[Senate Hearing 107-277]
[From the U.S. Government Publishing Office]



.                                                       S. Hrg. 107-277
                   PROMISE OF THE GENOMIC REVOLUTION

=======================================================================

                                HEARING

                                before a

                          SUBCOMMITTEE OF THE

            COMMITTEE ON APPROPRIATIONS UNITED STATES SENATE

                      ONE HUNDRED SEVENTH CONGRESS

                             FIRST SESSION

                               __________

                            SPECIAL HEARING

                     JULY 11, 2001--WASHINGTON, DC

                               __________

         Printed for the use of the Committee on Appropriations


 Available via the World Wide Web: http://www.access.gpo.gov/congress/
                                 senate

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                      COMMITTEE ON APPROPRIATIONS

                ROBERT C. BYRD, West Virginia, Chairman
DANIEL K. INOUYE, Hawaii             TED STEVENS, Alaska
ERNEST F. HOLLINGS, South Carolina   THAD COCHRAN, Mississippi
PATRICK J. LEAHY, Vermont            ARLEN SPECTER, Pennsylvania
TOM HARKIN, Iowa                     PETE V. DOMENICI, New Mexico
BARBARA A. MIKULSKI, Maryland        CHRISTOPHER S. BOND, Missouri
HARRY REID, Nevada                   MITCH McCONNELL, Kentucky
HERB KOHL, Wisconsin                 CONRAD BURNS, Montana
PATTY MURRAY, Washington             RICHARD C. SHELBY, Alabama
BYRON L. DORGAN, North Dakota        JUDD GREGG, New Hampshire
DIANNE FEINSTEIN, California         ROBERT F. BENNETT, Utah
RICHARD J. DURBIN, Illinois          BEN NIGHTHORSE CAMPBELL, Colorado
TIM JOHNSON, South Dakota            LARRY CRAIG, Idaho
MARY L. LANDRIEU, Louisiana          KAY BAILEY HUTCHISON, Texas
JACK REED, Rhode Island              MIKE DeWINE, Ohio
                     Terry Sauvain, Staff Director
                 Charles Kieffer, Deputy Staff Director
               Steven J. Cortese, Minority Staff Director
                                 ------                                

 Subcommittee on Departments of Labor, Health and Human Services, and 
                    Education, and Related Agencies

                       TOM HARKIN, Iowa, Chairman
ERNEST F. HOLLINGS, South Carolina   ARLEN SPECTER, Pennsylvania
DANIEL K. INOUYE, Hawaii             THAD COCHRAN, Mississippi
HARRY REID, Nevada                   JUDD GREGG, New Hampshire
HERB KOHL, Wisconsin                 LARRY CRAIG, Idaho
PATTY MURRAY, Washington             KAY BAILEY HUTCHISON, Texas
MARY L. LANDRIEU, Louisiana          TED STEVENS, Alaska
ROBERT C. BYRD, West Virginia        MIKE DeWINE, Ohio
                           Professional Staff
                              Ellen Murray
                              Jim Sourwine
                              Mark Laisch
                            Adrienne Hallett
                              Erik Fatemi
                               Adam Gluck
                       Bettilou Taylor (Minority)
                        Mary Dietrich (Minority)

                         Administrative Support
                             Carole Geagley
                       Correy Diviney (Minority)








                            C O N T E N T S

                              ----------                              
                                                                   Page
Opening statement of Senator Tom Harkin..........................     1
Opening Statement of Senator Arlen Specter.......................     2
Opening statement of Senator Larry Craig.........................     3
    Prepared statement...........................................     4
Statement of Francis Collins, M.D., Ph.D., Director, National 
  Humane Genome Research Institute, National Institutes of 
  Health, Department of Health and Human Services................     4
    Prepared statement...........................................     7
Human genome sequence............................................     7
Finishing the human genome sequence..............................     8
Human genetic variation..........................................     8
Gene expression..................................................     8
Protein structure, function, and interaction.....................     9
Promise for new treatments and prevention........................     9
Ethical, legal, and social implications..........................    10
Predictions for the future.......................................    10
Statement of Philip Needleman, Ph.D., senior executive vice 
  president, Pharmacia Corporation...............................    14
    Prepared statement...........................................    17
The human genome and innovative approaches to therapy............    17
Alzheimers disease...............................................    18
Schizophrenia....................................................    18
Kinase genes as targets for cancer treatment.....................    19
Therapeutic approach to colon cancer.............................    19
Statement of Stephen S. Rich, Ph.D., professor, Wake Forest 
  University School of Medicine..................................    20
    Prepared statement...........................................    22
Etiology of type 1 diabetes......................................    22
Genetic basis of type 1 diabetes.................................    23
Search for type 1 diabetes genes.................................    23
Paths to gene discovery..........................................    24
Promise of genomics..............................................    24
Statement of Jeffrey C. Murray, M.D., professor of Pediatrics, 
  Biology, and Preventive Medicine, University of Iowa...........    25
    Prepared statement...........................................    27
Statement of Ben Affleck, Actor..................................    30
Accompanied by:
    Brad Margus, president and co-founder, A-T Children's Project    30
    Joe Kindregan, A-T patient...................................    30
Prepared statement of Ben Affleck................................    33
Prepared statement Brad Margus...................................    35
My story.........................................................    35
Steps you could take to accelerate research......................    38











                   PROMISE OF THE GENOMIC REVOLUTION

                              ----------                              


                        WEDNESDAY, JULY 11, 2001

                           U.S. Senate,    
    Subcommittee on Labor, Health and Human
     Services, and Education, and Related Agencies,
                               Committee on Appropriations,
                                                    Washington, DC.
    The subcommittee met at 9:42 a.m., in room SD-192, Dirksen 
Senate Office Building, Hon. Tom Harkin (chairman) presiding.
    Present: Senators Harkin, Landrieu, Specter, Stevens, and 
Craig.


                opening statement of senator tom harkin


    Senator Harkin. Good morning, and welcome to today's 
hearing of the Labor, Health and Human Services, and Education 
Appropriations Subcommittee on the promise of the genomic 
revolution.
    Back in the 1980's when people first started talking about 
sequencing the human gene, no one expected that we would be 
finished by now. Scientists thought it would take decades to 
work through all 3 billion letters of our DNA code. But thanks 
to people like Dr. Francis Collins, who will be our lead-off 
witness here today, and thousands of researchers all over the 
world, that goal was completed, as we know, last year.
    Today, in fact, we can access our entire genetic 
instruction manual from a single CD-ROM. So, here is my entire 
lifetime right here on a CD-ROM. We can put the whole DNA 
sequence right now on one CD-ROM. That accomplishment ranks as 
one of the greatest intellectual achievements in our history. 
And I am proud to say that this subcommittee, working in a 
bipartisan effort, provided the funds to help make it possible.
    But sequencing the genome is only the beginning of the 
medical advances that lie ahead. Researchers are now turning to 
the even more important task of reading the human genome to see 
what clues it can offer for cures and treating of diseases. For 
the first time, scientists have learned how to turn off the 
mechanisms in a cell that cause cancer. They are producing 
drugs like Gleevec, which is showing promising results in 
fighting leukemia.
    They are also figuring out why a drug might work wonders on 
one person but have no effect on someone else with the same 
disease. Just imagine: One day soon, with the help of a simple 
genetic test, doctors will be able to prescribe exactly the 
right drugs for a person's particular genetic profile.
    Genomics will also revolutionize the way we prevent 
diseases. We will be able to find out in advance which 
conditions we are susceptible to so we can take steps to reduce 
the risks.
    But there is a darker side to this. What happens when 
someone gets fired or loses their health insurance because of a 
genetic predisposition to a certain disease? What is the value 
of knowing that you have a predisposition to a certain genetic 
disease if you are denied health insurance because of that very 
information?
    That is why we need to get legislation through that would 
make it illegal for employers or health insurance companies to 
discriminate against people because of their genetic makeup. 
All of us should enjoy the benefits of 21st century 
technologies without suffering from the hardship of 21st 
century discrimination.
    We have an outstanding panel of witnesses to discuss these 
issues this morning. We have a very special guest here this 
morning, who I am sure needs no introduction. Ben Affleck is a 
tremendous actor who, as many of you know, won an Academy Award 
for his first script, ``Good Will Hunting''. He has also 
starred in other terrific films like ``Armageddon'' and 
``Balance'', and ``Forces of Nature''. Of course, as I told him 
earlier, he is now my envy as a fighter pilot. I always wanted 
to fly the kind of fighters he flew in ``Pearl Harbor''.
    But Ben is here this morning for a different kind of war, 
the war against disease. He will testify this morning on the 
promise of the genomic revolution. He will talk about a 
terrible genetic disease called A-T that has stricken a young 
friend of his, Joe Kindregan. As a celebrity, Ben could use his 
fame for all kinds of purposes, but there are few causes more 
noble than fighting on behalf of those who need medical help. I 
want to thank him personally for being here with us this 
morning and taking up this cause.
    Before we turn to Dr. Collins, let me yield to my good 
friend and person that I have worked together with on a 
bipartisan basis to make sure we got the funding for the Human 
Genome Institute from the very beginning, Senator Specter.


               opening statement of senator arlen specter


    Senator Specter. Well, thank you very much, Mr. Chairman. I 
commend you for the outstanding work you have done on the 
genome project and for your leadership in this very important 
area.
    It is truly amazing that the 3 billion units are now within 
range of understanding the DNA makeup of the human body, and 
the potential is limitless. So, it is really an extraordinary 
accomplishment, and we have to utilize these opportunities to 
the maximum extent possible.
    This subcommittee has taken the lead over the past 6 years 
in advancing the funding for research at the National 
Institutes of Health. Senator Harkin and I introduced the first 
amendment to the budget to add $1 billion for NIH, which was 
defeated 63 to 37. We sharpened our pencils and found a way to 
prioritize funding and provide $1 billion to increase the NIH 
budget in the appropriations bill.
    Having failed in our efforts to get an additional billion 
dollars in the budget resolution, the next year we sought an 
additional $2 billion for the NIH. And again, we were 
unsuccessful, this time by a vote of 58 to 42. But again, with 
sharpened pencils, we found the dollars in the appropriation 
bill. That has progressed so that the funding for NIH has been 
increased from $12 billion to now in excess of $20 billion. 
Whereas the President has put in a hefty sum this year of an 
additional $2.8 billion, it will require $3.4 billion to stay 
on track to double the NIH funding over 5 years, which is our 
goal and which we are determined to undertake.
    But we are concerned as to limitations which exist in law 
prohibiting the use of Federal funding to extract stem cells 
from embryos. Senator Harkin and I introduced legislation on 
that 2\1/2\ years ago when it became apparent that stem cells 
have tremendous opportunities. In November of 1998, this 
subcommittee held seven hearings, and now I believe we have 
more than 70 votes, perhaps 75, maybe even more, to reverse 
that prohibition.
    In this morning's New York Times, there is a disquieting 
story about scientists creating scores of embryos to harvest 
cells, and where there is no legislation by the Federal 
Government in the field to regulate what is being done to 
liberate Federal funding for research at the NIH to be 
conducted with ethical standards, then the marketplace free 
enterprise proceeds and you have had these human embryos 
created expressly for medical experiments, which raises very, 
very profound ethical questions of propriety.
    So, it is my hope that these issues can be addressed, if 
not by the White House to liberate the prohibition against 
Federal funding, then perhaps by the Congress if that is 
necessary, because I do think we have the votes in the Senate, 
and some 40 Republicans signed on to stem cell research in the 
House. This is a matter which must be addressed very, very 
promptly in my judgment.
    Today's hearing is a very important one, along the lines of 
what science can do, and those of us in the Congress, the House 
and the Senate, ought to be doing our utmost to provide the 
support and the funding to see that this will become a reality.
    Permit me to extend my regrets that I cannot stay for the 
entire hearing. I am due on the Senate floor at 10 o'clock for 
a special order, and we have a very important hearing in the 
Foreign Operations Subcommittee of Appropriations. So, I will 
be here for a time and will be following the proceeds through 
staff and through the transcript.
    Thank you very much, Mr. Chairman.
    Senator Harkin. Thank you very much, Senator Specter.


                opening statement of senator larry craig


    Senator Craig. Mr. Chairman, thank you for putting together 
today's hearing on the Promise of the Genomic Revolution.
    Last year, a rough draft of the human genome was announced 
and ignited a worldwide fervor of the possibilities of this 
achievement. This advance can help people live longer and 
healthier lives. Diseases once thought incurable may soon be 
detectable and curable early in life. The Human Genome Project, 
by producing detailed maps of the 23 pairs of human 
chromosomes, has already identified the genes responsible for 
such diseases as glaucoma and cystic fibrosis.
    However, this enormous accomplishment has raised ethical 
and social questions related to genetic information. The 
potential for misuse of genetic information has extremely 
serious implications, especially in relation to privacy 
concerns. Access to employment and health insurance are just 
two of the areas that could be affected.
    As advances in medical technologies are developed using the 
mapping of the human genome, it will become increasingly 
important to protect patient privacy rights. The challenge will 
be to balance privacy concerns with the medical benefits of 
this new technology.
    Again, Mr. Chairman, thank you for looking at this 
important and exciting issue. I look forward to hearing from 
today's witnesses.
    [The statement follows:]

               Prepared Statement of Senator Larry Craig

    Mr. Chairman, thank you for putting together today's hearing on the 
Promise of the Genomic Revolution.
    Last year a rough draft of the human genome was announced and 
ignited a worldwide fervor of the possibilities of this achievement. 
This advance can help people live longer and healthier lives. Diseases 
once thought incurable may soon be detectable and curable early in 
life. The Human Genome Project, by producing detailed maps of the 23 
pairs of human chromosomes has already identified the genes responsible 
for such diseases as glaucoma and cystic fibrosis.
    However, this enormous accomplishment has raised ethical and social 
questions related to genetic information. The potential for misuse of 
genetic information has extremely serious implications, especially in 
relation to privacy concerns. Access to employment and health insurance 
are just two of the areas that could be affected.
    As advances in medical technologies are developed using the mapping 
of the human genome, it will become increasingly important to protect 
patient privacy rights. The challenge will be to balance privacy 
concerns with the medical benefits of this new technology.
    Again, Mr. Chairman, thank you for looking at this important and 
exciting issue. I look forward to hearing from today's witnesses.
STATEMENT OF FRANCIS COLLINS, M.D., Ph.D., DIRECTOR, 
            NATIONAL HUMANE GENOME RESEARCH INSTITUTE, 
            NATIONAL INSTITUTES OF HEALTH, DEPARTMENT 
            OF HEALTH AND HUMAN SERVICES
    Senator Harkin. Our first witness, Dr. Francis Collins, is 
the Director of the National Human Genome Research Institute 
and the leader of the International Consortium of Scientists 
for Sequencing the Human Genome. He has a Ph.D. in physical 
chemistry from Yale University, an M.D. from the University of 
North Carolina. Among many other accomplishments, he helped 
identify the genes for cystic fibrosis and Huntington's 
disease. He remains actively involved in research, and he has 
directed the National Human Genome Research Institute since 
1993.
    Dr. Collins, welcome back to the subcommittee.
    Dr. Collins. Well, thank you, Mr. Chairman and Senator 
Specter. Thank you also for the kind remarks about genomics. I 
want to say to both of you how much we at NIH appreciate your 
very strong leadership in the support of medical research that 
has brought us to this point and which, as we will be talking 
about this morning, holds the promise of carrying us to truly 
dramatic developments in the field of medicine. But none of 
this would be possible without the strong support of the 
Congress, and the two of you have taken a particularly bold 
stand in that regard. And it is deeply appreciated, and it 
makes a difference. In fact, I would say the investment that 
you boldly made about 10 years ago in the human genome project, 
even before many in the scientific community were completely 
convinced, is paying off in a spectacular way that we will talk 
about this morning.
    I am honored to be here at this hearing with a number of 
other distinguished witnesses who will outline some of the 
consequences. Let me say that I am particularly pleased to be 
here with Joe and his family. Joe who has ataxia-
telangiectasia, is a representative of the hundreds of 
thousands, millions of individuals who have health consequences 
of glitches in the DNA that we hope to learn more about an 
ultimately to be able to cure.
    Senator Harkin, you showed this CD-ROM containing the 3 
billion letters of the human DNA code. It is remarkable that it 
all fits. It took a special compression program that our 
colleagues in Santa Cruz designed to be able to make that 
information fit on a single CD-ROM.
    It is amazing that this was possible in the time table that 
it was. When I was a post-doctoral fellow 20 years ago, you 
could get a Ph.D. for sequencing 1,000 letters of the code. In 
order to do this, we had to sequence 1,000 letters a second, 7 
days a week, 24 hours a day for a sustained period of about a 
year and a half. What an amazing quantum leap forward in the 
speed.
    And that we did and it is all in the public domain. It is 
free on the Internet. Most people do not use that CD-ROM. They 
go to their computer and tens of thousands of them each day are 
logged on to the databases using this information to advance 
their understanding of disease. I keep an informal tally of 
disease genes that are identified using this information. Just 
in the last 2 years, it is over 50, and those are all diseases 
that otherwise would still be trapped in a bottleneck of 
ignorance but now are on the pathway towards understanding and 
ultimate prevention and cure.
    As another example of the speed with which things are 
advancing, I spent most of my scientific effort in the 1980's 
trying to identify the gene for cystic fibrosis. That effort 
took a number of groups, including my own, about 9 years to 
come up with the right gene.
    About 4 years ago, we talked with considerable excitement 
about finding a gene for Parkinson's disease. That took about 9 
days' worth of effort with the tools that were there.
    Just a few weeks ago, there was a publication in the 
journal called Nature about finding a gene for a very important 
problem involving the gastrointestinal tract, called Crohn's 
disease. In that instance, the investigator simply had to go to 
the Internet and look up the answer. So, less than 9 seconds 
involved in finding the responsible gene.
    So, 9 years to 9 days to 9 seconds. This is the kind of 
advance in speed that we hope to see happen as a consequence of 
the genome project.
    As you will hear from Dr. Needleman, that has also resulted 
in the fact that we now have not 480 drug targets, we have 
30,000 drug targets. And the advances in that field are truly 
dramatic.
    But I think it is fair to say if you drew the time line of 
genomics and you tried to say where are we, we are still at the 
beginning. We have a fantastic foundation here with that 
sequence of the human genome. We have the code but we need to 
understand it. I like to say we are now in the decryption 
business. We need to understand the cryptography of the genome 
to be able to understand its role in health and disease and 
then bring that to the clinic as quickly as possible. As a 
physician, that of course is my major personal goal.
    We are, in fact, at the National Human Genome Research 
Institute, in the midst of a vigorous and intense effort to 
engage hundreds of the brightest minds in the scientific 
community, both public and private sectors, in planning a 
visionary next phase of the genome project, building on this 
current foundation. That will include a number of exciting, new 
projects, such as building a comprehensive picture of how human 
variation is organized in the genome, which is the way that we 
are going to uncover the hereditary contributions to diabetes 
and heart disease and the common cancers and mental illness and 
multiple sclerosis and virtually every disease that has a 
hereditary contribution.
    We will also--and we had a very interesting workshop the 
last 2 days about this--need to sequence the genomes of a 
number of other organisms because they will inform the ability 
to decrypt the human genome by the comparisons. We need to be 
sure we are using our sequencing capabilities in the most 
scientifically robust way.
    We will be investigating the way in which proteins do the 
work of the genes. The genes are the instruction book. The 
proteins carry out the instructions. The field of proteomics is 
now the effort to understand that in a global fashion.
    Go with me, if you will, though, on the basis of these 
research developments to what might happen in interaction 
between a physician and a patient in the year 2015. Linda, age 
34, mother of two, comes in to see her physician because maybe 
for the first time she is beginning to think about the need for 
good prevention in her own medical care. Her physician mentions 
that now in 2015 there are a number of tests that are available 
to predict her future risk of illness or to make an early 
detection of a current illness. Fortunately, through the good 
efforts of people like yourselves, in 2015 she need not fear 
genetic discrimination because that was taken care of by the 
Congress of the United States way back early in the current 
century. So, she decides, yes, she would like to go through 
this battery of tests.
    The results indicate that she has an increased risk for 
heart disease, which surprises her, because her cholesterol is 
normal, but cholesterol is not everything. The good news is we 
have in 2015 dietary measures to reduce that risk and 
noninvasive methods to detect the first sign of actual disease 
at which point drug therapy is available that is precisely 
suited for her genetic situation.
    Another thing on her report card. It turns out that she is 
at increased risk for Alzheimer's disease. She is not as 
surprised there. Her grandmother had recently died of the 
disorder. In 2015--and Professor Needleman may very well say 
more about this--we will have interventions available, 
preventive strategies for Alzheimer's disease that I believe 
will be amazingly successful, both drug therapies and even a 
vaccine. So Linda, now at age 34 with no symptoms probably for 
a couple of decades to come, now has an intervention to keep 
that terrible outcome from occurring.
    Finally and perhaps initially most alarmingly to her, one 
of the tests done looked at actually the peripheral white cells 
in her blood stream which are, in 2015, effectively the 
canaries in the coal mine to tell you that something may be 
awry, using those white cells as a signal of what is going on 
within. They indicate that there is a high likelihood that she 
has the earliest stages of ovarian cancer. A subsequent 
laparoscopy does, in fact, reveal a very small nucleus of 
cancer cells, only a few hundred in number, which are easily 
removed. While she would not have developed symptoms for 
another 2 years, had this test not been obtained, it is likely 
at that point it would have been too late.
    This kind of molecular surveillance, using genetic tools, 
is not science fiction in the next decade or two. So, this 
scenario, which I would argue is not at all outside the realm 
of reality based on the trajectory we are now on, is a very 
exciting one, focusing our medical efforts on preventions, 
keeping people healthy.
    I would like to conclude this with a quote from Sir William 
Osler. He said this exactly 100 years ago: ``Osler is the 
father of medicine in most people's view because he brought the 
power of rational thinking to the field.'' When asked to 
describe what is medical research, Osler said, ``To wrest from 
nature the secrets which have perplexed philosophers in all 
ages, to track to their sources the causes of disease, to 
correlate the vast stores of knowledge that they may be quickly 
available for the prevention and cure of disease, these are our 
ambitions.'' Bold words a century ago. But we now have the 
tools to make this happen. With your strong support and the 
brightest minds of the scientific community, we can make 
Osler's vision come true.
    Thank you, Mr. Chairman. I would be happy to answer 
questions.
    [The statement follows:]
                Prepared Statement of Francis S. Collins
    Mr. Chairman, and Members of the Subcommittee, it is a pleasure to 
be here today to discuss the recent scientific advances in genetics 
that will lead to improved health, and the development of therapies to 
treat various illnesses. First I would like to thank the Subcommittee, 
and especially you Mr. Chairman and Ranking Member Specter, for your 
commitment and determination to invest in the Human Genome Project and 
other areas of basic biomedical research at the National Institutes of 
Health. Today I would like to focus my remarks on the recent 
developments in genetics in order to give you a sense of the great 
promise this field of research holds for all of us. Today you will also 
hear from patients and advocates who are fighting to find a cure for 
genetic diseases. All of us have gained a powerful new set of tools 
from the recent advances in human genetic research. As a physician who 
has taken care of patients, and as a medical geneticist who has devoted 
the last decade to the Human Genome Project, I know it is critical that 
we move the great promise of basic research into the clinic as quickly 
as possible, in order to make significant progress towards treating or 
preventing these devastating illnesses.
                         human genome sequence
    Last year, Human Genome Project scientists capped their 
achievements of the last decade with a historic milestone--the complete 
initial reading of the text of our genetic instruction book. This book 
is written in an elegant digital language, using a simple four-letter 
alphabet where each letter is a chemical base, abbreviated A, C, G, or 
T. At present, more than 95 percent of the 3.1 billion bases of the 
human genome are freely available in public databases. This is an 
awesome step toward a comprehensive view of the essential elements of 
human life, a perspective that inaugurates a new era in medicine where 
we will have a more profound understanding of the biological basis of 
disease and develop more effective ways to diagnose, treat, and prevent 
illness.
    Between March 1999 and June 2000 the international collaborators in 
the Human Genome Project sequenced DNA at a rate of 1000 bases per 
second, 7 days a week, 24 hours a day. After completing the working 
draft of the human genome sequence in June of 2000, Human Genome 
Project scientists and computational experts scoured the sequence for 
insights. They reported the first key discoveries in the February 15, 
2001 issue of the journal Nature. Among the findings were the 
following:
  --Humans are likely to have only 30,000 to 40,000 genes, just twice 
        as many as a fruit fly, and far fewer than the 80,000 to 
        150,000 that had been widely predicted.
  --Genes are unevenly distributed across the genomic landscape; they 
        are crowded in some regions and spread out widely in others.
  --Individual human genes are commonly able to produce several 
        different proteins.
  --The repetitive DNA sequences that make up much of our genome, and 
        commonly regarded as ``junk,'' have been important for 
        evolutionary flexibility, allowing genes to be shuffled and new 
        ones to be created. The repetitive DNA may also perform other 
        important functions, and provides fascinating insights into 
        history.
                  finishing the human genome sequence
    Because of the enormous value of DNA sequence information to 
researchers around the world, in academia and industry, the public 
Human Genome Project (HGP) has always been committed to the principle 
of free, rapid access to genomic information through well-organized, 
annotated databases. Databases housing the human genome sequence are 
being visited by tens of thousands of users a day. Over the coming two 
years, the HGP will increase the usefulness of the human genome 
sequence to the world's researchers by finishing the sequencing to 
match the project's long-standing goals for completeness and stringent 
accuracy. More than 40 percent of the draft sequence, including two of 
our 24 chromosomes, have already been finished into a highly accurate 
form--containing no more than 1 error per 10,000 bases. Finished 
sequence for the entire genome is expected by 2003.
                        human genetic variation
    While the DNA sequence between any two individuals is 99.9 percent 
identical, that still leaves millions of differences. For understanding 
the basis of common diseases with complex origins, like heart disease, 
Alzheimer disease, and diabetes, it is important to catalog genetic 
variations and how they correlate with disease risk. Most of these are 
single letter differences referred to as Single Nucleotide 
Polymorphisms (SNPs). With a draft of the human genome sequence in 
hand, the pace of SNP discovery has increased dramatically. In fiscal 
year 1999, NHGRI organized the DNA Polymorphism Discovery Resource 
consisting of 450 DNA samples collected from anonymous American donors 
with diverse ethnic backgrounds. NHGRI has funded studies looking for 
SNPs in these samples. The non-profit SNP Consortium came into being in 
April 1999, with the goal of developing a high-quality SNP map of the 
human genome and of releasing the information freely. Consortium 
members now include the Wellcome Trust, a dozen companies (mostly 
pharmaceutical companies), three academic centers, and NIH. This has 
been remarkably successful, with 5 times more SNPs being contributed to 
the public domain than the consortium originally planned. As of June 
22, the public database that serves as a central repository for SNPs 
has received 2,972,764 SNP submissions.
    With the increased knowledge about human variation, the genetic 
underpinnings of various diseases, including diabetes, are being 
discovered. The recent discovery of a gene, calpain-10, whose 
disruption contributes to diabetes, resulted from studies linking 
diabetes with genetic variations across the whole genome and then in a 
specific part of chromosome 2. The newly-discovered gene variant 
suggests that a previously unknown biochemical process is involved in 
the regulation of blood sugar levels.
                            gene expression
    The new-found abundance of genomic information and technology is 
propelling scientists out of the pattern of studying individual genes 
and into studying thousands at a time. Large-scale analyses of when 
genes are on or off (gene expression) can be used, for example, to 
study the molecular changes in tumor cells. This exciting new approach 
combines recombinant DNA and computer chip technologies to produce 
microarrays or DNA chips. Classifying cancer on a molecular level 
offers the possibility of more accurate and precise diagnosis and 
treatment. Intramural researchers at NHGRI have used large-scale 
expression studies to discover genetic signatures that can distinguish 
the dangers from different skin cancers, and that can distinguish 
between hereditary and sporadic forms of breast cancer.
              protein structure, function, and interaction
    We must remember that we are at the beginning of genomics era, not 
the end. With a global view of human genes now possible, scientists are 
eager to obtain a similarly comprehensive view of human proteins, a 
field called ``proteomics.'' Researchers want to know the functions of 
proteins and how the proteins work together in cells. Only a subset of 
all possible proteins are present in any given cells at any given time. 
To study protein function on a wide scale, various groups of 
researchers plan to identify the locations of proteins, their levels in 
different cells, their structures, the interactions among different 
proteins, and how they are modified. NHGRI is contributing to this 
field by developing technologies for efficient, large-scale analyses, 
particularly for determining protein interactions and measuring protein 
abundance in different cells.
               promise for new treatments and prevention
    With the availability of a comprehensive view of our genes, genetic 
testing will become increasingly important for assessing individual 
risk of disease and prompting programs of prevention. An example of how 
this may work involves the disease hereditary hemochromatosis (HH), a 
disorder of iron metabolism affecting about one in 200 to 400 
Americans. Those with the condition accumulate too much iron in their 
bodies, leading to problems like heart and liver disease and diabetes. 
The gene causing the condition has been identified, allowing early 
identification of those in whom HH may develop. Once people at risk are 
identified by genetic testing they can easily be treated by 
periodically removing some blood. The NHGRI and NHLBI are engaged in a 
large-scale project to determine the feasibility of screening the adult 
population for this very preventable disorder.
    Genetic testing is also being used to tailor medicines to fit 
individual genetic profiles, since drugs that are effective in some 
people are less effective in others and, in some, cause severe side 
effects. These differences in drug response are genetically determined. 
Customizing medicine to a patient's likely response is a promising new 
field known as pharmacogenomics. For example, a recent publication in 
the journal Hypertension showed how pharmacogenomics applies to high 
blood pressure. Researchers found a variation in a particular gene that 
affects how patients respond to a commonly used high blood pressure 
drug, hydrochlorothiazide. Other recent studies reveal that doctors 
should avoid using high doses of a common chemotherapy treatment (6-
mercaptopurine) in a small proportion of children with leukemia. 
Children with a particular form of a gene (TPMT) suffer serious, 
sometimes fatal, side effects from the drug.
    Genomics is also fueling the development of new medicines. Several 
drugs now showing promising results in clinical trials are ``gene-
based'' therapies, where an exact appreciation of the molecular 
foundations of disease guides treatment design. One of the first 
examples is Gleevec (previously called STI571), produced by Novartis 
for treating chronic myelogenous leukemia (CML), a form of leukemia 
that mostly affects adults. CML is caused by a specific genetic flaw--
an unusual joining of chromosomes 9 and 22 producing an abnormal fusion 
gene that codes for an abnormal protein. The abnormal fusion protein 
spurs uncontrolled growth of white blood cells. Novartis designed a 
small molecule that specifically inactivates that protein. In phase I 
clinical trials, this drug caused dramatically favorable responses in 
patients, while side effects were minimal. By targeting the fundamental 
biochemical abnormality associated with this form of cancer, rather 
than killing dividing cells indiscriminately as most chemotherapy does, 
the drug offers better treatment results and fewer toxic effects on 
normal cells. In May 2001, FDA approved Gleevec (imatinibmesylate, also 
known as STI-571) for the treatment of Chronic Myeloid Leukemia after a 
review time of less than three months. Meanwhile, Bayer and Millennium 
announced the development of another cancer drug born of genomics in 
January 2001. GlaxoSmithKline is testing a new genomics-derived heart 
disease drug that targets a protein involved in fat metabolism. 
Johnson&Johnson is testing a drug targeting a brain receptor identified 
through genomics, and involved with memory and attention. Human Genome 
Sciences has four clinical trials in progress to test gene-based drug 
candidates.
                ethical, legal, and social implications
    From its inception, NHGRI recognized its responsibility to address 
the broader implications of having access to genetic information and 
technology. Since the inception of the Human Genome Project Congress 
has provided funds for research to study the ethical, legal, and social 
implications (ELSI) of genome research. To that end one of the greatest 
areas of concern has been in the area of genetic discrimination. 
Recently President Bush addressed this issue in his Saturday radio 
address of June 23. In that address the President said, ``Just a few 
months ago, scientists completed the mapping of the human genome. With 
this information comes enormous possibilities for doing good. As with 
any other power, however, this knowledge of the code of life has the 
potential to be abused. Genetic discrimination is unfair to workers and 
their families. It is unjustified--among other reasons, because it 
involves little more than medical speculation . . . . To deny 
employment or insurance to a healthy person based only on a 
predisposition violates our country's belief in equal treatment and 
individual merit . . . . Just as we have addressed discrimination based 
on race, gender and age, we must now prevent discrimination based on 
genetic information. My administration is working now to shape the 
legislation that will make genetic discrimination illegal. I look 
forward to working with members of Congress to pass a law that is fair, 
reasonable, and consistent with existing discrimination statutes.''
                       predictions for the future
    We must not ignore the ethical, legal, social, and the commercial 
issues that genetic research raises, but the promise of this research 
is great for alleviating human suffering. If research continues to 
proceed vigorously, we can expect medicine to be transformed 
dramatically in the coming decades.
    We can predict that by the year 2010, predictive genetic tests will 
exist for many common conditions where interventions can alleviate 
inherited risk; successful gene therapy will be available for a small 
set of conditions; and primary care providers will be practicing 
genetic medicine on a daily basis. By the year 2020, gene-based 
designer drugs are likely to be available for conditions like diabetes, 
Alzheimer's disease, hypertension, and many other disorders; cancer 
treatment will precisely target the molecular fingerprints of 
particular tumors; genetic information will be used routinely to give 
patients appropriate drug therapy; and the diagnosis and treatment of 
mental illness will be transformed. By the year 2030, we predict that 
comprehensive, genomics-based health care will become the norm, with 
individualized preventive medicine and early detection of illnesses by 
molecular surveillance; gene therapy and gene-based therapy will be 
available for many diseases; and a full computer model of human cells 
will replace many laboratory experiments.
    Thank you Mr. Chairman. I would be happy to answer any questions.

    Senator Harkin. Dr. Collins, thank you very much for an 
outstanding statement and again for all of the wonderful work 
you have done in leading this project from its very beginning. 
We owe you a great debt.
    I would now like to recognize our former chairman of the 
full committee and our ranking member of the full committee now 
who has graced us with is presence for any opening statement 
that he might have. Senator Stevens.
    Senator Stevens. Well, thank you very much, Mr. Chairman. I 
am just surveying some of the hearings this morning. So, I 
stopped for a little while. I appreciate listening to Dr. 
Collins. Thank you very much, doctor.
    Dr. Collins. Thank you, Senator, and we appreciate your 
strong support for NIH.
    Senator Harkin. Senator Stevens has been a very strong 
supporter of NIH for a long, long time.
    I just have a couple of questions and I would like to ask 
you if you might just stay while I bring the other panel up.
    Dr. Collins. I would be delighted.
    Senator Harkin. I may have some follow-ups after the panel 
comes up.
    You sort of hinted at this but some people are under the 
impression that the human genome project is over now that we 
have completed a draft sequence. First, is that the case, and 
if not, what is left to be done?
    In your written testimony, you predicted that comprehensive 
genomics-based health care will become the norm by 2030. Is 
there any way that we can speed this up?
    So, that is sort of two parts. What is left to be done and 
can we speed it up?
    Dr. Collins. Well, the sequencing of the genome, getting 
those 3 billion letters all determined, was the most obvious 
and visible goal of the genome project. But from the outset, 
this has been a multi-component effort. While it is true that 
most of the original goals defined in 1990 have now been 
achieved or will be in the next couple of years, all the way 
along, the ability to decode, to decrypt the information has 
emerged as a new and important phase of the effort.
    So, you might say we are experiencing an analogy to the 
field of chemistry. We are now at the point of having defined 
the periodic table of the elements. The periodic table for 
human biology has elements that are the normal human genes. It 
has isotopes which are the variants in those genes. But just as 
one would have said the field of chemistry began with the 
periodic table, I think it is fair to say the field of genomics 
now begins with our own human periodic table of the genes.
    Now, the important issues of how do they work and how do 
they interact together and how are they affecting health and 
disease can get underway in earnest. I view all of that as the 
natural continuation of the genome project. In fact, genomics 
now spills out into virtually every area of research. Some now 
argue genomics has become the central science of medical 
research that every institute at NIH is investing in in a big 
way and, as you will hear later, in the private sector as well.
    Senator Stevens. Mr. Chairman, may I ask just two 
questions?
    Senator Harkin. Sure.
    Senator Stevens. Dr. Collins, when will your project be 
completed?
    Second, how soon will it be before the information that you 
have developed in the project will trickle down and be 
available to the family physician?
    Dr. Collins. Actually deciding when the human genome 
project is completed is a bit of a semantic question. You could 
say that the original goals set in 1990 are close to being 
completed, but at the same time the project has evolved. 
Certainly genomics as a research enterprise has probably more 
promise and more applicability now than it did 5 years ago and 
certainly more than 10 years ago. So, it is a little hard for 
me to know exactly what to call the human genome project 
anymore. Maybe you will argue that we should be more precise 
about that, and that is something that we are discussing a bit 
with our advisors in terms of the definitions here.
    Senator Stevens. Well, should we evolve it? Should we say 
that it is more than the original project now?
    Dr. Collins. Well, it has become so, as we have in the 
process of deciding what our goals are, and we do that very 
regularly, every 3 to 5 years, with input from hundreds of 
scientists. If you look at the 5-year plan for 1990 and 1993 
and 1998 and the one we are building now, we have added new and 
exciting components along the way because of their scientific 
opportunity. The genome project is not what it was at the 
beginning. I think the way to do that is to ask the scientific 
community, what are the opportunities here, and then let us go 
after them. That is pretty much the strategy we followed.
    As far as the availability to the primary care physicians, 
this is a major area of concern because most physicians have 
not had much exposure to the field of genetics. The 
implications of this are very quickly going to come to pass. 
Every physician in primary care is going to need to practice 
genetic medicine in the relatively near future. Working with 
the American Medical Association and the American Nurses 
Association, we have a rather ambitious agenda for trying to 
provide that kind of educational information so that doctors 
and nurses will be in a position of being able to implement 
these exciting new opportunities and not just confuse 
themselves and patients by an unfamiliarity with the new area 
called genetics. We have a lot of work to do in that regard, 
but I think the medical community is enormously interested in 
this. The American Medical Association identifies this as the 
biggest advance since antibiotics, and they are clearly 
motivated to get their members up to speed and ready to 
practice this kind of medicine in the most effective way.
    Senator Stevens. Well, I am afraid it is so esoteric that 
rural America may be left behind in this first decade of this 
new century.
    Dr. Collins. Well, I worry about that, Senator. Yet, at the 
same time, the esoteric aspects of genetics are partly the 
scientists' fault, that we tend to enshroud these developments 
in complex language and using large terms with too many 
syllables. In my view, genetics is actually the simplest of the 
biological sciences. It makes enormous sense. If you understand 
a few principles, the rest of it kind of makes sense by 
immediate deduction. But we have not done, necessarily, a very 
good job of explaining that.
    We have recently put out--and every high school biology 
teacher in this country has now access to--and we have sent out 
60,000 of these--an educational kit about genetics and the 
genome project to get the next generation of consumers who are 
currently juniors or seniors in high school ready to 
incorporate this kind of information into their thinking about 
their own health.
    Senator Stevens. Sorry to belabor this, Mr. Chairman.
    Will we be able to link the family physician, the primary 
care provider, by telemedicine to centers where he or she could 
get instant consultation.
    Dr. Collins. Senator, I think that is a great idea and I 
think that is in fact quite potentially viable because many of 
the questions that need to be answered probably could be done 
electronically. I envision a circumstance where primary care 
providers are provided with the kind of information that 
enables them to handle the basic level of interactions about 
genetic questions, but when something more complicated arises, 
they are going to have to have some connection, some way to get 
advice, and I think the electronic telemedicine approach is 
going to be the way to go. We have a limited number, but a very 
well-trained group, of medical geneticists and genetic 
counselors who I believe could provide that next level of 
expertise, and we have to figure out how to organize the system 
and make sure the services are reimbursed for so that it 
actually happens.
    Senator Stevens. Thank you very much.
    Thank you, Mr. Chairman.
    Senator Harkin. Thank you, Senator Stevens.
    Dr. Collins, one last thing before I bring the panel up. We 
read yesterday that the National Cancer Institute is going to 
allow its researchers to pay for access to Celera Genomics 
database. I would like to have your thoughts on that since NIH 
already has access to its own database for free. So, I am 
wondering why would NIH be willing to pay Celera for that 
information. I do not understand that.
    Dr. Collins. Well, I am glad for the question because I 
think it has been a little confusing what really happened here. 
Basically the NCI worked out with Celera what the terms would 
be if one of their intramural investigators working on cancer 
decided they wanted to subscribe to the Celera database. The 
cost of that runs in the neighborhood of $16,000 per year. The 
researcher would have to decide whether it was worth $16,000 to 
them to gain access to this private database. The Celera 
database, of course, has a lot of human sequence, but 95 
percent of the human sequence is available in the public 
domain. And I think relatively few investigators would find it 
worth the cost to go to this alternative database because the 
information is in fact very similar. The Celera database also 
contains information about the laboratory mouse, but in the 
public sequence databases, there is about 95 percent of the 
mouse sequence.
    I think therefore it is unlikely that any but a handful of 
investigators will probably choose to sign up for this. But I 
think the NCI was anxious not to put up some artificial barrier 
for the small number of investigators who for some reason could 
not find what they were looking for in the freely available 
databases and felt it was worth their while to make this 
investment. Time will tell how many of them actually decide to 
take that step.
    Senator Harkin. I see. So, it is not something that is 
going to take place. It is just sort of if somebody wanted to 
access it, what would the arrangement be.
    Dr. Collins. Exactly.
    Senator Harkin. Well, I guess I would have to follow up on 
this. If researchers wanted to, I would want to know why, and 
if they are using Government money to do that, if the data is 
already available, I would like to know more about why that 
would be the case.
    Dr. Collins. I can understand your wanting to know those 
answers, and perhaps with a little time going by, we will see 
whether people actually do sign up and if so why, and if so, 
did they get what they were looking for.
    Senator Harkin. Right, exactly.
    Dr. Collins, thank you very much. Now I am going to bring 
the panel up. I wonder if you could just wait, maybe we might 
have some additional questions later on.
    Dr. Collins. I would be delighted.
    Senator Harkin. Our panel includes Dr. Needleman, Senior 
executive vice president and chief scientific officer for 
research and development for Pharmacia Corporation. He will 
discuss how pharmaceutical companies are translating basic 
research into actual drugs.
    Dr. Steven Rich, a professor of public health sciences and 
a genetic epidemiologist at the Wake Forest University School 
of Medicine. He specializes in type 1 juvenile diabetes.
    Dr. Jeffrey Murray, Professor of Pediatrics, Biology, and 
Preventive Medicine at the University of Iowa. He was the 
principal investigator of the first human genome center at the 
University of Iowa. He has served as a member of the NIH review 
panel on ethical, legal, and social implications of the human 
genome project.
    And Mr. Ben Affleck, a movie star and a screen writer, 
currently appearing in the film ``Pearl Harbor''.
    Mr. Affleck. It sounds so pathetic after the rest of those.
    Senator Harkin. Did I really have to introduce him as being 
the star of----
    Mr. Affleck. Ph.D., genetics expert, CEO, schmuck actor.
    Senator Harkin. Now that I will take issue with.
    As I said earlier, a few years ago, Mr. Affleck befriended 
a boy with a fatal genetic disease called A-T, ataxia-
telangiectasia.
    Mr. Affleck. I cannot even pronounce it. I call it A-T.
    Senator Harkin. And he has taken up the cause of raising 
awareness about it. This young man, Joe Kindregan, is here. Mr. 
Affleck will be joined by Brad Margus, the President and Co-
founder of the A-T Children's Project. He is available to 
answer questions also.
    But what the heck. Can we bring Joe up too? Come on, Joe. 
Why do you not join us? Maybe you sit between Mr. Margus and 
Mr. Affleck. Bring Joe up here. We are proud to have you here, 
Joe.
    I would like to ask if you could keep your comments down 
to, let us say, in the realm of about 5 to 7 minutes. Then we 
can get through this. We can open it up for a general 
discussion. Dr. Needleman, we will start off with you and 
welcome to the committee.
STATEMENT OF PHILIP NEEDLEMAN, Ph.D., SENIOR EXECUTIVE 
            VICE PRESIDENT, PHARMACIA CORPORATION
    Dr. Needleman. Thank you, Mr. Chairman. I think my role 
here is to bring the industrial perspective of the implications 
and the use of human genome data.
    For a perspective, I have actually lived in both worlds. I 
spent 25 years in academia at the Washington University Medical 
School. I was the chairman of the Department of Pharmacology. I 
had wonderful support from the NIH and have actively 
participated in NIH study sections. I was on the Varmus 
Advisory Committee and have a great affection and appreciation 
for what has been done about the NIH. I am a member of the 
National Academy of Sciences and the Institute of Medicine, and 
I have spent the last 12 years in Pharmacia as the head of R&D 
really in the translational research to bring these discoveries 
into important drugs.
    We prepared a document which I hope we could enter in the 
record which describes at least four uses of the human genome 
in the practical development of drugs, and I will just 
highlight two of those issues.
    To give you perspective, I have been doing biomedical 
research in the drug hunt for 40 years. The first 20 years 
could really be characterized in fact by the imprinting of the 
NIH. So, in the 1960's and 1970's, the supported research into 
the biochemical basis of diseases really led to the selection 
of some protein targets, either enzymes or receptors, that 
drugs were designed around. The fruit of the labors of those 
decades were drugs in hypertension, in atherosclerosis, in 
ulcers, in arthritis, and some drugs in the central nervous 
system.
    The next 20 years have been spectacular. There have been 
profound advances in chemistry, in analytical chemistry, in 
computational sciences, in cell and molecular biology, and most 
recently and perhaps with the most attention, the availability 
of genomic data in bacteria, in fruit fly, in roundworm, in 
mouse, and in man now creates a tool kit to attack problems and 
disease and drugs which were inconceivable to me and my 
colleagues through much of our career.
    Now, I would turn to a consideration of maybe two examples 
to show you how the use of the human genome's implication is 
not something far off in the future, but it happens now. I am 
going to pick two, work in Alzheimer's and work in cancer.
    In this devastating disease Alzheimer's, if you have an 
unfortunate patient who died and analyzed the brain, what you 
will see is that the nerves are surrounded by tangles of 
proteins known as amyloid plaque which virtually crush and 
destroy the nerves. Based on genetic mapping of mutations, two 
mutations were found, the so-called Swedish mutation and the 
London mutation, where that protein which was wrapped around 
was characterized to be over-produced. It is a small 42 amino 
acid protein and it is massively over-produced in these small 
families that have genetic predisposition to early Alzheimer's, 
and it is insoluble, that protein derived from a large protein, 
which was floating around and innocuous. So, clearly the 
disease process was hypothesized to be due to something that 
was a scissor that cut the big protein into a small piece that 
then gloms onto the nerve and then destroys it.
    The nature of the protein told us at Pharmacia what kind of 
enzyme could be the scissor. We then turned to the genome 
database. Understand what Francis Collins says, having other 
species gives you insight. So, we were able to turn to the 
worm, C. elegans, and we found a family of enzymes that had 
that property. Then when we hit those genes, we went to the 
human genome and fished out a human gene for a similar enzyme.
    We then took that gene and put it into mice and removed 
that gene from mice. It was a 90 percent reduction in the 
mice's ability to make this protein that would crush the 
nerves. We then published that in Nature and put it immediately 
into the public database.
    I can tell you this is one of the hottest targets in the 
entire pharmaceutical industry. We have dozens and hundreds of 
scientists, molecular biologists, chemists, and others, and we 
will be advancing a drug that will start and test the 
hypothesis in Alzheimer's in a reasonable period of time. This 
is a high urgency.
    Second problem. Let us talk about colon cancer. The history 
of that actually began in my NIH days when we were studying 
what was the body chemistry of arthritis, and we discovered an 
enzyme called cox-2, or cyclooxygenase, which is not present in 
normal cells but is turned on by disease. It is a silent gene 
and it has to be turned on. We went on and discovered the drug 
Celebrex, now used in millions of people, which treats the 
signs and symptoms of arthritis, but it is free of many of the 
side effects.
    Put that aside. We then had the genetic tools and the 
proteins and antibodies which we used and we supplied to 
academia. We quickly learned that every stage of colon cancer 
has over-expression of the cox-2 gene and protein, and that is 
not normally present in the colon.
    Some very elegant work in other places, especially Johns 
Hopkins, showed that many colon cancer patients have a mutation 
of a gene called APC. In fact, there are only a couple of 
thousand of patients in the world where they have inherited 
mutation, and those poor children by 10 years old have 
thousands of polyps in their colon. By 30, they have cancer, 
and the median death age is in the 40's. Those polyps are 
loaded with cox-2.
    You could take that mutation now and genetically modify a 
mouse and reconstitute that disease called familial adenomatous 
polyposis, FAP. When you get the polyposis, you get the cox-2, 
and Celebrex suppresses those tumors in mice.
    Based on that, we did a large clinical trial for 6 months, 
and the FDA has now awarded us approval for the first drug 
Celebrex which is a nonsurgical treatment which reduces the 
volume and the number of tumors in the FAP patient. But that is 
just a couple of thousand.
    The much bigger disease is colon cancer called SAP. In the 
United States, there may be 90,000 to 100,000 new patients a 
year; 50,000 deaths. It works out that almost half of those 
patients acquire the APC mutation. They express cox-2, and now 
we are doing trials in thousands of patients with Celebrex 
based on the genomic information, based on the mouse data and 
the FAP, and we will see if we can really do something with the 
third most prevalent of the cancers.
    So, the other examples in the text show how genetic 
information has pulled out a schizophrenia marker, and then you 
have talked about Gleevec. We used genetic information. There 
are 500 kinases of the nature that Gleevec hits, of which we 
now could reduce to a half a dozen which are possibly involved 
in cancer.
    So, in summary, I would say the availability of the human 
genome, the wealth of information in science from the NIH and 
now other foundations has really created a fairly awesome 
circumstance. It is not hard to predict that:
    No. 1, you will have new disease targets. Francis Collins 
realizes we move by 10- to 100-fold the number of disease 
targets.
    No. 2, we can have genetically modified animals that really 
recapitulate human disease.
    No. 3, as you said in your opening statement, 
pharmacogenomics, understanding the genetic information that 
tells us why patients are variable in their response and what 
are the subtypes of patients will now be possible, and we can 
target individual therapy for those patients.
    So, I would just close by saying that it is not hard for us 
in Pharmacia to see real hope in Alzheimer's, for significant 
advances in cancer and arthritis. With these spectacular 
advances, we will change the nature of the disease and the 
quality of life with these remarkable tools that we have.
    Thank you, Mr. Chairman, for letting me share this with 
you, and I would be glad to answer any questions.
    [The statement follows:]
                 Prepared Statement of Philip Needleman
    My role in today's proceedings is to provide an industry 
perspective on the promise and utility of human genomic data. For your 
information I am Chief Scientist of Pharmacia and Chairman of Research 
& Development. Prior to joining the pharmaceutical industry (in 1989) I 
spent 25 years in academia serving as Chairman of the Department of 
Pharmacology at Washington University Medical School. My laboratory was 
actively supported by funds from the National Institutes of Health. I 
am a member of the National Academy of Science and the Institute of 
Medicine.
    I have been engaged in the drug hunt for novel approaches to treat 
unmet medical needs for more than 40 years. When I started in the 60's, 
the identification and development of a new drug was a hit and miss 
affair. Often the target for the drug was unknown or its mechanism 
enigmatic. Many drugs entered development wholly because they showed 
activity in animal models. In this way advances in drug therapy were 
incremental. Furthermore, the clinical assessment of new drug 
candidates in man relied on ``traditional'' physician assessment, which 
in many case had no relationship to the mechanism of action of the drug 
or the pathology of the disease (if either were known). With time 
studies of the biochemical and cellular basis of disease led to the 
discovery of putative target proteins (enzymes and receptors) that 
served as the basis for drug development. During that period (roughly 
70's and 80's) important progress had been made in the treatment of the 
signs and symptoms of a number of critical diseases including: 
hypertension, atherosclerosis, ulcers, AIDS, arthritis and some nervous 
systems disorders.
    Modern therapeutic strategies emerged from NIH supported research 
discoveries in academia and new drugs arose from the translational 
research in industry that is required to advance a promising hypothesis 
or lead to a safe, effective drug. The exciting scientific progress of 
the last couple of decades has been remarkable and is highlighted by: 
profound advances in chemistry; information technology and 
computational power; the evolution and application of cell and 
molecular biology, and most recently the solution of the genome 
structures of bacteria, fruit fly, worm, human and mouse. This means we 
can now focus our efforts on specific genes that might be suitable drug 
targets. When we understand the disease mechanism we want to impact we 
have much greater control of the whole drug development process. 
Furthermore, because we can now easily compare the genomes of different 
species we can be much more astute decisions about the relevance of 
animal models in drug development. Genomics science has given us a 
toolset of sufficient sensitivity to analyze tiny samples of human 
tissue, looking for biological changes associated with drug response.
    Without a doubt we are in the greatest period in the history of 
biomedical research and these advances will enable us to attack the 
most serious debilitating diseases, including: the central nervous 
system diseases (Alzheimers; schizophrenia, and depression); the many 
types of cancer; the deforming effects of severe arthritis; and 
diabetes. These approaches were inconceivable during much of my 
scientific career.
         the human genome and innovative approaches to therapy
    Diseases are caused by multiple genes and have both a genetic and 
an environmental contribution. Hence it is important to know the genes 
that constitute humans and also to know the exact DNA sequence (or code 
of each gene) so that we can identify the changes that are responsible 
for causation or modification of human disease. Clearly once we know 
the genes that cause human disease, we can then devise therapies for 
such diseases. Already, however, we at Pharmacia (and others) are 
making significant in-roads in this regard. Pharmacia was one of the 
early access partners that subscribed both to Celera and the public 
database of the human genome. Some specific examples of how we are 
using genomic information to discover and validate new targets (ie; the 
smoking guns of the disease process) and how we are carrying out the 
hunt for targeted mechanism based drugs will be briefly discussed.
                           alzheimers disease
    The study of Alzheimers Disease is one area where we at Pharmacia 
have been applying Genomics. This devastating disease is characterized 
by the deposition of insoluble protein known as amyloid plaques that 
coil into tangles around nerves ultimately destroying the brain cells. 
These plaques are small fragments that are cut by functional scissors 
from a larger inactive protein called Amyloid Precursor Protein (APP) 
that in itself is biologically inactive. The cuts of APP are made by 
enzymes called beta-secretase (1st cut) and gamma-secretase (2nd cut) 
led to the neurotoxic fragment A-beta 42.
    We have focused our study on this gene pathway. Families that have 
mutation of genes in this pathway develop early onset Alzheimers 
Disease. Examples of such mutations are the so-called APP Swedish gene 
mutation and the APP London mutation which are found on human 
chromosome 21, the chromosome that is extra in Down Syndrome who 
develop Alzheimers-like plaques in their brains. These mutations 
increase the production of the APP fragment (A-beta 42).
    We wanted to identify the gene that served as the scissors, the so 
called beta-secretase with a view that decreasing its activity would 
reduce the production of the A-beta that forms plaques in Alzheimers 
Disease. We searched the genomic database of worms (C.elegans) and 
found a number of possible candidate genes that may function as the 
beta-secretase (we had an idea that such a gene belonged to a specific 
gene family). We then searched the human genome database and found the 
corresponding human genes and these were tested for their function as 
beta-secretase. (The gene was found and we published this information 
in the prestigious journal ``Nature'' Vol 402: 533, 1999).
    To prove that beta-secretase was important in the genesis of the 
Abeta fragment we generated mice that have all of their genes intact 
with the exception of the beta-secretase gene. The engineered mice that 
lack secretase make less than 10 percent of the A-beta fragment that 
accumulates in Alzheimers plaques. Hence providing powerful evidence 
that turning down beta-secretase will reduce the production of the 
noxious material that deposits in Alzheimers plaques. Importantly also, 
we were able to show that the mice appeared normal thus suggesting that 
we would not expect major toxicities from drugs that reduce beta-
secretase activity. We, like many companies, plan major clinical trials 
in Alzheimer's patients with selective secretase inhibitors.
                             schizophrenia
    Similarly we have found a number of new genes that may be important 
in Schizophrenia. We have identified the location of novel genes from 
the human genome sequence database that belong to a specific family of 
genes. These genes are found in regions on human chromosomes that are 
thought to harbor schizophrenia genes (these regions are identified by 
studying families that individuals with the disease and others that are 
disease free and identifying regions that track with the disease). Thus 
these genes are candidates for targeting schizophrenia therapy.
    We have further studied one of these genes (on material purchased 
from the National Institute of Mental Health) and found a change (SNP = 
Single Nucleotide Polymorphism) that occurs more frequently in 
schizophrenic patients as compared with non-affected family members, 
adding further evidence that this gene may be a target for 
schizophrenia therapy.
    In addition, it is clear to many of us in the industry that 
patients vary in their response to drugs. A significant component of 
this variation is likely to lie in the subtle changes we see between 
different genomes. Through the discovery and utilization of single 
nucleotide polymorphisms (as described by Francis Collins) we hope to 
be able to identify patients best suited for certain therapies as well 
as those who might be a risk when exposed to certain drugs.
    We are on the first step of the way to personalized medicine, where 
patients can be given the best therapy based on their condition and 
gene background. Pharmacia was a member of the consortium that invested 
in a Public effort which detailed approx. 800,000 SNP throughout the 
genome and that this facility assists in enabling this type of research 
both in academic and industrial settings.
    If Genomics is the study of how genetic differences contribute to 
disease, Pharmacogenomics is the science of how genetic variation 
influences the efficacy and safety of medicines. Doctors have always 
known that many medicines work differently in different patients. 
Pharmacogenomics will tell us how and why.
    At Pharmacia we have begun a pioneering program to find out how 
genetic type influences outcome among people who take part in our 
clinical trials. This is a long term and costly exercise but we believe 
it will result in better, safer clinical trials and, in turn, better 
targeted drug treatments for people with different genetic types. Our 
aim is to improve human health and to produce new medicines that are 
safer, have more predictable side effects and are more efficacious.
              kinase genes as targets for cancer treatment
    Kinase genes are a class of genes that have important function in 
signaling cellular responses such as cell growth and multiplication. 
Changes or mutations in these genes that make them more active and 
which signal an enhanced rate of cell multiplication have been found in 
several human cancers and in several cancer-causing viruses.
    We at Pharmacia have searched the human gene database for novel 
members of the kinase class with a view of investigating which of these 
may be drugable targets for cancer treatment. Upon the completion of 
the sequencing of the entire human genome and its assembly (sticking 
together of the different pieces of the genome) we have now determined 
that there are about 500 of kinase genes.
    We have initiated the important task of evaluating which of these 
kinase genes play a role in cancer formation as well as working out 
what they normally do for a living. We have focused our search on 
kinase genes that are too active in cancers with the idea that we may 
develop drugs that could reduce their activity. An example of such a 
kinase is the Vascular Endothelial Growth Factor Receptor (VEGFR). This 
gene is involved in the formation of blood vessels (angiogenesis) which 
the tumors need for a blood supply to keep them nourished. A drug that 
inhibits blood vessel formation may therefore have therapeutic utility 
in the treatment of cancers. One such drug that is in clinical trials 
at Pharmacia targets the VEGFR. We also have several other drugs that 
target different kinase genes in various tumor types at various stages 
of our drug discovery program.
    In addition, we have studied a family of kinases that appear to be 
actively involved in the symptoms and progression of rheumatoid 
arthritis and we have started initial clinical trials to establish the 
safety and efficacious of these novel drugs.
                  therapeutic approach to colon cancer
    Our studies into the underlying processes that cause the swelling, 
pain and stiffness of osteo- and rheumatoid- arthritis led to the 
discovery of a protein/gene called cox-2 (cyclooxygenase) that is not 
present in normal stomach or colon tissue but is turned on by tissue 
injury, inflammation, and various body chemicals released by disease 
processes. We ultimately developed a mechanism-based drug, Celebrex, 
that specifically inhibits the abnormal cox2, and which relieves the 
signs and symptoms of arthritis with a much lower level of side effects 
than pre-existing therapy.
    These discoveries led to the availability of new analytical tools 
which allowed us and several academic laboratories to identify the 
presence of cox2 in precancerous, cancerous and malignant colon cancer. 
Additional experiments demonstrated that colon cancer produced in rats 
with chemical treatment was associated with the appearance of cox2 and 
we found that Celebrex treatment suppressed the animal tumors.
    Many human colon cancers are known to involve a change (mutation) 
in the human tumor suppressor gene adenomatous polyposis coli or the 
APC gene. This gene is known to be ``switched off'' in these patients 
and hence these colon polyps grow unchecked. A mouse model where this 
gene has been ``knocked out'' or switched off also develop colon polyps 
analogous to that in humans providing compelling evidence that the loss 
of this gene is causative for colon cancers. These transgenic mice with 
mutated APC recaptiulate the genetic and the intestinal polyps of a 
human precancerous colon cancer known as Familial Adenomatose Polyposis 
(FAP). The polyps from the APC mutated mice indeed exhibited cox2 
expression and, again, inhibition of cox2, either with Celebrex or by 
the genetic elimination of cox2, reduced the number and volume of the 
precancerous polyps. Based on the demonstrated presence of cox2 in 
human colon cancer; and in chemically and genetically induced colon 
cancer, we conducted a 6 month clinical trial in FAP patients and 
Celebrex treatment reduced the tumor volume and size of the 
precancerous polyps which resulted in FDA approval of the first non-
surgical treatment of this condition. These trials provide the 
essential proof of concept for a major contributory role of this 
protein in the initiation and progress of tumors. However, FAP is a 
rare inherited disease which occurs in just a few thousand patients. 
The much larger colon cancer population, the so called Sporadic 
Adenomatosis Polyposis (SAP) results in about 50,000 deaths per year in 
the United States alone. Many of these patients acquire an APC mutation 
and exhibit elevated cox2 levels. Based on the successful FAP data and 
the compelling data strongly suggest the involvement of cox2. We are 
now in the midst of large, international, clinical trials in SAP 
patients being treated with Celebrex.
                               conclusion
    In summary, the availability of the human genome database, in the 
context of the years of productive discovery that have arisen from the 
funding of basic research by the NIH and other foundations provides 
industry with a unique toolbox for novel drug development. The 
implications are awesome. You can anticipate the identification and 
validation of the targets that are the engines of disease. The 
candidate genes will be useable both to make reliable animal models of 
human disease and will provide the reagents to start the hunt for drugs 
that will alter the targets and suppress or ameliorate the disease 
process. Furthermore, genomic information provides the potential 
markers that will allow the identification of disease subtypes and that 
hopefully would allow rapid, small trials and which might predict 
responders from non-responders. We therefore can look forward to 
targetted, optimal, individualized therapy. Finally, I expect that our 
efforts will be providing important new treatments that will change 
patient anguish, suffering and especially their quality of life. I 
foresee in our own Pharmacia efforts the prospects for: disease 
modification in rheumatoid and osteoarthrits; in the progression of 
Alzheimers; and leading to significant advances in the treatment of 
cancer.

    Senator Harkin. Thank you very much, Dr. Needleman, for a 
very provocative statement. I mean provocative in terms of 
making people think. I really appreciate it. A very good 
statement.
    Dr. Rich, we will turn to you now.
STATEMENT OF STEPHEN S. RICH, Ph.D., PROFESSOR, WAKE 
            FOREST UNIVERSITY SCHOOL OF MEDICINE
    Dr. Rich. Thank you, Chairman Harkin. Again, I am Stephen 
Rich and I am a professor of public health sciences at Wake 
Forest University School of Medicine. I would like to mention 
that I will come back to the issue of public health at the end 
of my short presentation here. But I would also like to mention 
I serve as the chairman of the International Type 1 Diabetes 
Genetics Consortium, which I will also come back to, which was 
mentioned by Dr. Spiegel some time ago.
    What has actually been accomplished in the genetic basis of 
type 1 diabetes? I will just give some perspective on that. 
When I first took my faculty position at the University of 
Minnesota, just north of Iowa I think, some time ago, in 1980, 
very little was known about the genetic basis of type 1 
diabetes. We and others spent about the next 7 years 
understanding that there was probably a major gene that 
contributes to the genetic basis of type 1 juvenile onset 
diabetes in the region that contains the major 
histocompatibility complex, or the HLA region, which is 
involved in transplantation and autoimmunity. So, it made 
sense.
    Unfortunately, at that time in the mid to late 1980's there 
really was not very much known about the genetics of that 
region, and we did not have the genomics resources to really go 
after the genes in those very complex regions. So, we turned 
our attention to did this region really contribute to 
everything that contributed to genetic risk of type 1 diabetes, 
and it turned out it did not. We found out that there are 
multiple genes that probably contribute in addition to how it 
interacts with environmental triggers. So, we know that there 
are things in the environment which trigger this autoimmune 
cascade that causes type 1 diabetes. So, it is the interaction 
of genes and environment that really is the fundamental basis 
of how this disease gets started in kids and why this is the 
third most common chronic disease in children.
    So, we then decided to try to find those additional genes. 
In the early 1990's, it was very difficult because there still 
was not the genomics material available to allow us to do that. 
They were being developed, but it was only with the advent of 
the human genome project that we were able to scan the entire 
genome to try to find out where in the genome were potential 
genes that could cause increased risk for type 1 diabetes.
    This was actually a major breakthrough from the standpoint 
of science of genetic basis of chronic disease or other 
diseases. In the early 1990's, we began making progress. At the 
same time, we were not able to find those specific genes. The 
reasons were really twofold. First, we became convinced that 
individual scientists working as individuals could not have 
sufficient resources to track down these genes. Second, it 
became apparent that the genomics material were at not the 
stage to allow us to identify specific genes.
    So, it has only been in the last few years that we have 
been able to, No. 1, decide that united we stand and can 
succeed, divided we fail. So, we formed the Type 1 Diabetes 
Genetics Consortium of investigators across the world who are 
interested in finding genes that cause risk for type 1 
diabetes. This will allow us to collect approximately 2,500 
families with two children with type 1 diabetes, two parents, 
an additional child unaffected with diabetes to reform the 
genome screen, to look through the entire genome to find these 
genes, at least the regions, and then use the material that the 
human genome project has provided us in the sequencing of the 
DNA to start looking more closely at what is actually there. 
This will allow us to continue to search and to characterize 
these genes to help decide who is at increased risk.
    Now, remember that I mentioned earlier that type 1 diabetes 
is probably an interaction. It is not just genetic risk. There 
are environmental triggers that cause this cascade of problems 
in the pancreas that in susceptible people lead on to diabetes. 
So, with the genes in hand, we can then decide what are those 
environmental risk factors and then decide on a public health 
basis individual screening.
    Now, this gets at two issues. As Dr. Collins mentioned, you 
need to take the findings from the bench to the clinic. From a 
public health standpoint, we want to take the findings from the 
bench to the clinic and to the community. That is where we can 
actually then process our knowledge of genomics and our 
knowledge of the environment and determine who really is at 
risk genetically and define the interventions, as well as 
defining the drug targets and the new therapies.
    So, I know that the support of this committee has been 
crucial in development of the genomics initiatives and the 
initiatives for the Diabetes Institute to continue with the 
research and the genetic basis and finding cures for diabetes 
and complications. I would just like to end by saying that 
timing is everything. I think we are at the stage now where the 
timing for continued support in the genomics initiatives and 
timing for support in the diabetes initiatives will certainly 
lead us in the next, I would say, 10 years to understanding 
better this terrible disease in children and hopefully come up 
with a means for identifying those at risk and hopefully curing 
this disease.
    Thank you, and I would be happy to answer any questions.
    [The statement follows:]
                 Prepared Statement of Stephen S. Rich
    Mr. Chairman, and Members of the Subcommittee, it is an honor to be 
asked to discuss with you the prospects of using the tools of the Human 
Genome Project to gain an understanding of the genetic basis of type 1 
diabetes and its complications. My name is Stephen Rich and I am a 
Professor of Public Health Sciences and a genetic epidemiologist at the 
Wake Forest University School of Medicine. I am also the Chair of the 
Type 1 Diabetes Genetics Consortium and a member of the Juvenile 
Diabetes Research Foundation Medical Science Review Committee.
    Today I would like to focus my comments on genetic complexity of 
type 1 diabetes and the accelerating progress made in understanding 
genetic predictors of disease risk. I also want to describe to you the 
role that the Human Genome Project has played in serving as a catalyst 
for genome research in type 1 diabetes, and how we are now at a 
critical phase in this research. Finally, I will present to you the 
problems that need to be resolved to identify genes for type 1 diabetes 
and how continued support of the National Institutes of Health, 
particularly the National Human Genome Research Institute (NHGRI) and 
the National Institute of Diabetes & Digestive & Kidney Diseases 
(NIDDK), can address these problems.
                      introduction to the problem
    Type 1 diabetes is the third most common chronic disease in 
children, estimated to affect over 120,000 in childhood and about 
300,000 to 500,000 Americans of all ages. There are about 30,000 new 
cases of type 1 diabetes each year. In addition, there is growing 
evidence that the number of new cases of type 1 diabetes is increasing, 
perhaps by as much as 5 percent per year. All children are at risk of 
type 1 diabetes (although the highest incidence is among Caucasians, 
followed by Mexican-Americans and African-Americans) and the 
complications of type 1 diabetes. Although the economic impact of type 
1 diabetes is large (over $40,000 per case), the medical and social 
impact on the person with type 1 diabetes and their families is 
enormous.
    In contrast, type 2 diabetes is a highly prevalent disease of 
adults, with over 8 million individuals diagnosed with disease, a 
prevalence rate of 3 percent of the population of the United States. 
The incidence of type 2 diabetes appears to be increasing, with the 
concomitant increase in obesity and physical inactivity in adults and 
children. As is the case of type 1 diabetes, the risk of type 2 
diabetes is present for all ethnic groups, although the non-Caucasian 
populations appear to be at higher risk of disease. Mortality in people 
with type 1 and type 2 diabetes is usually from the complications of 
disease. Diabetes, and particularly diabetic retinopathy, is the 
leading cause of new cases of blindness in the United States. It is 
estimated that 12 percent of new cases of blindness are attributable to 
diabetes. Neuropathy, the inflammation and degeneration of peripheral 
nerves, occurs in nearly one-third of type 1 diabetic subjects. 
Diabetes now accounts for almost 40 percent of all new cases of end-
stage renal disease in the United States, and persons with diabetes 
make up the fastest growing group of renal dialysis and transplant 
recipients. Diabetes is also a leading risk factor for atherosclerosis, 
myocardial infarction and stroke. Elimination of type 1 and type 2 
diabetes will necessarily eliminate diabetic complications.
                      etiology of type 1 diabetes
    Type 1 diabetes was described more than 2,000 years ago by Aretaeus 
of Cappadocia (150 A.D.) who described the disorder as ``. . . a moist 
and cold wasting of the flesh and limbs into urine . . .; the secretion 
passes in the usual way, by the kidneys and the bladder.'' The role of 
the pancreas in diabetes was defined in 1889 by von Mering and 
Minkowski, which led to the discovery of therapeutically active insulin 
for the treatment of human diabetes. Epidemiological studies, beginning 
with those by Elliott Joslin in the 1920's, but clarified by others in 
the 1980's, demonstrated that type 1 diabetes clustered in families. At 
the same time, immunological studies found that the autoimmune 
destruction of pancreatic islets in type 1 diabetes was a chronic 
process that could be slowly active for years prior to development of 
clinical disease. Evidence of the importance of genetic factors in the 
etiology of type 1 diabetes came from twin and family studies, in which 
it was estimated that nearly one-half of the risk for type 1 diabetes 
was due to genetic factors. Finally, an association was established 
between risk of type 1 diabetes and variants of genes in the human 
major histocompatibility complex (MHC), confirming the importance of 
genetic factors on risk.
    The etiology of type 1 diabetes remains unresolved. The 
environmental factors that are required to ``trigger'' the autoimmune 
destruction of pancreatic islets have yet to be identified. The genetic 
factors that determine an individual's level of susceptibility to 
environmental triggers are known to exist, yet most have not been 
isolated. It is also likely that the interaction between an 
individual's genotype with environmental exposure is important in 
determining ultimate risk. Thus, type 1 diabetes is an example of a 
complex genetic disease. However, given the progress made to date in 
genetics of type 1 diabetes and the tools now available from the Human 
Genome Project, there are data suggesting that these genes can be 
identified. Type 1 diabetes may serve as a model for use of genomic 
tools to understanding disease etiology, prevention, treatment and 
cure.
                    genetic basis of type 1 diabetes
    Type 1 diabetes clusters in families. The risk of diabetes in a 
sibling of a person with type 1 diabetes is about 8 percent, compared 
to a risk of 0.5 percent in the general population. This 16-fold 
increase in risk is attributable to multiple genes, including those in 
the human major histocompatibility complex (MHC) that account for 
nearly one-half of the genetic susceptibility. The complexity of the 
genes in the human MHC (on chromosome 6) is only now being understood, 
due to the available DNA sequence data obtained through the Human 
Genome Project.
    Genes that confer risk for (or protection against) type 1 diabetes 
also exist outside the human MHC. The availability of highly 
polymorphic genetic markers (that is, a gene with alternate forms) have 
made genome-wide searches possible for a number of complex human 
diseases. Type 1 diabetes was one of the first diseases to be explored 
in this fashion. To date, three groups have used large numbers of 
polymorphic genetic markers to scan the genome at regular intervals 
(roughly every 10 million base pairs of DNA sequence) in families with 
type 1 diabetes. These ``genome-wide searches'' for type 1 diabetes 
susceptibility genes have been performed with varying number of 
families and with different level of success. The results confirm the 
presence of at least one type 1 diabetes genes in the human MHC on 
chromosome 6. Another gene may likely be near the insulin gene on 
chromosome 11. Based upon the individual data, the number and location 
of additional risk genes has been difficult to determine. In order to 
maximize the available genetic data, the individual researchers have 
agreed to collaborate on an international scale to help find the genes 
responsible for genetic risk of type 1 diabetes. This collaborative 
effort is being supported by the NIDDK and the JDRF, and has resulted 
in the establishment of the Type 1 Diabetes Genetics Consortium. The 
Consortium currently is combining all available genome screen data for 
type 1 diabetes in order to identify potential regions of importance, 
but recognizes that a much larger set of human and genomic resources 
are needed to identify genes. A similar consortium, supported by the 
NIDDK, is underway for type 2 diabetes.
                    search for type 1 diabetes genes
    While specific regions of potential interest have been identified, 
it has become apparent that the number of families to be collected to 
provide adequate statistical power to detect type 1 diabetes genes is 
much larger than originally anticipated. Recent evaluation of research 
needs have estimated that 2,400 families will be needed to successfully 
scan the human genome for type 1 diabetes genes. To collect the 
required 2,400 families (with two parents, two children with type 1 
diabetes, and one child without diabetes), to obtain important clinical 
and immunological data and to perform the genome-wide search, a major 
collaborative research effort will be required. This first phase of the 
genome search will be followed by a collection of 5,000 families (with 
two parents, one child with type 1 diabetes and one child without 
diabetes), in which the resources of the Human Genome Project will be 
used to narrow our region of search. Finally, the DNA and clinical 
resources collected through the Consortium will be made available to 
scientists to identify the genes responsible for type 1 diabetes 
genetic risk. The Consortium represents an outstanding example of 
public-private partnership in scientific discovery for the improvement 
of public health.
                        paths to gene discovery
    The purpose of the Type 1 Diabetes Genetics Consortium is multi-
fold. The first purpose is to collect human materials in a consistent, 
ethical, and standardized manner that will expedite the identification 
of disease susceptibility genes. Collection by individuals using 
different protocols fail in the size of the sample collected and in the 
ability to provide a common framework for sample distribution and data 
collection. Having a large resource of materials that provide adequate 
statistical power to discover genes has yet to be accomplished for type 
1 diabetes, or other common diseases. The collection of human resources 
is expensive but represents a necessary first step.
    The application of existing genomic technologies is the second step 
in discovery. The Human Genome Project has made available the reagents 
available for the genome-wide search. Through the remarkable public-
private partnership called The SNP Consortium, there are now genetic 
maps of densely spaced SNP markers that make the search for genes more 
efficient. Importantly, these resources are freely available and in the 
public domain. The technology for using the SNP maps is still evolving, 
however, and continued support for automation and development of high 
through-put technologies is needed to enable a rapid evaluation of 
specific intervals in the human genome.
    Development of future genomic technologies is a critical third 
step. The search for genes currently requires scanning hundreds, if not 
thousands, of SNP variants within a given genetic region to determine 
which of many small genetic segments require further exploration. The 
continued efforts of the Human Genome Project to formulate a genetic 
map of conserved chromosomal segments (a ``haplotype'' map) would 
facilitate an efficient screening of these candidate regions that 
contain type 1 diabetes susceptibility genes. Ultimately, the 
``currency'' of the Human Genome Project, the DNA sequence, will be 
critical to identify those genes that affect risk of type 1 diabetes. 
In that regard, it is critical that NIH efforts to sequence the genomes 
of other organisms such as the mouse and the rat go forward with all 
due haste. The comparison of human sequence to mouse and rat sequence 
will help us pinpoint the critical regions of our own genome. In 
addition, support of the animal research will accelerate the 
development and exploration of better animal models of diabetes for 
testing of interventions and new therapeutics.
                          promise of genomics
    The outcome of the Type 1 Diabetes Genetics Consortium, using 
resources and reagents from the Human Genome Project, will lead to the 
discovery of potential type 1 diabetes susceptibility genes. This 
outcome will represent the ``end of the beginning'' in genetics of type 
1 diabetes. The next phase of research will focus on the function of 
the candidate genes, the way they act (both in isolation and in concert 
with other susceptibility genes) to increase genetic risk of type 1 
diabetes, and how they are affected by environmental exposure to cause 
the autoimmune cascade. The manner in which the genes interact and the 
way in which the proteins are modified to increase or decrease disease 
risk will require new and emerging technologies that are the future of 
genomics and proteomics. These investigations will likely continue the 
productive partnerships already established between the public (NIH) 
and non-profit foundations.
    The understanding of the genes and the gene products and their 
interactions will lead to improved risk prediction based upon genotype, 
not just family history and presence of immune markers. This knowledge 
will permit more efficient clinical trials of compounds developed using 
genomic information that holds the promise of prevention of type 1 
diabetes. An example of the infrastructure for development of these 
clinical trials is TrialNet, supported by the NIDDK. TrialNet 
establishes a consortium of clinical centers and core support 
facilities that would perform intervention studies to preserve 
pancreatic beta cell function for the purpose of preventing type 1 
diabetes. In early stages of molecular medicine, knowledge of genetic 
risk and the identification of the environmental triggers could 
establish vaccination against (for example) a virus that acts as the 
autoimmune ``trigger''. Thus, the knowledge of genetic risk would first 
establish a pathway to prevention against exposure. As scientific 
knowledge expands, a ``genetic vaccine'' could be made available which, 
in combination with the protection from environmental exposure, could 
eliminate an individual's risk of type 1 diabetes.
    There are enormous potential benefits of genomic research to 
individuals who may carry a ``genetic load'' for type 1 diabetes, and 
it is important for this research to go forward quickly. However, a 
major impediment to participation in genomic investigations is the 
participant's concern about potential discrimination based upon genetic 
information and violations of genetic privacy. Assurance of legal and 
social protection of an individual's rights from genetic discrimination 
will increase participation in genetic studies, facilitate gene 
discovery and enhance evaluation of novel therapeutics in clinical 
trials. The use of molecular medicine and genomic public health 
approaches will facilitate individual genetic risk assessment and pre-
symptomatic treatment of complex human disease. The potential to bring 
an end to type 1 diabetes and its complications is real and possible, 
with your continued support.
    Thank you Mr. Chairman. I would be happy to discuss any questions 
that you or others may have.

    Senator Harkin. Dr. Rich, thank you very much for all your 
work on type 1 diabetes.
    Now we turn to Dr. Murray, Professor of Pediatrics at the 
University of Iowa. Dr. Murray.
STATEMENT OF JEFFREY C. MURRAY, M.D., PROFESSOR OF 
            PEDIATRICS, BIOLOGY, AND PREVENTIVE 
            MEDICINE, UNIVERSITY OF IOWA
    Dr. Murray. Well, Senator Harkin, I would also have to lead 
out by thanking you and the committee for the wonderful support 
that you have given to NIH and the other health related Federal 
agencies over the years. With the self-effacing Mr. Affleck on 
my left, I would also have to say that I guess I am the simple 
country doctor representative that is here.
    I have had the opportunity to work as a pediatrician in 
both our nurseries and our genetics clinics at the university 
for about 15 years now. I would like to tell you two quick 
stories about patients that I saw just last week whose lives 
have been very much impacted by the genome project.
    The first is Rebecca and she is a 2-year-old now, who I 
first saw when she was 1 day of age, who was admitted to my 
nursery for a combination of birth defects that included heart 
problems and inability to move her legs. Rebecca's dad is a 
minister and her mom is a teacher, and she has four older 
brothers and sisters. Over the last couple of years, through 
the combined efforts of a number of different physicians and 
nurses, we have been able to improve her life.
    When I saw her a week ago, her older brother asked me, as 
he had once before, if I knew what the cause of Rebecca's 
problems were, and I can genuinely and honestly say that 5 
years ago I would not have been able to give him an answer. But 
just in the last several months, in fact particularly through 
the efforts of Dr. Collins' colleague, Eric Green, at the 
Genome Institute in Bethesda, we have been able to show that a 
very small region on the end of chromosome 7 is missing in 
Rebecca and is responsible for this collection of birth defects 
that she has.
    Now, while this finding by itself is not going to directly 
lead to improvements or a cure for what she has, it does 
provide answers for her family that they are very genuinely 
seeking, and in fact, it will enable her brothers and sisters 
to understand what their own reproductive risks might be when 
they become older. This kind of advance is entirely due to the 
very powerful resources that are available through the computer 
databases and the CD that you hold up there that enable us to 
look at this genetic material in a very, very fine way.
    To Senator Stevens, who asked earlier about the impact on 
family physicians, we have also been able to share this 
information with Rebecca's family doctor in Cedar Rapids, and 
he has been very appreciative of the larger body of knowledge 
that he now has as well.
    A second patient that I have spent a lot of time with is 
Sam. Sam was born with a kind of a neural tube defect. The most 
common description is something called spina bifida or an open 
spine. Sam is also from Iowa, from Solon, and has had very, 
very terrible mental retardation and movement problems as a 
result of this.
    Now, as we have just heard from Dr. Rich, the genome 
project not only teaches us about genetics, but it also helps 
us to understand how genes and environment interact with one 
another. In the last 2 years, there has been an amazing success 
story that is built off of the genetic findings of the genome 
project and coupled with the work that epidemiologists and 
private volunteer organizations such as the March of Dimes have 
done.
    We have known for several years now that folic acid, a 
common B vitamin, can be used to prevent spina bifida and 
related birth defects if the mother takes it beginning before 
pregnancy occurs. Starting 2 years ago, the FDA mandated that 
all enriched cereals and breads in the United States be 
supplemented with folic acid, much in the way that vitamin D is 
put in milk.
    In these last 2 years, there have now been, as shown in a 
report that came out a month ago from the CDC, 1,000 fewer 
babies born with spina bifida in the United States. This is an 
amazing achievement and the fact that there are now 1,000 
healthier, happier, wonderful children running around who do 
not have to suffer the pain and expense of this terrible 
disability is an amazing preventive success story.
    Just as Dr. Collins and Dr. Rich have told us, we now have 
the opportunity to use these genomic advances to understand not 
only things that we will be converting into treatments and 
preventions 15 years from now, but ones that we can do today 
and tomorrow and the next day. This is really a marvelous 
benefit for someone like myself and I think for all of us who 
have family members who might be affected with these kinds of 
disorders.
    I do want to also sound a couple of cautionary notes. You 
brought several of these up in your introductory statements.
    First of all, we need to, as you have said, temper our 
enthusiasm for the excitement of these findings with concerns 
about how the information might be used. When I was a member of 
the Ethical, Legal, and Social Panel, we frequently had 
families ask us about whether this information was going to be 
used in a way that could discriminate against them in either 
employment or for insurance purposes. You and others have 
already made efforts in trying to minimize and limit the kind 
of discrimination that can take place. But I think that this is 
still a concern, and again, as Dr. Collins told us, we need to 
be very vigilant that this kind of information is not used 
against the very families that it is designed and meant to try 
and help.
    A related area to this is in the area of research that many 
of us here on this panel are directly involved in and patients 
who will benefit from that research. Scientists and physicians, 
such as myself and others up here today, need to have access to 
the families, to have families voluntarily participate in these 
kinds of studies in a way that that information can be used to 
be converted into the kinds of treatments and preventions and 
cures that they would like to have.
    At the same time, the families need to be reassured that 
that information is not going to be used against them in some 
way. So, scientists and physicians need to have access to 
databases, the information and the DNA samples that are 
contained in those, in an easy way that allow them to pursue 
their scientific investigations. Families need to go through an 
important process of informed consent where they give their 
full and open permission to participate in these studies. And 
then those same families need to be protected so that the 
information contained in these research databases is not 
misused in any way.
    Then finally, also as we hear alluded to today as well, for 
some of the findings that are taking place today, it may not be 
a year or two, but it may be 5 or 10 or 15 years before the 
findings are converted directly into those treatments and 
preventions. We as scientists and physicians need to be careful 
that we do not over-promise to families, that the fruits of the 
genome project will all immediately be converted into cures and 
treatments.
    All of us recognize here in this room that the genome 
project is also an international effort, and that involves not 
only the people in the United States but many other countries 
as well. It also involves many other kinds of organisms, and we 
have heard that from Dr. Needleman.
    The health problems of the world today include not only 
things that the genome project will directly solve, but are 
still built around things such as unsafe drinking water, poor 
nutrition and treatable or preventable infections like HIV or 
measles. So, at the same time that we are taking advantage of 
these very powerful immediate advances, we need to also ensure 
that the genome project is applied in a beneficial way across 
all strata of society and everywhere.
    Again, I want to thank you and the committee for the 
wonderful support and job that you have done over the years for 
NIH and the CDC and the other Federal organizations. As a 
genuine practicing physician and one who really on a daily 
basis gets to see these applications put into direct practice 
for families, as Dr. Collins has told us, we are really at the 
beginning of the genome project, not the end of the genome 
project. Now we have the opportunity to convert these very, 
very wonderful findings into things that are going to benefit 
all of us and even more importantly I think our children.
    Thank you.
    [The statement follows:]
                Prepared Statement of Jeffrey C. Murray
    First, I would like to thank you, Senator Harkin, and the other 
members of the panel for the opportunity to speak with you today. I am 
a pediatrician and a molecular biologist who has spent the last 20 
years of my career caring for children with prematurity and birth 
defects and working in the laboratory to better understand the genetic 
and environmental causes of these terrible disorders. For the last two 
days, I have been attending a meeting in Bethesda, sponsored by the 
Child Health Institute. This meeting brought together investigators to 
see how advances in the genome project can be put to use to decrease 
the terrible impact of birth defects. Birth defects afflict one in 
thirty newborns and can lead to a lifetime of disability. Just last 
week, before leaving for this meeting, I was seeing patients in our 
genetics clinic. One is Rebecca, a now two-year-old girl I first took 
care of in the intensive care nursery at our university and who is the 
youngest of four siblings born to a minister father and teacher mother 
in Marion, Iowa. At birth, Rebecca had several different birth defects 
that prevented her from moving her lower legs and also affected her 
bowels and her heart. Through the combined efforts of many physicians 
and nurses caring for her, she now has a life that is far better than 
could have been anticipated even a decade ago. Her parents and oldest 
brother asked me what caused Rebecca to be born like this. Five years 
ago, I would not have had an answer, but now I can say that through the 
advances in the Human Genome Project, we have been able to identify a 
very specific region on chromosome number seven that seems to be 
missing in Rebecca. While this information by itself will not change 
the care that we provide for her, it does provide answers for her 
family and relatives and holds out the promise for us being able to 
better prevent or treat children with disorders similar to Rebecca's in 
the future. Up until a few years ago, it might have taken our 
laboratory ten or even twenty years of work to identify this cause 
while now it was completed through the work of a single graduate 
student in a few months, making use of the very powerful computer 
databases that contain the DNA sequence information and using genetic 
maps constructed in part in the Iowa Genome Center.
    Another patient I have cared for now for three years is Sam, who 
comes from Solon, Iowa, and who I also first took care of in our 
intensive care nursery. Sam has a very severe brain malformation of a 
type called neural tube defects, which are most commonly represented by 
spina bifida, or an open spine. We have known for some time that folic 
acid taken as a prenatal vitamin can prevent spina bifida. Just one 
month ago, in work that was sponsored by the CDC, the NIH, and the 
March of Dimes, the first report appeared demonstrating that since the 
FDA requirement for the fortification of folic acid in cereal grains 
was instituted in 1998, the prevalence of spina bifida and related 
neural tube defects has dropped by 20 percent in the United States. It 
was possible to document this change by using the information provided 
by birth defects registries which have received critical support from 
the CDC and March of Dimes at a time when our concerns about the 
genetic and environmental causes of birth defects has never been 
greater or more available to change. This is an amazing success story 
and a strong testament to how federally sponsored research and law can 
work together to improve the lives of children and adults. This 20 
percent reduction means that there are 300 fewer babies born per year 
with spina bifida in the United States, sparing their families and 
themselves years of pain, suffering, and expense. In this case, a 
simple and safe environmental change--food fortification--has had a 
dramatic impact and will now stop many other Sam's from a future of 
surgery and mental retardation. This illustrates the close connection 
between genes and environment and how knowledge of one can interact 
with outcomes of the other. The partnerships that have led to these 
remarkable findings and advances are a wonderful testament to the 
support that the Senate, the House, and the President have provided 
with their generous increase in funding to the NIH and in particular to 
the Human Genome Project over the last several years. By continuing to 
provide this kind of support, we will be able to build upon the 
developments that have already taken place to provide an even more 
promising future for our children filled with possibilities rather than 
disabilities.
    At the same time that these remarkable advances are taking place, 
we need to temper our enthusiasm with a few concerns. First, the power 
of DNA and gene sequencing has also raised concerns about the use of 
this information in both the public and private sector. Our families 
frequently ask us whether this diagnosis will have an impact on their 
children's ability to obtain health insurance. The treatments for these 
disorders are incredibly expensive and far beyond the means of all but 
a few very wealthy families, so families need resources and assurances. 
Similarly, these children, when they grow up, and their siblings are 
concerned about opportunities in employment and education and whether 
their genetic background will in some way influence decisions that may 
affect their life choices. The Congress and the President have already 
begun to address these concerns through legislation protecting 
individuals from discrimination in employment or insurability, but 
these regulations as well as a system of comprehensive health coverage 
needs further strengthening.
    In parallel with this have been similar concerns raised by 
participants in research projects who provide the necessary information 
to use the genome project to investigate inherited disorders. The 
genome project has provided powerful tools for genetic study, but still 
only tools that must now be used with real people and real diseases 
like you see here today to realize the promise of the technology. The 
successes that we have and will hear about in diabetes, ataxia 
telangiectasia, spina bifida, and others have all been built on the 
cooperation of patients and families who have these conditions and who 
willingly provide information as well as blood and tissue samples for 
scientific research. This information and samples reside in databases--
an essential tool for the physician-scientist in determining causes. 
Yet, these individuals must be protected in their participation in 
research and not have this information used in any way to discriminate 
against them. While serving as a member of the Genome Project, ELSI 
(Ethical, Legal, and Social Issues) Review panel, we were confronted 
time and again with this seeming disparity. The potential conflict 
arises in the desire for families to participate in research that will 
benefit them and others balanced against their need for privacy. We 
must be able to strike a balance of proper informed consent from 
individuals enrolled in studies, safeguards to ensure that no outsider 
can intrude on the data stored and smooth access by scientists and 
physicians to the critical data and samples needed to convert genome 
information into genome based treatment and prevention.
    A second reality test of our enthusiasm must be that even the 
identification of DNA sequence information does not itself immediately 
lead to preventions and cures. One oft-sited example is that we have 
known since 1949 and the work of Linus Pauling what the cause of Sickle 
Cell Anemia is, a common genetic disorder frequently found in African 
Americans. Although the care for individuals with Sickle Cell Anemia 
has improved dramatically over the last 50 years through the efforts of 
many kinds of caretakers, the promise of the genome has not yet allowed 
us to cure or prevent this disorder in a primary way. We hope that many 
of the findings being discovered today will lead more quickly to these 
cures and prevention, but we also need to be careful not to over-
promise to the public that the fruits of our research will be immediate 
in their application to their own specific disorders.
    A final tempering comes from the realization that the genome is 
international. In my own work in the Philippines and Brazil I have come 
to know that the major problems of world health are not those of 
genetics, but are simple problems best addressed through basic 
sanitation and clean drinking water, with immunization against tetanus 
or measles, by providing basic nutrition or population control methods 
and through programs to prevent HIV, malaria, or TB. At the same time 
that we are excited and enthusiastic about the work of the Genome 
Project, we need to continue to be aware of the need for these 
approaches to preventive medicine so often taken for granted in the 
developed world.
    It has been a great honor and privilege for me to have participated 
in some small way in the mapping of the human genome and to have lived 
at a time when I can see the successful realization of so many 
scientific projects now becoming a reality in their direct application 
to patient care and treatment. I can only hope that you and others like 
you will continue to provide the necessary support for these projects 
in creating a truly brighter future for our children and their children 
to follow.

    Senator Harkin. Thank you very much, Dr. Murray.
    Dr. Murray gave a couple of examples. Now we turn to really 
what this is all about, about a human being, about a person, 
about someone for whom this promise of genomic research and the 
applications that your scientists, all of you have been talking 
about, is meaningful and is real.
    I have the highest respect, as you know, for each one of 
you, and for all of the wonderful work that you have done in 
the scientific realm to bring us to this point and which you 
will be continuing to do in the future. I also have the highest 
respect for those who have attained a position of celebrity 
status in our society because of their abilities in other areas 
and who take the time and the effort to get involved in 
bringing to the public conscience what we are doing here.
    It is in that vein that I welcome Ben Affleck to this 
table, Joe Kindregan's friend. Maybe I should introduce you 
that way. Right? Joe Kindregan's friend.
    Mr. Affleck. Most appropriate probably, yes.
    Senator Harkin. And also Joe and Mr. Margus.
    We thank you very much, Mr. Affleck, for being here and 
again, as I said, for being willing to step out in front and to 
publicize in a very meaningful way what it is we are all about 
here.
STATEMENT OF BEN AFFLECK, ACTOR
ACCOMPANIED BY:
        BRAD MARGUS, PRESIDENT AND CO-FOUNDER, A-T CHILDREN'S PROJECT
        JOE KINDREGAN, A-T PATIENT

    Mr. Affleck. Thank you, Senator, and I thank you and 
Senator Specter for your brave leadership in this regard, your 
pursuit of funding for stem cell research, the genome project, 
and the model of bipartisanship and leadership that you and 
this committee represent. Frankly, I am impressed and I feel 
very honored to be asked to be here and I thank you very much.
    Second, I am really inspired by all you gentlemen. It is 
really a pleasure to sit next to you. It is truly impressive, 
and what is really marvelous, beyond even all of your day-to-
day work in the business of helping of people, is your 
capacity, I think equally important in many ways, to make that 
process, which, as Senator Stevens mentioned, can sometimes 
seem a little obtuse and complex and nebulous, tangible and 
accessible to folks and to our leadership. I think that is 
equally important. You have done a fine job and I am honored 
and a little humbled to sit in your company.
    I will try to stick to the 5-minute rule, although, you 
know, in Hollywood we get 15 minutes.
    To the horror of the folks I came with, I am going to speak 
extemporaneously for a few moments before I go into the 
prepared text and just say that ultimately why I am here is I 
am obviously neither a politician nor a doctor nor even 
whatever this woman does who appears to be sucking on ether 
over there.
    Is that not what that looks like?
    That is why you look like you are falling asleep, ma'am.
    It is impressive really. Able to maintain consciousness 
throughout the proceedings.
    I am here because of my friendship with a guy who has 
really moved me and am here to talk about the human toll in 
this. Sometimes we get into debates and we talk about policy 
and appropriations and funding and pharmaceuticals and genome, 
and it is all really tremendous and important work. But what is 
also important is to remember the human costs in these things, 
to remember that there is a time pressure, to remember that 
they are real people doing real suffering who otherwise could 
be living wonderful, normal lives.
    This is why I would urge you and the committee to go to a 
vote on the stem cell question, which I think has support not 
only of Congress, of the Senate, but of the vast majority of 
the American people who understand that this research, 
particularly recently we have come to understand, can be 
enormously helpful in neurological disorders and spinal cord 
disorders. I am sure you would do a lot better job of 
explaining why exactly, but it is.
    You were asking what is A-T. It is actually pronounced 
ataxia-telangiectasia.
    I met Joe a few years ago. I was working at Dulles Airport. 
We were filming a movie and he wanted to get a better view of 
what we were doing. We just kind of hit it off. At the time I 
met Joe, he was in a wheelchair but he was using a power 
wheelchair, but I also learned that he loved karate and he had 
a yellow belt. Since then Joe has stopped his lessons because 
it has become too difficult for him to stand and balance at 
attention as a result of the neurological deterioration from A-
T.
    A-T affects the body's coordination. It predisposes 
children to lethal cancers. It severely compromises their 
immune systems. Most children with A-T are sentenced to a life 
in a wheelchair. If you can imagine a disease that combines the 
worst aspects of muscular dystrophy, cancer, and AIDS, you 
would have a pretty good idea of what a kid with A-T and their 
families endure on a daily basis. A-T is a progressive disease. 
It gradually robs children of their muscle control. They lose 
ability to walk, to talk, to read, and to play games. A-T is 
exceptionally cruel because children with A-T lose their 
physical capabilities inch by inch, but they never lose their 
intellect or mental faculties. And I can assure you that Joe is 
every bit as sharp and mentally alert as I am. Although there 
are people who will tell you that is not saying much, he is 
young.
    I promise you he is a very bright, spirited young guy.
    Since we first met, I have had the pleasure of seeing Joe 
on a number of occasions. In fact, this past spring Joe and his 
family joined me in Hawaii for the premier of ``Pearl Harbor''. 
I have seen firsthand the progression of Joe's A-T. Where Joe 
and I used to carry on a conversation, his mom now often has to 
translate more and more of what Joe says because his speech has 
been affected by A-T, although sometimes his mom jumps in a 
little too much and henpecks him, and I have to tell her just 
give him a minute or he tells her.
    Joe and I used to be e-mail pals, and he has written me 
some very funny and interesting and wonderful e-mails. It used 
to be something that I really looked forward to on a daily 
basis. But Joe can no longer type his part of the conversation, 
so his mom does that for him now.
    As Joe is entering his adolescence, he is becoming more and 
more dependent upon those around him to assist him with daily 
tasks. As I recall, adolescence was a time for increasing 
independence. Some of us too much independence, but for Joe, A-
T has made this normal right of passage for a teenager go 
backwards.
    The great thing about him, however, is that he is full of 
hope and optimism, just like every other kid in America. But in 
his case, his hopes are somewhat different than most 12- or 13-
year-olds. He hopes the benefit of medical research on diseases 
like A-T will help him to walk again, speak easily, play with 
friends, and I look forward one day to playing sports with him. 
These dreams will only be possible if the vision of the A-T 
Children's Project is realized, which is a cure for A-T.
    The A-T Children's Project is a nonprofit organization 
established by Brad and Vicki Margus. Since its inception 8 
years ago, the Children's Project has raised over $10 million. 
They have done what many small disease organizations do, 
raising money through numerous grassroots events, such as walk-
a-thons, dinners, and auctions. They have successfully garnered 
the guidance from a respected board of objective scientists to 
award these funds to researchers around the world studying A-T. 
The A-T Children's Project has established tissue and cell 
banks so that researchers interested in studying A-T can easily 
obtain patient tissue or DNA. They have successfully encouraged 
international collaborations among scientists from the United 
States, the United Kingdom, Australia, Israel, Turkey, Italy, 
France, and Germany. In addition, these collaborative efforts 
have generated numerous research strategies as a result of 
their two scientific conferences that they host annually.
    Research funded by the A-T Children's Project has led to 
the identification of a defective gene that causes A-T in 
children. In addition, the A-T Children's Project has funded 
the work of several labs to use genetic engineering to develop 
mice with A-T. These mice have many of the same symptoms seen 
in A-T kids. Now that an animal model exists, it is possible to 
explore potential therapies to treat the effects of A-T and 
hopefully one day find a cure.
    Mr. Chairman, members of the committee, this is a 
remarkable track record of progress for a small foundation in a 
short time. Now it is vitally important that your leadership 
ensure that kids like Joe get to the finish line.
    When you have a disease that affects such a small number of 
Americans like A-T, it is imperative that the resources of the 
NIH be devoted to it. One of the things I am asking you here to 
do is to support not only A-T but other what they call orphan 
diseases, just because there are very few people who have the 
disease relative to, say, Dr. Needleman's favorite disease, 
which was colon cancer. There are many similar small clusters 
of diseases that fall under a larger umbrella. There are 
various variations of neurological disorders, and I am here to 
urge you to increase funding for these diseases which 
oftentimes get lost even in places like NIH because, obviously, 
you are focused on diseases that afflict more people.
    My message is simply this. A-T needs a bigger piece of the 
NIH pie. I was just speaking extemporaneously again. The 
support of the Congress and the investment of the NIH in A-T 
research is vitally important if kids like Joe are to have 
their hopes and dreams fulfilled.
    Another important aspect of research for children with A-T 
that needs to be considered is the training of clinical 
researchers. As a result of the competitive health care 
marketplace, it is extraordinarily difficult for clinical 
researches to devote time and academic resources to 
translational and clinical research initiatives. While strides 
have recently been made through the passage of the clinical 
research legislation in the last Congress, it is imperative 
this aspect of our biomedical research infrastructure be 
monitored carefully.
    Increased funding for NIH will give children and adults 
with neurological disorders, such as A-T, an increased chance 
of reaching their full potential. With an increase in funding 
at this time, along with monumental advances in genomics, 
researchers will learn not only how to prevent diseases like A-
T, but how to reverse the neurological damage that has already 
been done. The research is not only critical for A-T but also 
for many other neurodegenerative diseases, including 
Parkinson's and Alzheimer's. This Congress has the ability to 
make a tremendous impact on the future of modern medicine and 
the suffering of individuals and their families.
    My friend Joe often refers to the time when he gets well. 
He knows that the reality of his recovery is just around the 
corner. Right now funding means hope for all of these families, 
hope that medical research will produce a miracle in Joe's 
lifetime. For Joe, it will mean a second chance at being a kid. 
For me, I intend to work with him on his next karate belt as 
soon as research advances get him out of his wheelchair. With 
your help, these dreams will become a reality.
    This concludes my formal statement. Brad and I will be 
happy to answer any questions that you may have for us. Thank 
you.
    [The statements follow:]
                   Prepared Statement of Ben Affleck
    Mr. Chairman, Members of the Committee, thank you for the 
opportunity to appear before you today on behalf of the A-T Children's 
Project. Brad Margus, President and Co-Founder of the A-T Children's 
Project joins me at the witness table. Eight years ago two of Brad's 
four sons, Jarrett and Quinn were diagnosed with a disease called 
ataxia-telangiectasia or A-T for short. I am also honored to be 
accompanied to today's hearing with a friend of mine, Joe Kindregan. 
Joe is 13 years old and has A-T.
    You may be asking, as I did a few years ago, ``what is A-T?'' A-T 
is a genetic disease that attacks its victims in early childhood. It is 
very rare, only about 600 children in the United States have the 
disease, and this fact makes it all the more difficult to get doctors, 
researchers, the government and pharmaceutical companies interested in 
investing the millions of dollars necessary to develop innovative ways 
to diagnose and treat A-T.
    A-T affects the body's coordination; it predisposes children to 
lethal cancers, and severely compromises their immune systems. Most 
children with A-T are sentenced to a life in a wheelchair and rarely 
live beyond their teens. If you could imagine a disease that combines 
the worst aspects of muscular dystrophy, cancer and AIDS you would have 
a pretty good picture of what a child with A-T and their families 
endure daily. A-T is a progressive disease that gradually robs children 
of their muscle control; they lose their ability to walk, to talk, to 
read and to play games. A-T is exceptionally cruel because while 
children with A-T lose their physical capabilities inch-by-inch, 
children with A-T never lose their intellect or mental faculties. 
Regrettably, they are trapped in a body that progressively fails them. 
In addition to the neurological deterioration, their chance of getting 
leukemia and lymphoma and succumbing to cancer is 1,000 times higher 
than normal. In short, the outlook for these kids is horribly grim.
    So, it is for Joe, Jarrett and Quinn and the hundreds of other 
children with A-T across America, that I bring their plight to Congress 
today. I would like to help the Committee, and your colleagues in the 
Senate, understand the human aspects of this horrendous disease and 
suggest some ways that Congress can assist these children and their 
families.
    I first met my friend Joe 3 years ago at Dulles Airport while 
filming ``Forces of Nature.'' He had come to Dulles with his mom and 
sister to see what it was like on a movie set. He was in a wheelchair 
and couldn't see through the crowds of people so he was allowed down on 
the set to get a better view.
    Joe was 10 years old at the time and had just started using his 
power wheelchair. During the course of the afternoon I learned that Joe 
loved karate and even had attained a yellow belt. Unfortunately, Joe 
had to stop his lessons when it became too difficult for him to stand 
and balance at attention as a result of his neurological deterioration 
from A-T.
    Since we first met, I have had the pleasure of seeing Joe on a 
number of occasions. In fact, this past spring Joe and his family 
joined me in Hawaii for the premiere of Pearl Harbor. I have seen 
firsthand the progression of Joe's A-T. Where Joe and I used to carry 
on a conversation, his mom now has to translate more and more of what 
Joe says because his speech has been affected by A-T. Joe and I used to 
be e-mail pals, but Joe can no longer type his part of the conversation 
so his Mom does that for him now. As Joe enters adolescence he is 
becoming more and more dependent upon those around him to assist him 
with daily tasks. As I recall, adolescence is a time for increasing 
independence, but for Joe, A-T has made this normal right of passage 
for a teenager go backwards.
    One thing that I have learned about Joe is that he is full of hope 
and optimism, just like every other kid in America. But in Joe's case, 
his hopes are somewhat different than most 12 or 13 year olds. Joe 
hopes that the benefit of medical research on diseases like A-T will 
help him to walk again, speak easily, play with his friends, and maybe 
even someday play sports again. These dreams will only be possible if 
the vision of the A-T Children's Project is realized: a cure for A-T.
    The A-T Children's Project is a non-profit organization established 
by Brad and Vicki Margus. Since its inception eight years ago, the 
Children's Project has raised over $10 million. They have done what 
many small disease organizations do, raising money through numerous 
grass-roots events such as walkathons, dinners and auctions. They have 
successfully garnered the guidance from a respected board of objective 
scientists to award these funds to researchers around the world 
studying A-T. The A-T Children's Project has established tissue and 
cell banks so that researchers interested in studying A-T can easily 
obtain patient tissue or DNA. They have successfully encouraged 
international collaborations among scientists from the United States, 
the U.K., Australia, Israel, Turkey, Italy, France and Germany. In 
addition, these collaborative efforts have generated numerous research 
strategies as a result of their two scientific conferences that they 
host annually.
    Research funded by the A-T Children's Project has led to the 
identification of the defective gene that causes A-T in children. In 
addition, the A-T Children's Project has funded the work of several 
labs to use genetic engineering to develop mice with A-T. These mice 
have many of the same symptoms seen in A-T kids. Now that an animal 
model exists it is possible to explore potential therapies to treat the 
effects of A-T and hopefully, one day, find a cure. Mr. Chairman, 
Members of the Committee, this is a remarkable track record of progress 
for a small foundation in a short period of time. Now, it is vitally 
important that your leadership ensure that kids like Joe get to the 
finish line.
    On behalf of the A-T Children's Project, we urge your continued 
support of the doubling of the budget of the National Institutes of 
Health (NIH). The Congress has been an incredible ally in pushing the 
frontiers of research through the investment you have made in medical 
research. It is vitally important that the fourth installment in 
meeting this important objective be made this year.
    When you have a disease that afflicts such a small number of 
Americans, like A-T, it is imperative that the resources of the NIH be 
devoted to it. I am confident that you have hundreds of requests 
annually for funding specific initiatives at the NIH. With that said, 
my message is simply this--A-T needs a bigger piece of the NIH pie if 
we are to fully exploit the scientific possibilities that exist. The 
support of the Congress and the investment of the NIH in A-T research 
is vitally important if kids like Joe, Jarrett, and Quinn are to have 
their hopes and dreams fulfilled.
    The A-T Children's Project has directed resources to support basic 
research looking at the biological defect and the role of the A-T gene/
protein in cells in academic laboratories. They have demonstrated the 
capacity to bring together scientists on a global basis, not allowing 
geographic boundaries to inhibit fully exploiting the best and 
brightest scientific minds to tackle this disease. What the A-T 
Children's Project does NOT have the capacity to support is the 
translational research that seeks to apply the findings from basic 
research to the kids with A-T. We need the government to intercede here 
and encourage the NIH intramural program to work in partnership with 
industry on translating the basic science advances. The new Clinical 
Center at the NIH has the capacity to enhance translational research in 
this crucial area.
    Another important aspect of research for children with A-T that 
needs to be considered is the training of clinical researchers. As a 
result of the competitive healthcare marketplace, it is extraordinarily 
difficult for clinical researchers to devote time and academic 
resources to translational and clinical research initiatives. While 
strides have recently been made through the passage of the Clinical 
Research legislation in the last Congress, it is imperative that this 
aspect of our biomedical research infrastructure be monitored 
carefully.
    In spite of the boom in biotechnology venture funding, progress in 
developing new tools to accelerate research is not fast enough for kids 
with A-T. While the gene was identified six years ago, faster methods 
and tools for figuring out exactly what the gene and its proteins do in 
healthy people and how we can compensate for its absence in A-T kids 
have not been forthcoming. These types of assays and tools are vitally 
important and NIH should be encouraged to pursue them.
    Increased funding for NIH will give children and adults with 
neurological disorders such as A-T an increased chance of reaching 
their full potential. With an increase in funding at this time along 
with the monumental advances in genomics, researchers will learn not 
only how to prevent diseases like A-T, but also how to reverse the 
neurological damage that has already been done. This research is not 
only critical for A-T, but also for many other neurodegenerative 
diseases including Parkinson's and Alzheimer's. This Congress has the 
ability to make a tremendous impact on the future of modern medicine 
and suffering of individuals and their families.
    My friend Joe often refers to the time when he gets well. He knows 
that the reality of his recovery is just around the corner. Right now, 
funding means hope for all of these families. Hope that medical 
research will produce a miracle in Joe's lifetime. For Joe, it will 
mean a second chance at being a kid. For me, I intend to work with him 
on his next karate belt as soon as research advances get him out of his 
wheelchair. With your help, dreams will become reality.
                                 ______
                                 
                   Prepared Statement of Brad Margus
    Mr. Chairman and Members of the Committee, thank you for giving me 
the chance to tell you how a terrible disease has affected two of my 
sons and how families like mine have tried to accelerate research 
toward a cure. After describing my background to you, I would then like 
to explain four specific actions your committee could consider taking 
to increase the effectiveness of research--not only on my sons' brutal 
disorder but on many other diseases as well.
                                my story
    Not too long ago, in the early nineties, I knew nothing about the 
Human Genome Project, nothing about serious health problems, and 
nothing about how researchers in pharmaceutical companies, academic 
institutions and government laboratories were trying to exploit 
molecular biology to discover drugs and treatments for diseases. I knew 
only about running a small, entrepreneurial business.
    After graduating from business school in 1986, instead of going to 
Wall Street or into venture capital or consulting, I went somewhere few 
Harvard MBAs go--into the shrimp industry! There, I grew a successful, 
but admittedly low-tech, seafood company. I also married a beautiful, 
intelligent woman, and together we had had three sons within less than 
four years. Vicki and I purchased our dream house on a tree-filled lot 
in sunny Florida and imagined growing old watching our sons turn into 
strong, healthy men someday. Life seemed perfect.
    Then one day, everything changed. We suddenly lost control of our 
perfect lives. In the spring of 1993, two of my young sons were 
diagnosed with a terrible genetic disease known as ataxia-
telangiectasia (pronounced ``ayTACK-see-uh teh-LAN-jick-TAY-sha''), or 
``A-T'' for short.
    Our boys with A-T had seemed normal until about the age of two when 
their walk had become a little ``wobbly'' and their speech had become 
slurred. Doctors took nearly two more years, and we spent over $70,000 
in tests to figure out what was wrong, and the final diagnosis was a 
brutal one. We were told that by the age of nine or ten, our boys with 
A-T would lose so much control of their muscles that they would need to 
rely on wheelchairs. And, by their early teens, controlling eye 
movement and throat muscles would make reading and swallowing extremely 
difficult for them.
    On top of hearing about the neurological progression, we were also 
told that the boys each had a 40 percent chance of developing leukemia 
or lymphoma and a 70 percent chance of having a weakened immune system 
that would make common infections much more serious. Most children with 
A-T, we were told, died in their late teens or early twenties. And, as 
the diagnosis kept sinking in, we realized that the quality of their 
lives would deteriorate long before then.
    Devastated by the news about our boys, my wife and I did what many 
parents do in similar situations. We started learning everything we 
could about the disease. As I plunged into reading papers about A-T 
published in scientific journals, I grew to realize that A-T--affecting 
only about 600 children in the United States--was truly an ``orphan'' 
disease. No one with fame or money had ever had a child with this 
disease and funds to support medical research were extremely limited. 
Therefore, in the fall of 1993, we started a non-profit organization 
called the A-T Children's Project.
    I also realized that to have any effectiveness at all, I needed to 
learn enough molecular biology so that I could comprehend the research 
strategies being taken and could appreciate which scientists were 
competent and which were not. I enlisted the help of several Ph.D. 
scientists who tutored me every night by phone and fax.
    At the same time, I made an effort to ask many scientists and 
grant-giving organizations for their impressions about other non-
profits whom they believed were especially effective. I wanted to learn 
from other model organizations so that I would avoid common pitfalls. I 
could not afford to learn by trial and error. As a result of this 
process, I immediately recruited a team of objective, first-rate 
scientists and physicians to serve on my Scientific Advisory Board. I 
didn't want to take any chance that a particular scientist or physician 
might sway me too much (as often happens to parents desperately seeking 
a cure for their kids' disease). I also began to visit the National 
Institutes of Health regularly to learn how our government funded 
research and to try to encourage increased interest in my kids' obscure 
disease.
    While continuing to manage my shrimp company, I learned how to 
raise money by leading a grass-roots effort that organized walkathons, 
dinners and diverse other events around the nation to support research. 
We started by writing letters and gradually developed a base of 
wonderful volunteers who helped us raise money. Events included 
walkathons, celebrity golf tournaments, horse shows, races, dinner 
dances, auctions, retail-level point-of-purchase ``heart'' sales, and 
hundreds of other ideas . . . The funds we raised grew from a few 
hundred thousand to over two million dollars per year.
    Raising money for a rare disease with a name that is nearly 
impossible to pronounce is not easy. And, because this disease is so 
rare, we could never depend solely on the help of volunteers who have a 
personal connection with an affected child in the way that 
organizations for more common diseases can. Instead, we had to persuade 
total strangers to reach out and help us.
    Of course, besides raising money, it was critical to recruit first-
rate scientists and to persuade them to work on A-T. At least twice a 
year, we orchestrated and sponsored scientific workshops that brought 
together researchers from different disciplines to compare results, 
generate new research approaches and form collaborations. At each of 
these meetings, I worked hard to concoct the right mix of scientists 
and to provide the perfect atmosphere so that they would candidly share 
their latest, unpublished data and work cooperatively with each other 
even after the meeting ended.
    Our organization also played an important role in making sure 
researchers had easy access to patient tissue samples. We set up an 
international cell bank for blood and skin samples and a brain tissue 
bank as well.
    In the summer of 1995, the laboratory of a researcher at Tel Aviv 
University in Israel, Dr. Yosef Shiloh, succeeded in finding the gene 
that, when mutated, causes this disease. The NIH laboratory of Dr. 
Francis Collins--who is also testifying at today's hearing--had 
collaborated with the Israeli team, and we will always be thankful to 
Dr. Collins for the contribution his group made to our gene hunt.
    Having found our gene, we could not celebrate for long. Instead, we 
quickly recruited geneticists who were experts in frogs, zebra-fish, 
fruit flies, worms, yeast and fungus so that we could utilize their 
experiences with similarly spelled genes in these lower organisms. We 
also assisted several laboratories in developing strains of ``knock-
out'' mice that had the A-T gene disrupted so that we would have a 
model of the disease in a mammal. We helped several scientists raise 
antibodies against the A-T protein--an important tool for studying the 
activity of the protein in various tissues. And then, we helped to make 
sure these antibodies were freely shared with any new researcher who 
became interested in our kids' rare disease.
    Still other labs were encouraged to use bacteria to make 
``recombinant'' A-T protein with which experiments could be performed, 
and two groups succeeded at tagging the A-T protein so that its 
movement could be followed in the cell. We also used various methods 
such as yeast-two-hybrid screens and mass spectrometry to identify 
other proteins and protein complexes that interacted with the A-T 
protein.
    Besides finding the A-T gene in 1995, we realized that year that we 
needed one place in the world where a multidisciplinary team of 
physicians were accumulating data on this disease (until then, most 
physicians overseeing a child with A-T had never seen another case). 
Therefore, after seeking proposals from many leading medical centers, 
we established an A-T Clinical Center at Johns Hopkins Hospital in 
Baltimore, Maryland. It included physicians covering every field 
relevant to A-T (such as neurology, immunology, oncology, 
ophthalmology, and pulmonary) as well as experts in brain imaging, 
brain pathology, swallowing problems, physical therapy, occupational 
therapy, speech therapy, and assistive technology.
    About the same time, we set up an internet web site plus a list 
server that provided a forum by which A-T families and caregivers 
around the world could shares ideas about managing the disease day-to-
day and give each other emotional encouragement.
    The scientific research continued to move swiftly as our sons' rare 
disease became quite well known in biological research and especially 
among cancer researchers. Because the A-T protein missing in my sons 
was found to interact with a famous tumor suppressor gene called 
``p53'' as well as a gene called BRCA-1 that is associated with breast 
cancer, oncologists around the world became increasingly interested in 
A-T. The A-T protein, known as ``ATM,'' was found to play an important 
cellular role in sensing DNA damage and regulating the copy-and-divide 
cycle of cells that when corrupted, leads to cancer or brain cell 
death.
    Other researchers published new findings that the A-T gene was 
misspelled in the tumors of most patients with a particular form of 
leukemia. And, the chromosomes inside the cells of A-T children were 
also found to have shortened ends (or ``telomeres''), that are known to 
shorten with age, making A-T an intriguing model of premature aging.
    After studying how major medical progress had been made through 
history, I realized that significant medical discoveries often have 
roots in unrelated basic breakthroughs. Therefore, I concentrated on 
surveying every area of science in hopes of finding new approaches and 
brilliant investigators. I worked late into the night, struggling to 
keep up with the science while sending faxes and e-mails in hopes of 
engaging world-class scientists to study my sons' disease. I often 
fantasized about a day when every scientist on the planet would be 
aware of this disease. And gradually, researchers working on cancer, 
neurodegeneration, immune deficiency and aging became involved.
    In 1997, we thought for a moment that we had found a treatment! A 
research team had discovered that in mice engineered to lack the A-T 
protein, a certain type of brain cell was dying that was also known to 
die in people who have Parkinson's disease. When the scientists 
injected a common drug for Parkinson's Disease called ``L-dopa'' into 
the mice, the animals seemed to improve a little. As a result, we 
immediately organized a blinded clinical trial of L-Dopa in A-T kids, 
but the results were disappointing (no significant improvement compared 
with children receiving the placebo). Nevertheless, running our first 
clinical trial helped us realize the important issues in designing drug 
trials for children with A-T (such as establishing reliable, 
quantitative, clinical end-points with which to measure and observe any 
changes in the kids resulting from the drug).
    Children with A-T have an extreme risk of developing cancer, and 
because radiation is lethal to them, treating A-T children for cancer 
is especially challenging. Therefore, in 1999, we established a cancer 
clinic for A-T kids at St. Jude Children's Research Hospital in 
Memphis, Tennessee where pediatric oncologists are now striving to 
develop unique protocols that should improve the management of cancer 
in children with A-T.
    Besides running several scientific meetings each year that were 
attended by M.D.s and Ph.D.s, we also organized and sponsored other 
types of meetings that brought families of A-T children together with 
doctors to learn about managing the symptoms of A-T and coping with the 
exhausting lives they endured. We also published a manual that provided 
a lot of practical information to physicians, parents and therapists 
who took care of children with A-T.
    Recently, much of the research we supported held promise for other 
diseases besides A-T. For example, by this past year, we were funding 
work on cultured neural stem cells that not only held the potential of 
helping to ``reseed'' the brains of A-T kids, but might also help 
patients with Alzheimer's, Parkinson's, ALS, spinal cord injury and 
stroke. We were also funding work aimed at transferring and expressing 
a healthy copy of the A-T gene into the brain cells of A-T children. If 
this virus-based system of gene therapy worked, it could also be 
applied to numerous other neurological disorders.
    We were also supporting trials of new ``super antioxidant'' 
compounds on A-T mice that had been shown to extend the lives of worms 
by 40 percent, and we were working with still other researchers to 
combine gene targeting and nuclear transfer (cloning) techniques to 
make animal models of A-T in monkeys, cows and pigs. We were even 
checking to see if neural auto-antibodies, ion channel defects, 
mitochondrial dysfunction, nuclear inclusions or cytokines were playing 
roles in the disease, and whether growth factors might have therapeutic 
potential.
    In short, we had done our best to ``catch up'' with the efforts of 
the big, well-known disease organizations. And many people therefore 
said that we had made much progress. But we had not succeeded. We had 
still not found a single way to slow the progression of this relentless 
disease for even one day.
    I received various accolades for our work, including invitations to 
serve on advisory councils that directed the National Institutes of 
Health and chances to tell Senate committees how I would improve the 
government's funding of medical research. I was also given the 
opportunity to serve as a board member of the Genetic Alliance--an 
umbrella organization that represents over 300 genetic disease 
organizations. Barbara Walters hosted an hour-long ABC News television 
show in 1996 about our efforts. And this past year, I was given the 
opportunity to become Chief Executive Offcer of a new Silicon Valley-
based biotech company called Perlegen Sciences that recently raised 
$100 million in first-round financing from private investors (this 
career move has allowed me to leave the food industry and to focus all 
facets of my life on scientific research aimed at understanding and 
treating diseases).
    Yet, in spite of these votes of confidence, I am compelled every 
day to realize that until now, I have still failed in finding a 
treatment or cure for children with A-T . . .
    Time has passed quickly, and A-T children like my boys have 
continued deteriorating and dying. My son Jarrett is now twelve years 
old, and Quinn is ten. Time is running out. Both boys now use power 
wheelchairs and rely on full-time aides in school. Their minds are 
unaffected by the disease, but they are trapped inside bodies that are 
letting them down. As they become less able to share activities with 
healthy friends, my wife and I struggle to figure out how we're going 
to help them deal with their social isolation and physical limitations.
    Of course, my fight to cure or treat A-T has now reached far beyond 
merely fighting to save my own two sons. I have visited families of 
hundreds of children who have A-T, some of whom have subsequently lost 
their lives to this disease. My wife and I are no longer alone in this 
fight but now share our mission with other families of A-T children 
around the world who are doing whatever they can to raise money and 
increase awareness. Several of those families are here in this room 
today.
    And, I cannot tell you how thrilled I am today that such a talented 
and admired motion picture actor and Academy Award-winning screenwriter 
has stepped forward to help us in our fight. Today, families like mine 
across America are overwhelmed with joy, realizing that Ben Affleck is 
not merely testifying before you today about A-T but--through his 
friendship with thirteen year-old Joey Kindregan--truly knows what our 
kids face.
              steps you could take to accelerate research
    The question I am most often asked is, ``What do you still need to 
accomplish in order to find a cure or treatment for A-T?'' My answer 
always includes the same four themes: ``translational research,'' 
``physicians willing and able to do clinical research,'' ``new tools 
and technology,'' and ``a more involved NIH.'' Please allow me now to 
explain four steps that you could take to help us in these areas:
Encourage the NIH to support translational research on diseases like A-
        T
    Even though my small organization, the A-T Children's Project, has 
been able to support basic research conducted by academic laboratories 
looking at the biological defect and the role of the A-T gene/protein 
in cells, it has been exceedingly difficult for us to persuade clinical 
researchers to conduct what is referred to as ``translational 
research.''
    Translational research seeks to apply the findings from basic 
research in a clinical setting. This type of research is typically done 
by pharmaceutical companies rather than by academics, and I am sure you 
can imagine how difficult it is for us to persuade drug companies to 
devote resources to a rare disease that represents a miniscule market 
potential. Therefore, we really need the help of the National 
Institutes of Health (NIH) in encouraging this kind of applied research 
on A-T, even though it is a rare disease.
    I know that from time to time, I have heard discussion in your 
hearings about why there is a need for an intramural program at the 
NIH. The best reason I have heard is so that research can be done there 
that cannot be done anywhere else. It would be great if you could 
encourage the NIH's intramural clinical researchers to focus more 
attention on diseases like A-T. We cannot help hoping that the new 
clinical center being built on the NIH campus might undertake some 
clinical research projects involving A-T.
Provide for physicians to do more clinical research
    Everyone who wants to find a treatment for a disease, and 
especially families affected by pediatric neurological diseases, want 
to see more physicians who are able to do clinical research. But over 
the last few years, we have found that the time clinicians have for 
doing clinical research on diseases like A-T at leading medical 
centers--even at teaching hospitals--is quickly shrinking.
    We need your committee to allocate more funds so that excellent 
physicians with the talent to contribute as researchers can do so. Some 
tactics tested by the NIH have already helped, such as repaying medical 
school loans for physicians who agree to go into research, but we need 
you to encourage the development of more solutions to this problem. 
Important strides were recently made on this front through the passage 
of the Clinical Research legislation in the last Congress, but it is 
important that this aspect of our biomedical research infrastructure be 
monitored carefully.
Encourage the development of new tools for ``downstream'' biological 
        research
    The progress in creating new tools to accelerate research has not 
been fast enough for families like mine who watch our kids slip a 
little further from us each day. Keep in mind that researchers found 
the gene that causes A-T over six years ago but there is still not a 
single treatment available. Since then, the progress in understanding 
the function and role of that gene in the human body has been 
substantial but still not adequate. Just as breakthrough technologies 
such as automated DNA sequencers and polymerase chain-reaction (PCR) 
have super-charged the hunts for disease genes, we need new high-
throughput methods and tools for elucidating the protein pathways 
directed by those genes in order to know what to do about the genetic 
defect.
    With your direction, the NIH and other government agencies could 
scale-up their efforts and be more innovative in encouraging scientists 
and engineers with inventive skills to create these technologies, even 
when they have risky ideas for which venture capital funding may not be 
possible or when they have approaches that would benefit only rare 
diseases with limited markets.
Support greater interaction between NIH program directors and the 
        research and disease community
    At each NIH institute, a different program director typically 
oversees each specific area of research. This individual plays a 
critical role in implementing the research priorities and strategic 
plans that are conceived by NIH leaders and Congress. Program directors 
must therefore represent first-rate talent and must be given ample 
support.
    My organization has found that when program directors are more 
aware of the research activities on any particular disease, announced 
requests for proposals are more appropriate, redundant research 
projects are minimized, and fewer scientific opportunities are missed. 
In other words: the NIH's funds are stretched much farther. These 
individuals tend to be extremely dedicated to keeping up on 
developments in their scientific areas, comparing notes with disease 
advocate groups, and providing guidance to investigators preparing 
grant proposals. But they are also spread very thin, and their travel 
budgets to meet with researchers and patients are often restricted.
    More program directors are needed, and their proactive involvement 
in the research community needs to be encouraged. While allocating 
funds to this ``administrative expense'' instead of toward direct 
research grants may at first glance seem wasteful to you, in our 
experience, having highly-qualified program directors with more time 
and resources to keep on top of their areas would be tremendously 
worthwhile. In addition, in order to encourage more translational 
research, we feel it would be valuable for the NIH to take steps to 
recruit more program directors who have clinical experience.
    Mr. Chairman and Members of the Committee, as you can see, none of 
the steps I have suggested requires you to set aside funds specifically 
for my sons' disease. And yet, I am confident that these steps would 
ultimately accelerate research progress on A-T as well as many other 
diseases.
    I would be happy to answer any questions you may have, and I would 
also be eager to work with your staff to develop legislative language 
for insertion in the appropriations bill to cover these areas of 
concern.
    Thank you.

    Senator Harkin. Thank you very much, Mr. Affleck.
    Joe, you have got a good friend there. He says he is going 
to help you get your next belt.
    Mr. Margus, welcome also. I understand you also have a 
couple of children with A-T. Is that right?
    Mr. Margus. Yes. Joe knows them. They are Jarrett and 
Quinn. Quinn is 10 and Jarrett is 12. They also have A-T.
    Senator Harkin. Is Joe's mother here? Do I understand that? 
Hi, mom.
    Ms. Kindregan. I am not allowed to speak.
    Senator Harkin. You are not allowed to speak? You are 
allowed to speak if you would like to speak.
    Mr. Affleck. It was Joe that told her she was not allowed 
to speak.
    Senator Harkin. Well, Joe, where are you from?
    Mr. Kindregan. Springfield, Virginia.
    Senator Harkin. Oh, Springfield, Virginia. Oh, not too far 
from here.
    How did you two meet? At Dulles?
    Mr. Kindregan. Yes.
    Mr. Affleck. Yes. I was shooting ``Forces of Nature'' and 
we were at Dulles and Joe was heckling me.
    Mr. Affleck. I told him to clam up and we almost got in a 
fist fight. It was an awkward thing, but then we made up.
    Remember that?
    Mr. Kindregan. Yes.
    Senator Harkin. So, Joe, you went to the premiere of the 
movie, ``Pearl Harbor''?
    Mr. Kindregan. Yes.
    Senator Harkin. That is pretty exciting. Did you see him in 
``Good Will Hunting'' also?
    Mr. Kindregan. Yes.
    Mr. Affleck. Did your mom let you see that movie? The 143 
swear words in that movie.
    Some of the benefits of being in a wheelchair is mom lets 
you watch the R-rated movies.
    Mr. Kindregan. Some of them.
    Senator Harkin. Well, Joe, we are really proud that you are 
here and proud you brought your friend Ben here. If you had 
anything that you wanted us to know or if you want to say 
anything, by gosh, the floor is yours.
    Mr. Kindregan. No.
    Senator Harkin. Well, okay. Did Ben say it all for you? 
Pretty much.
    Mr. Kindregan. Yes.
    Senator Harkin. Good. Well, we thank you for being here, 
Joe, and I can assure you that these people who are sitting 
down the table from you here, all these scientists and Dr. 
Collins and Dr. Rich and Dr. Needleman and Dr. Murray, I know 
that every day they go to work they think about you and they 
think about the people out there that are going to be helped by 
the research and the investment of time and their lives that 
they have done. This is who they think about. I do not know 
them all. Some of them I know better than others, but I know 
that this is what they are about. I have a great deal of faith 
in their abilities to get the research done and the 
interventions and cures that we need for a lot of these 
illnesses and especially for the one that is affecting you, A-
T.
    I was not aware of it either until you came here today. 
Believe me, I am now aware, and I am going to be asking more 
and more questions of NIH of what they are doing to make sure 
that we get more research into this area.
    But I just turn to all of you, all the scientists who are 
here. When I think of Joe and A-T--I do not know if any of you 
are familiar with A-T. I sure was not, but Dr. Collins is. Tell 
me what we are here for this morning in terms of the human 
genome project and finishing it and moving ahead with it. Tie 
that in with Joe Kindregan. How does that work for Joe?
    Dr. Collins. Well, I will take a try at that. I think Joe's 
situation is emblematic of hundreds of thousands of other folks 
who have disorders that may not make the headlines but which 
are very real every day for them and their families.
    The genome project has, I think, a view that every gene 
matters and therefore every disorder matters. In fact, the 
ability to look at the whole thing is one of the best antidotes 
against that tendency to only focus on common illnesses. When I 
mentioned 50 disease genes had been found in the last couple of 
years, most of those are for relatively rare conditions like A-
T. Wearing my research hat, I was honored to be part of the 
team that found the A-T gene about 5 years ago, and part of the 
team that helped develop this mouse model that Brad Margus 
referred to.
    Yet, now with those powerful tools we are poised to unravel 
at the biochemical level why the single gene that is not 
working in that condition causes the havoc that it does. We 
still have several steps to traverse. That means understanding 
this particular protein. It is a very large, complicated 
protein. What is it normally there for and why, when it is not 
doing its job, does this wide array of problems occur, the 
immune system, the neurologic system, the risk of cancer?
    I would give Mr. Margus a huge amount of credit for the way 
in which his A-T Children's Project has worked very effectively 
with NIH--and over the years Brad and I have grown to be good 
friends--in a very productive, effective partnership to try to 
get the best science applied to this problem. Most of the 
scientists working on A-T today had not heard of it until 
somebody like Brad came along and invited them to a conference.
    So, I think it is fair to say this relatively rare 
condition has now become the focus of a lot of scientific 
interest, and it turns out that while inherited alterations in 
this gene are relatively uncommon and afflict people like Joe, 
that you can acquire a misspelling in this gene during your 
lifetime. That plays a significant role in the risk of things 
like lymphomia and leukemia. Once again, the study of a rare 
condition sheds light on a much broader array of issues, in 
this case cancer, and that in turn draws more people into the 
area of interest.
    But what we really need to understand now is what does this 
protein do, what other proteins does it interact with, and how 
can you compensate for it not working in a certain 
circumstance, like what Joe lives with every day. I think the 
tools to do that that are now marshaled, that attack the 
problem, are profoundly more powerful than they were even 5 
years ago. But complexity is still the norm in human biology, 
and to unravel all that in the direction of an actual cure 
takes a lot of steps, a lot of support, a lot of good science.
    Senator Harkin. But can I tell Joe, sitting here today, 
that there are more people working on unraveling this mystery 
than there was a year ago or 2 years ago?
    Dr. Collins. Absolutely, and I think Brad would agree with 
that. We are getting to the point now where there may be more 
people working on A-T than have the disease, and I think that 
is great.
    Senator Harkin. That is good.
    Mr. Affleck. Correct me if I am wrong. My understanding 
this is a disease which falls under a much, much larger 
umbrella, the set of diseases which all could benefit from stem 
cell research. These cells have been demonstrated, as I am sure 
you know, Senator, when extracted and then reinserted into 
brains and spinal cords of mice, to go to the place in the 
brain that is deteriorating and regrow in the brain and to 
regrow some spinal tissue. So, I think that is very important. 
I think A-T would benefit enormously at least from that 
research.
    And the Federal Government plays an important role in that. 
Being a Democrat, of course, I am a great fan of regulation. 
So, I think it is research that needs to be regulated, and I 
think it is one that needs to be supported by the Federal 
Government. And I admire and appreciate your bipartisan support 
of that.
    Senator Harkin. Thank you very much, Mr. Affleck.
    I am going to turn to Senator Landrieu. When Senator 
Landrieu gets finished, I am going to come back to a question I 
want you to ponder. I want you to tie together stem cell 
research and genomic research for me.
    Senator Landrieu, welcome. Again, Senator Landrieu 
represents a number of highly respected national research 
institutions in her State of Louisiana.
    Senator Landrieu. Thank you, Mr. Chairman. Let me begin by 
thanking you for your focus on this important work. I can see 
from the numbers of people here and from the numbers of people 
who are tuned into this hearing that it is a vitally important 
issue for our Nation. There are many parents and doctors and 
communities and children who are looking very carefully at the 
policies that are laid out here to provide the kind of hope and 
excitement that has been talked about this morning. So, I want 
to thank all of you and thank you, Mr. Chairman, for keeping us 
focused so that we can take the steps every week and every year 
here in Congress whether through policies or appropriations to 
further this important work.
    Joe, I want to thank you so much for being so brave and so 
wonderful to be such a good example to all of us to come here 
to Washington, not the easiest place to get to and not the most 
comfortable place sometimes to testify, but for your braveness, 
being an example to children everywhere and to adults about the 
ways that you can become a great advocate so we can continue to 
do the kind of work that we do. To you, Ben, and to you, Mr. 
Margus, for your stepping out.
    Brad, I was not here for your opening statement. But what 
could we do immediately to help you as you have done so 
successfully to bring this particular disease to the forefront? 
What could we do in Congress to help sort of multiply your 
efforts in a faster, more direct way so that we can really 
build on the great work that Joe has done and that Ben has 
done?
    There are many larger policy issues that this Congress is 
going to grapple with and there will be some controversies 
about these issues of morality and responsibility and 
liability, et cetera. But there are some things that should not 
at all be controversial about the Federal Government stepping 
up to help you and these other ``orphan'' diseases to try to 
expedite the good results. Could you just comment maybe 
briefly? I think the chairman and I would both be interested.
    Mr. Margus. I would love to give you a nice example of 
something that is on our wish list that would not just benefit 
A-T but would benefit a lot of diseases.
    When we first started the A-T Children's Project, my kids 
were diagnosed and there was really nothing going on, to speak 
of, in A-T research. We reached out to do everything that had 
been done for more common diseases. So, we said, why can we not 
get our gene if cystic fibrosis has theirs? Why can we not do 
mouse models or other animal models and other organisms like 
Drosophila and fruit flies? But there were things that were 
already being done for the more common diseases, and we said, 
we deserve to have that for ours. That was kind of my spiel 
with NIH and if I could run into any of you.
    Today a lot of what needed to be done has been done, and a 
lot of the obstacles we run into are the same ones that are for 
more common diseases. I will not dig into all the more 
controversial ones, but the one that is really clear Dr. 
Collins mentioned. We have been really fortunate in that our 
disease gene--the protein that is missing in Joe because the 
gene is misspelled is a protein that plays a real critical role 
in cell biology. It is involved in cancer. The protein actually 
interacts with another protein called P53 that has been found 
to be mutated or misspelled in the majority of all tumors. It 
also interacts with another gene or protein called BRCA-1 that 
is involved with breast cancer. So, it is really this hot, 
popular protein in cell biology, even though most of you have 
never heard of A-T. Because of that, there are a lot of great, 
first-class scientists, basic biologists working on the 
mechanism of the A-T protein and what it is doing.
    The frustrating thing for parents like me and for kids like 
Joe is that even though all this great science is being done 
downstream from finding the gene--we found the gene 6 years 
ago--it is not a treatment. If you look at how long it might 
take to figure out the complete biological pathway of how that 
one gene causes all these symptoms, it could be 20 or 30 years, 
maybe longer.
    If you look at the history of medical discovery and most of 
the drugs that the drug companies are selling, I hate to say 
it, but they do not develop them by this rational approach of 
figuring it all out. Most of them have been chance discoveries 
or discoveries that came about from looking for one thing and 
something else became useful.
    That may all change now because the tools have really 
improved. The human genome project will change that 
tremendously and there are a lot of other technologies coming 
out that should accelerate molecular biology.
    But what we really need is ways to apply it. So, how can we 
get, even before we have all the answers, to something that we 
can treat our kids with? I think one of the real obstacles that 
maybe you can help us with is to get more clinicians, doctors 
involved in research. We have some great scientists working on 
the basic cell biology, but we do not have many doctors who are 
trained neurologists and trained immunologists who are able or 
willing to go into research.
    Part of the reason is what Ben mentioned in his testimony; 
that is, there are a lot of pressures on doctors today with 
managed care and so on. Doctors have less and less time to 
spend doing research. But we really need to find a way to find 
really good physicians who can translate or take the basic 
research and apply it in the clinic.
    If A-T were a disease like it is but kids die a month after 
they were diagnosed, then you would be going nuts doing 
everything you could just applying things just the way they 
treat really aggressive cancers, but because it is kind of over 
time most of the time, scientists tell us, wait till we have 
the answers completely figured out on the biology. And we 
really cannot wait for that. What we need is more physicians 
who are also able to go into research.
    I know that the NIH has done some things recently, repaying 
student loans for med school and things like that, to encourage 
physicians, doctors to go into research.
    Senator Landrieu. Mr. Chairman, could I follow up with one 
question on this? Because I think you and I would be 
particularly interested. Because children cannot wait and 
neither can parents, I would like Dr. Collins or Dr. Murray to 
follow up, adding to that some specific things that we could 
take action on now that has limited or no controversy 
associated with it, that we could expedite the treatment and 
hope for Joe and for his family and for Mr. Margus and his 
family. Is there something that you could add to the testimony 
that could help us to really focus in this budget cycle on what 
could be done along those lines?
    Mr. Margus. You have a really great, huge clinical center 
being built on the NIH campus I noticed. Obviously, there is a 
big push now to do more clinical research. We just hope some of 
that will be done on A-T.
    Senator Landrieu. Anybody for the record?
    Dr. Collins. Well, I think your question is very 
appropriate. Certainly for myself as a physician, I have been 
deeply concerned to watch, over the last 20 years, the number 
of physicians doing clinical research gradually decline. That 
decline got quite precipitous a few years ago, particularly 
because with the advent of managed care, a physician who wanted 
to do clinical research in a medical center out in one of our 
great universities increasingly was under pressure not to do 
the research but to be out there in the clinic or on the ward 
seeing patients and getting reimbursements because all the 
academic centers were struggling so much. This is a big part of 
the dynamic, the way in which our change in reimbursement has 
placed academic centers in a position of basically providing 
disincentives for physicians to do research. And that issue is 
far from resolved.
    NIH has made a number of bold steps I think to try to 
provide some backstopping of those who would like to do this. 
And I think it has, to some degree, turned the tide so that 
that steady decline has begun to reverse, but we are still way 
behind where we need to be.
    Certainly I am the first to agree, genomics is a wonderful 
basic science, but it does not matter a whole lot if it does 
not end up benefiting individuals, people with diseases. That 
translational process requires people who understand the 
practice of medicine, those clinical researchers, and we do not 
have enough of them.
    The loan repayment program may be a way to get rid of one 
of the financial disincentives to people who come out of 
medical school already owing $100,000 or more. Being a clinical 
researcher will not make you rich. You will be driving a 10-
year-old car when your friends out there are getting their 
second Mercedes of the year. It is not the sort of thing that 
somebody without a great deal of personal commitment is going 
to be able to do. Yet, there are ways I think that we could 
make that financial situation a little less onerous and provide 
some encouragement to those who do want to do this, that they 
do not have to be forced into just delivering patient care for 
reimbursement all the time the way their medical centers often 
ask.
    I would be glad to provide some more information for the 
record about the programs that NIH has already put in place and 
some ideas about other things that we could do that are even 
more ambitious.
    Senator Landrieu. That was very helpful and I appreciate 
it.
    [The information follows:]

         Department of Health & Human Services,    
                     National Institutes of Health,
                  National Human Genome Research Institute,
                                      Bethesda, MD, August 7, 2001.
Hon. Tom Harkin,
Chairman, Subcommittee on Labor, Health and Human Services, Education, 
        and Related Agencies, Washington, DC.
    Dear Senator Harkin: It was a pleasure to testify before your 
committee on July 11, 2001. During that hearing Senator Landrieu asked 
about efforts by the National Institutes of Health to promote clinical 
research. Below is a description of some of the activities currently 
underway at the NIH to promote clinical research.
    In 1999, following a detailed analysis by a subcommittee of the 
Advisory Committee to the NIH Director, the NIH launched three clinical 
research programs: the Clinical Research Curriculum Award (K30), the 
Mentored Patient-Oriented Career Development Award (K23) and the Mid-
Career Investigator in Patient-Oriented Research Award (K24). The K30 
program provides support to institutions for the development and 
conduct of didactic courses for clinical investigators to enhance their 
fundamental knowledge in study design, biostatistic, ethical and 
regulatory issues with clinical trials. The NIH has awarded a total of 
55 K30 awards. The K23 program provides didactic training and mentored 
research experience for investigators who are interested in doing 
patient-oriented research. Since their inception, the NIH has funded 
279 K23 awards. The K24 program provides protected research time and 
mentoring opportunities to mid-career investigators by relieving them 
of patient care and administrative responsibilities. The NIH has 
awarded 158 K24 awards since 1999. These programs have been successful 
and continue to attract enthusiastic response from the clinical 
research community.
    The NIH also sponsors a loan repayment plan (LRP) which assist in 
increased participation in clinical research by young scientists. The 
LRPs pay a maximum of $35,000 a year toward participants' outstanding 
eligible educational debts. In return, participants must sign a 
contract agreeing to conduct qualified research activities as NIH 
employees. Participants in the LRP may apply for additional, 1-year 
renewal contracts and continue to receive loan repayment benefits. 
There are four different types of LRPs:
  --The NIH AIDS Research Loan Repayment Program (AIDS-LRP) is designed 
        to attract highly qualified physicians, nurses, and scientists 
        to HIV/AIDS research and research training.
  --The NIH Clinical Research Loan Repayment Program (CR-LRP) is 
        designed to recruit highly qualified physicians, nurses, and 
        scientists from disadvantaged backgrounds to serve as clinical 
        researchers.
  --The NIH General Research Loan Repayment Program (General-LRP) is 
        designed to attract highly qualified physicians, nurses, and 
        scientists to conduct research at the NIH.
  --The NIH General Research Loan Repayment Program for ACGME Fellows 
        (ACGME-LRP) is a pilot initiative of $5,000 per year in loan 
        repayment currently available to fellows employed by the NIH in 
        subspecialty and residency training programs accredited by the 
        Accreditation Council for Graduate Medical Education (ACGME). 
        Qualifying fellows must hold a three year appointment at the 
        NIH beginning July 2000, 2001, or 2002.
    In 2000 Congress passed the Clinical Research Enhancement Act as 
part of the Public Health Improvement Act (H.R. 2498). The legislation 
instructs the director of NIH to expand the agency's role in clinical 
research by awarding grants for the establishment of new General 
Clinical Research Centers (GCRCs), creating new enhancement awards, and 
expanding the NIH loan repayment program for clinical researchers to 
include extramural investigators.
    In addition to these programs, the NIH is currently developing a 
program announcement to provide support to institutions to develop 
degree-granting programs in clinical research. It is anticipated that 
the National Center for Research Resources will take the lead in this 
initiative and launch it in fiscal year 2002. We believe that these new 
programs, along with the existing clinical career development awards, 
e.g., K08, K12, etc, have gone a long way in addressing the need for 
training more qualified physician scientists.
    I hope this gives you an idea of the programs the NIH is working on 
with regard to clinical research. Please let me know if you have any 
further questions.
            Sincerely,
                           Francis S. Collins, M.D., Ph.D.,
                                                          Director.

    Senator Landrieu. Dr. Needleman.
    Dr. Needleman. Senator, it occurs to me--what is the 
distance between getting a drug to a patient and the 
discoveries and what are some of the limitations? So, it is 
really extremely important on the genomic end to understand all 
the multiple implications of the expressed genes. The human 
genome is like the Lewis and Clark trip. It did not tell us 
what the country was. It was the map. We have to figure it out.
    I will go to the back end. Maybe the NIH ought to think 
about the development of genetic or biological markers that 
enable assessment of clinical trials so clinical trials could 
be done in patient populations that are diagnostic and help 
invest the science because the regulatory environment is not 
yet built for genetic markers and biomarkers. You might have to 
do trials now till mortality. So, if you want to change a 
chronic disease that slowly evolves, then I think a wise 
investment, both in industry and in fundamental science, in how 
to use genetic markers to see the progression of the disease 
and the maintenance of its factors and the proofs that are 
necessary to change the regulatory environment, then you could 
truncate years off the process between a great idea, a lead 
molecule, and when it is approved for use. No sacrifice of 
safety. But we need a revolution in genetic and biological 
markers.
    Senator Landrieu. Thank you.
    Dr. Murray. I would like to also follow up on Dr. Collins' 
comments. I do think this question about the clinical research 
is one that you do need to address right now. We are going to 
lose a whole generation of physician scientists soon if we are 
not careful. When I see young faculty coming into our own 
university, it is impossible for them to be both researchers 
and clinicians, the way Dr. Collins and myself and others were 
when we started out 15 or 20 years a go. The financial demands 
now on the clinicians force them to spend 100 percent of their 
time seeing patients, with no opportunity for them to begin 
these kinds of research projects, often that come directly from 
the clinic. Just as Mr. Affleck met Joe here and became 
interested and a friend of his, that is how clinicians get 
interested in problems and then take them into the laboratory. 
If the clinicians, especially beginning ones, do not have the 
time and the resources, the protected time, to do that, they 
will not be able to begin and start these projects that can 
lead to the kinds of successes that we are hearing today. So, I 
think you need to support through things like loan repayment, 
through medical scientist training programs, through the full 
reimbursement of the clinical people working in academic 
centers to allow them opportunities to do this.
    Senator Harkin. I look forward to working with you on this, 
Senator Landrieu, to make sure that we can get those various 
things implemented. This has bedeviled us for a few years now 
and we have not worked our way out of it yet. But we really do. 
The academic health centers have--well, I would not say they 
have been forgotten, but they have been kind of pushed aside in 
a number of ways, and we need to focus more on them and to 
provide the kind of financial support to the academic health 
centers whereby people do not have to see patients day after 
day after day, where they can go back in the lab. But I tell 
you, it is a real problem and we need your best thoughts on how 
to solve it.
    The tax thing, the forgiveness of the loans is one thing. 
The other thing is also to make sure the academic health 
centers get the kind of financial support they need to continue 
this research. That comes right from here, and it has to do 
with priorities and what we are spending our money on in this 
country and things like that. With the budget constraints we 
have right now, it is going to be tough to get that done. But 
it has to be done and we are going to do everything we can on 
this subcommittee to provide those funds.
    I just had one last question. Then we need to wrap it up. 
But I asked, before Senator Landrieu asked her questions, you 
to tie together for me stem cell research and genomic research. 
We have the human genome project. We have done the research. 
You, Francis, talked about how we have got to keep going 
forward on it. Now we have got the whole area of stem cell 
research that hopefully we are going to get a favorable 
decision on here soon. Tie the two together. Where do they 
meet? How do they support one another?
    Dr. Murray. One example that I think of that will really 
bring this together really well. Unfortunately for the rest of 
you, it comes from again Iowa. But 10 days ago, I went to a 
party that was a celebration for a friend of my daughter who is 
a 15-year-old girl who a year ago exactly on Sunday had 
received a kidney transplant. Her family has a very unusual and 
as-yet undefined genetic immunologic disorder. She has an older 
brother with diabetes who would love to have a cure for that. 
She received a kidney transplant a year ago from her father.
    Her father turns out actually to be a pediatric surgeon and 
loves his daughter just as much as mom loves her son and all of 
us love our own children. And he made a tremendous sacrifice 
for her to give her this kidney.
    The genome project holds out the prospect for their 
particular disorder to be identified and studied in the same 
way that A-T is in many of the other disorders that we have 
heard about today. But even once that has happened, we need to 
convert that information into something that is useful for that 
particular family. Certainly stem cell research and related 
projects hold out the prospect of fathers in the future not 
having to give up their own kidneys or organs to their children 
or someone else doing that, but to be able to use those stem 
cells to generate a kidney, an artificial organ on the outside, 
which will now be compatible with that child that she could 
receive herself. And it will be through those kinds of findings 
we can do it.
    Senator Harkin. Very good. Anything else? Does anyone want 
to add anything?
    Mr. Margus. I have a good example you might be interested 
in. We have 18 mice that do not have the gene and therefore 
have the same disease the kids have. We have, obviously, been 
excited that stem cells could reseed the brains of these mice. 
So, if you inject in those stem cells that have not decided 
what kind of cells they are going to become yet and migrate to 
different areas, hopefully they will have an affinity for the 
areas that are damaged and that is where they will go and 
produce growth factors and become wired.
    The problem is it is a very exciting field that everyone 
has hopped on, but it is really an early stage of the field. 
There is not a lot known about what those stem cells really do. 
So, one thing that a lot of stem cell researchers are doing 
right now is they are looking at the genes that are turned on 
or off in the environment inside the brain at different stages 
of life. So, when you stick stem cells in an elderly person who 
has a stroke, they may not do very much, and if you stick those 
stem cells into a baby mouse, these stem cells seem to go to 
the right place. Well, there must be other things turned on in 
there at that stage of life that direct those stem cells.
    So, one of the things a lot of researchers are doing is 
using different technologies to find out which genes are turned 
on and which ones are off so that they can really guide and 
control those stem cells.
    Now, once you have used those technologies to pull out 
genes that are involved at different stages, you have to know 
what those genes are. At that point, you can get on the 
Internet today and probably find that gene in the human genome 
project's data.
    The reason I know this is because I explain it to families, 
not just mine, but my wife, a lot of other families. We are all 
hoping that stem cells may have great promise. But the thing I 
warn them of is that what if it kind of works but not great. If 
it worked perfectly, then, hurray, we have got a home run, and 
we do not care if we know how those stem cells work. But 
chances are it will almost work but not quite, and if you do 
not know exactly what is going on, you cannot tweak it. You 
cannot really perfect it. And the way to know what is going on 
is by knowing those genes that are turned on and off. So, the 
genome project and genetics really does enlighten and elucidate 
what is going on when stem cells are doing their thing.
    Senator Harkin. Thank you very much, Mr. Margus.
    Does anyone else have anything to add?
    Dr. Needleman. You do not know the traffic cops for stem 
cells, so you really have to use genomics and proteins to say 
when am I going to differentiate into a heart cell or a brain 
cell. So, you really need a lot of fundamental discoveries yet. 
It is not just taking a cell and growing it for an organ, but 
we can take control some day of the direction of the cells even 
in the body. So, you really need genomics and fundamental 
studies to understand the traffic cops and when it is on and 
when it off. It is like your red light.
    Dr. Rich. Just one thing, reflecting on what Dr. Collins 
said earlier, is that even though we are probably 99 percent 
similar at our DNA level to other organisms, you can tell that 
that little 1 percent or less than 1 percent is highly 
variable. I am not much like Francis. He has a lot more hair 
than I do for one thing.
    But that means that there is a lot of variation in stem 
cells potentially, and we need to have lots of stem cells to 
track that variation. So, in a sense we need to have the 
variation in the stem cell resource that we do in people to 
help provide this information and decide what is the traffic 
cop and how it works.
    Dr. Collins. Senator, I think this group has described it 
extremely well.
    It always comes as a surprise to those who hear it for the 
first time that we have the same instruction book, the same set 
of DNA in a liver cell or a brain cell or a cell in the islet 
of the pancreas or a cell in the muscle. They all have that 
same instruction book, and one of the most amazing developments 
of the last 3 or 4 years is the recognition of the plasticity 
that seems to exist of how cells can reprogram themselves from 
being a bone marrow cell to a heart muscle cell, as has 
recently been demonstrated, or a variety of other such 
examples.
    That all has to come about because the genome, that set of 
instructions, has the ability to be modulated down different 
pathways, and the understanding of that is critical to our 
medical applications of this really surprising set of new 
biological insights.
    Senator Harkin. Well, thank you all very much. This has 
been terribly enlightening, and it has been great. I compliment 
you all for moving these frontiers of knowledge. This committee 
will do what it can to continue to provide the funding, and 
hopefully we can get the money to do that.
    Mr. Margus, thank you for being here. Mr. Affleck. Joe, do 
you have any last thing you want to say to all these 
scientists?
    Mr. Kindregan. No.
    Senator Harkin. How about I say for it for you? Hurry up.

                         CONCLUSION OF HEARING

    Thank you all very much for being here, that concludes our 
hearing.
    [Whereupon, at 11:15 a.m., Wednesday, July 11, the hearing 
was concluded, and the subcommittee was recessed, to reconvene 
subject to the call of the Chair.]

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