DEPARTMENT OF HEALTH AND HUMAN SERVICES

NATIONAL INSTITUTES OF HEALTH

Fiscal Year 2006 Budget Request

Witness appearing before the

House Subcommittee on Labor-HHS-Education Appropriations

Dr. Jeremy M. Berg, Director

National Institute of General Medical Sciences

March 9, 2005

William Beldon, Deputy Assistant Secretary, Budget

Mr. Chairman and Members of the Committee:

I am pleased to present the Fiscal Year (FY) 2006 President's budget
request for the National Institute of General Medical Sciences (NIGMS).
The FY 2006 budget includes \$1,955,170,000, an increase of \$11,103,000
over the FY 2005 enacted level of \$1,944,067,000 comparable for
transfers proposed in the President's request.

**UNDERSTANDING DISEASE REQUIRES UNDERSTANDING NORMAL FUNCTION**

As we go about our daily lives, most of us probably forget about the
biological processes that make our bodies work. Our cells are constantly
making new components, dividing, moving, and even dying. Complex
mechanisms underlie each of these processes and elaborate networks
integrate them to promote normal, healthy function. If any of these
processes break down, the result can be cancer, diabetes, Alzheimer's,
or a host of other diseases.

To improve our understanding of basic biological processes, we need to
employ a wide range of approaches. These include conducting basic
research, developing new technologies, and training tomorrow's
scientists. In essence, this is the core mission of NIGMS. For more than
40 years, the Institute has focused on deepening understanding of
critical life processes and the molecular underpinnings of disease. In
this way, NIGMS lays the foundation for advances in the diagnosis,
treatment, and prevention of many different illnesses.

**PARADIGM-SHIFTING IDEAS AND THEIR APPLICATION**

NIGMS has an impressive track record of investing in research with big
payoffs. One indication of this success comes from the many prestigious
awards our grantees receive for their research. In each of the last 8
years, at least one Nobel Prize has been given to an NIGMS grantee. This
year continues the trend: The 2004 Nobel Prize in chemistry went to
Irwin Rose, Ph.D., a biochemist at the University of California, Irvine,
whose work has been supported by the Institute for several decades. He
brings the number of NIGMS-supported Nobel laureates to 57.

Rose shared the prize for his studies on how cells control the breakdown
of unneeded proteins. The mechanism for this controlled breakdown
underlies many processes in health and disease and is now the focus of
literally thousands of research studies. The discoveries flowing from
this basic research are increasingly being translated into new
therapies. For example, Alfred Goldberg, Ph.D., an NIGMS grantee at
Harvard Medical School in Boston, initiated research that led to a new
drug called Velcade^®^. This drug is used to treat multiple myeloma, a
deadly type of bone marrow cancer. Velcade^®^ works by targeting the
proteasome---the molecular machine that breaks down unneeded proteins
that Rose and his coworkers discovered. Velcade^®^ is likely to be the
first of a number of drugs based on the discovery of this process that
is so fundamental to much of cell biology.

The path to new approaches for promoting health and preventing and
treating diseases has several key elements. These include creatively
exploring a range of biological systems, developing tools for expanding
knowledge, finding appropriate ways to integrate this knowledge into
practical applications, and, of course, having a workforce of scientists
who have the motivation and the knowledge to drive these advances.

**FROM CARNIVOROUS SNAILS TO A NOVEL PAIN TREATMENT**

It is tough to make a living as a carnivorous snail. A large family of
such creatures, called cone snails, relies on extremely potent venom to
paralyze prey almost instantly. Baldomero Olivera, Ph.D., a biologist at
the University of Utah in Salt Lake City, has been studying cone snails
for more than 25 years with NIGMS support, carefully separating the
venom into its components and studying each one.

Remarkably, the venom components are small proteins that target
structures within the neuromuscular system with exquisite specificity.
Because of the roles of their targets and this great specificity, these
proteins are powerful research tools and show great promise as drugs.
The first drug to result from this work, Prialt^®^, was approved by the
FDA in December 2004 to treat the chronic, intractable pain often
endured by people with cancer, AIDS, or certain neurological disorders.
One thousand times more powerful than morphine, this new pain medication
is thought to be non-addictive.

Other recently discovered pathways are leading to new drugs as well. The
process of RNA interference, first characterized in roundworms by NIGMS
grantees, can specifically silence individual targeted genes. Harnessing
this process has allowed scientists to precisely control genes, leading
to exciting new research tools and promising new ways to treat diseases
including HIV, hepatitis, and cardiovascular disease. An RNA
interference-based drug to treat the blinding eye disease of macular
degeneration is currently in clinical trials.

**THE SHAPES OF THINGS TO COME**

The human genome is expressed primarily through proteins, the molecules
that perform virtually all of the body's activities. Based on their
amino acid sequences, proteins fold into complex shapes that determine
their functions, including which other molecules they bind to form
complex assemblies. Powerful techniques have been developed for
determining protein structures in great detail. Thousands of such
structures have been determined, providing deep insights into how
biological systems function in health and disease and driving the
development of new drugs and other therapies. Much of this work has been
performed by individual investigators working on individual proteins
chosen based on their biological context. A productive laboratory might
determine two to four structures per year. This approach continues to be
effective, but it is too slow to keep up with the vast number of
potential protein targets now accessible through genomic studies.

To complement the contributions of individual investigators, NIGMS
launched the Protein Structure Initiative (PSI) in 2000 with the goal of
developing technologies and processes to enable researchers to quickly,
cheaply, and reliably determine the three-dimensional structures of
proteins. After 4 years, the nine PSI pilot centers can produce several
structures each week, and the total number of structures solved by the
PSI centers has now passed the milestone of 1,000!

With the second phase of the initiative beginning this summer, the PSI
will use the tools and methods developed in the pilot phase to continue
technology development and to determine more protein structures,
including some that were too complex to tackle during the pilot phase.
Researchers will use these structures to determine and understand
protein function, predict the structures of other proteins, identify
targets for drug development, design molecules to fit those targets, and
compare proteins from normal and diseased tissues.

An important activity related to the PSI is the structural biology
component of the NIH Roadmap for Medical Research, which funded two
Centers for Innovation in Membrane Protein Production to aid structural
studies of this major class of proteins. Difficulties inherent in
studying membrane proteins mean that we know relatively little about
them, despite the fact that they represent up to a third of all proteins
and are the targets for a large number of therepeutic drugs. NIGMS is
actively involved in other Roadmap initiatives, as well, including those
in the areas of high-risk research (specifically, the NIH Director's
Pioneer Award), bioinformatics and computational biology, molecular
libraries and imaging, and interdisciplinary research.

**COMPUTERS MODEL COMPLEX SYSTEMS**

Today's biomedical research has moved beyond describing the parts of
living systems to focusing on the complex, dynamic interactions of those
parts. One of the best ways to approach this formidable challenge is to
use computers to model and manipulate the systems.

Among the places this is happening are the five NIGMS Systems Biology
Centers. Multidisciplinary teams of researchers at these centers are
addressing such fundamental questions as how cells divide,
differentiate, and communicate and how different kinds of environmental
stress affect cell and tissue function.

At the other end of the spectrum, NIGMS-supported researchers are
investigating how human systems contribute to the spread of infectious
diseases. The researchers, part of the Institute's Models of Infectious
Disease Agent Study (MIDAS) initiative, use computational approaches to
simulate disease outbreaks, whether they occur naturally or result from
bioterrorism. In much the same way as weather forecasters use computer
models to predict the landfall of hurricanes, scientists can use the
MIDAS models to make predictions about potential epidemics. These models
will assist policymakers, public health workers, and other researchers
in understanding and responding to new infectious disease outbreaks.

Responding to the medical community's growing concern that avian
influenza could cause the next flu pandemic, the MIDAS network currently
is simulating the outbreak of a deadly bird flu strain in a hypothetical
human community. The computer models incorporate data on population
density and age structure, distribution of schools, locations of
hospitals and clinics, travel, and the infectiousness of the virus. The
models will predict the effects of different strategies to contain the
spread of infection, such as vaccinating specific groups of people or
restricting travel. Preliminary results from the avian flu modeling
project should be available by mid-2005.

**DIVERSITY DRIVES DISCOVERY**

To continue making rapid progress in biomedical research and improving
human health, we need to ensure that the pool of biomedical scientists
reflects the great diversity of our nation. This diversity can spark new
research questions and offer different approaches to answering them.
NIGMS promotes this diversity in a number of ways.

Through our Division of Minority Opportunities in Research, we offer
programs that encourage and prepare underrepresented minority students
for research careers. Other programs enhance science curricula and
faculty research capabilities at institutions with substantial minority
enrollments.

We require our institutional training programs to recruit and retain
underrepresented minority students, as well. And we promote diversity of
ideas through interdisciplinary training programs and through efforts to
bring the expertise of researchers in a variety of fields, from the
physical to the behavioral sciences, to bear on biomedical questions.
One example is our partnership with the National Science Foundation that
supports more than 30 research grants at the interface of biology and
mathematics.

**EXPANDING THE HORIZON**

Our increasing knowledge of the biological processes that underpin
health and disease holds great promise for new drugs and better
diagnostic techniques in the future. A more complete picture of how
these processes work---and don't work---may lead to new methods for
preventing illness altogether.

At the same time, it is important to remember that breakthroughs are
often based on years of scientific research, with each new result
building on many previous ones. Each discovery pushes back the frontier
and reveals intriguing new questions and avenues for future study. While
we can't always predict what we'll find, we can guarantee that the
journey will bring us closer to our goal of understanding human health
and disease.

Thank you, Mr. Chairman. I would be pleased to answer any questions that
the Committee may have.

DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institute of General Medical Sciences

CURRICULUM VITAE

Name: Jeremy Mark Berg

Position: Director, NIGMS

Birthplace Stanford, California

And Date: April 10, 1958

EDUCATION: B.S., Chemistry, Stanford University, 1980

M.S., Chemistry, Stanford University, 1980

Ph.D., Chemistry, Harvard University, 1985

EXPERIENCE:

Nov. 2003 B Present Director, National Institute of

> General Medical Sciences, NIH

1990 B 2003 Professor and Director, Department of

> Biophysics and Biophysical Chemistry
>
> Director, Markey Center for
>
> Macromolecular Structure and Function,
>
> The Johns Hopkins University, Baltimore, MD

1992 B 2003 Professor of Chemistry, The John Hopkins University,
Baltimore, MD

2001 B 2003 Director, Institute for Basic Biomedical Sciences, The Johns
Hopkins University

> School of Medicine, Baltimore, MD
>
> Co‑Director, Keck Center for Rational Design of Biologically Active
> Molecules, The Johns Hopkins University, Baltimore, MD

1986 B 1990 Assistant Professor, Department of Chemistry, The Johns
Hopkins University, Baltimore, MD

1984 B 1986 Jane Coffin Childs Memorial Fund Postdoctoral Fellow, The
John Hopkins University School of Medicine, Baltimore, MD

1980 B 1983 National Science Foundation Predoctoral Fellow, Harvard
University, Cambridge, MA

1979 B 1979 Visiting Research Associate, Charles F. Kettering Research
Laboratory, Yellow Springs, Ohio

Department of Health and Human Services

Office of Budget

William R. Beldon

Mr. Beldon is currently serving as Deputy Assistant Secretary, Budget in
the Department of Health and Human Services. He has been a Division
Director in the Budget Office for sixteen years, most recently as
Director of the Division of Discretionary Programs. Mr. Beldon started
in federal service as an auditor in the Health, Education and Welfare
Financial Management Intern program. Over the course of more than 30
years in the Budget Office, Mr. Beldon has held Program Analyst, Branch
Chief and Division Director positions. Mr. Beldon received a Bachelor=s
Degree in History and Political Science from Marshall University and
attended the University of Pittsburgh where he studied Public
Administration. He resides in Fort Washington, Maryland.