may have died in utero and deteriorated before being miscarried. Some persons argue

that research involving fetuses from induced abortions, whether the fetus be living or dead, is morally

impermissible on the grounds that it constitutes

cooperation with an immoral practice. The point was

made in the following way:

If one objects to most abortions being performed

in our society as immoral, is it morally proper to

derive experimental profit from the products of such

an abortion system? Is the progress achieved through

such experimentation not likely to blunt the sensitivities of Americans to the immorality (injustice) of the

procedure that made such advance possible, and

thereby entrench attitudes injurious and unjust to

nascent life? This is, in my judgment, a serious moral

objection to experimentation on the products of most

induced abortions (whether the fetus be living or

dead, prior to abortion or post abortional) (32).

Many State fetal research laws regulate research only where it involves a fetus that is the

subject of an abortion, and some impose a stricter

standard on research involving fetuses to be aborted

than on research involving fetuses to be carried to

term. Against this view it is possible to argue that,

even if abortion represents a moral wrong in some

people’s minds, the use of dead abortuses for certain

types of research is not only morally legitimate but

obligatory. It has been argued that research with

fetuses to be aborted is morally justified, provided

the research is aimed at deriving information potentially beneficial to other fetuses. This would be

unlikely in the case of fetal tissue transplants to

Parkinson’s patients (7). One neurosurgeon has

argued that there is a moral obligation to do good

where possible; since the fetal cadaver is beyond

help or hope, to waste its tissues is a moral wrong

(50). It has been stated that, by allowing research

intended to benefit future fetuses, “what we have

done is add a moral good to a morally tragic

situation” (28). On the other hand, it has been

argued that this practice is comparable to the use of

data obtained by Nazi researchers (44).

Payment in Connection With

Fetal Experimentation

One of the greatest concerns regarding neural

grafting-and the concern that State legislatures are

likely to address first-is the possibility that the

need for fetal tissue may encourage women to

conceive for the sole purpose of donating tissue to

relatives or selling it for profit. This could lead to the

exploitation of women and intended recipients (33).

Currently, 16 State fetal research statutes prohibit

the sale of fetal tissue, 7 of them for any purpose and

9 for research purposes (see table 7-2). Some of these

statutes apply only to induced abortions and thus

would not preclude the sale of a miscarried fetus for

tissue transplantation. The penalties attached to

some of these laws are very stiff. Selling a viable

abortus for experimentation in Wyoming, for example, subjects a person to a fine of not less than

$10,000 and imprisonment of 1 to 14 years [Wyo.

Stat. 35-6-115]. Several States have nonuniform

UAGA provisions that prohibit transfer of organs or

tissues, including fetal organs and tissues, for value.

Moreover, some State laws would forbid the sale of

fetuses even when they are not being used for

research purposes, thus covering payment for neural

grafting in the clinical setting.

Biotechnology companies create cell lines from

fetal tissue, a fact which raises the possibility that a

woman may donate fetal tissue to a company which

may then exploit it commercially (57). The issue of

commercial exploitation of cell lines was examined

in a recent California case (42) (see ch. 8 for

discussion). The court held that an individual has a

protectable monetary interest in products made from

his or her genetic material. The fact that a corporation might profit from fetal tissue whereas the

woman who donated it is prevented from receiving

consideration for it seems to violate the principle of

this case. However, on appeal the California Supreme Court held that the plaintiff did not have a

property right to his tissues and cells but did have a
Chapter 7--Legal and Regulatory Issues ● 137

right to informed consent for any use by others of his

tissues and cells (43).

It is possible that, because a cell line is new tissue

produced from the genetic material of, but not

originally apart of, the aborted fetus, laws proscribing the sale of fetal tissue may not apply to cell lines.

In fact, a Minnesota law prohibits the sale of living

conceptuses or nonrenewable organs but does allow

‘‘the buying and selling of a cell culture line or lines

taken from a non-living human conceptus . . .“

[Minn. Stat. Ann. 145.1627(3)]. In contrast, Nevada’s broadly worded statute making it a crime for

anyone to use or “make available. . . the remains of

an aborted embryo or fetus for any commercial

purpose” could conceivably outlaw the production

of cell lines from fetal tissue [Nev. Rev. Stat. Ann.

451.015]. Moreover, it could outlaw cell line transplants.

Interstate Transfer of a Fetus

Some State statutes also contain restrictions on

the interstate transfer of fetal tissues. An Indiana

law, for example, forbids transporting a fetus from

an induced abortion to another State “for experimental purposes” [Ind. Code Ann. 35-l-58.5-6].

In Arkansas, there is a ban on ‘possession” of the

organ, tissue, or material of an aborted fetus [Ark.

Stat. Ann. 20-17-802(d)]. However, the Arkansas

statute expressly exempts from its provisions physicians and the instructional and research programs of

institutions of higher education [Ark. Stat. Ann.

20-17-80 (e)].

GOVERNMENT OVERSIGHT

Issues and questions raised by the introduction

and development of neural grafting procedures

could make other government regulatory mechanisms relevant. For example, special concerns surrounding neural tissue transplants may require

government oversight to protect the interests of the

parties involved. Also, fetal rights is a relatively new

area of the law, and many of the existing laws

designed to protect human subjects in biomedical

research do not cover fetal issues. Some of the

anticipated problems are discussed below.

Potential Constitutional Challenges to

Restrictions on Research

Not all regulations on research are constitutional.

Laws restricting research may be struck down as too

vague or as violating the equal protection clause of

the Constitution. Those applying to experimentation

on fetuses or in the context of abortion may violate

the right to privacy (48). In addition, some legal

commentators posit that there is a constitutional

right to undertake or participate in research. Even if

undertaking and participating in research were

constitutionally protected, however, certain restrictions to further health and safety would be constitutionally permissible.

Laws governing research must meet certain standards of clarity in order to be constitutional. A

Louisiana law prohibiting nontherapeutic experimentation on fetuses was declared unconstitutional

by a Federal appeals court, because the term

‘‘experimentation’ was so vague that it did not give

researchers adequate notice about what kind of

conduct was banned. The court said that the term

‘‘experimentation’ was impermissible vague because physicians do not and cannot distinguish

clearly between medical experimentation and medical tests. It noted that “even medical treatment can

be reasonably described as both a test and an

experiment,” for example, “whenever the results of

the treatment are observed, recorded, and introduced

into the database that one or more physicians use in

seeking better therapeutic methods” (37).

Although there is no specifically enumerated right

to research in the Constitution, some commentators

assert that support for such a right could be derived

from the 14th amendment right to personal liberty

and the first amendment right to free speech (52).

Arguably, the right to participate as a research

subject is protected by the 14th amendment’s right

to privacy, since an individual’s decision to use his

or her body in an experiment designed to further

medical knowledge or to be of personal benefit is a

private matter (52). This right to research consists of

the freedom to pursue knowledge and the freedom to

choose the means to achieve that knowledge (52).

On the other hand, it has been argued that means

have their own morality (44). The Supreme Court

has stated that the right to liberty guaranteed by the

14th amendment encompassed freedom to “acquire

useful knowledge . . . and generally to enjoy those

privileges long recognized at common law as

essential to the orderly pursuit of happiness by free

men” (41). This language, arguably, applies not

only to the researcher’s right to scientific inquiry,

but also to an individual’s right to participate as a

research subject (52). It could be interpreted as
138 ● Neural Grafting: Repairing the Brain and Spinal Cord

supporting an individual’s right to help acquire

knowledge by participating as an experimental

subject (52).

Some arguments hinge on the first amendment’s

protection of free speech, which, it can be argued,

includes a right to learn new information. However,

one must distinguish the freedom to pursue knowledge from the right to choose the method for

achieving that knowledge. Although it is argued that

government may not prohibit research in an attempt

to prevent the development of new knowledge, it

may restrict or prohibit the means used by researchers if the means intrude on interests in which the

state has a legitimate concern (52). Therefore, both

the Federal and State governments may regulate the

researcher’s methods in order to protect the rights of

research subjects and community safety (52). Research may be restricted, for example, to protect the

subject’s right to autonomy and welfare by requiring

informed, free, and competent consent; however, the

state cannot arbitrarily regulate research solely

because it deems the knowledge sought to be

distasteful or subject to harmful use (52).

Fetal Remains Laws

Every jurisdiction makes some provision for the

registration of deaths (usually by death certificate)

and the disposition of dead bodies. Most States have

a vital statistics statute governing death registration

and issuance of permits for transporting or disposing

of dead bodies. In most States, dead bodies must be

disposed of in an authorized manner within a

specified period of time, usually 72 hours after

death. Any disposition of a dead body usually

requires a permit, which is generally issued only

after a death certificate has been filed. Most of these

statutes also specify when fetal deaths must be

registered and how to dispose of fetal remains. In

addition, some States make separate provision for

reporting fetal deaths and disposing of fetal remains.

These statutes are important, not only because they

provide penalties for unauthorized uses of dead

bodies, but also because they determine what must

be done with fetal remains once their research or

clinical value has been exhausted and what reports

must be filed.

The two most common sources of authority for

conducting research are research statutes and the

UAGA. In addition, many States establish an

administrative agency to distribute unclaimed dead

bodies for scientific and educational purposes. Since

these statutes typically require a lengthy holding

period or embalming of the body, they do not

provide useful authority for the use of fetal tissue in

neural grafts. Moreover, anyone who conducts fetal

tissue research that is not authorized by one of these

statutes may be charged with corpse abuse or

unauthorized dissection. The most common corpse

abuse statute follows the Model Penal Code 250.10

and prohibits any use of a corpse that would offend

“family sensibilities.”

Most jurisdictions exempt fetuses in early stages

of development from death certification and registration requirements. These States define “fetal

deaths” or “stillbirths” requiring registration in

terms of a minimum gestational period, a minimal

weight, or both. Eight States apparently require fetal

death certificates regardless of the age or weight of

the fetus. Of the statutes that require fetal death

certificates, at least five exempt deaths resulting

from induced abortions. Finally, 13 States do not

require death certificates for fetuses of any particular

age or weight but do require at least some fetal

deaths to be reported. Three of the statutes requiring

some report of fetal deaths make special provision

for reporting deaths resulting from induced abortions.

Some States require disposition permits regardless of the age or weight of the fetus, while at least

six States directly exempt fetuses in early stages of

development from permit requirements. Eighteen

other States apparently obtain the same result

indirectly, by anticipating that disposition permits

will be issued only on the filing of a death certificate,

but exempting fetuses in early stages of development from death certification requirements. In a few

States, whether a permit is required depends on the

kind of disposition planned rather than on any

characteristic of the fetus.

The most common kinds of dispositions of fetal

remains are burial, cremation, and entombment.

Kentucky apparently allows only burial of fetal

remains [Ky. Rev. Stat. 213.160]. At least 16 statutes

anticipate that a health-care institution will dispose

of fetal remains and require the institution to report

these dispositions. Finally, seven States that provide

for fetal death certificates or death reports explicitly

exclude fetuses in early stages of development from

disposition requirements, make no specific provi-
Chapter 7--Legal and Regulatory Issues ● 139

sion for fetal remains, or authorize an administrative

agency to decide what disposition is appropriate.

At least seven of the statutes governing the

general disposition of dead bodies make some

provision for parental consent to the disposition of

fetal remains, while five statutes require parental

consent for any disposition of a dead fetus, regardless of gestational age. One of the five statutes

requires the pregnant woman’s but not the partner’s

consent when the pregnant woman is unmarried,

while the two remaining statutes require consent of

a parent only in certain circumstances.

The reamer in which fetal remains are disposed of

is also covered under the statutes of some States. The

California penal statute clearly does not affect neural

grafts; it merely prohibits disposition of fetal remains in sites open to public view [Cal. Penal Code

643]. The California Health and Safety Code requires that fetal remains be incinerated at the

conclusion of research, but this provision does not

apply to educational institutions [Cal. Health &

Safety Code 25957(a)]. The Arkansas statute requires physicians performing abortions to ensure

that fetal remains are disposed of in a similar manner

to other human tissue [Ark. Stat. Ann. 20-17-

802(a)], namely, ‘‘incineration, cremation, burial, or

other sanitary means prescribed by the State health

department” [Ark. Stat. Ann. 20-17-801(a)]. The

laws of Florida, Georgia, Minnesota, and North

Dakota allow any manner of disposition approved

by the State health department. The Florida statute

also requires the health department to promulgate

rules consistent with the disposition of other human

tissues [Fla. Stat. Ann. 390.012(2)]. Whether neural

grafts are allowed in these States depends on what

regulations are currently in force. Finally, the

Massachusetts statute requires fetal remains to be

disposed of at the parent’s direction, whether by

burial, entombment, cremation, or, if the hospital or

attending physician is to dispose of the remains, by

any method that does not create a public health

hazard [Mass. Ann. Laws ch. 11,202]. In addition,

the statute requires the hospital or attending physician to inform parents of their right to direct

disposition and of any hospital policy governing

disposition of fetal remains.

The fetal remains laws in some States have been

subject to successful constitutional challenges. A

recent Supreme Court case held that an ordinance

requiring fetal remains to be disposed of in a humane

UNIFORM DONOR CARD

of Print or type name of donor

In the hope that I may help others, I hereby make this anatomical

gift, if medically acceptable, to take effect upon my death. The words

and marks below indicate my desires

I give (a) — any needed organs or parts

(b) — only the following organs or parts

Specify the organ(s) or part(s)

for the purposes of transplantation, therapy, medical research or

education,

(c) — my body for anatomical study if needed

Limitations or

special wishes, if any

08-21-81 100M/81

Signature of Donor Date of Birth of Donor

Date Signed City & State

Witness Witness

This iS a legal document under the Uniform Anatomical Gift Act or

similar laws

For further information consult your physician or

National Kidney Foundation of the National

Capital Area, Inc.

2233 Wisconsin Ave., NW, Suite 320

Washington, DC 20007

Photo credit: Office of Technology Assessment

An organ donation card.

and sanitary manner was impermissible vague (16).

In addition, laws that specifically required a woman

to decide, in advance of an abortion, whether the

aborted fetus was to be buried, cremated, or disposed

of at the hospital’s discretion have been struck down

as unconstitutionally interfering with the woman’s

right to privacy (29).

Uniform Anatomical Gift Act

The Uniform Anatomical Gift Act (47) is the only

uniform body of law that might regulate acquisition

or donation of fetal tissue implants. Forty-seven

States and the District of Columbia presently conform to some form of the 1968 version of the UAGA.

California, Connecticut, and Hawaii have adopted a

new version of the UAGA, approved by the National

Conference of Commissioners on Uniform State

Laws in 1987. In fact, in the 25 States that lack fetal

tissue research statutes, the UAGA is the primary

legislation that would affect this technology (57).

Specifically, the UAGA affects fetal tissue implants by including “a stillborn infant or fetus’ in
140 . Neural Grafting: Repairing the Brain and Spinal Cord

the definition of “decedent” and by stating that

“parts” includes “tissues” (47); however, not all

States have included a fetal tissue provision in their

version of the UAGA. According to the 1987 version

of the Act, either parent may consent to the donation

of fetal tissue; in reality, the consent of both parents

is necessary because if either objects, a donor who

knows of the objection may not accept the gift (47).

The UAGA would appear to allow the parents of an

aborted or stillborn fetus to designate a recipient,

even though this practice would be in direct opposition to the recommendations of the Report of the

Human Fetal Tissue Transplantation Research

Panel (67). The panel expressed concern that such a

practice might encourage abortions in order to

donate fetal tissue for the treatment of relatives.

Furthermore, because of the genetic nature of

diseases such as diabetes and Huntington’s disease,

the effectiveness of the treatment might actually be

jeopardized by implanting fetal cells which possess

the same defect that the procedure is supposed to

ameliorate (67). The UAGA and the NIH report

differ on several points because the UAGA was

written before the NIH report and before fetal

transplants were thought to have so many possible

applications (13).

In adopting the UAGA, many States added

sections designed to facilitate and regulate the

donation of tissue. The most common nonuniform

provisions found in State laws either require hospitals to adopt an organ procurement protocol, which

is designed to facilitate the procurement of donor

tissue while recognizing the sensitivity of the

relatives who must consent to the donation, or

simply require hospital personnel to request the

relative of a suitable decedent to make the decedent’s organs available for donation (see table 7-2).

In either case, physicians wishing to obtain fetal

tissue would be required to request parental consent

in a professional and sensitive manner. Those laws

which require that consent be obtained would

require doctors to inform all abortion patients of the

possibility of donation for transplants, preferably

after the abortion decision had been made. If the

consent were sought prior to the decision to abort, it

might conceivably influence the decision. For this

reason, the Human Fetal Tissue Transplantation

Research Panel recommends that the decision to

obtain an abortion precede any request to donate

tissue for implantation (67). These two procedures probably should be handled by two separate advisers, the supervising physician and the

researcher (55).

In 1987 the National Conference of Commissioners on Uniform State Laws approved a new model

UAGA, which has been adopted by at least seven

States. The new version retains provisions allowing

the next of kin to designate the fetal tissue recipient

and incorporates changes designed to increase the

number of organ donations, particularly through

required request policies. Organ procurement professionals have traditionally gone to great lengths to

assure the public that organ donation will not

compromise the patient’s medical care in any way.

Accordingly, the family is approached about possible donation only after the patient has been declared

dead by the physician. Following these guidelines,

parents can be approached about possible donation

only after the abortion and after the fetus has been

declared dead. Language in the new version of the

UAGA, however, suggests it may be permissible to

seek consent before the abortion. The new version

allows consent to be sought after or immediately

before death (14).

The laws of at least eight States would protect

recipients of fetal tissue by requiring that all donors

be tested for HIV. An additional two States, while

not requiring HIV testing of donors, have established standards that decrease the likelihood of

AIDS-infected tissues being made available for

donation.

Overall, the UAGA and its various manifestations

provide some guidelines in the area of fetal tissue

transplants. Because this Act was drafted before

neural grafting technology became known, it is

obviously not designed to address the specific and

unique problems that these implants raise.

Compensation for Fetal Tissue in a

Nonresearch Setting

There is much concern about the possibility that

women will be paid for fetal tissue for transplantations. One commentator points to ‘‘the fear that

permitting the commercialization of the fetal tissue

transplantation system will result in the exploitation

of the women who bear tissue for profit and of the

critically-ill patients who want to acquire it” (59).

The NIH panel recommended that sale of fetal tissue

not be allowed, for two reasons:
Chapter 7&gal and Regulatory Issues ● 141

. so as not to influence a woman’s decision to

abort; and

. so as not to induce an abortion facility to base

its choice of abortion procedure on the profitability of the fetal tissue to be retrieved (22).

The prohibition on payment to organ donors generally prohibits payment to women for fetal tissue. In

addition, a variety of State statutes also have the

same prohibition (table 7-2).

The National Organ Transplant Act, passed under

Congress’ commerce clause authority, bans the sale

of certain listed organs (including certain fetal

organs and their subparts) [42 U.S.C. 274(e)] and

provides that the Secretary of DHHS list additional

organs under the ban. Since the brain is not listed as

one of the organs, payment for use of fetal brain

tissue for transplantation will not be banned until the

Secretary so designates.

In addition to the 16 State fetal research statutes

that prohibit the sale of fetal tissues for purposes

including research, seven State laws forbid the sale

of fetuses or fetal material (see table 7-2). The

Florida statute places a flat ban on selling, purchasing, or transferring a human embryo for valuable

consideration and on offering or advertising to do so

[Fla. Stat. Ann. 837.05(1)]. Nevada prohibits any

commercial use of an aborted fetus or fetal material

resulting from an abortion [Nev. Stat. Ann.

451.015]. Missouri prohibits knowingly offering or

receiving any valuable consideration for the organs

or tissues of an abortus, except payments for burial

or other final disposition and for pathological

examinations [Mo. Ann. Stat. 188.036(5)]. Utah

prohibits sales and purchases of, or offers to buy or

sell, unborn children [Utah Code Ann. 76-7-311].

The Georgia statute prohibits buying or selling a

human fetus or fetal part [Ga. Code Ann. 48-401 et

seq.], but the prohibition does not apply to donations

under the UAGA, reimbursement of a living donor’s

actual expenses, or payment of costs associated with

collecting, storing, and implanting a donated part

[Ga. Code Am. 26-9957(b)]. Similarly, the Texas

statute prohibits knowing and intentional transfers

of fetal tissue for valuable consideration but excludes from ‘‘valuable consideration’ fees paid to

physicians, hospitals, and clinics for services rendered in the usual course of medical practice,

reimbursement of legal or medical fees incurred to

benefit the ultimate receiver of the tissue, and the

donor’s travel and housing expenses and lost wages

[Tex. Penal Code 48.02]. Finally, in an unusual

provision, Kentucky prohibits selling or purchasing

a child for adoption or any other purpose [Ky. Rev.

Stat. Ann. 199.590(2)]. Since the statute specifically

excludes from its coverage in vitro fertilization in

which the genetic donors are a married couple and

the fertilized ovum is to be implanted in the wife, the

Kentucky legislators seem to have intended ‘child”

to include the human organism from conception and

“any purpose” to include medical and scientific

procedures. Thus, this statute could be used to

prohibit any agreement to pay the pregnant woman

for fetal tissue made while the fetus is still alive.

At least 18 jurisdictions have laws forbidding

payment to organ donors. Ten of the statutes are

nonuniform UAGA provisions. The Delaware

UAGA provision clearly does not prohibit payment

to the pregnant woman for fetal tissue: it applies only

to payments to a donor for disposition of his or her

own body [Del. Code Ann. tit. 16, 2713(f)]. Whether

the nine remaining UAGA provisions prohibit

payment to the pregnant woman depends on two

factors—whether any or all of the payment can be

considered reasonable costs associated with the use

of the tissue, and when the tissue will be removed.

The nonuniform provisions of nine States prohibit

the purchase or sale of organs or tissue for valuable

consideration but exclude from the definition of

“valuable consideration’ the costs of removing,

transporting, inspecting, preserving, and reimplanting the organ or tissue. Three States exclude

from “valuable consideration” “the expenses of

travel, housing, and lost wages” incurred by the

“donor.” This suggests that the pregnant woman

cannot be reimbursed for nonmedical losses and

expenses without specific statutory authority. Moreover, under the UAGA, the term “donor” applies

only to ‘an individual who makes a gift of all or part

of his body” (47). In the case of fetuses, the

pregnant woman is not a donor, but someone

authorized to consent to the gift of a decedent’s

remains. Thus, the pregnant woman may not be paid

for agreeing to transfer the fetal remains, even under

State laws (47).

Under the nonuniform provisions of four States,

California, Hawaii, Idaho, and North Dakota, payment to the pregnant woman may be banned for

another reason. These States prohibit sales and

purchases of organs and tissues for valuable consideration when the organ or tissue is to be removed
142 ● Neural Grafting: Repairing the Brain and Spinal Cord

after the decedent’s death. Unless the fetal tissue is

to be removed while the fetus is still alive (which

may be forbidden under the State’s fetal research or

other statute), payment to the pregnant woman is

forbidden under these anatomical gift act provisions.

The California Anatomical Gift Act is supplemented

by a penal provision that prohibits a person from

knowingly acquiring, receiving, selling, or promoting the transfer or otherwise transferring any organ

for transplantation for valuable consideration. It also

prohibits the use of an organ known to have been

transferred for valuable consideration. The law is

directed against brokering organs rather than the

direct sale by a donor to a recipient.

Of the eight statutes remaining that prohibit the

sale of organs but are not part of the State UAGA,

one clearly does not prohibit payments to the

pregnant woman. The Tennessee statute prohibits

only transfers of organs for valuable consideration

that “affect commerce” [Tern. Code Ann. 68-30-

401] and is presumably aimed at brokers. The law of

the District of Columbia clearly prohibits such

payments, and it excludes nothing of value from the

definition of valuable consideration [D.C. Code

Ann. 6-260(b)]. The remaining statutes are similar to

the nonuniform anatomical gift act provisions previously discussed. Six allow reimbursement of reasonable expenses associated with the removal, preservation, and use of the donated organ, and four make an

additional allowance for the donor’s losses and

expenses.

The Federal and State laws prohibiting payment

to organ donors would ban more than just a cash

payment to women. They would also cover payment

of a woman’s abortion expenses in order that she

may donate fetal tissue (54). The reach of some State

laws may also extend to payment to agencies that

retrieve and process the fetal tissue. These agencies

would not be able to “sell’ tissue to physicians or

patients; however, they would be able to recover

their costs and overhead for obtaining the tissue. For

example, the New York and West Virginia statutes

exclude from the definition of ‘valuable consideration” reimbursement of expenses incurred by nonprofit agencies and corporations in offering services

related to the location, maintenance, and distribution

of the donated organ [N.Y. Public Health Law 4307;

W.Va. Code 16-19-7(a)].

Most of the statutes prohibiting transfers of

organs for value define organ quite broadly and

would cover most types of tissues and organs to be

transplanted from fetuses. Other statutes are more

limited in the body parts they cover and would

require regulatory agency action to cover brain

tissue. The Florida statute bans the sale of the

kidney, liver, heart, lung, pancreas, bone, skin, or

any other organ or tissue specified by rules adopted

by the Department of Health and Rehabilitative

Services [Fla. Stat. Ann. 873.01(3)(a)]. The New

York statute begins with a larger list of items and

then provides for regulatory expansion. It defines

“human organ’ as ‘the human kidney, liver, heart,

lung, bone marrow, and any other human organ or

tissue as maybe designated by the commissioner but

shall exclude blood” [N.Y Public Health Law

4307]. To the New York list, Wisconsin adds the

pancreas, cornea, eye, bone, skin, and any other

organ specified by the department except blood,

blood products, and semen [Wisc. Stat. Ann.

146.345]. Michigan has by far the most comprehensive list: “human kidney, liver, heart, lung, pancreas, bone marrow, cornea, eye, bone, skin, cartilage, dura mater, ligaments, tendons, fascia, pituitary gland, and middle ear structures, and any other

human organ specified by rule promulgated by the

department’ [Mich. Comp. Laws Ann .

333. 10204(3)(a)].

Finally, 10 States prohibit “trafficking” in dead

bodies—that is, transferring dead bodies for valuable consideration (see table 7-2). These statutes are

arguably drafted broadly enough to prohibit either

payment to or receipt of payment by the pregnant

woman for the use of fetal remains. Only one statute

explicitly covers all bodies and bodily parts [La.

Rev. Stat. Ann. 17:2280]. The remaining either

cover bodies but do not refer to parts or limit their

coverage to unclaimed bodies (those that have not

been claimed for burial). The majority of States ban

both purchases and sales of dead bodies, but three

States prohibit only sales, and one State more

broadly proscribes “delivering or receiving for

speculation or pecuniary profit.” In addition, five

statutes prohibit transporting dead bodies out of

State.
Chapter 7--Legal and Regulatory Issues . 143

SUMMARY AND CONCLUSIONS

The use of neural grafts raises many legal issues,

despite the fact that this procedure is showing some

promise in the treatment of several disorders. There

are grounds for Federal action in this area. To the

extent that Federal funds are used to support research

involving neural grafting or to pay for the clinical

use of such procedures, Federal regulations may

establish mandatory policies governing the conduct

of such research. Even if Federal funds are not used,

the Federal Government has powers under the

commerce clause to regulate this activity. This

power has served as the basis for the establishment

of the FDA, the prohibition on payment to organ

donors for transplantation involving interstate commerce, and the regulation of medical laboratories

engaged in interstate commerce.

It is difficult to predict how the FDA will choose

to regulate the various tissues and products of

biotechnology that may be used in neural grafting.

Questions of safety and the FDA’s current regulation

of similar products make it likely that the agency

will seek to regulate most neural grafting materials.

Questionable jurisdiction under the Public Health

Service Act may limit the ability of the FDA to

regulate these materials, since it is unclear whether

neural tissue grafts, cell lines, and products of

biotechnology to be used as neural grafting materials

are analogous to the other articles listed as biologics

in the statute. Other legal issues include questions of

FDA jurisdiction in relation to when a neural graft is

produced and performed intrastate and in relation to

the practice of medicine.

Some existing Federal policies governing experimentation and organ transplantation could affect

tissue transplants. However, the Federal regulations

on fetal research and the Federal law on transplantation were developed before the extensive, recent

debate on fetal tissue transplantation. It might be

appropriate to amend existing policies to address

more directly the concerns raised by neural grafting.

In particular, Federal regulations and law might be

modified to provide that a woman not be paid

valuable consideration for fetal tissue for transplantation and not be allowed to designate a donor.

Federal regulations might also be amended to ensure

that health-care professionals undertaking counseling and persons involved in abortion procedures are

not also involved in the harvest and transplantation

of fetal tissue.

1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

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Chapter 8

Ethical Issues
CONTENTS

Page

ISSUES RELATED TO RESEARCH FUNDING . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149

What kinds of diseases might be treated with this technology? . . . . . . . . . . . . . . . . . . . . . 150

What impact do these diseases currently have on society and what threat do they

hold for the future?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150

What alternative surgical or medical treatments are available? . . . . . . . . . . . . . . . . . . . . . 150

To what extent does the Federal Government’s commitment to funding biomedical

research extend to neural grafting research?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .151

Would finding neural grafting require the government to redirect limited funds

from other areas of research?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151

ISSUES RELATED TO TISSUE SOURCE. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151

Fetal Tissue.**. *.. ... ... ..*. . *.....................**..*.**...@*..**.***+*.*.* 151

Cell Lines. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159

ISSUES RELATED TO GRAFT RECIPIENTS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161

Risks to Research Subjects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161

Informed Consent. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162

SUMMARY AND CONCLUSIONS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163

CHAPTER 8 REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165

Boxes

Box Page

8-A. Just Distribution of Resources and the Funding of Heart Transplants . . . . . . . . . . . 150

8-B. Moore v. Regents of the University of California . ....*.*.,..*.........***.,*** 160

Figure

Figure Page

8-1. Types of Abortion and Morally Relevant Differences Among Them . . . . . . . . . . . 153
Chapter 8

Ethical Issues

Neural grafting is a complex subject for ethical

discussion because of the scope of the issues it

raises. Ethical arguments surrounding neural grafting are part of the continuing debates about the

morality of abortion and genetic manipulation, and

they rekindle discussions about the treatment of

research subjects and the meaning of informed

consent. This chapter discusses ethical aspects of the

various neural grafting technologies currently being

researched.

Some ethical issues raised by neural grafting are

not unique to this technology. One such issue is the

allocation of scarce Federal resources, since funds

committed to neural grafting might be spent on

alternative biomedical research or other areas altogether. Questions about funding can be addressed

with empirical evidence of the number of individuals affected by diseases, the availability of alternative treatments, and the economic costs that both the

diseases and the treatments create for society.

Another general ethical concern is the tension

between the Federal Government’s commitment to

promoting the public health and funding biomedical

research, and its responsibility to respond to public

concern about certain research and its possible

applications.

The various grafting materials used also raise

ethical issues. Human fetal tissue, in particular, has

generated extensive discussion in several forums. A

moratorium on federally funded fetal tissue transplantation research was declared in March 1988 by

the Secretary of Health and Human Services and was

continued indefinitely in November 1989 (see app.

A). As a result of this moratorium, a National

Institutes of Health (NIH) advisory panel was

convened and in 1988 issued a report on the ethics

of fetal tissue transplantation (54). The panel’s

policy recommendations were accepted by a large

majority of its members and were accepted unanimously by the NIH Director’s Advisory Committee.

However, the points on which panel members

disagreed were never resolved, and no action was

taken on the recommendations by the NIH Director

or the Assistant Secretary for Health.

As the technology develops, the use of continuous

cell lines as a source of grafting material may also

create general concern. Advances in molecular

biology suggest it may be possible to develop

effective brain and spinal cord grafts by genetically

manipulating cells before transplantation. Genetic

manipulation of cells has generated considerable

controversy since it was first introduced (49), but the

somatic cell alterations that would be used for neural

grafting are less troublesome than germ cell gene

therapy. On the other hand, as cell lines have been

developed, questions have been raised about ownership of tissues. Uncertainty about how to determine

the rightful ownership of cell lines could complicate

the use of this material considerably.

The treatment of patients who receive neural

grafts is another area of ethical concern. Issues of

protecting patients from undue risk and obtaining

adequate informed consent are not unique to neural

grafting, but they warrant special attention for this

technology. At this stage of research, some persons

question whether the risks to research subjects are

comparable to the expected benefits. It is also

questionable whether requirements for informed

consent can be met, given the vulnerability of some

persons with neurological disorders.

This chapter describes the ethical concerns that

have been raised about neural grafting. It identifies

issues and presents the various arguments surrounding them in order to represent the spectrum of

attitudes expressed in public debate.

ISSUES RELATED TO

RESEARCH FUNDING

Public funding of biomedical technology involves

broad analyses of the economic benefits and costs,

as well as the social benefits and ethical consequences, a new technology might have. Knowledge

of economic consequences is necessary for financial

planning but it is also integral to ethical decisionmaking, since the allocation of public funds raises

questions about justice and equity. Some persons

believe that justice requires the expenditure of funds

in areas where they can benefit the greatest proportion of the population rather than a few disadvantaged individuals. If neural grafting techniques are

very expensive to study or to provide as medical

–149-
150 . Neural Grafting: Repairing the Brain and Spinal Cord

Box 8-A—Just Distribution of Resources and

the Funding of Heart Transplants

“On February 1, 1980, the 12 lay trustees of the

Massachusetts General Hospital announced their

decision not to permit heart transplants at that

institution ‘at the present time. They noted that it

was difficult to turn away even one patient in need

of a heart transplant, but they underlined the

importance of making such decisions ‘in terms of

the greatest good for the greatest number. ’ In June

of that same year, Patricia Harris, then secretary of

the Department of Health and Human Services,

withdrew an earlier tentative authorization for

Medicare to pay for heart transplants because of the

need to evaluate the technology’s ‘social consequences,’ including its costs. In 1987, legislators in

Oregon made an equally dramatic change in the

Oregon Medicaid program (the State-Federal program that provides funds to cover medical needs for

financially needy citizens in the State). They

decided not to pay for most transplants in order to

use their limited budget for other purposes, In

particular, they noted that the money that would

have covered approximately 30 heart, liver, bone

marrow, and pancreas transplants would instead be

used to provide regular prenatal care for 1,500

pregnant women. The altered allocation was justified by its proponents because it would save more

lives. ’

The controversy about the funding of heart

transplants is an example of the generic ethical

issues that may surround an expensive medical

therapy. Neural grafting could provoke similar

considerations.

SOURCE: T.L. Beauchamp and J.F. Childress, “The Principle

of Justice,” Principles of Biomedical Ethics (New

York, NY: Oxford University Press, 1989), pp.

286-287.

therapy, budget restrictions could require that neural

grafting activity be limited (see box 8-A).

Questions arise about whether the research and

application of technologies such as neural grafting

ought to receive Federal support. Some critics

consider it unjust to spend a great deal of money to

benefit a few persons or to develop a surgical

technique for a relatively uncommon condition

when the same funds might be used to develop

medical treatments that would benefit many more

persons. In order to determine whether expenditure

of public funds for neural grafting research constitutes just allocation of resources, some background

information is required. The following questions are

not ethical issues, but answers to them could help the

Federal government decide whether to fund neural

grafting.

What kinds of diseases might be treated

with this technology?

It has been argued that the government ought to

fund research that seeks to cure neurological disorders that affect large numbers of U.S. citizens (2).

Neural grafting is a possible therapy for Parkinson’s

disease, Huntington’s disease, Alzheimer’s disease,

spinal cord injury, and other neurological disorders,

although whether neural grafting will be successful

in any of these remains to be seen (see ch. 5).

What impact do these diseases currently have

on society and what threat do they hold

for the future?

Neurological disorders exact a high financial toll

from society, although measures of their costs and

statistics on the number of persons affected vary

considerably (see ch. 6). Neural grafting has been

suggested as a possible therapy for some age-related

diseases, e.g., Parkinson’s disease, Alzheimer’s

disease, and stroke. Should neural grafts prove

effective for such diseases and should the prevalence

of these diseases increase with an aging society, the

demand for neural grafts might increase as well.

What alternative surgical or medical

treatments are available?

If neural grafting is more effective and less

expensive than alternative treatments for neurological disorders, an ethical argument could be made for

Federal support of neural grafting. For most neurological disorders, however, including Parkinson’s

disease, Huntington’s disease, spinal cord injury,

and Alzheimer’s disease, no cures are available and

control of symptoms is inadequate. Symptoms of

Parkinson’s disease are often treated with L-dopa,

but this drug is palliative (it treats only the symptoms of the disease and not the cause), and its

benefits diminish as the disease progresses. Some

alternative treatments are available or in the process

of being developed. For example, a new drug called

deprenyl shows promise for slowing the progression

of Parkinson’s disease (see ch. 6), although it does

not stop the progression or affect advanced stages of

the disease (45). While neural grafting is a promising
Chapter 8-Ethical Issues ● 151

treatment for Parkinson’s disease at this time, it, too,

may be only palliative (see ch. 5). Fair allocation of

health care resources may require that the financial

costs of neurological disorders now and in the future

be estimated and compared to the costs of neural

grafting and alternative treatments. However, fair

allocation may also require that resources spent on

neurological disorders reflect the impact of these

diseases on society.

To what extent does the Federal Government’s

commitment to funding biomedical research

extend to neural grafting research?

Because neural grafting techniques are still being

studied, the question at this point is whether the

government has an obligation to support neural

grafting research. Given the government’s commitment to support basic scientific research and to

further the health of the Nation, it might be expected

that basic research which could aid in developing

new neural grafting technologies would be funded.

This is, in fact, the case: Only research on the

implantation of human fetal tissue from induced1

abortions does not receive Federal funds (53,57).

The moratorium on Federal funding for human fetal

tissue grafting research was declared because specific ethical issues surrounding this research came

into conflict with the government’s general commitment to fund basic research. The ethical issues

related to fetal tissue grafting will be discussed later

in this chapter.

Would funding neural grafting require the

government to redirect limited funds from

other areas of research?

It has been suggested that, in order to fund neural

grafting research, resources might be provided at the

expense of other projects that could lead to more

effective or less controversial treatments for neurological disorders (38) or increased “understanding

of the fundamental biological principles underlying

the normal function and dysfunction of the human

nervous system” (11). In general, Congress allocates funds for biomedical research to Federal

research agencies, but the distribution of those funds

to the institutes within the agencies and then to

individual investigators falls outside Congress’s

purview (12). Federal research grants are made on

the basis of merit, as determined through peer review

of research protocols. Neural grafting research

receives Federal funding when grant proposals

scientifically warrant that support. Withholding

research funds from neural grafting frees resources

for other projects, but there is no guarantee that those

funds will be put toward other neurological research.

ISSUES RELATED TO

TISSUE SOURCE

Questions about the propriety of federally funded

neural grafting research are not limited to resource

allocation-they also address the propriety of using

various graft materials. As discussed in chapter 4, a

number of neural grafting materials are used, some

of which are more ethically problematic than others.

Autografts and allografts using adult tissue are

relatively free of ethical controversy: For example,

the primary ethical reasons for not doing adrenal

medullary autografts to treat Parkinson’s disease are

likely to be related to protection of the research

subject rather than to the source of the grafting

material.

Fetal Tissue

Adult human neural tissue is not a suitable

material for grafting, so scientists have turned to

human fetal neural tissue. Fetal tissue is promising

from a scientific point of view, but it is also the most

ethically controversial grafting material because it is

usually obtained from abortions.

While use of aborted fetal tissue in research is not

new, the current ethical arguments surrounding its

use and the Federal attitude toward funding such

research reflect a different level of concern than has

previously been demonstrated. The use of human

fetal cells played an important role in the development of vaccines for polio and other childhood

diseases (20,48), and research on the transplantation

of fetal thymus glands into infants with DiGeorge’s

syndrome was performed in the United States 20

years ago (7,30). The National Commission for the

Protection of Human Subjects of Biomedical and

Behavioral Research (hereafter referred to as the

National Commission) scrutinized ethical issues

related to the use of fetal tissue in research and

l~e Department of He~~ and Human Services referred to “induced abortion” in the fetal tissue IIanSpk@XiOn mOrWOriUm (57).~e~tie

moratorium orFederal activity surrounding it is discussed in this chapter, “induced abortion” will be used. Where a distinction is made between different

types of induced abortio~ more specific terminology will be used.
152 . Neural Grafting: Repairing the Brain and Spinal Cord

developed the guidelines used to create the 1975

Federal regulations for use of fetal tissue in research

(52). The National Commission’s report and the

regulations that developed from it [45 CFR 46]

focused on research performed on living fetuses and

paid little attention to fetal cadavers. Both specified

only that research on cadaveric fetal tissue should

“be conducted in accordance with commonly held

convictions about respect for the dead, and in

accordance with State and local laws” (10). No

moral distinction was made about the means of fetal

death. As a result, research using aborted fetal tissue

for experimental purposes has been, and continues to

be, relatively uncontroversial. The moratorium on

Federal funding of research involving transplantation of human fetal tissue obtained from induced

abortions into humans is a recent exception (see app.

A).

Fetal Research v. Fetal Tissue

Transplantation Research

What makes transplantation research different

from other research that uses cadaveric fetal tissue?

Some persons perceive a significant ethical difference. In fetal research,2 cadaveric fetal tissue is used

to develop a treatment; in fetal tissue transplantation

research, fetal tissue is the treatment (43). These

persons question whether fetal tissue should be used

to benefit an individual recipient.

On the other hand, some persons perceive no

ethical difference between the transplantation of

cadaveric adult organs and tissues and those of

cadaveric fetuses. Unless the decedent has explicitly

refused to donate body parts, adult cadaveric tissues

may be donated by the next of kin as a gift and may

be removed for transplantation by a coroner or

medical examiner. Once these conditions are met,

tissues may be used to benefit a single recipient. In

this view, cadavers do not have protectable interests,

and tissue from dead fetuses is no different than

tissue from dead adults.

Procurement of Fetal Tissue

Most ethical objections to the use of fetal tissue

for neural grafting relate to tissue procured from

nontherapeutic induced abortions (to be referred to

hereafter as elective abortions) (see figure 8-l).

Many persons who object to the use of fetal tissue

from elective abortions have suggested that fetal

tissue from spontaneous abortions (miscarriages)

could be used for transplantation without ethical

objection because fetal death is not intended. The

first human fetal nervous system grafts used tissue

from spontaneous abortions (29), but since spontaneous abortions are seldom anticipated and usually

take place outside a hospital, it is difficult to collect

the tissue for grafting. Tissue from therapeutic

induced abortions for cervical cancer or ectopic

pregnancy has also been suggested as an ethically

unobjectionable alternative, since protection of the

pregnant woman’s life, not the termination of

pregnancy, is the primary purpose of the abortion.

There is some question, however, as to whether a

physiological anomaly that caused the pregnancy to

be terminated (as evidenced by spontaneous abortion, ectopic pregnancy, or cancer) would make the

tissue inappropriate for grafting (10,39). Ectopic

pregnancy is more likely to result from a physiological anomaly of the woman than a defect in the fetus

(17), but without thorough genetic and physiological

testing, the use of tissue from spontaneous and

therapeutic induced abortions for neural grafting

might be considered unethical because of the risk to

the recipient if the graft material is infected with a

virus or bacteria or has a genetic anomaly that could

affect the recipient (3,10,39). While grafting fetal

tissue from spontaneous abortions and therapeutic

induced abortions could avoid association of neural

grafting with elective abortion, it may not be a

practical source of graft material.

Some persons object to the use of electively

aborted fetal tissue for grafting because procurement

of the neural tissue might cause pain or even death

to the fetus. Research has indicated that neural tissue

from electively aborted fetuses between 8 and 12

weeks of development is the most clinically appropriate for neural grafting (48). This early stage of

development makes it unlikely that a fetus would be

viable after an abortion procedure (5). First-trimester

abortions are usually performed by vacuum aspiration, a procedure that seldom results in a live, or even

intact, fetus (10). Concern has been expressed,

however, that elective abortions performed at a later

gestational age might allow a fetus to survive the

procedure and that the separation of neural tissue for

the graft would not only cause great pain but could

me National Commission report and the Federal regulations for fetal research identify several types: activities &ted toward fetuses in utero as

subjects, activities directed toward viable fetuses ex utero, activities directed toward nonviable fetuses ex utero, and activities involving the dead fetus,

fetal material, or the placenta [45 CFR 46].
Chapter 8--Ethical Issues ● 153

Figure 8-l—Types of Abortion and Morally Relevant Differences Among Them

Without any qualification, the term “abortion” reveals nothing except that a pregnancy has ended.

This termination is not usually considered morally bad in itself. Spontaneous abortions may be

considered unfortunate but are not usually considered morally blameworthy. The abortions that usually

generate ethical controversy are those that are induced.

There are two types of induced abortions: therapeutic and nontherapeutic. Although some persons

object to any induced abortion on the grounds that the premature termination of fetal life constitutes

murder, others find that moral distinctions may be made, depending on the reason for the abortion.

Conditions such as cancer of the cervix or uterus and ectopic pregnancy will usually lead to the death

of both the pregnant woman and the fetus if the pregnancy is not aborted. If the life of the woman is

endangered by cervical cancer, the Roman Catholic Church teaches that “the treatment is not really an

abortion, even though the fetus dies. The intent of the action is the removal of the life threatening

rendition, and the death of the fetus is a foreseen but unintentional consequence.” Other persons argue

that when a fetus’s and a woman’s rights to life conflict, the woman’s life maybe saved at the expense

of the fetus’s. There are many other points of view on this question. Although there is some disagreement

as to whether a pregnancy maybe terminated if bringing the pregnancy to term will result in the death

of the woman but the birth of a baby, therapeutic induced abortion is not as controversial as

nontherapeutic induced (elective) abortion. Many reasons have been put forth for both the morality and

the immorality of nontherapeutic induced abortion.

SOURCES: Adapted from M.B. Mahowald, “Neural Fetal Tissue Transplantation: Should We Do What We Can Do?”

Neuro/ogic C/inics 7:745-757, 1989; A. Moraczewski, regional director, Pope John XXIII Medical, Moral,

Research, and Education Center, Houston, TX, personal communication, April 1990.

actually cause the death of the fetus (27). The use of

a living fetus for transplantation is a form of

vivisection, which is generally recognized to be

unethical and which, moreover, is prohibited by

Federal law: As long as the fetus is alive, its tissues

may not be removed for any research or therapeutic

procedure [45 CFR 46]. The distinction between a

live fetus and a dead fetus with living tissue is

extremely important in this regard.

Arguments For and Against Human Fetal Tissue

Transplantation Research

Arguments for and against using electively

aborted fetal tissue for neural grafting address the

issues raised by research already under way and the

future use of fetal tissue grafting on a large scale.

These arguments raise four main questions:

. Is the means of fetal death ethically relevant to

any subsequent use of the tissue?

. Is it ethical to use electively aborted fetal tissue

as therapeutic treatment for another individual?

. What are the ethical implications of a public

policy that supports fetal tissue transplantation

research?

● Whose consent, if any, is necessary for the use

of aborted fetal tissue for neural grafting?

Is the means of fetal death ethically relevant to

any subsequent use of the tissue ?-While disputes

over the morality of abortion have complicated and

politicized discussions about the use of electively

aborted fetal tissue for neural grafting, the ethical

relevance of an elective abortion to the transplantation of fetal tissue is the true subject of public

debate. Both opponents and supporters of elective abortion rights have articulated a number of

reasons for supporting fetal tissue transplantation research, and both have also identified

reasons for not doing so.

The main argument supporting fetal tissue transplantation states that there is no relevant difference

between the transplantation of cadaveric fetal tissue

(i.e., tissue from a dead fetus) and any other

cadaveric tissue. (This position has been taken by

both supporters and opponents of elective abortion.)

The argument, which claims that it is not unethical

to use tissue from elective abortion, is based on the
154 ● Neural Grafting: Repairing the Brain and Spinal Cord

premise that by the time the fetus becomes a possible

source of transplantation tissue it is already dead and

that the reamer of death is irrelevant to any

subsequent use. The NIH Human Fetal Tissue

Transplantation Research Panel compared the use of

tissue from a dead fetus and the use of tissue from

accident and murder victims. The persons from

whom organs are obtained are already dead, and

using the organs in no way harms them, deprives

them of respect, objectifies them, or uses them as a

means to another’s end. Neither does it indicate

approval of the death or the manner in which it was

brought about. On the contrary, using organs and

tissues from these victims is thought to allow some

good to come from their death and thus is morally

permissible.

Another argument suggests that there is a moral

obligation to help others when it is possible to do so

and thus it is unethical not to use tissue from elective

abortions. Some persons believe that since the

aborted fetus is already dead and its tissue legally

may be used for research and medical treatments,

and since fetal tissue grafts may benefit others,

preventing use of that tissue is ethically reprehensible. They believe that since the dead have no

interests to protect, using fetal tissue does not harm

the fetus physically or morally. They believe that

using cadaveric fetal tissue for grafts that relieve

suffering is morally good and thus perceive an

ethical imperative to use that tissue to help others.

Other persons disagree with the claim that the

means of fetal death is morally irrelevant to the use

of the tissue for grafting and perceive a moral

obligation not to use fetal tissue for transplantation.

Many of these persons also strongly oppose abortion. One argument is that using electively aborted

fetal tissue for neural grafting indicates indifference

to the means of fetal death. Another argument says

that using aborted fetal tissue for neural grafts

constitutes post facto complicity in murder (8).

Those who hold this position argue that because

abortion is murder, the procurement of fetal tissue

from abortion clinics requires collaboration with

murderers. For example, since surgeons who perform neural grafting must have access to fetal tissue,

they must work hand-in-hand with abortionists to

obtain the tissue while the cells are still alive. Unlike

surgeons who retrieve organs from murder or

accident victims, those who retrieve and transplant

aborted fetal tissue participate retroactively in the

killing by obtaining the consent of the pregnant

woman for use of the tissue (in cases where this is

done), by collecting fetal tissue from those who

perform abortions, and in some cases by killing

nonviable abortuses when separating neural tissue

for grafting.

Is it ethical to use tissue from an electively

aborted fetus as therapeutic treatment for another

individual?—While transplantation of cadaveric

tissues has become a common practice and is

regulated under the Uniform Anatomical Gift Act

(UAGA) in all 50 States (see ch. 7), some persons

object to the use of fetal tissue for transplantation

into individual recipients on the principle that one

should not treat the fetus as the means to another’s

end. They believe the “consideration of any class of

human subjects as no more than a commodity to be

used for the benefit of others is wrong” (27). They

do not believe that the alleviation of suffering

justifies the use of aborted tissue. In their belief, no

matter how good an outcome might derive from fetal

tissue transplantation, it does not justify the moral

devaluation of the fetus necessary for that outcome

to occur.

Other persons question why the transplantation of

cadaveric fetal tissue should be treated differently

from the transplantation of any other cadaveric

tissue. The use of cadaveric adult organs is rarely

regarded as indicative of disrespect, commodification, or devaluation (56). Why, then, should transplantation of cadaveric fetal tissue be considered a

moral devaluation? Some persons believe transplantation of cadaveric tissue into individuals is more

acceptable than using it for general research, since

‘‘it may do more good to heal than simply learn how

to heal” (31).

What are the possible consequences of a public

policy that supports fetal tissue transplantation

research?—Some persons are concerned that Federal funding of fetal tissue transplantation research

would lead to an increase in the number of abortions

performed in the United States. The Department of

Health and Human Services (DHHS) expressed this

concern in continuing the human fetal tissue transplantation research moratorium in November 1989.

These persons believe women may decide to abort if

they believe fetal tissue could help another person

and that women who are ambivalent about their

pregnancies will consider fetal tissue grafting a

justification for having an abortion (35). If fetal

tissue grafting research shows promise for Parkin-
Chapter 8--Ethical Issues . 155

son’s disease or other disorders, they argue, the

supply of fetal tissue will not satisfy the demand.

Elective abortion might implicitly or explicitly be

encouraged in order to make more fetal tissue

available. Some persons believe it would be ethically unacceptable if the ability to donate fetal tissue

for grafting influenced even one woman’s decision

to have an abortion (35).

Other persons disagree that elective abortion

would have to be encouraged to make fetal tissue

available for grafting. Some claim that the number

of elective abortions already being performed in the

United States would provide adequate tissue even if

neural grafting became standard practice (13). As is

the case with kidneys, hearts, and other body tissues

that are transplanted, the number of neural grafting

procedures performed could be limited to the

amount of fetal tissue already available (30). Also,

the development of continuous cell lines might make

it unnecessary in some cases to procure newly

aborted tissue. Fetal tissue might be used to start a

cell line without increasing the number of abortions

that take place and might not therefore be ethically

objectionable to some persons (34). Currently, there

is no evidence to support or refute the contention that

fetal tissue grafting research would cause an increase

in the number of abortions performed, either because

of a need for grafting material or because women

perceive an altruistic justification for elective abortion.

Women’s groups in particular have objected to the

claim that the opportunity to donate fetal tissue for

transplantation after an elective abortion would

affect a woman’s decision to terminate a pregnancy,

even if she did believe that this use of fetal tissue

would do good. Other persons argue that requiring

anonymity between tissue donors and graft recipients would make specified donation impossible in

the event that a woman wanted to provide neural

grafting material for a specific recipient.

Whose consent, if any, is necessary for the use of

aborted fetal tissue for neural grafting?--Consent

is generally required for participants in research

protocols and for donors of tissue. It is not certain,

however, what role consent would play in donating

fetal tissue for neural grafting research, and there is

debate about who should give it.

The donation of adult cadaveric tissue for transplantation, and fetal tissue in some States, is

32-801 0- 90 - 6 : QL 3

regulated under the UAGA (see ch. 7). As fetal tissue

grafting research progresses, the models for obtaining consent may have to be modified to include fetal

tissue donation, or a new model may have to be

created. Those who believe fetal tissue transplantation is analogous to the transplantation of other

cadaveric tissue find it appropriate for the next of

kin, in this case the woman who has the abortion, to

give consent to use fetal tissue for transplantation.

However, some persons challenge the woman’s

authority to give this consent, since, according to

their view, she is also the cause of the fetus’s death.

Consent for fetal tissue use in neural grafting falls

between existing regulations and practices.

Some persons hold that a woman’s prerogative to

donate fetal tissue stems not from her legal status as

next of kin, but from a basic right to control her own

body and its products. They believe that seeking

consent to examine or use fetal remains is consistent

with the treatment accorded any other tissue or organ

removed during surgery, thus to deny a woman the

opportunity to specify what should happen to

aborted fetal tissue would be to deny her autonomy

(10). Consent should be obtained out of respect for

the interests of the woman, who may want the tissue

to be handled a certain way after the abortion

procedure. For example, some women may hope to

benefit another person by donating aborted fetal

tissue for transplantation, while other women may

want to dispose of the tissue. Whatever the decision

and whatever the reason for it, these persons argue

that the decision should be the woman’s.

Some persons believe that fetal tissue is not the

woman’s to donate. They believe that no fetus is

property merely because it is sustained by another

person’s body; more important, they believe that

after the abortion has taken place and the fetus is no

longer part of the body, a woman’s claim to bodily

property carries even less weight (8,11). These

persons argue that the only reason to obtain the

consent of the pregnant woman would be for her to

act as proxy for a fetus to be used in research [under

the Protection of Human Subjects Act [45 CFR 46].

Proxy decisionmaking assumes the surrogate decisionmaker’s commitment to act in the interests of the

incompetent. Since the woman clearly does not

intend to protect the fetus, they believe it is

inappropriate for her to act as the fetus’ proxy; she

should have no say over what happens to the tissue

(8).
156 ● Neural Grafting: Repairing the Brain and Spinal Cord

The donation of cadaveric tissue need not be seen

strictly in terms of property or proxy, however. The

donation of adult cadaveric tissues by family members is done in the context of a gift-giving model that

neither recognizes property rights on the part of the

family nor grants guardianship or proxy. The fact

that the woman’s consent is obtained does not

necessarily mean she acts as proxy for the fetus,

since her role would be to consent to tissue donation,

not research participation. Some persons believe

fetal tissue donation is consistent with the accepted

gift-giving model for organ donation and constitutes

an altruistic act women are morally free to take.

Others, however, believe that electively aborted fetal

tissue is an inappropriate gift (10).

It has also been suggested that no consent is

needed to use fetal tissue for grafting research. Since

electively aborted fetal tissue is normally discarded

without any specification on the woman’s part, it

might be justifiable to consider the abortus abandoned and to use it without consent. This method

might avoid the obstacles created by views of

competing rights (the woman v. the fetus); however,

refusing to acknowledge protectable interests on the

part of either the woman or the fetus could be

interpreted as exploitation. Although tissues and

organs from adult cadavers can be used for transplantation without the consent of family members,

some women might prefer that the tissue not be used

for transplantation. Using the fetal tissue without the

consent of the woman could create more problems

than it solves.

If it is decided that it is ethically appropriate or

necessary to obtain the woman’s consent, the

question of when to solicit consent is raised. There

is some agreement that consent should be obtained

only after the woman has conclusively decided to

abort, in order to separate the decision to abort from

the decision to donate fetal tissue (1,32,48,54). It

may also be possible to obtain consent tier the

elective abortion has been performed and the tissue

has been identified as suitable for transplantation,

especially if the tissue is frozen before transplantation, although this option is not entirely free of

ethical problems (see box 4-A).

The protocol used in one privately funded fetal

tissue transplantation trial solicited consent from the

woman after the abortion had been completed (16).

The consent form specified that fetal tissue was

being solicited for research purposes, which could

include fetal tissue transplantation research. This

approach provides the woman an opportunity to

prevent the use of the tissue for grafting, while not

influencing her decision to maintain or terminate the

pregnancy. Other investigators may choose not to

request consent immediately after abortion because

it could be emotionally stressful for the woman (14),

although some persons believe that there is no

difference between requesting consent for tissue

from a woman who has just aborted a pregnancy and

requesting organ donation from the family of a

deceased adult.

The consent forms used for other fetal tissue

research may not be comprehensive enough to

address all aspects of grafting. It is not clear whether

the abortion consent forms which allow fetal tissue

to be donated for research should include clauses

specifying that the tissue might be used for transplantation. A separate consent form for fetal tissue

transplantation might be appropriate.

Relationships Among the Questions-Attitudes

toward consent for the donation of fetal tissue for

transplantation are likely to be consistent with

beliefs about the relevance of the means of fetal

death to fetal tissue transplantation, the appropriateness of using cadaveric fetal tissue for therapeutic

purposes, and the ethical implications of public

policy that supports this research. The present

discussion delineates issues for the sake of illustrating different aspects of the debate, but the arguments

of individuals and groups who discuss the ethics of

fetal tissue transplantation research are often more

fluid.

For example, some persons who oppose fetal

tissue transplantation research because they believe

such grafting is complicitous with murder readily

link three of the four questions discussed above.

They feel that the means of fetal death is relevant to

grafting fetal tissue because elective abortion is the

unjust killing of innocent human beings. A woman

who has an abortion therefore should not serve as its

proxy. Public support should not be given to fetal

tissue transplantation research because it would

constitute public approbation for unjust killing (26).

Similarly, some persons who do not object to fetal

tissue grafting research argue that the means of fetal

death is irrelevant. They believe that once a fetus is

dead, it has no interests to protect and maybe treated

in the same reamer as adult cadaveric tissue.

Consent for its use should therefore be solicited from
Chapter 8--Ethical Issues ● 157

the next of kin, which in this case is likely to be the

woman who has the abortion. These persons feel that

public support of fetal tissue transplantation research would be consistent with other fetal tissue

research and cadaveric organ donation and would

have no specific ethical implications.

Issues Surrounding Fetal Tissue Transplants as

Standard Therapy

The preceding arguments have been presented in

public debates about the ethical implications of fetal

tissue transplantation research. Some of the potential

problems can be illustrated dramatically by describing the consequences should fetal tissue grafting

become standard therapy. (“Standard therapy”

describes procedures that are no longer regulated as

research.)

Some persons have expressed concern that Federal support of fetal tissue transplantation through

funding or regulation of the procedure would

legitimize and institutionalize elective abortion.3

Others persons contend that since elective abortion

is legal, and since the Federal Government profits

from it by taxing abortion clinics (3), it is already

both legitimate and institutionalized. They argue

that claims that Federal support of neural grafting

research would further institutionalize the practice

carry no weight. Fetal tissue from elective abortions

would be used after the abortion has already taken

place and would have no effect on law or policy

concerning abortion itself. Still other persons believe that even though elective abortion is legal, it

should not be encouraged. If fetal tissue transplantation is accepted as a medical treatment, they believe

it maybe impossible to make abortion illegal again.

Even some persons who support the freedom to have

an abortion do not necessarily consider it a practice

they would like to see endorsed by a public policy;

i.e., while abortion should be legal, it does not follow

that fetal tissue should be used for neural grafting.

Another concern is that the use of electively

aborted fetal tissue as standard therapy may lead to

commercial exploitation of fetuses. This concern has

also been expressed in more extreme terms: Some

argue that using aborted fetal tissue for neural

grafting may make it a commercially desirable

commodity and lead to the establishment of a fetal

tissue industry. As in the development of reproductive technologies and the increase of surrogate

motherhood, the growing demand for neural grafts

might cause the fetus to be increasingly perceived

only as a potential source of grafting material. It has

been argued that the fetus should neither be endowed

with a financial value, as it would be in a commercial

exchange, nor be conceived for the sole purpose of

using its tissue for transplantation (1,13,48,54). In

1988, the National Organ Transplant Act was

amended to prohibit the sale of certain fetal organs

and tissues, although neural tissue is not specified

[Public Law 100-607].

Precautions against this consequence have been

suggested. If it were likely that women could be

coerced into conceiving and aborting in order to

provide fetal tissue to benefit others, profit restrictions might create a disincentive. Payments to

women who abort, including compensation for the

cost of the abortion procedure, might be prohibited,

as might payments to doctors, clinics, or any other

parties involved in the abortion procedure. Tissue

banks used to distribute fetal tissue maybe prohibited from profiting from their role. To prevent

women from conceiving in order to provide tissue

for grafts, specification of tissue recipients, including the woman herself, might also be prohibited

(1,32,48,54).

Concern has been expressed that women, as the

‘‘producers’ of fetal tissue, could also be commercially exploited in order to obtain tissue in adequate

quantities and of useful gestational age. There has

been some suggestion that women who are ambivalent about terminating their pregnancies may be

vulnerable to coercion by a physician who wants the

fetal tissue for research or for another patient. This

threat might be removed by requiring absolute

separation of the doctors who perform abortions and

those who do transplantation. One way to accomplish this might be to establish tissue banks for fetal

tissue distribution, as is being done in Great Britain

(44).

On the other hand, there have been strong

objections to the assumption that women have

limited abilities to make their own reproductive

choices and that they can be easily coerced. Similar

concerns have been raised about women who act as

3~@~tion is described by the center for Biom~icalEthics (10) as the justifkation of an act or practice “in such a manner that Others become

more inclined to regard it as acceptable and to engage in it. ” Institutionalization may be seen to carry legitimation one step further, in that institutions

(in this case the U.S. Government), by incorporating a practice, accept and engage in it, and in some cases profit fmncially from it.
158 . Neural Grafting: Repairing the Brain and Spinal Cord

surrogate mothers. The charge that the practice of

surrogacy exploits women has been called paternalistic because:

It questions women’s ability to know their own

interests and to enter into a contractual arrangement

knowingly and competently. There may well be a

coercive aspect to commercial surrogacy, since

money. . . can serve as a coercive inducement to do

something a person might not otherwise do voluntarily. . . . What they are really saying is that those who

elect to enter surrogacy arrangements are incompetent to choose and stand in need of protection (28).

Many persons also have rejected the argument that

women need to be protected from solicitation of fetal

tissue.

The question of whether a woman’s medical care

might be altered (either with or without her consent)

in order to obtain tissue of an appropriate gestational

age and in the best possible condition for grafting

has also been raised (33). There is general agreement

that the means and timing of an abortion should be

based on the pregnant woman’s medical needs and

not on the future use of the fetal tissue (32,48,54). On

the other hand, not all variations in medical treatment will cause harm to the woman. Requiring that

the woman’s medical care always be placed first,

that the timing and method of abortion not be altered,

that separate doctors perform abortion and neural

grafting procedures, and that only first-trimester

abortuses be used might ensure that obstetrical care

is not compromised for the sake of neural grafting.

Some fear that using electively aborted fetal tissue

for grafting would gradually erode respect for

human life. This argument can be seen in terms of a

slippery slope, and what is perched at the top of the

slope is our view of humanity. The concern is that,

as society becomes accustomed to a new technology

and its social consequences, social effects which

now seem extreme or immoral might become

acceptable. The increments by which society moves

toward policies that are now appalling to some

persons may pass unnoticed, and the result might be

a society that by current standards is ethically

unacceptable. A gradual acceptance of new developments, however, does not necessarily mean that

ethical standards erode. Another interpretation of the

same evidence might be that society learns from

experience and that as current fears are proven

unfounded or preventable, they are cast away.

When the practice of retrieving organs from

accident and homicide victims first began in the

1960s, many persons held similar fears about

whether transplanting those organs was morally

acceptable without the prior consent of either the

deceased or the deceased’s next of kin (21). This

concern was alleviated to a large extent as it became

clear that cadaveric tissue could be transplanted

without violating most ethical standards for treatment of the dead [although some religious traditions

continue to oppose the practice (40)]. Each State

established standards for the use of cadaveric tissue

that respected not only the cadaver, but the families

who were asked to make the decision to donate.

Although familial consent for cadaveric organs is

not a legal necessity in all cases, it is customarily

obtained before organs are removed. This practice

has alleviated many fears about moral violations

against both the deceased and the living. Fetal tissue

use might be regulated in a similar manner.

There is some concern that, since there is no

distinct time when a procedure stops being research

and becomes standard therapy, fetal tissue grafting

might be put into widespread use despite ethical

objections to it and without ethical norms to guide it

(see ch. 7). If such research becomes standard

therapy, there may be no way to control or restrict its

use, even if ethical reasons are found for doing so. If

an experimental therapy, especially one funded with

tax dollars, proves successful, it might be extremely

difficult to deny that treatment to a demanding

public, whatever social and ethical consequences it

might have and whatever alternative treatments

might be forthcoming. It can also be argued that it is

unfair to withhold a treatment from the taxpayers

who funded the research that developed it.

It is not necessarily the case, however, that fetal

tissue grafting techniques will become standard

therapy (41). While it is reasonable to expect that

they will, continuing research could reveal information about the etiologies of diseases and the mechanisms of neural repair that suggest better or less

controversial alternatives to fetal tissue. Fetal tissue

transplantation research may lay the groundwork for

other therapies without ever being used widely itself.

In that case, present concerns could prove unfounded.

At this stage of scientific research it is difficult to

predict accurately what the consequences of widespread fetal tissue grafting are likely to be. By the
Chapter 8--Ethical Issues ● 159

time adequate research has been done and a procedure is proven effective, there maybe a more certain

factual basis for any ethical discussions. At the same

time, Federal standards for the procurement of tissue

and regulation of technology transfer might prevent

many of the anticipated consequences.

Cell Lines

Continuous cell lines (CCLs) promise selfperpetuating cells that can be propagated indefinitely. When the small number of cells used to

initiate a cell line are derived from a consenting

participant, there are few ethical implications related

to the tissue itself, although there may be questions

of ownership of the cell lines (50). CCLs derived

from fetal tissue may be one of the more scientifically promising neural grafting materials, but ethical

issues arise from the fact that cadaveric fetal tissue

may be used to start them, and ownership of the

tissue will be difficult to determine.

The use of CCLs could either perpetuate or

resolve the debate about the use of electively aborted

fetal tissue for transplantation, depending on which

of the arguments described in the previous section

are accepted. Those who believe that elective

abortion is immoral and that any subsequent use of

the tissue is also immoral are likely to object to fetal

tissue CCLs for the same reason they object to fetal

tissue transplantation (8).

Objections may be weaker, however, on the part

of persons who object to fetal tissue transplantation

on the grounds that it might promote abortion

(11,34), decrease the value of human life, or use the

fetus as the means to another’s end. Theoretically,

only a few cells from a fetus would be needed for all

future fetal tissue grafting. Thus, far less tissue

would be needed to start a CCL than would be

needed to provide a neural graft. If fetal tissue from

spontaneous or therapeutic abortions is thoroughly

tested for any genetic anomalies or disease, such

tissue might be used for cell lines, ensuring that fetal

tissue grafts will not increase the number of elective

abortions that take place. Using CCLs might also

make it improbable that a woman would conceive in

order to provide aid to a specific recipient. Continuous fetal cell lines may make it possible to use fetal

tissue for transplantation without leading to anticipated undesirable consequences.

Ownership of Tissue Used in Cell Lines

The question of whether the person whose cells

are used to start a cell line has proprietary claim over

the line is another new and as yet unresolved issue.

A California appellate court ruled in 1988 in Moore

v. Regents of the University of California (37) that

a plaintiff whose tumorous spleen was used to start

a commercially profitable CCL without his permission has property claims over his body tissues and

any commercial products derived from them. The

California Supreme Court reversed this decision in

July 1990-the majority, consenting, and dissenting

opinions were all based on ethical concerns, although they reached different conclusions (see box

8-B). Until this issue is decided by legislative action

or the U.S. Supreme Court, however, there are no

clear legal rules for identifying property rights over

body parts.

The question of ownership of fetal CCLs adds to

the confusion. Claims that women have property

rights over fetal tissue have been challenged in

debates about abortion and consent for tissue donation, and these claims may be more contentious if

bodily property becomes marketable.4 Because the

development of CCLs can be very profitable,

questions of ownership of body tissues and cell lines

derived from them have become increasingly important.

As previously discussed, it has not been established whether the basis for requiring consent for the

use of aborted fetal tissue from the woman who

elects the abortion is an acknowledgement of her

ownership or her guardianship of fetal tissue, or even

whether her consent is seen as appropriate at all. If

fetal tissue donation is an act of altruism, the same

justification used for other types of fetal tissue

research may hold. It is arguable, however, that

altruism is not the motivation for a gesture that could

be extremely profitable to the person who gives

consent. If the consent requirement is based on an

assumption of ownership, consent provides a means

for the donation of personal property. But should a

pregnant woman be considered a partial owner of the

cell line, based on proprietary rights? Is it ethical to

regard the woman as the owner of fetal tissue that

can be used in a commercial undertaking? Is she

4,,htie Moore ~me, rheappelkkcomheld tit “O 00 even though full property rights are not recognized in a dead body, a limited property interest

has been found. . . . Eowever, w]e are not called upom nor are we attempting, to resolve the complex issues relating to the human fetus’’.
160 ● Neural Grafting: Repairing the Brain and Spinal Cord

Box 8-B—Moore v. Regents of the University of California

The case John Moore brought against the investigators who used his body tissues to start a commercial

continuous cell line raises fundamental questions concerning a patient’s right to the control of his or her own body

and whether the commercial exploitation of a patient’s cells by medical care providers, without the patient consent,

gives rise to an action for damages.

In 1976, Moore sought medical treatment at the Medical Center of the University of California, Los Angeles,

for a condition known as hairy-cell leukemia As a necessary part of the treatment for this disease , Moore’s spleen

was removed.

Without the patient’s knowledge or consent to donate his cells for research, the medical staff examined the

excised tissue and determined that Moore’s spleen cells had unique qualities. Through genetic engineering, they

developed from the spleen cells a cell line that is capable of producing pharmaceutical products of enormous

therapeutic and commercial value. The university patented the cell line, along with methods of producing many

products from it, The university also entered into a series of commercial agreements for rights to the cell line and

its products with two corporations. The commercial value of the products was predicted to be approximately $3

billion by 1990.

Moore sued the university and the corporations on several grounds, one of which was that “had he known what

was taking place, he would not have consented to the splenectomy for these research and commercial activities;

would have insisted on participating in control of the use of his blood and bodily substances; would not have

permitted these materials to be used by defendants solely for their independent research, commercial activity, and

economic benefit; would have considered treatment at another medical facility where his wishes would have been

carried out; and would have sought participation in the economic benefit.

The first court dismissed the case. The appellate court found that:

The Protection of Human Subjects in Medical Experimentation Act, adopted m 1978, expresses a strong public

policy that medical experimentation on human subjects "shall be undertaken with due respect to the preciousness of

human life and the right of individuals to determine what is done to their own bodies” [Cal. Health & Safety Code

24171] [emphasis added]. . . . The essence of a property interest-the ultimate right of control--therefore exists with

regard to one's own human body.

The California Supreme Court found in July 1990 that:

Neither the Court of Appeals’ opinion, the parties' briefs, nor our research discloses a case holding that a person

retains a sufficient interest in excised cells to support a cause of action for conversion. . . . There are three reasons

why it is inappropriate to impose liability for conversion based upon the allegations of Moore’s complaint. First, a

fair balancing of the relevant policy considerations counsels against extending the tort. Second, problems in this area

are better suited to legislative resolution. Third, the tort of conversion is not necessary to protect patients’ rights.

Rather than deciding on property rights over body tissues, the Supreme Court held:

. . . that a physician who is seeking a patient’s consent for a medical procedure must, in order to satisfy his fiduciary

duty and to obtain the patient’s informed consent, disclose personal interests unrelated to the patient’s health, whether

research or economic, that may affect his medical judgment.

This decision applies only to California Without congressional action or a ruling by the U.S. Supreme Court, State

courts and legislatures are free to decide for themselves whether an individual who donates body tissue should be

thought to own it or be able to profit from its use in the development of cell lines and other biologics.

SOURCES: Moore v. Regents of tbe University of California, 202 Cal. App.3d 1230,249 Cal. Rptr. 494 (1988), reh. granted, 252 Cal. Rptr.

816, 763 P.2d 479 (1988); Moore v. Regents of the University of California, Supreme Court of the State of California, case No.

S006987, July 9, 1990.

entitled to profit from the fetal cell line, or would that any profit from products of her own body but

constitute exploitation of the fetus? allowing others to-profit may be exploitative of and

discriminatory against those women.

It might be possible to prevent women who donate

fetal tissue from profiting from cell line develop- Waiving the consent requirement might be one

ment, but what about allowing investigators to profit way of avoiding these pitfalls. This would indicate

from the cell line? This, too, could be perceived as that a woman does not have proprietary rights to the

exploitation of the fetus. Also, denying the woman fetus and that a proxy donation is inappropriate in
Chapter 8--Ethical Issues . 161

this case. It might ensure that fetal tissue is not

donated purely for personal profit and eliminate

competition for women to donate their fetuses in

order to profit. On the other hand, if consent is not

obtained from women, this omission could be seen

as denial of autonomy or exploitation. The recent

Moore decision could make patients more reluctant

to donate tissues and organs for research.

The question of ownership of fetal tissue used for

CCLs will have to be addressed by State or Federal

legislatures at some point. The fact that cell line

development may be financially profitable complicates fetal tissue donation for scientific purposes. If

a woman who undergoes an abortion donates fetal

tissue for cell line development and profits from the

cell line, it could be perceived as exploitation of the

fetus. If she does not receive any payment from a

commercially profitable cell line, but other persons

do profit from it, it could be perceived as exploitation of both her and the fetus. If consent is not

obtained from the woman, it may constitute a denial

of her autonomy. Finally, if one believes that the

individual from whom cells are obtained to start a

CCL is the only one who should consent to this use,

then consent should only be obtained from the fetus.

Should fetal tissue cell lines be prohibited? Should

the scientists who develop cell lines be denied the

opportunity to profit financially from them? Are

there justifications for using fetal tissue to start

CCLs that make it unnecessary to decide whether

fetal tissue ought to be considered property? These

questions are only beginning to be addressed.

Genetic Manipulation of Cells Used for Grafting

Genetically modified cells have been used for

neural grafting in animal experiments. The possibility of using them in humans raises the question of

whether it is ethical to manipulate genes that would

be passed on to future generations. As this debate has

developed, it has become clear that somatic cell gene

therapy (which modifies the DNA of certain differentiated cells in the body that cannot be passed to

offspring) is relatively uncontroversial; it is germ

cell gene therapy (which modifies undifferentiated

cells that may later become gametes and thus may be

passed to offspring) that creates concern (49).

Genetic manipulation of CCLs for neural grafting

would constitute somatic cell gene therapy and thus

remove any possibility of inheritance.

Many of the fears expressed about genetic manipulation have to do with possible eugenic misuses—

namely, the use of gene therapy to promote or

exaggerate desired qualities in individuals rather

than to correct anomalies that lead to illness. At this

time it is difficult to see how gene therapy could be

performed on cells for enhancement purposes: Not

enough is known about the brain to design grafts that

would improve particular physical or intellectual

abilities. Instead, gene therapy might be used to

design grafts that could alleviate specific neurological disorders in a host—by producing neurotrophic

factors or neurotransmitters, for example. Grafts

could be engineered to compensate for specific

deficiencies in the recipient.

ISSUES RELATED TO GRAFT

RECIPIENTS

Neural grafting also presents ethical issues related

to the graft recipients. These ethical questions exist

for any new procedure, but they may be especially

pertinent to clinical (human) trials of neural grafting.

Federal law dictates that federally funded protocols must be sent to an Institutional Review Board

(IRB) for approval of the legal and ethical features

of protocol design [45 CFR 46], particularly features

relating to treatment of research subjects. Of the

seven criteria for IRB approval of research, two may

pose problems for neural grafting research. These

are the requirements that risks to subjects be

reasonably comparable to the expected benefits and

that the investigator obtain the subject’s informed

consent to participate in research.

Risks to Research Subjects

Risks to subjects are always difficult to determine

at the beginning of clinical trials; it has been

suggested that the lack of knowledge about how

grafts work may make the risks associated with

neural grafting particularly difficult to determine

(27). The question that arises when anew therapy is

presented for experimentation on human subjects is

whether there is evidence that it promises significant

benefit to the patient and does not present undue risk.

This risk-benefit analysis is performed by several

parties involved with the research protocol: the

investigator, the IRB, and the prospective research

subjects and their families.

Considerable debate surrounds the experimental

use of fetal and adrenal tissue grafts to treat persons

with Parkinson’s disease (see ch. 5). In fact, some

persons believe investigators had not gathered

.
162 . Neural Grafting: Repairing the Brain and Spinal Cord

enough data from animal studies to warrant progressing to clinical trials (22,36) and, therefore, may

have been unable to meet their responsibilities to

vulnerable human research subjects. Some persons

claim that it is impossible for investigators or

subjects involved in neural grafting research to

balance risks and benefits unless they can estimate

realistically what those benefits and risks will be.

That claim, however, may be made of all clinical

research (25). Some persons have argued that the

patient undergoing neural grafting for the treatment

of Parkinson’s disease may be risking more than is

justified if the graft is unsuccessful, if it is affected

by the same neurodegenerative processes that made

the graft necessary in the first place (19,27) [although it has been pointed out that the original

degeneration in Parkinson’s disease takes place over

the course of several decades (5)], or if there is a

delayed immunological response to the graft that

proves more harmful than the disease.

Information should be obtained from the least

possible amount of research conducted during the

shortest possible period of time (9). The number of

trials performed is another important consideration

in protecting research subjects from unnecessary

risks. Some observers suggest that controlled studies

and pooled results from different locations may be

the most efficient means of deriving data. This

suggests single-protocol research pursued at multiple centers, formation of a comprehensive database,

constant monitoring and interpreting of data, as well

as constant updating of information given to subjects

for informed consent (18). On the other hand, if

neural grafting research on a particular disease is

deemed an important public health priority, it might

proceed more quickly and in accordance with

diverse research protocols. In order for the transition

to be made from clinical trials to therapeutic use in

this case, many more patients will have to be enlisted

as subjects; the human costs, as well as the medical

and research costs, may be very high (18).

Informed Consent

One important ethical question is whether neural

grafting protocols conform to standards of protection for research subjects. Since informed consent

requires “[a] description of any reasonably foreseeable risks or discomforts to the subject [and] a

description of any benefits to the subject or to others

which may reasonably be expected from the research’ [45 CFR 46.116], each patient must conduct

e

a risk-benefit analysis of his or her own. This entails

two kinds of information, the scientific and the

personal (15). The first is made up of the objective

data about the disease, alternative treatments, and

social support systems and agencies; the second

encompasses the subjective data related to the

patient’s experience.

The objective data for this analysis must be

provided by the researcher. It should include the

prognosis if the disease runs its course, the availability of alternative treatments, the fact that the

procedure is experimental, the extent of uncertainty

involved in the surgery, the intended and possible

long-term outcomes of surgery, the availability of

social support systems and agencies to aid recovery,

and a thorough description of what the surgery will

involve, including the pain and suffering likely to

accompany the procedure and the immediate recovery from it, as well as risks of complications. The

hard data will vary depending on the disease, the age

of the patient, and the type of graft used.

The subjective data needed for a risk-benefit

analysis can only come from the patient, for they

involve the patient’s perception of his or her quality

of life. Quality of life is a concept that describes the

experience of the individual, what kind of life is

possible given the person’s condition, and whether

that condition will allow the individual to have a life

that he or she views as worth living (23). There may

be differences, however, between how a person

perceives the quality of his or her own life, how an

observer assumes he or she perceives the quality of

his or her life, and how an observer evaluates the

quality of that person’s life (51). The severe physical

and emotional suffering associated with neurological disease and injury are frequently thought to

create poor quality of life, but it is important that

patients have the freedom and medical information

necessary to make their own quality of life evaluations.

The same conditions that depreciate the quality of

life of individuals with neurological diseases and

spinal cord injuries may make these persons especially susceptible to coercion. While the possibility

of undue influence exists in any research situation,

patients with neurological disorders may be especially vulnerable to judgments about their quality of

life made by researchers or family members. One

reason is that patients who have an apparently

permanent injury or an incurable disease may be
Chapter 8--Ethical Issues ● 163

tempted to try anything that might be of help. In

many cases, there are few or no alternative treatments or support services for neurological disorders,

and what treatments there are may have limited

efficacy. For some patients, this lack of alternatives

constitutes sufficient reason to participate in neural

grafting research. A necessary condition for all

research subjects, however, is that they be free to

make uncoerced, informed choices.

Some patients with neurological injuries or disease may be incapable of performing the ethical

cost-benefit analyses necessary for truly informed

consent (6). In these cases, a patient may have to rely

instead on the judgment of a family member or legal

guardian. The proxy decisionmaker should attempt

to evaluate the quality of the patient’s life on the

same basis the patient would have used. Open

communication about what investigators and patients (or their proxies) perceive as the relevant

factors in the decision to participate in research is

necessary if a patient is to do a risk-benefit analysis

without coercion. Given adequate scientific data by

the researcher, the patient or proxy can predict more

realistically what benefits the patient is likely to gain

by undergoing neural grafting surgery.

Three factors make it difficult for investigators to

give accurate information about the probable risks

and benefits of neural grafting procedures. First, it is

uncertain at this early stage of research what the risks

and benefits of neural grafting are likely to be.

Second, it maybe tempting for investigators to paint

a more positive picture than is warranted because of

their own high expectations. Finally, researchers

may filter empirical evidence through their interpretations of the patient’s current or future quality of

life, rather than allowing patients to draw their own

conclusions (18). These factors apply to all clinical

research, but sensitivity to limitations may be

especially important for neural grafting research.

The solicitation of informed consent from neurological patients or their families must be done with their

vulnerability in mind, making clear to the patient or

family the degree of uncertainty for the experimental

procedure. Although it is impossible in any research

setting for a patient to be totally informed of risks

and benefits, in the case of neural grafting it may be

extremely important for patients to be aware of the

scientific limitations at this time.

There may be reasons besides possible changes in

quality of life for an individual to turn down the

opportunity to receive a neural graft. For some

subjects, neural grafting presents a chance for

medical science to overcome disease; but for others,

neural grafting may present a threat to personal

identity and sense of self, aspects of the human mind

that are, to some persons, the very essence of

humanity (18). The ability to do neural grafting

raises questions about whether the mind can be

explained in terms of the brain. It is difficult to know

what physical functions of the brain define a

person’s existence as a unique individual or are

essential to the retention of his or her personal

identity across time. Consequently, some would

argue, there is no way to predict the extent to which

neural grafting in the brain will or will not interfere

with the functions of the mind that determine

individuality, personhood, or a sense of self. These

are metaphysical questions rather than ethical ones,

but they are important considerations for persons in

a position to receive neural grafts.

SUMMARY AND CONCLUSIONS

Neural grafting includes a variety of materials and

surgical procedures used to investigate and treat a

number of neurological disorders. As the grafting

materials and techniques viny, so do the ethical

issues surrounding them. Whether the Federal Government becomes involved in funding or regulating

fetal tissue grafting or not, research in fetal tissue

transplantation continues.

Some of the ethical issues surrounding neural

grafting are common to any new area of biomedical

research or treatment. They include whether to use

public funds to support neural grafting research or

neural grafting as a standard medical treatment.

They also include economic questions about how to

establish health-care priorities and how to allocate

resources for research.

There are currently few alternative treatments for

neurological disorders. Some persons feel that,

because neural grafting is an exciting and possibly

profitable area of research, it may get more support

than alternatives and reduce the impetus to find less

expensive, less risky, and less controversial treatments for neurological disorders (38). Decreased

support for neural grafting research, however, does

not necessarily make funds available for research

into other treatments for neurological disease and

injury (12). In order to resolve some of the questions

about fair distribution of resources, it might be
164 Neural Grafting: Repairing the Brain and Spinal Cord

helpful to evaluate neural grafting in relation to

treatments for other diseases and other treatments for

neurological disorders, keeping in mind the priorities set and the amount of research funded. In order

to make decisions about funding neural grafting

research, it will be necessary to estimate the efficacy

of the technology, the number of people now

affected by neurological disorders, and the number

of people likely to be affected in the future.

Ethical issues arising from the surgical procedures and the materials used in the neural grafting

process also demand attention. Some of these issues

are analogous to issues that have been dealt with

already and are reflected in Federal regulations; e.g.,

informed consent and the protection of research

subjects were addressed in the 1970s. Existing

regulations, however, may not adequately protect

neural graft recipients from the risks unique to brain

implantation surgery. The possibility of doing a

sufficient risk-benefit analysis has been challenged

on the grounds that not enough animal research has

been done to know what the benefits of neural

grafting are likely to be. Obtaining informed consent

from persons with neurological disease may be

difficult, both because the risks and benefits cannot

be realistically estimated at this time and because of

the possible cognitive limitations of persons with

some neurological disorders.

On the other hand, there are several reasons why

the Federal Government should not involve itself in

surgical development. Research risks to the subject

are almost always unknown in early clinical trials

(24). Furthermore, much surgical innovation, including neural grafting, is therapeutic as well as

experimental (25) and, therefore, may be more likely

to hold the promise of benefit for the subject

[although some commentators have called “therapeutic research” an oxymoron (46)]. Neural grafting

investigators should conduct research in a noncoercive manner consistent with the treatment of other

research subjects. While it is important for persons

developing new surgical techniques to be aware of

moral considerations, ethical and practical arguments may be made for allowing, even encouraging,

such innovation.

Thus far, the greatest ethical controversy surrounds the use of fetal tissue from elective abortions

for neural grafting. Positions taken on the morality

of fetal tissue grafting, however, do not depend

strictly on a person’s beliefs about the morality of

elective abortion. Both supporters and opponents of

abortion have articulated reasons for denying funding for fetal tissue grafting research, and both have

identified reasons for providing it. Tissue from

spontaneous abortions, ectopic pregnancies (42),

and fetal tissue cell lines have been suggested as

ethically acceptable alternatives.

Many different positions are taken regarding the

ethics of using fetal tissue obtained from elective

abortions for neural grafting. Some of these considerations include the implications of a public policy

that either supports or restricts the use of aborted

fetal tissue for grafting and the possible consequences of such a policy. It has been suggested that

using electively aborted fetal tissue for neural

grafting will both harm individual fetuses and deny

fetuses respect. It has also been suggested that

groups besides fetuses-e. g., women and society at

large-may be adversely affected by a policy that

endorses fetal tissue transplantation. A number of

the arguments against fetal tissue transplantation are

based on predictions about its future social effects.

While it is important to anticipate potential problems, it is impossible to know at this time whether

the consequences predicted will come to pass.

Some persons believe that once a fetus is dead, it

no longer has interests to protect and that it is

inappropriate for the Federal Government to withhold funding for research that may benefit many

sufferers of neurological disorders. A number of

groups in the United States and abroad have

proposed safeguards for protecting social values and

vulnerable groups, while allowing biomedical science to move forward (32,48,54,55) (see app. A, box

A-2). It has been suggested that these protections

would be most effective with Federal involvement in

the research process (4,47). Despite the similarities

of the safeguards recognized by the various study

groups and the fact that both existing DHHS

regulations and Federal laws already implement

many of the suggested guidelines (58), some persons

remain skeptical about the feasibility of implementing these measures.

The solicitation of consent for the use of tissue

from cadaveric fetuses presents another ethical

question. Controversy exists about whether the

woman who elects the abortion is the appropriate

person to give consent and when consent should be

solicited. Both the regulations for the protection of

research subjects and those for the donation of
Chapter 8--Ethical Issues ● 165

cadaveric body parts can help in determiningg the

appropriate donor of electively aborted fetal tissue,

but these regulations do not explicitly cover the

donation of fetal tissue for transplantation research.

The use of fetal tissue to start continuous cell lines

further complicates the issue of consent, because

questions are raised about whether the donor of

tissue used to start a CCL may profit financially

from it. Although it maybe deemed appropriate for

a woman who aborts to give her consent to use of

fetal tissue, it may not be considered appropriate for

her to profit financially. While questions regarding

the ownership of tissues used for commercially

profitable cell lines are being addressed by the

courts, discussion has been limited to the ownership

of adult tissues. Questions pertaining to the proper

treatment of fetal tissue remain unanswered.

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32-801 0- 90 - 7 : QL 3
Appendixes
Appendix A

DHHS Moratorium on

Human Fetal Tissue Transplantation Research

While human fetal tissue transplantation research is a

promising and exciting area of scientific study at this

time, it has also created considerable controversy. The

public debate is in one sense a straightforward, although

complicated, discussion about the ethics of public funding

of research that uses electively aborted human fetal tissue.

for transplantation; however, the Federal Government’s

response to the controversy has itself raised questions.

In March 1988, a moratorium was imposed on the use

of human fetal tissue from induced abortions for transplantation until the ethical issues surrounding this use

could be adequately studied. Nineteen months after it was

initiated, the moratorium was extended indefinitely by the

new Secretary of Health and Human Services. Added to

the ethical issues initially presented for discussion, the

Federal Government’s actions in this matter have been

questioned on legal and ethical bases (3). It may be

instructive to trace the events leading up to the moratorium, the activities of the National Institutes of Health

(NIH) Human Fetal Tissue Transplantation Research

Panel, and the events following the panel’s report(l 1) and

its acceptance by the NIH Director’s Advisory Committee.

Events Preceding the Moratorium

Fetal tissue has long been used in research (2,4)-

including research involving the transplantation of fetal

thymus tissue into humans—and the ethical questions it

raises have been addressed by an executive branch

commission and in Federal regulations [45 CFR 46].

When fetal tissue began to be used for neural grafting in

the mid-1980s, however, some questioned whether these

regulations adequately address all the issues raised by this

research. In fiscal year 1987, NIH funded about $11.2

million of nontherapeutic human fetal-tissue research

(10). In 1987, a research protocol for implantation of fetal

neural tissue from induced abortions into persons suffering from Parkinson’s disease was proposed by a researcher at the National Institute of Neurological Disorders and Stroke (NINDS). The Institutional Review Board

at the NIH clinical center reviewed the scientific, legal,

and ethical issues raised by the protocol and accepted it

for funding, yet the nature of the research was considered

sufficiently controversial by the director of NINDS to be

submitted for the approval of the Director of NIH. The

Director voluntarily sought approval from the Department of Health and Human Services (DHHS) to review

and approve the protocol. In response, the Assistant

Secretary for Health issued a temporary moratorium on all

fetal tissue transplantation research using tissue from

induced abortions until NIH could convene an advisory

committee to examine the use of human fetal tissue from

induced abortions for transplantation and make recommendations for its use. The advisory committee was asked

to address 10 questions (see box A-l).

Although the intramural NIH proposal stimulated

significant ethical debate, NIH funds had already been

granted that year for an extramural protocol to study the

effects of fetal pancreatic islet cells on juvenile diabetes.

It is unclear why the intramural proposal received closer

scrutiny than the extramural protocol.

One factor that may have impeded the decisionmaking

processes within NIH is the lack of an authoritative body

within the Federal Government to address ethical issues

raised by biomedical research and treatment and to make

policy decisions regarding them. The Ethics Advisory

Board (EAB) that had existed within DHHS to address

questions of this sort was disbanded in 1980. While the

scientific, ethical, and legal features of the Parkinson’s

disease protocol were approved by the NIH Institutional

Review Board, the protocol was regarded as problematic

first by the director of the Institute performing the

research and then by the Director of NIH. The Director of

NIH was forced to turn to the Assistant Secretary for

Health for advice on appropriate action.

Although the conditions of the moratorium were not

retroactive, the investigators who had received NIH funds

for fetal pancreatic islet cell transplantation voluntarily

suspended their research because of the controversy.

Since that time, only research funded by private institutions has continued. Although most privately funded fetal

tissue transplantation has been stopped voluntarily, some

initiatives in this area have continued. In late 1988, at the

University of Colorado Health Sciences Center, physicians implanted fetal cells obtained from an induced

abortion into the brain of a 52-year-old Denver man who

had been suffering from Parkinson’s disease for 20 years

(l). Also in late 1988, physicians at Yale Medical School

implanted human fetal cells into the brain of a woman

suffering from Parkinson’s disease, after first freezing the

cells and testing their viability (6). The fetal cells used in

this surgery were donated by a woman who had had an

induced abortion in her first trimester (6).

The Report of the NIH Human Fetal Tissue

Transplantation Research Panel

In response to the questions presented by the Assistant

Secretary for Health, the Human Fetal Tissue Transplan-

–171–
172 . Neural Grafting: Repairing the Brain and Spinal Cord

Box A-l--Questions Addressed to the NIH Human Fetal Tissue Transplantation Research Panel

● Is an induced abortion of moral relevance to the decision to use human fetal tissue for research? Would the answer

to this question provide any insight on whether and how this research should proceed?

* Does the use of the fetal tissue in research encourage women to have an abortion that they might otherwise not

undertake? If so, are there ways to minimize such encouragement?

. As a legal matter, does the very process of obtaining informed consent from the pregnant woman constitute a

prohibited ‘‘inducement’ to terminate the pregnancy for the purposes of the research-thus precluding research

of this sort under HHS regulations?

● Is maternal consent a sufficient condition for the use of the tissue, or should additional consent be obtained? If

so, what should be the substance and who should be the source(s) of the consent, and what procedures should

be implemented to obtain it?

● Should there be and could there be a prohibition on the donation of fetal tissue between family members, or friends

and acquaintances? Would a prohibition on donation between family members jeopardize the likelihood of

clinical success?

● If transplantation using fetal tissue ❆❒❏❍ induced abortions becomes more common, what impact is likely to occur

on activities and procedures employed by abortion clinics? In particular, is the optimal or safest way to perform

an abortion likely to be in conflict with preservation of the fetal tissue? Is there any way to ensure that induced

abortions are not intentionally delayed in order to have a second trimester fetus for research and transplantation?

● What actual steps are involved in procuring the tissue from the source to the researcher? Are there any payments

involved? What types of payments in this situation, if any, would fall inside or outside the scope of the Hyde

Amendment?

● According to HHS regulations, research on dead fetuses must be conducted in compliance with State and local

laws. A few States’ enacted version [sic] of the Uniform Anatomical Gift Act contains restrictions on the research

application of dead fetal tissue after an induced abortion. In those States, do these restrictions apply to therapeutic

transplantation of dead fetal tissue after an induced abortion? If so, what are the consequences for NIH-funded

researchers in those States?

● For those diseases for which transplantation using fetal tissue has been proposed, have enough animal studies

been performed to justify proceeding to human transplants? Because induced abortions during the first trimester

are less risky to the woman, have there been enough animal studies for each of those diseases to justify the reliance

on the equivalent of the second trimester human fetus?

● What is the likelihood that transplantation using fetal cell cultures will be successful? Will this obviate the need

for fresh fetal tissue? In what time frame might this occur?

SOURCE: U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, Report of the Human Fetal

Tissue Transplantation Research Panel (Bethesda, MD: 1988).

tation Research Panel convened, heard testimony from a Events Following Acceptance of the

variety of experts and interest groups, and submitted a Panel Report

report to the NIH Director late in 1988. A unanimous

agreement was not reached among the 21 panel members,

but the panel’s report concluded (17 to 4) that the funding

of research involving the transplantation of human fetal

tissue obtained from induced abortions is acceptable

public policy as long as carefully crafted safeguards are in

place (see box A-2).

Although adamant dissent was voiced by four panel

members, the report and its recommendations were

accepted unanimously by the NIH Director’s Advisory

Committee. The advisory committee recommended that

the moratorium on fetal tissue transplantation research be

lifted. The Director of NIH concurred with this position

in a memorandum to the Assistant Secretary for Health in

January 1989 (12).

The Assistant Secretary, upon the instruction of the

DHHS Secretary, deferred action on the panel’s recommendation that the Federal Government lift the moratorium (5). The new administration took no action until the

new Assistant Secretary for Health recommended to the

new DHHS Secretary in October 1989 that the ban be

continued. The Secretary continued the moratorium

indefinitely in November 1989 (9). No action was taken

to implement any of the recommendations of the advisory

panel’s report.

The legal and ethical bases of the continuation of the

moratorium have since been challenged. The moratorium

was originally declared as a temporary measure until the

ethical issues raised by fetal tissue transplantation could

be addressed and recommendations could be made. The

fact that it has been continued indefinitely without any
Appendix A--DHHS Moratorium on Human Fetal Tissue Transplantation Research ● 173

Box A-2—Recommendations of the NIH Human

Fetal Tissue Transplantation Research Panel

●

●

●

●

●

●

●

●

The decision to terminate a pregnancy and the

procedures of abortion should be kept independent from the retrieval and use of fetal tissue.

The timing and method of abortion should not be

influenced by the potential uses of fetal tissue for

transplantation or medical research.

Fetal tissue from induced abortions should not be

used in medical research without the prior

consent of the pregnant woman.

The decision and consent to abort must precede

discussion of the possible use of the fetal tissue

and any request for such consent as might be

required for that use.

The pregnant woman should be prohibited from

designating the recipient of the fetal tissue

transplant.

Payments and other forms of remuneration and

compensation associated with the procurement

of fetal tissue should be prohibited, except

payment for reasonable expenses occasioned by

the actual retrieval, storage, preparation, and

transportation of the tissues.

Potential recipients of such tissues, as well as

research and health care participants, should be

properly informed as to the source of the tissues

in question.

Procedures must be adopted that accord human

fetal tissue the same respect accorded other

cadaver human tissues entitled to respect.

SOURCE: U.S. Department of Health and Human Services,

Public Health Service, National Institutes of Health,

Report of the Human Fetal Tissue Transplantation

Research Panel (Bethesda, MD: 1988).

official announcement or opportunity for public debate

has caused some to challenge its legal basis (7). The

ethical basis of the continuation has also been challenged,

since the reasons for its continuance had been rejected by

the advisory panel upon whose recommendations the

moratorium was supposed to be contingent (8).

On April 2, 1990, the U.S. House of Representatives

Committee on Energy and Commerce’s Subcommittee on

Health and the Environment held hearings on human fetal

tissue transplantation research. The subcommittee heard

testimony from members of the NIH Human Fetal Tissue

Transplantation Research Panel, representatives of organizations representing persons with various diseases that

fetal tissue grafting may treat, members of the scientific

community, and the Assistant Secretary for Health.

Strong views for and against the continued moratorium on

fetal tissue transplantation research were expressed.

While on one level the ethical debate was clearly and

publicly articulated, the events leading up to the moratorium and those that followed the NIH advisory committee’s acceptance of the panel’s recommendations raise

questions of their own. These events add another layer of

ethical considerations to the fetal tissue transplantation

controversy: Is the procedure for ethical decisionmaking

in government subject to the same scrutiny as the issues

it is used to address? Again, the absence of a Federal

agency for deliberation of bioethical issues maybe noted.

These events may also be interpreted as a question about

the relationship between personal moral or ethical convictions and the appropriate shape of public policy in a

pluralistic society.

1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

Appendix A References

Associated Press, “Denver Scientists To Keep Using

Tissue,” Apr. 19, 1988.

Hansen, J.T., and Sladek, J.R., Jr., “Fetal Research,”

Science 246:775-779, 1989.

Hilts, P.J., “U.S. Aides See Shaky Legal Basis for Ban on

Fetal Tissue Research,” New York Times, Jan. 30, 1990.

Lehrman, D., Summary: Fetal Research and Fetal Tissue

Research (Washington, DC: Association of American

Medical Colleges, 1988).

Mesce, D., “Former NIH Director Wants Fetal Tissue

Research Ban Ended,” Associated Press, Oct. 16, 1989.

New York Times, “Doctors Implant Frozen Fetal Cells,”

Dec. 13, 1988.

Palca, J., ‘‘Fetal Research Ban on Shaky Ground?’ Science

247:629, 1990.

U.S. Congress, House of Representatives, Committee on

Government Operations, Subcommittee on Human Resources and Intergovernmental Relations, letter from Ted

Weiss, chairman, to Louis W. Sullivan, Secretary of Health

and Human Services, Jan. 26, 1990.

U.S. Department of Health and Human Services, statement

by Louis W. Sullivan, secretary, Nov. 2, 1989.

U.S. Department of Health and Human Services, Public

Health Service, National Institutes of Health, Report on

Human Fetal Tissue Research Supported by the National

Institutes of Health in Fiscal Year 1987.

U.S. Department of Health and Human Services, Public

Health Service, National Institutes of Health, Report of the

Human Fetal Tissue Transplantation Research Panel

(Bethesda, MD: 1988).

Wyngaarden, J.B., Director, National Institutes of Health,

memorandum to Robert E. Windom, Assistant Secretary for

Health, U.S. Department of Health and Human Services,

Jan. 19, 1989.
Appendix B

Participants in the

Workshop on New Developments in Spinal Cord Injury:

Acute Interventions and Neural Grafts

Douglas Anderson, Ph.D.

VA Hospital

Cincinnati, OH

June 12, 1989

Sponsored by the Office of Technology Assessment

and

American Paralysis Association

Paralyzed Veterans of America

Jerry Silver, Ph. D., Workshop Chairman

Case Western Reserve University

Cleveland, OH

Thomas E. Anderson, Ph.D.

General Motors Research Laboratories

Warren, MI

Jerry Bernstein, Ph.D.

VA Medical Center

Washington, DC

Barbara S. Bregman, Ph.D.

Georgetown University

Washington, DC

Carson J. Cornbrooks, Ph.D.

University of Vermont College of Medicine

Burlington, VT

Allan I. Faden, M.D.

VA Medical Center

San Francisco, CA

Earl R. Feringa, M.D.

VA Medical Center

Augusta, GA

Barth Green, M.D.

University of Miami School of Medicine

Miami, FL

Marston Manthorpe, Ph.D.

University of California, San Diego

La Jell% CA

Paul J. Reier, Ph.D.

University of Florida College of Medicine

Gainesville, FL

Fredrick J. Seil, M.D.

VA Medical Center

Portland, OR

Brad T. Stokes, Ph.D.

Ohio State University

Columbus, OH

Wise Young, M.D.

New York University Medical Center

New York, NY

Jean R. Wrathall, Ph.D.

Georgetown University

Washington, DC

Contractor:

Julie Ann Miller

Washington, D.C.

Edward Hall, Ph.D.

UpJohn Co.

Kalamazoo, MI

–174-
Appendix C

Decade of the Brain

Public Law 101-58, 101st Congress,

Joint Resolution

Whereas it is estimated that 50 million Americans are

affected each year by disorders and disabilities that

involve the brain, including the major mental illnesses;

inherited and degenerative diseases; stroke; epilepsy;

addictive disorders; injury resulting from prenatal events,

environmental neurotoxins, and trauma; and speech,

language, hearing, and other cognitive disorders;

Whereas it is estimated that treatment, rehabilitation

and related costs of disorders and disabilities that affect

the brain represents a total economic burden of $305

billion annually;

Whereas the people of the Nation should be aware of

the exciting research advances on the brain and of the

availability of effective treatment of disorders and disabilities that affect the brain;

Whereas a technological revolution occurring in the

brain sciences, resulting in such procedures as positron

emission tomography and magnetic resonance imaging,

permits clinical researches to observe the living brain

noninvasively and in exquisite detail, to define brain

systems that are implicated in specific disorders and

disabilities, to study complex neuropeptides and behavior

as well as to begin to learn about the complex structures

underlying memory;

Whereas scientific information on the brain is amassing

at an enormous rate, and the field of computer and

information sciences has reached a level of sophistication

sufficient to handle neuroscience data in a manner that

would be maximally useful to both basic researches and

clinicians dealing with brain function and dysfunction;

Whereas advances in mathematics, physics, computational science, and brain imaging technologies have made

possible the initiation of significant work in imaging brain

function and pathology, modeling neural networks and

simulating their dynamic interactions;

Whereas comprehending the reality of the nervous

system is still on the frontier of technological innovation

requiring a comprehensive effort to decipher how individual neurons, by their collective action, give rise to human

intelligence;

Whereas fundamental discoveries at the molecular and

cellular levels of the organization of the brain are

clarifying the role of the brain in translating neurophysiologic events into behavior, thought, and emotion;

Whereas molecular biology and molecular genetics

have yielded strategies effective in preventing several

forms of severe mental retardation and are contributing to

promising breakthroughs in the study of inheritable

neurological disorders, such as Huntington’s disease, and

mental disorders, such as affective illnesses;

Whereas the capacity to map the biochemical circuitry

of neurotransmitters and neuromodulators will permit the

rational design of potent medications possessing minimal

adverse effects that will act on the discrete neurochemical

deficits associated with such disorders as Parkinson’s

disease, schizophrenia and Alzheimer’s disease;

Whereas the incidence of necrologic, psychiatric,

psychological, and cognitive disorders and disabilities

experienced by older persons will increase in the future as

the number of older persons increases;

Whereas studies of the brain and central nervous

system will contribute not only to the relief of necrologic,

psychiatric, psychological, and cognitive, disorders, but

also to the management of fertility and infertility,

cardiovascular disease, infectious and parasitic diseases,

developmental disabilities and immunologic disorders, as

well as to an understanding of behavioral factors that

underlie the leading preventable causes of death in this

Nation;

Whereas the central nervous and immune systems are

both signaling systems which serve the entire organism,

are direct connections between the nervous and immune

system, and whereas studies of the modulatory effects of

each system on the other will enhance our understanding

of diseases as diverse as the major psychiatric disorders,

acquired immune deficiency syndrome, and autoimmune

disorders;

Whereas recent discoveries have led to fundamental

insights as to why people abuse drugs, how abused drugs

affect brain function leading to addiction, and how some

of these drugs cause permanent brain damage;

Whereas studies of the brain will contribute to the

development of new treatments that will curtail the

craving for drugs, break the addictive effects of drugs,

prevent the brain-mediated “high” caused by certain

abused drugs, and lessen the damage done to the

developing minds of babies, who are the innocent victims

of drug abuse;

Whereas treatment for persons with head injury,

developmental disabilities, speech, hearing, and other

cognitive functions is increasing in availability and

effectiveness;

Whereas the study of the brain involves the multidisciplinary efforts of scientist, from such diverse areas as

physiology, biochemistry, psychology, psychiatry, mo-

–175–
176 ● Neural Grafting: Repairing the Brain and Spinal Cord

lecular biology, anatomy, medicine, genetics, and many

others working together toward the common goals of

better understanding the structure of the brain and how it

affects our development, health, and behavior;

Whereas the Nobel Prize for Medicine of Physiology

has been awarded to 15 neuroscientist within the past 25

years, an achievement that underscores the excitement

and productivity of the study of the brain and central

nervous system and its potential for contributing to the

health of humanity;

Whereas the people of the Nation should be concerned

with research into disorders and disabilities that affect the

brain, and should recognize prevention and treatment of

such disorders and disabilities as a health priority;

Whereas the declaration of the Decade of the Brain will

focus needed government attention on research, treatment, and rehabilitation in this area: Now, therefore, be it

Resolved by the Senate and House of Representatives of

the United States of America in Congress Assembled,

That the decade beginning January 1, 1990, hereby is

designated the “Decade of the Brain,” and the President

of the United States is authorized and requested to issue

a proclamation calling upon all public officials and the

people of the United States to observe such decade with

appropriate programs and activities.

Approved July 25, 1989.

LEGISLATIVE HISTORY--H.J. Res. 174 (S. J. Res. 173):

CONGRESSIONAL RECORD, Vol. 135 (1989):

June 29, considered and passed House.

July 13, considered and passed Senate.
Appendix D

Acknowledgments

OTA would like to thank the members of the advisory panel who commented on drafts of this report, the

contractors who provided material for this assessment, and the many individuals and organizations that

supplied information for the study. In addition, OTA acknowledges the following individuals for their review

of drafts of this report.

Douglas Anderson

VA Hospital

Cincinnati, OH

Thomas E. Anderson

General Motors Research Laboratories

Warren, MI

Lori Andrews

American Bar Foundation

Chicago, IL

Michael Appuzzo

American Association of Neurological Surgeons

Los Angeles, CA

Adrienne Asch

New Jersey Bioethics Commission

Princeton, NJ

Nancy Beang

Society for Neuroscience

Washington, DC

Barbara S. Bregman

Georgetown University

Washington, DC

Margaret Brown

American Paralysis Association

Springfield, NJ

David W. Cahill

University of South Florida

Tampa, FL

Margaret Calvano

National Multiple Sclerosis Society

New York NY

Sarah Carr

Association of American Medical Colleges

Washington, DC

Charles E. Carson

Spinal Cord Society

Fergus Falls, MN

Ronald A. Carson

University of Texas Medical Branch

Galveston, TX

Cheryl M. Chanaud

Paralyzed Veterans of America

Washington, DC

K. Danner Clouser

The Milton S. Hershey Medical Center

Hershey, PA

Carl W. Cotman

University of California, Irvine

Irvine, CA

Philip Cohen

Huntington Disease Society of America

New York, NY

Arthur Coquelin

Texas Tech University Health Sciences Center

Lubbock TX

Keith Crutcher

University of Cincinnati College of Medicine

Cincinnati, OH

Miriam Davis

National Institute for Environmental Health Sciences

Bethesda, MD

Gary B. Ellis

Institute of Medicine

Washington, DC

Anne Etgen

Albert Einstein College of Medicine

Bronx, NY

R. Mark Evans

American Medical Association

Chicago, IL

Alan Fine

Dalhousie University School of Medicine

Halifax, N.S.

Thomas Freeman

University of South Florida

College of Medicine

Tampa, FL

–177–
178 ● Neural Grafting into the Brain and Spinal Cord

Elizabeth D. Gee

University of Colorado at Boulder

Boulder, CO

Christopher Goetz

United Parkinson Foundation

Chicago, IL

Lawrence Golbe

Robert Wood Johnson Medical School

New Brunswick NJ

Rachel Benson Gold

The Alan Guttmacher Institute

Washington, DC

Murray Goldstein

National Institute of Neurological Disorders and Stroke

Bethesda, MD

Roger Gorski

University of California-Ire Angeles,

School of Medicine

Los Angeles, CA

Debra S. Grega, Ph.D.

Boehringer Mannheim Biochemical

Indianapolis, IN

W. Allen Hauser

G. H. Sergievsky Center

New York NY

John T. Howard

University of California, Irvine

Irvine, CA

William Ketterer

National Institutes of Health

Bethesda, MD

Frances Kissling

Catholics for a Free Choice

Washington, DC

Lynn Kline

The Amyotrophic Lateral Sclerosis Association

Woodland Hills, CA

Jeffrey H. Kordower

University of Illinois at Chicago

Chicago, IL

Mary Grace Kovar

National Center for Health Statistics

Hyattsville, MD

L.T. Kurland

Mayo clinic

Rochester, MN

Edward R. Laws, Jr.

American Association of Neurological Surgeons

Washington, DC

Carl Leventhal

National Institute of Neurological Disorders and Stroke

Bethesda, MD

Abraham Lieberman

Barrow Neurological Institute

Phoenix, AZ

David E. Lilienfeld

The Mount Sinai School of Medicine

New York NY

Ronald M. Lindsay

Regeneron Pharmaceuticals, Inc.

Tarrytown, NY

Rev. Donald McCarthy

St. Antoninus Church

Cincinnati, OH

Gianpaolo Maestrone

American Parkinson’s Disease Association

New York NY

Anne C. Maher

Chester Springs, PA

Stephen E. Nadeau

VA Medical Center

Gainesville, FL

David Orentlicher

American Medical Association

Chicago, IL

Creighton H. Phelps

Alzheimer’s Association

Chicago, IL

Roger Porter,

National Institute of Neurological Disorders and Stroke

Bethesda, MD

Ali H. Rajput

University of Saskatchewan

Saskatoon, Canada
Appendix D--Acknowledgments . 179

Michael R. Rask

American Academy of Neurological and

Orthopedic Surgeons

Las Vegas, NV

Robert B. Raskin

UpJohn Co.

Kalamazoo, MI

Robert A. Ratcheson

Case Western Reserve University School of Medicine

Cleveland, OH

Donald E. Redmond

Yale University School of Medicine

New Haven, CT

Paul J. Reier

University of Florida College of Medicine

Gainesville, FL

Donald J. Reis

Cornell University Medical College

New York NY

Clifford Rose

World Federation of Neurology

London, England

Jeffrey M. Rosenstein

The George Washington University

School of Medicine

Washington, DC

Judy Rosner

United Parkinson Foundation

Chicago, IL

Leslie Steven Rothenberg

University of California-Los Angeles,

School of Medicine

Los Angeles, CA

Thomas A. Shannon

Worcester Polytechnic Institute

Worcester, MA

Daniel Sosin

Centers for Disease Control

Atlanta, GA

Caroline Tanner

Rush Medical Center

Chicago, IL

John M. Tew

University of Cincinnati College of Medicine

Cincinnati, OH

Bruce D. Weinstein

West Virginia University School of Medicine

Morgantown, WV

Robert M. white

Howard University

Washington, DC

Daniel Wilder

University of Wisconsin

Madison, WI

Janet Woodcock

Food and Drug Administration

Bethesda, MD
Appendix E

List of Contractor Documents

For this report, OTA commissioned eight papers on various topics related to neural grafting.

“Epidemiology and Etiology of Parkinson’s Disease,” A.H. Rajput, 1988.

“The Immunological Aspects of Neural Grafting,” W.F. Hickey, 1989.

“Neural Grafting in the Treatment of Parkinson’s Disease: Past, Present, and Future,” T. Freeman, 1989.

“Transplantation of Adrenal Tissue into the Nervous System,” A. Fine, 1989.

“Reconstructing the Brain: New Strategies for Brain Disease,” R. McKay, 1989.

“Legal and Regulatory Issues for Neural Grafts,” L. Andrews, 1989.

“New Developments in Neuroscience: Neural Transplants and Nerve Regeneration Technologies, Ethical Issues,”

K. Gervais, 1989.

“New Developments in Neuroscience: Historical and Ethical Issues in Neural Transplants,” R. Pinkus, 1989.

-180-
Appendix F

Acronyms and Glossary of Terms

Acronyms

AANs —American Association of Neurological

Surgeons

ACTH —adrenocorticotropic hormone

ADAMHA —Alcohol, Drug Abuse, and Mental Health

AHCPR

AIDS

ALS-P-D

BEAC

BMAA

CCL

CNS

CSF

DHHS

FDA

FFDCA

GABA

GRAFT

HCFA

HIV

LC

MAO-B

MPP+

NDA

NGF

NINDS

NOTA

6-OHDA

PHSA

PMA

PNS

PSP

TH

UAGA

UPF

VP

Administration

—Agency for Health Care Policy and Research

—acquired immunodeficiency syndrome

—amyotrophic lateral sclerosis-Parkinson’s

disease-dementia

—Biomedical Ethics Advisory Committee

—Beta-N-methyl amino-L-alanine

-continuous cell line

-central nervous system

-cerebrospinal fluid

—Department of Health and Human Services

—Food and Drug Administration

—Federal Food, Drug, and Cosmetic Act

—gamma-aminobutyric acid

—gonadotrophin-releasing hormone

--General Registry of Adrenal-Fetal Transplantation

—human amnion membrane matrix

—Health Care Financing Administration

—human immunodeficiency virus

—investigational new drug application

—Institutional Review Board

—locus ceruleus

—monoamine oxidase B

—motor neuron disease

—methylpyridine

—l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine

—new drug application

—nerve growth factor

—National Institutes of Health

—National Institute of Neurological Disorders and Stroke

—National Organ Transplant Act

-6-hydroxydopamine

—Public Health Service Act

—premarket approval

—peripheral nervous system

—progressive supranuclear palsy

—tyrosine hydroxylase

—tetrahydroaminoacridine

—Uniform Anatomical Gift Act

—United Parkinson Foundation

—vasopressin

Glossary of Terms

Abortion: The termination of pregnancy, whether spontaneous (occurring naturally, a miscarriage) or induced. Induced abortions may be therapeutic (to treat

a medical condition of the pregnant woman) or

nontherapeutic (elective).

Abortus: An aborted fetus. See fetus.

Acetylcholine: A neurotransmitter involved in learning

and memory. Acetylcholine is diminished in Alzheimer’s disease. See neurotransmitter.

Adrenal medulla: The innermost region of the adrenal

gland; cells from this region can produce dopamine in

the brain and are potential candidates for neural

grafting, particularly to relieve the symptoms of

Parkinson’s disease. See chromaffin cell.

AIDS, acquired immunodeficiency syndrome: A condition in which the body’s immune system is depressed

due to infection by a retrovirus. See HIV, retrovirus.

Allograft: Tissue or cells transplanted between individuals of the same species.

Alzheimer’s disease: A neurodegenerative disease

caused by abnormality and death of nerve cells in

several areas of the brain; the nerve cell loss is

associated with a deficit of several chemicals in the

brain, notably acetylcholine, resulting in dementia. The

cause of the nerve cell abnormality and loss is

unknown.

Amyotrophic lateral sclerosis, ALS, Lou Gehrig’s

disease: A neurodegenerative disease caused by death

of nerve cells in the central nervous system that control

muscle movement. Paralysis, but not dementia, results.

The cause of the nerve cell death is unknown.

Animal model: An animal that shares or in which can be

replicated features of human disorders and that is used

in experimental studies of those disorders. Animal

models may be homologous (sharing a common

origin) or analogous (being similar in effect) to the

human disease or injury being studied.

Astrocyte: A type of glial cell in the central nervous

system; after injury to the central nervous system,

astrocytes form a scar at the site of nerve damage and

block regeneration of axons. See glial cell.

Autograft: A transplant in which the recipient’s own

tissue or cells are use& autografts pose no problem of

rejection by the recipient and provide a ready source of

grafting material. Adrenal medullary grafts are an

example of autografts. See adrenal medulla, rejection.

Autonomic nervous system: Cells in the central and

peripheral nervous systems that control such involuntary functions of the body as temperature, metabolism,

and response to stress.

–181–
182 ● Neural Grafting: Repairing the Brain and Spinal Cord

Axon: The long extension of the neuron along which

electrical impulses travel. See neuron.

Basal ganglia: A group of nuclei in the upper part of the

brain that help mediate movement. See substantial

nigra, striatum.

Biologic: A biological product for the prevention, treatment, diagnosis, or cure of human diseases or injuries;

examples are vaccines, blood, and antitoxins.

Blood-brain barrier: A layer of tightly juxtaposed

endothelial cells in blood vessel walls that protects

much of the central nervous system by selectively

filtering out some substances while allowing others to

pass from the blood into the brain. See endothelial cell.

Brain: One of the two components of the central nervous

system, the brain consists of the cerebral cortex, the

cerebellum, the upper brain, and the brain stem. The

brain is the center of thought, action, and emotion. It

receives sensory impulses and transmits motor impulses.

Brain stem: The lowest part of the brain, connecting the

cerebral cortex and upper brain to the spinal cord.

Nuclei in the brain stem regulate essential bodily

functions such as heart rate, blood pressure, and

respiratory activity. See nucleus.

Cadaveric fetal tissue: Tissue obtained from a dead

fetus.

Catecholamine: A class of neurotransmitter including

dopamine, norepinephrine, and epinephrine (a

hormone secreted by the adrenal medulla).

Cell body: The relatively compact portion of the neuron,

which contains the nucleus. Compare axon, dendrite.

Cell culture: Cells grown in the laboratory; although the

cells proliferate, they do not organize into tissue. See

primary cell culture, cell line, and continuous cell line.

Cell line: A group of cells derived from a primary culture

at the time of first subculture; an established cell line

has the potential for indefinite subculture in vitro. See

continuous cell line.

Cell suspension: Individual cells separated out from solid

tissue and placed in a supporting fluid; also, as a form

of neural grafting, injection of such cells into a host

central nervous system. Compare solid tissue graft.

Central nervous system, CNS: One of the two major

divisions of the nervous system, made up of the brain

and spinal cord. Compare peripheral nervous system.

Cerebral cortex: The rounded upper portion of the brain,

consisting of layers of neural cells and the pathways

that connect them. The cerebral cortex is divided into

four lobes on each side and is the part of the brain in

which “thinking and decisionmaking take place. See

brain.

Cerebrospinal fluid: Fluid manufactured in the brain and

contained within the brain and spinal cord; it circulates

in the central nervous system and is absorbed into and

removed by veins.

Chromaffin cell: A nonneuronal cell in the adrenal

medulla derived from precursor cells that also generate

neurons in the autonomic nervous system. Chromaffin

cells produce neurotransmitters that are chemically

related to those synthesized in the autonomic and

central nervous systems. See adrenal medulla, precursor cell.

Clinical test, clinical research: Experimental analysis

(as of drugs or surgery) using human beings.

Conceptus: The product of conception. See embryo,

fetus.

Continuous cell line: Sustained, self-propagating cells in

culture; such cells may arise spontaneously in primary

cell culture, be derived from tumors, or be created

through genetic engineering. See cell culture, genetically engineered cell.

Cryopreservation: The freezing and storage of cells or

tissue at -1960 centigrade for use later.

Dementia: Loss of intellectual function.

Demyelinating disorder: See demyelination, multiple

sclerosis.

Demyelination: Destruction of the myelin sheath,

whether through injury or disease. See myelin sheath.

Dendrite: Branched extension of the neuron cell body

which receives impulses from another neuron. See

synapse.

Deprenyl: A drug shown to slow the progression of

Parkinson’s disease in clinical trials by blocking the

activity of MAO-B. See MAO-B.

Device: Broadly, an instrument, apparatus, implant, in

vitro reagent, or other similar or related article intended

for use in the diagnosis, cure, mitigation, treatment, or

prevention of disease, or intended to affect the structure

or function of the body, that works through nonchemical, nonmetabolic means.

Differentiation: The stage of development during which

brain cells stop dividing and acquire distinct characteristics and functions. Compare migration, proliferation.

Dopamine: A neurotransmitter that in insufficient

amounts produces the symptoms of Parkinson’s disease. See catecholamine, neurotransmitter.

Dorsal root: The portion of the nerve root that brings

sensory information from the body to the spinal cord.

See nerve root.

Drug: An article (other than foods or devices) intended

for use in the diagnosis, cure, mitigation, treatment, or

prevention of disease and designed to affect the

structure or any function of the body.

Dura mater: The tough, outermost membrane surrounding the brain and spinal cord.

Elective abortion: See abortion.

Embryo: The conceptus from fertilization until the end of

the eighth week See fetus.

Endocrine system: The endocrine glands (such as the

thyroid and pituitary glands) and the hormones they

secrete.
Appendix F--Acronyms and Glossary of Terms ● 183

Endothelial cell: A type of cell lining the blood vessel

wall that can trigger an immune response (and hence

graft rejection). See blood-brain barrier.

Epilepsy: Disruption in the normal electrical activity of

the brain, resulting in seizures; epilepsy is diagnosed if

more than one seizure occurs and those seizures are due

to central nervous system dysfunction.

Excitotoxin: A chemical substance (kainic acid, ibotenic

acid, or quinolinic acid) that, when injected into the

brain, kills nerve cells by overstimulating them.

Ex utero: Outside the uterus.

Fetus: In a legal context, the conceptus at all stages of

development; in a Federal regulatory context, the

conceptus after implantation; in a scientific context, the

conceptus from the end of the eighth week to the

moment of birth. Compare embryo.

Fibroblast: A connective tissue cell, found in the skin,

that can be induced through genetic engineering to

produce some chemicals (such as dopamine and nerve

growth factor) found in the brain.

Ganglion, ganglia: Term for a group of neurons that are

usually located outside the central nervous system.

Compare basal ganglia.

Genetic engineering: Altering the genetic makeup of a

cell.

Genetically engineered cell: A cell into which new genes

have been inserted

Germ cell: A reproductive (egg or sperm) cell or its

precursors. Compare somatic cell.

Glial cell, glia: A basic cell type of the nervous system.

Glial cells appear to perform support functions for

neurons: namely, nutrition, insulation (through the

production of myelin), and structural support. Compare neuron. See astrocyte, microglia, oligodendrocyte, Schwann cell.

Hippocampus: A nucleus in the brain crucial to learning

and memory.

HIV, human immunodeficiency virus: The retrovirus

associated with AIDS and AIDS-related complex. See

retrovirus.

Huntington’s disease: A genetic neurodegenerative

disease caused by death of nerve cells in the striatum

(producing abnormal movement) and elsewhere in the

cerebral cortex (producing dementia). The cause of the

nerve cell death is unknown.

Hypothalamus: A collection of nuclei in the brain that

control such behaviors as eating and drinking and are

involved in regulating the endocrine system. The

hypothalamus also produces hormones itself. See

endocrine system.

Immune response: Reaction of the immune system to

foreign matter. See immune system.

Immune system: A collection of organs, tissues, cells,

and molecules in mammals that seeks out, identifies,

destroys, and remembers foreign organs, tissues, cells,

and molecules; the immune system protects the animal

from disease-causing organisms in the environment.

See rejection.

Immunological privilege: The concept that the central

nervous system is not as closely monitored by the

immune system as the rest of the body and is therefore

less susceptible to graft rejection.

Immunoreactive: Capable of provoking a response from

the immune system.

Immunosuppression: The use of drugs to prevent graft

rejection by restraining the response of the immune

system to foreign material.

Incidence: The number of new cases of a disorder

occurring during a given period of time (usually 1 year)

within a given geographical area. Compare prevalence.

Incidence rate: Incidence per unit of population. See

incidence.

Induced abortion: See abortion.

Informed consent: As applied to human research, the

agreement of a person (or his or her legally authorized

representative) to serve as a research subject, in full

knowledge of all anticipated risks and benefits of the

experiment. Informed consent requires that the researcher impart to the prospective subject any information that might influence the subject’s decision to

participate or not participate in the research, including

an explanation of the methodology to be used, the

availability of alternative therapies, and the prospective subject’s freedom to withdraw from the experiment at any time, without prejudice.

Institutionalize: To incorporate an act or practice into a

structured, often formal, system. Compare legitimate.

Institutional Review Board, IRB: A group established

by an institution conducting medical research to assess

the legal, ethical, and scientific aspects of that research

on human subjects. IRB approval is required by the

Department of Health and Human Services before

proposals can receive Federal funding. IRBs must

review research protocols on a regular basis, but not

less than once a year.

In utero: In the uterus.

Investigational device exemption: Application to FDA

by a manufacturer for permission to ship a device prior

to obtaining premarket approval, in order to conduct

studies of safety and efficacy. See premarket approval

application.

Investigational new drug application, IND: Request by

a manufacturer for exemption from FDA’s premarket

approval requirement; an IND is sought for shipment

of a drug for investigational use by qualified experts,

in order to study the safety and efficacy of the drug.

In vitro: Literally, in glass; in the laboratory; outside the

body.

In vivo: In the body.

Isograft: Tissue transplanted from one identical twin to

another; isografts pose no problem of rejection by the

identical twin who receives the graft.
184 ● Neural Grafting: Repairing the Brain and Spinal Cord

Kindled model: An animal model of epilepsy that is

thought to be analogous to temporal lobe epilepsy in

humans. See animal model.

L-dopa, Levodopa: The precursor of the neurotransmitter

dopamine. L-dopa is the standard therapy for persons

with Parkinson’s disease.

Legitimate: To give legal status to an actor practice; to

show or affirm an act or practice to be justified.

Compare institutionalize.

Limbic system: Structures in the brain that are associated

with some aspects of emotion and behavior. See

hippocampus, hypothalamus.

Locus ceruleus: A nucleus of the brain that inhibits the

ability to induce seizures in the kindled model of

epilepsy. See kindled model.

Lymphatic drainage: The movement of fluids, molecules, foreign particles, and cells from various tissues

in the body through the lymph system to the immune

system; a means by which grafted cells reach the host’s

immune system and trigger rejection.

MAO-B, monoamine oxidase B: An enzyme that breaks

down certain neurotransmitters. It can also convert

other chemicals to toxins that destroy substantial nigra

cells, thereby producing parkinsonism. See parkinsonism.

Microglia: A type of glial cell in the central nervous

system thought to enter the immune system and initiate

graft rejection.

Migration: The movement of immature cells in the brain

to the site where they will mature and remain permanently. Compare differentiation, proliferation.

Minimal risk: Term used to denote that the chance of

harm anticipated in proposed research is no greater

than that encountered in daily life or during the

performance of routine physical or psychological tests.

Mortality rate: The number of deaths during a given

period of time (usually 1 year), within a given

geographical area, per unit of population.

Motor neuron disease: A type of neurodegenerative

disease in which neurons in the central nervous system

that control muscle movement are destroyed. See

amyotrophic lateral sclerosis.

MPTP, l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine: A synthetic narcotic that can cause parkinsonism

in humans.

Multiple sclerosis, MS: A demyelinating disease characterized by an array of symptoms (such as loss of

coordination, slurred speech, and dizziness), depending on wherein the central nervous system the lesions

occur. See demyelination.

Myelin: A fatty substance (of which the myelin sheath

surrounding axons is made) that acts as an electrical

insulator to speed the conduction of nerve impulses.

Myelin is formed in the peripheral nervous system by

Schwann cells and in the central nervous system by

oligodendrocytes. See myelin sheath, oligodendrocyte,

Schwann cell.

Myelin sheath: Concentric layers of myelin surrounding

the axons of some neurons. The myelin sheath speeds

the conduction of electrical impulses. See myelin,

oligodendrocyte, Schwann cell.

Nerve fiber: An axon and its surrounding myelin sheath.

Nerve growth factor, NGF: A protein that promotes

axon growth in some areas of the peripheral nervous

system and plays a role in the development of

vertebrate sensory and autonomic systems. In the

central nervous system, it appears to protect from

damage some populations of cells that synthesize

acetylcholine.

Nerve root: One of a collection of nerves that are attached

to and demarcate the 30 segments of the spinal cord.

Nerve fibers enter and leave the spinal cord at one of

the 31 nerve roots. These fibers link the peripheral and

central nervous systems, bringing sensory information

from the body to the spinal cord and motor information

from the spinal cord to the body. See dorsal root.

Neural grafting: The transplantation (implantation) of

cells or tissue into the brain or spinal cord. As used in

this report, it refers to various treatment goals (such as

promotion of growth or provision of needed chemicals), materials (such as adrenal medulla or fetal central

nervous system tissue) and methods (such as cell

suspensions or cell lines) of grafting. See cell line, cell

suspension.

Neuritic plaque: Abnormal cluster of degenerating

neurons, other brain cells, and protein in the areas

between neurons; found in the brains of persons with

Alzheimer’s disease.

Neurodegenerative disorder: A class of neurological

disease marked by loss of a particular population or

populations of nerve cells in the central nervous

system. Symptoms vary and depend on the neurons

lost. See, for example, Parkinson’s disease, Huntington’s disease, Alzheimer’s disease, and amyotrophic

lateral sclerosis.

Neurofibrillary tangle: Accumulation of twisted protein

filaments inside nerve cells; found in the brains of

persons with Alzheimer’s disease.

Neurological disorder: Disease of, or injury to, the

central nervous system.

Neuron, nerve cell: The basic functional unit of the

nervous system. The neuron is typically composed of

a relatively compact cell body containing the nucleus;

several short, radiating extensions, or processes (dendrites); and one long process (the axon) with twig-like

branches along its length and at its end. Information in

the form of electrical impulses travels from the

dendrites, through the cell body, and along the axon to

other cells. Sensory neurons send information to the

brain and spinal cord; motor neurons send instructions

to muscles, organs, and glands. See axon, dendrite.
Appendix F--Acronyms and Glossary of Terms . 185

Neurotransmitter: Specialized chemical messenger (e.g.

acetylcholine, dopamine, norepinephrine, serotonin)

synthesized and secreted by neurons that sends a nerve

impulse from one nerve cell to another. Neurotransmitters are released into the synaptic space between

neurons, bind to the dendrites of other neurons, and

initiate a message in those neurons. Some neurotransmitters stimulate the release of neurotransmitters from

other neurons, while others inhibit the release of

neurotransmitters from other neurons. Neurotransmitters are also released at synapses between neurons and

other targets (e.g., muscles, glands). See synapse,

synaptic space.

Neurotrophic factor: Chemical produced by some

neurons and glial cells that affects the growth and

development, maintenance of function, and response to

injury of neurons. See trophic factor, tropic factor, and

nerve growth factor.

New drug: A drug not generally recognized by qualified

experts as safe and effective for use under the

conditions prescribed, recommended, or suggested on

the label, 01 which has been recognized as safe and

effective but which has not been used to a material

extent or for a material time.

New drug application, NDA: Submission by a manufacturer to the FDA of information on a new drug,

including full reports of studies of safety and efficacy,

specimens of proposed labelling, and methods of

manufacture, processing, and packing. Approval of the

NDA is required before a new drug can be introduced

into commerce. See investigational new drug application.

Nontherapeutic abortion: See abortion.

Nontherapeutic research: Studies involving human

subjects designed to further scientific knowledge about

a disorder or process, with no anticipated direct benefit

to the subjects themselves.

Norepinephrine: See catecholamine, neurotransmitter.

Nucleus, nuclei: A group of cells in the brain, but

generally outside the cerebral cortex, that share the

same anatomical region and to varying degrees the

same function. The hippocampus, locus ceruleus, and

substantial nigra are examples of nuclei.

Oligodendrocyte: A type of glial cell that forms myelin

in the central nervous system; oligodendrocytes appear

to inhibit the regrowth of damaged axons in the central

nervous system. Compare Schwann cell; see glial cell,

myelin, myelin sheath.

On-off phenomenon: In Parkinson’s disease, alternating

periods in which the patient’s motor symptoms are

under control (on) or severe and uncontrolled (off); the

phenomenon occurs regardless of drug dosage.

Paraneuron: Cells that share a common heritage with

cells in the nervous system. See chromaffin cells.

Paraplegia: Paralysis and loss of sensation from the waist

down as a result of damage to the middle or lower

portions of the spinal cord.

Parkinsonism: A group of neurological disorders with

various causes (e.g., drugs, toxic chemicals, brain

tumors, and recurrent head injury). Symptoms include

abnormally decreased motor activity, tremor, and

rigidity. The most common type of parkinsonism is

Parkinson’s disease. See Parkinson’s disease.

Parkinson’s disease, idiopathic Parkinson’s disease: A

neurodegenerative disease caused by death of nerve

cells in the substantial nigra and the resulting loss of

dopamine in the brain; symptoms are tremor, slowing

of movement, and rigidity. The cause of the nerve cell

death is unknown. Compare parkinsonism.

Peripheral nervous system, PNS: One of the two major

divisions of the nervous system, made up of the nerves

and ganglia outside the brain and spinal cord. Nerves

in the peripheral nervous system connect the central

nervous system and sensory organs, other organs,

blood vessels, glands, and muscles. Compare central

nervous system.

Precursor cell: An undifferentiated embryonic cell that

may develop into one or another type of mature cell.

See differentiation.

Premarket approval application, PMA: Application

required by the FDA for certain devices; this application demonstrating safety and efficacy must be submitted to and approved by the FDA before the device can

be introduced to the market.

Prevalence: Total number of cases of a disorder in

existence at any given time in a given area. Compare

incidence.

Prevalence rate: Prevalence per unit of population.

Primary cell culture: Cells taken directly from an

organism and grown in vitro; most replicate a fixed

number of times or not at all. Compare continuous cell

line.

Proliferation: The reproduction or multiplication of

similar forms of brain cells; the stage of development

preceding migration and differentiation. Compare

differentiation, migration.

Protocol, research protocol: A complete description of

a proposed scientific experiment.

Quadriplegic: Paralysis and loss of sensation from the

shoulders down as a result of damage to the upper

spinal cord.

Regeneration: Regrowth of tissue. In the nervous system, regeneration often refers to regrowth of a damaged

axon. See axon.

Rejection, graft rejection: The destruction by the

immune system of foreign tissue; specifically, destruction of foreign tissue transplanted into a recipient’s

body from a donor’s body.

Replication: The process of duplicating or reproducing

itself, as cells. Compare proliferation.

Retrograde cell death: The killing, due to axonal

damage, of neurons located some distance away from
186 . Neural Grafting: Repairing the Brain and Spinal Cord

the site of an injury in the central nervous system.

Retrovirus: Any of a group of RNA-containing viruses

that produce reverse transcriptase, which catalyzes the

production of DNA using the virus’s RNA as a

template; the DNA is incorporated into the genome of

the infected cells. The AIDS virus is a retrovirus, as are

many infection- and tumor-producing viruses.

Risk-benefit analysis: A determination of whether the

risks to health of using a drug or procedure exceed the

therapeutic and quality-of-life benefits that accrue

from its use.

Schwann cell: A glial cell in the peripheral nervous

system that produces myelin for the myelin sheath

surrounding axons. Schwann cells also support regrowth of the axons of peripheral nerves. Compare

oligodendrocyte; see myelin, myelin sheath.

Solid tissue graft: Apiece of tissue placed into the brain

or spinal cord; such tissue contains more than one type

of cell and therefore may be more likely than a cell

suspension to provoke an immune response. See

endothelial cell; compare cell suspension.

Somatic cell: Any cell in the body except reproductive

cells and their precursors. Compare germ cell.

Spinal cord: A component of the central nervous system,

the spinal cord is a core of neuronal cell bodies

surrounded by axons that extends from the bottom of

the brain down the spinal column. The spinal cord is

divided into 30 segments. See brain, central nervous

system.

Spontaneous abortion: See abortion.

Standard therapy: Procedures no longer regulated as

research.

Stereotactic surgery: A type of brain surgery; specifically, the implantation of tissue into the brain by means

of a needle inserted through a small hole in the skull.

Striatum, corpus striatum: Part of the basal ganglia

located in the upper part of the brain; the striatum

receives dopamine from cells in the substantial nigra.

See substantial nigra.

Stroke: A sudden interruption of normal blood flow to the

brain, caused by blockage or rupture of a blood vessel,

that may result in a wide range of neurological deficits

(such as coma, paralysis, or inability to speak),

depending on wherein the brain the lesion occurred.

Substantial nigra: A nucleus in the brain; neurons in the

substantial nigra produce dopamine and send their

axons to the striatum. The cells of the substantial nigra

degenerate in Parkinson’s disease. See striatum, Parkinson’s disease.

Synapse: The site at which an impulse is transmitted from

the axon of one nerve cell to the dendrite of another

nerve cell, typically by a neurotransmitter. See neurotransmitter.

Synaptic space: A narrow gap between two adjacent

neurons into which neurotransmitters are secreted. See

neurotransmitter, synapse.

Synaptic sprouting: A process of limited regrowth

following damage to the central nervous system

whereby fibers from nearby, undamaged axons form

new branches and establish new synapses to replace

some of the lost ones.

Thalamus: A collection of nuclei in the brain that are

involved in analyzing sensory and motor information.

Therapeutic research: Studies involving human subjects that are designed to cure or palliate a disorder

existing in those subjects.

Trophic factor: A chemical that promotes the growth of

axons and the survival of neurons.

Tropic factor: A chemical that provides a surface or

substrate for axon growth and guides the axon toward

its target.

Upper brain: The portion of the brain between the

cerebral cortex and the brain stem. See brain stem,

cerebral cortex.

Vector: Transmitter of disease.

Ventricle: Cavity in the brain that contains cerebrospinal

fluid. See cerebrospinal fluid.

Viable: Capable of living; specifically, a fetus capable of

living outside the womb.

Xenograft: Tissue transplanted from one species to

another.
Index

abortion

and fetal tissue transplantation, 6,8, 10-12,22,24,39,43,72,

135-136, 151-159

informed consent issues, 13

types of, and morally relevant differences among them, 153

acetylcholine, 35,74-75,97,98

acetyl-L-carnitine, 99

adrenal cells, see adrenal cell grafts; chromaffin cells

adrenal cell grafts

age of donor and, 66,71,93-94

animal experiments with, 65-66

with antiparkinson drugs, 70-71

cell survival rates, 65-66

clinical studies of, 68-71

developmental state of material and success of, 49

disruption of blood-brain barrier, 53

effectiveness of, 65, 66,69-71

for Huntington’s disease, 73

mortality rates, 68, 69-70

with nerve growth factor, 66, 71

for Parkinson’s disease, 6, 7, 21-22, 23, 45, 52, 62, 65-66,

68-71

for progressive supranuclear palsy, 71

psychological effects of, 52

registries, 69-70

adrenocorticotropic hormone, 106

Agency for Health Care Policy and Research, 15, 129

AIDS, 53, 140

alcohol-dated memory loss, 74

Alcohol, Drug Abuse, and Mental Health Administration

funding of neural grafting research, 4,24

peer review process, 12

allografts, 23,50,52,78

FDA regulation of, 126

aluminum and aluminum binding, 98

Alzheimer’s disease, 7, 19

animal model of, 74

cause of, 98

diagnosis of, 98

incidence and prevalence of, 3,93,99

nature of fictional loss in, 20,74,98

pharmacological treatment of, 98-99

potential of neural grafts for, 7,74-75,99

symptoms, 98

Alzheimer’s disease-associated protein, 98

amantadine, 97

American Association of Neurological Surgeons, 70

amygdala, 98

amyotrophic lateral sclerosis, 7, 20

cause of, 99

diagnosis of, 99-100

incidence and prevalence of, 3, 93, 100

medical interventions for, 100

mortality rates, 100

nature of functional loss in, 99

potential of neural grafts for, 75, 100

symptoms of, 99

amyotrophic lateral sclerosis-Parkinson’s disease-dementia, 96

animal models

of Alzheimer’s disease, 74

analogous, 61

of epilepsy, 82

excitotoxin, 73

homologous, 61

MPTP, 63-64,69

need for, 61, 84

of neuroendocrine deficits, 8 3

6-OHDA, 63,65,66

of parkinsonism, 23,43,45,63

of spinal cord injury, 78

of stroke, 81, 104

animal research on neural grafting

with adrenal medullary tissue, 65-66

for Alzheimer’s disease, 74-75

for amyotrophic lateral sclerosis, 75

for brain injuries, 81-82

for epilepsy, 82

extrapolation to humans, 63

with fetal CNS tissue, 42-43,63, 65, 72

focus of, 61

with genetically engineered cells, 66-67

for Huntington’s disease, 73

with mature CNS tissue, 49

for multiple sclerosis, 84

for Parkinson’s disease, 6,63-67

with peripheral nerve tissue, 43-44

for spinal cord injuries, 78-79,80

transition to human studies, 11, 14,22-23,39, 127-128

typeS of, 61

antioxidant, 101

aspirin, 104

astrocytes, 29, 30

effects of grafts from, 47

function of, 35

genetic engineering of, 48

autografts, 23,43,48,50,65,69,78

FDA regulation of, 126, 127

of genetically engineered cells, 127

autonomic nervous system, structure of, 32

axons

communication along, 32

function of, 30,31,76

growth/regrowth of, 34-36,43,66,78

structure of, 29

synaptic pattern of, 34

basal forebrain, 98

basal ganglia, 31, 102

basic research on neural grafting, 3

Federal funding of, 3,4

focus of, 61

needs, 3,4, 19, 21, 39, 53

–187–
188 . Neural Grafting: Repairing the Brain and Spinal Cord

benztropine, 97

beta-amyloid, 98

Beta-N-methyl amino-L-alanine, 96

biological rhythms, 42-43

Biomedical Ethics Advisory Committee, 131

Biomedical Ethics Board, 131

blood-brain barrier, 40

development within grafts, 50,51

disruption by implantation of tissue in CNS, 50,52,53

species differences in, 64

brain

developmental sequence in humans, 33-34

immunological privilege, 23, 51

injury response mechanisms, 66

replacement of lost structures in, 41-42

structure of, 30-31

ventricles, graft placement in, 51, 52

brain-derived neurotrophic factor, 36

brain injury, 7, 19

animal experiments on, 81

causes of, 101-102

function of neural grafts in, 7,20,82

functional recovery from, 81,82,103-104

incidence and prevalence of, 3, 93, 102-103

mortality rates, 103

nature of, 20

neurotrophic activity at wound site, 36

from surgical procedure for graft placement, 52

see also stroke

brain stem, 31,32,80

bromocriptine, 97

calcium channel antagonists, 101

captopril, 99

carbidopa, 96

carotid body cells, 45,65

catecholamines, 79, 80

cell lines, 39

fetal tissue to start, 10

see also continuous cell lines

cell suspensions, 46-47,49,62,72,79,82

blood vessel formation in, 51

cells in culture

advantages of, 47-48

allographs, FDA regulation of, 127-127

see also continuous cell lines

central nervous system

fetal, 5

immunological privilege, 50, 51

lymphatic drainage, 50

organization/structure of, 4,5, 29, 30-32

regrowth/regeneration in, 4, 34-35

see also brain; CNS tissue grafts; spinal cord; and other

specific components

cerebral cortex, 30, 31,74, 81, 97, 98

cerebrospinal fluid, 51

cerebrovascular disease, 102

CHAMPUS insurance program, 14

chromaffin cells, 23, 45; see also adrenal cell grafts

ciliary neurotrophic factor, 36

clinical research on neural grafting

with adrenal cells, 67, 68-71

cognitive limitations of patients and, 10

coordination of, 15, 72-73

ethical issues, 3, 10, 161-163

Federal regulation of, 8, 13, 14, 113

with fetal CNS cells, 67, 71-72; see also fetal CNS tissue

grails

grievance mechanisms for patients, 121

informed consent for, 8, 10, 113, 114-116, 119-121

for Parkinson’s disease, 14,21,43,61,67-73, 161-162

on particularly vulnerable groups, protection of, 116, 119,

121-122

privately funded, 11, 12

protection of neural graft recipients, 8,10,12,13,23,113-129

protocol review and approval, 8, 14

selection of subjects, 8, 113

State regulation of, 12, 113-116

surgical procedures, 67-68

withdrawal from experiments, 120

see also human studies

CNS tissue grafts

adult, 23,49

for demyelinating disorders, 84

see also fetal CNS tissue grafts

continuous cell lines

excessive growth of, 52

grafting with, 47-48

ownership of, 159-161

Coordinated Framework for the Regulation of Biotechnology,

122

corticosteroids, 101

cryopreservation

of adrenal medullary tissue, 68

of fetal CNS tissue, 43,45,46

cycads, and ALS-P-D syndrome, 96

dementia, prevalence in United States, 99, 102

demyelinating disorders, 7,20, 102

nature of functional loss, 21, 83

see also multiple sclerosis

dendrites

communication along, 32

growth of, 34

structure of, 29

Department of Defense, 8, 14

Department of Health and Human Services

Ethics Advisory Board, 12

moratorium on Federal funding of human fetal transplantation

research, 6,11,24,39,67,72,128, 149,151,154,171-173

protection of neural graft recipients, 8, 12, 13,23, 113

see also Food and Drug Administration; Public Health

Service

Department of Veterans Affairs, 14-15, 129

funding of neural grafting research, 4,8,24

spinal cord injury centers, 102

deprenyl, 64,96, 150

DiGeorge’s syndrome, 151

dopamine-producing cells, 23,45,62,67

dorsal roots, regeneration of, 78

Dunn, E., 21

encephalitis, 53

endothelial cells, 51
Index ● 189

epidermal growth factor, 36

epilepsy, 7, 20, 21

animal model of, 82

characteristics of, 21, 104

chug management of, 105

function of neural gratis in, 7, 105

incidence and prevalence of, 3, 93, 102, 105

types of seizures, 104-105

ethical issues

continuous cell line ownership, 159-161

Federal funding and, 9-10, 149-151

fetal tissue, 151-159

human subjects in research, 3, 10, 161-163

Nuremberg Code, 114

research abuses, 114

sources of materials for transplantation, 3, 6, 10, 22, 23-24,

151-161

see also medical research ethics

excitotoxins, 73

experimental allergic encephalomyelitis, 53

Federal Food, Drug, and Cosmetic Act, 122, 123, 125

Federal funding

ethical issues in, 149-151

moratorium on human fetal tissue transplantation research, 6,

11,24,39,67,72, 128, 149, 151, 154, 171-173

of neural grafting research, 3, 24, 151

regulations affecting, 8

fetal research

abortion and, 135-136

on cadavers (fetal), 135, 152

disposition of remains, 138-139

ethical issues in, 152

Federal policy development on, 130-131

Federal regulations on, 131-132, 138-139

grafting, see fetal CNS tissue grafts

guidelines on, 8-9

interstate transfer of a fetus, 137

on live fetuses, 131-132, 135, 153

State regulations on, 9, 132-135

fetal CNS tissue grafts, 39

acetylcholine-producing, 75

advantages over other tissues, 43,49

for Alzheimer’s disease, 74,75

animal experiments with, 4243,63,65

behavioral control with, 4243,83

blood vessel formation in, 51

for brain injuries, 82

brain stem cells, 80

from cell suspensions, 46

clinical trials, 71-72

constraints on use of, 4, 6,43, 65, 67, 73

continuous cell lines from, 136

cryopreservation of cells, 43,45, 46

effectiveness of, 4, 22,42, 53, 65, 66,72

for epilepsy, 82

ethical issues in use of, 151-159

FDA regulation of, 23, 126, 127

Federal oversight of, 9, 138-139

for Huntington’s disease, 73

identification of fetal brain region for materials, 43

from induced abortions, 6, 10, 12, 13,39, 152-157

informed consent conditions, 12,13, 120,132, 155-156

integration into mature CNS, 42

manner and timing of procurement of tissues, 12,23-24

norepinephrine-containing, 75

number of cells used, 43

for Parkinson’s disease, 6,22,43,52,62,63,65, 67,71-72

and property rights, 10

protection of donors of, 8-9, 129-137

and respect for fetal life, 10, 152-152

risks to recipients, 43, 136, 152-153

sale of materials, 9, 12, 13, 24, 130, 131, 136-137, 140-142,

157-159

for spinal cord injuries, 78-80

spinal cord tissue, 78-79

spinal motor neurons, 75

as standard therapy, 157-158

survival of grafts, 72

fibroblast growth factors, 36

fibroblasts

genetic engineering of, 48

risk from use in grafts, 48, 53

tyrosine hydroxylase production by, 66

Food and Drug Administration, regulatory authority

biological products, 123

devices, 123

drugs, 122-124

interstate commerce and, 124-125

limits on, 124-126

neural graft materials, 8, 14, 23, 122, 126-127

practice of medicine and, 125-126

product safety and efficacy, 123-124

funding, see Federal funding

gamma-aminobutyric acid, 82, 97, 105

ganglia, 32

General Registry of Adrenal-Fetal Transplantation, 70

genetically engineered cells, 39,65

animal studies with, 66-67

autografts of, 127

ethical issues related to, 161

FDA regulation of, 127

grafting methods, 6,48,67

NGF-producing, 75

glia-derived nexin, 36

glial cells

differentiation of, 34

function of, 29-30,83

inhibition of neuron regrowth, 40

primary cultures of, 47

replication of, 34

Structure of, 29-30

types of, 29,30

gonadotrophin-releasing hormone, 83

Health Care Financing Administration, 8, 13, 129

heart transplants, funding controversies, 150

hepatitis, 53

herpes simplex, 53

hippocampus, 74-75,82,98

HIV, 140

human amnion membrane matrix, 45

human studies, see clinical research on neural grafts
190 . Neural Grafting: Repairing the Brain and Spinal Cord

Huntington’s disease, 7,20

cause of, 73, 97

functional loss from, 73,97

incidence and prevalence of, 3,93,97-98

potential of neural grafts in, 7,73

symptoms of, 73, 97

treatment of, 97

hyperexcitable nerve cells, 105

hypothalamus, 31,82,83

idebenone, 99

immune system response

to allografts, 52

to cell suspensions versus solid tissue grafts, 47

developmental state of graft material and, 49

to fetal CNS tissue, 43,49

to genetically engineered cells, 48

multiple sclerosis and, 106

Parkinson’s disease and, 52

prevention of, 50

source of tissue and, 5,45, 50-51,53

to surgical procedure, 52

immunological privilege, 23, 50,51

immunoreactive molecules, 50-51

immunosuppression, risks to graft recipients, 52

infections from grafting materials, 53

informed consent

for donation of continuous cell lines, 159-161

ethical issues, 162-163

for fetal tissue donation, 12, 13, 132, 155-156

information to be provided for, 119-120

from particularly vulnerable populations, 121-122

from patients in clinical studies, 8, 10, 113, 119-121

penalties for violation of, 120-121

State regulations on, 114-116, 119-121

withdrawal from experiments, 120

injury, see brain injury; spinal cord injury

Institutional Review Boards, 8, 12, 14, 15,23, 161

composition of, 118

criteria for authorization of human research, 117

ethical guidelines, 117-118

Federal requirements for review by, 129

procedure for obtaining approval of, 118

purpose of, 113, 116-119

State requirements for review by, 122

insulin and insulin-like growth factors, 36

Interagency Head Injury Task Force, 102-103

interstate commerce, and regulation of neural grafting, 124-125

isografts, 50

Joint Commission on Accreditation of Healthcare Organizations, 8, 129

L-dopa

production by genetically engineered cells, 48

treatment of Parkinson’s disease with, 95-97, 150

laminin, 36

legal/regulatory issues

constitutionality of restrictions on research, 9, 137-138

disposition of cadavers/fetal remains, 9, 13, 138-139

Federal oversight, 9, 14, 137-142

fetal research, 131-132, 138-139

grievance mechanisms for patients, 121

indirect regulation, 8, 14, 129

informed consent, 8, 12, 13, 119-121

neural graft materials, see Food and Drug Administration

ownership of continuous cell lines, 159-161

payment of donors, 8,9,140-142

protection of donors of fetal tissue, 8-9, 129-137

protection of human subjects in research, 8, 13,22, 113-129;

see also clinical research on neural grafting; informed

consent; State laws

see also specific statutes

limbic system, 31

locus ceruleus, 82,98

Lou Gehrig’s disease, see amyotrophic lateral sclerosis

Medical Device Amendments of 1976, 124

medical malpractice, 8

medical research ethics, genesis of, 114

Medical Treatment Effectiveness Program, 15

Medicare/Medicaid coverage, 14, 129

l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine, 64,95

methylprednisolone, 101, 106

methylpyridine, 64

microglia, 29, 30

milacemide, 99

monoamine oxidase B, 64

moratorium on Federal funding of human fetal transplantation

research, 6,11,24,39,67,72,128, 149,151,154,171-173

motor neurons, neural grafting with, 100

motor neuron disease

potential of neural grafts in, 7,75

see also amyotrophic lateral sclerosis

MPTP model of parkinsonism, 63-64,95

multiple sclerosis, 7, 21

causes of, 105-106

death rates, 106

diagnosis of, 106

drug therapy, 106

and immune system function, 106

incidence and prevalence, . of, 3, 93, 106-107

potential of neural grafts in, 84, 106

symptoms of, 105

myelin

formation of, 34,43,47,83

function of, 29,43

loss of, 21, 105; see also multiple sclerosis

naloxone, 101

National Academy of Sciences, 12

National Commission for the Protection of Human Subjects of

Biomedical and Behavioral Research, 130, 151-152

National Conference of Commissioners on Uniform State Laws,

13, 140

National Institute of Neurological Disorders and Stroke, 70

National Institutes of Health

budget, 113

funding of neural grafting research, 4,24

guidelines for neural grafting research protocols, 15

guidelines for research on vulnerable subjects, 121

Human Fetal Tissue Transplantation Research Panel, 12,154

peer review process, 12

National Organ Transplant Act
Index ● 191

components covered under, 13-14

fetal tissue regulation under, 9, 12-13, 141, 157

National Research Act, 130

National Science Foundation, funding of neural grafting research, 4, 24

nerve fibers, 45,62

nerve growth factor

with adrenal cell grafts, 66,71

and Alzheimer’s disease, 98

production by genetically engineered cells, 48

protection of acetylcholine neurons, 75,98-99

role of, 36

stimulation by grafts, 41

nerve roots, 31-32

nervous system

cellular components of, 29-30; see also glial cells; neurons

chemical-electrical communication in, 32-34

fetal (human), 43

organization/structure of, 4,5, 29-32

see also brain; central nervous system; peripheral nervous

system; spinal cord; and other specific components

neural grafting

age of host and, 51-52,53,78-79

alternatives to, 150-151

and blood vessel formation, 51, 53

definition of, 3,4,39

effectiveness on neurological disorders, 19,61,63-64,93

Federal interests in, 22-24

historical perspective, 21-23,42

with immature versus mature tissue, 5, 21,49,52,53,66

number of cells used in, 52

number of recipients, 19

Nuremberg Code applied to, 114

psychological effects of, 52,69

replacement of chemicals with, 19,20, 3940,42

replacement of lost structures with, 19,20,39,41-42

risks to recipients, 5, 42, 52-53, 81, 152-153, 161-162; see

also immune system response

site for transplantation, 44, 62, 63,72

stimulation of cell growth and survival with, 19,20,40-41,63,

80

success factors in, 5,49-51

therapeutic strategies, 4, 19,39-42

neural grafting materials, 4-5,6, 53

ethical and legal questions, 42, 151-161; see also ethical

issues; legal/regulatory issues

excessive growth of, 52

immunological problems of, 42

infections from, 53

man-made, coated with growth-promoting chemical, 45

regulation of, 8, 23, 122

sources of, 23,39,42

see also adrenal cell grafts; fetal CNS tissue grafts; genetically modified cells

neuritic plaques, 98

neuroblastoma cells, 47

neurodegenerative disorders, 20

characteristics of, 20

potential function of neural grafts in, 7

see also specific diseases

neuroendocrine deficits, 7, 82-83

neurofibrillary tangles, 98

neurological disorders

animal models of, 43

costs of, 7, 93, 150

disease, 20-21; see also neurodegenerative disorders, and

specific disorders

epidemiology of, 94-100

incidence and prevalence of, 3, 19,93

injury, 20; see also brain injury; spinal cord injury

nature of, 20-21

potential of neural grafting for, 150

treatment approaches, 3,7, 19,21

in veterans, 102

see also specific disorders

neuromuscular diseases, 102

neurons

death of, 34,41,94,97,98

differentiation of, 34

injured, 40-41

number of, 34

peripheral autonomic, 5

primary cultures of, 47

regeneration of, 29, 34-35,40,45

structure of, 29

survival of grafting procedures, 43,47

see also axons; dendrites

neurotransmitters, 7,44,45,73

function of, 32-33

implants in CNS, 40

kinds of, 33-34

see also specific neurotransmitters

neurotrophic factors, 34, 36,66,79, 82

neurotrophin-3, 36

neurotropic factors, 34, 36,79

nimodipine, 99

noradrenaline, 82,98

nucleus/nuclei

defined, 30

purpose of, 31

Nuremberg Code, 114

6-OHDA, 63,65,66

oligodendrocytes

function of, 29,30,35,47,83

primary cultures of, 47

organic brain syndrome, 102

paraneurons, 45

Parkinson, James, 94

Parkinson’s disease and parkinsonism, 7, 19

adrenal cell grafts for, 21-22,45,62,65-66,67, 68-71, 128

animal research on, 23,43,45,63-67

causes of, 95

clinical trials of neural grafting, 14, 21, 43, 61, 67-72, 128,

161-162

drugs used for treatment of, 97, 150

epidemiology of, 94-97

fetal CNS grafts for, 6,22,43,52,62,63,65, 67,71-72,136

genetically engineered cell grafts for, 66-67

incidence and prevalence of, 3,93,95,96-97

mortality rates, 68, 69-70

MPTP model, 63-64,66,95

nature of functional loss in, 20, 62, 94
192 ● Neural Grafting: Repairing the Brain and Spinal Cord

neural grafting applications, 3, 5, 6,96

number of recipients of neural grafts, 6, 67

on-off phenomenon, 68

registries, 69-70

site for transplantation, 62, 63

success of neural grafting in, 5,39,63,71,72,84,93, 150-151

surgical procedures for grafts, 67-68

symptoms, 62,64,94,95

treatment of, 95-96

PC12, 47

peripheral autonomic tissue

animal experiments with, 44-45

developmental state of, and success of graft, 49

peripheral nerve cells

function of, 44

grafts with, 23,39,43-44,45,78,84

regrowth of, 44

peripheral nervous system

organization/structure of, 4, 29, 32

regrowth/regeneration in, 4, 34-35

tissues used for grafting, 5

physostigmine, 99

pituitary gland, 82

policy issues and options

Federal funding of fetal tissue transplantation research, 11-12

Federal Government role in development of neural grafting

procedures, 14-15

laws and regulations applicable to fetal tissue transplantation,

12-14

practice of medicine, and regulation of neural grafting, 125-126

progressive supranuclear palsy, 71

Protection of Human Subjects Act, 155

Public Health Service Act, 8, 122, 123, 125-127

regulatory issues, see legal/regulatory issues

research, see animal research; basic research; clinical research

retrograde cell death, 76, 78

S100 protein, 36

scar formation, 41

astrocytes and, 35, 47

reduction of, 47,78

Schwann cells, 29,30

axonal regrowth into, 35

function of, 34,43,47,83

from peripheral nerves, 84

in primary cultures, 47

seizures, 21, 53, 82, 104; see also epilepsy

sexual potency/sexual behavior, restoration of, 83

spinal cord

immunological privilege, 51

regenerative capacity, 80

replacement of lost structures in, 41-42, 76

structure of, 31-32, 76

spinal cord injury, 7, 19

age of host and effectiveness of grafts, 78-79

animal models of, 78

causes of, 75, 100

demyelination in, 84

effectiveness of grafts on, 80-81

fetal brain tissue grafts, 79

fetal spinal cord tissue grails, 78-79

fictional losses from, 102

functional recovery from, 79-80,80-81, 101

incidence and prevalence of, 3,93, 101, 102

and neurotrophic and neurotropic factors, 79

peripheral nerve grafts for, 78

potential function of neural grafts in, 7,76-78, 101

rehabilitative therapy, 81

repair of nerve fibers, 76

research needs on, 80

risks to graft recipients, 81

sources of graft materials, 79

survival rates, 101

State laws

on clinical research, 12, 113-116, 121-122

on compensation for fetal tissue, 140-142

on disposal of fetal remains, 138-139

on fetal research, 9, 132-135

on informed consent, 114-116, 119-121

licensing, 8

on protection of fetus, 132-135

on protection of particularly vulnerable populations, 121-122

on protection of pregnant women, 140; see also informed

consent

striatum, 62,67-68,72, 73,97

stroke, 7, 19

animal model of, 81

causes of, 102

functional losses from, 103

incidence and prevalence of, 3, 93, 104

intracranial hemorrhage, 103

ischemia, 103

potential of neural grafting for, 81-82, 104

substantial nigra, 62, 63, 70, 94

surgical procedures

adrenalectomy, 68,69-70

clinical trials of, 128

complications of, 68, 69-70

effect of graft placement during, 52

effect on success of graft, 66

for epilepsy, 105

open surgery, 67, 69

for Parkinson’s disease grafts, 67-68,72

regulation of, 8, 127-129

stereotactic, 67, 72

suronacrine maleate, 99

sympathetic ganglia, 65

synapses

between graft and host, 40,62-63,73,82

structure of, 32-33

synaptic contacts, 34, 36, 76, 80

synaptic space, defined, 32

synaptic sprouting, 34-35

tetrahydroaminoacridine, 99

thalamus, 31

Thompson, W. G., 21

thyrotropin-releasing hormone, 101

transplants, tissue and organ, number of recipients, 19

trihexyphenidyl, 97

tumor formation, from continuous cell lines, 48,52

Tuskegee syphilis study, 114

tyrosine hydroxylase, 66
Index ● 193

Uniform Anatomical Gift Act vasopressin, 83

amendment of, 13 velnacrine maleate, 99

applicability to fetal tissue implants, 9,13, 135,136,138-141,

154 Willowbrook hepatitis study, 114

uniform donor card, 139

United Parkinson Foundation, 70 xenograft, 50, 53
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