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Mr. Chairman and Members of the Committee:
Thank you for the opportunity to appear before you. I welcome the chance to
share with you my thoughts about the opportunities in biomedical research made
possible by the success of the human genome project, and the role that NIH might
play in bringing these opportunities to fruition. Congress led in the initiation
of the project at a time when many scientists were skeptical, and generous
support by Congress throughout the project was essential. Congress will continue
to play a major role in determining the next steps.
I will begin by providing you with some brief background about myself and my
role in the Human Genome Project. I'll then describe how the genome project
worked from a grantee's perspective. Finally I'll describe where we are today
and some of the opportunities that lie ahead for NIH and biomedical research.
BACKGROUND
I am currently Professor and William Gates III Chair of the Department of
Genome Sciences at the University of Washington. But until December of last year
I was the director of the Genome Sequencing Center at Washington University in
St. Louis, where I experienced first hand the emergence of this project. I saw
it grow from the ideas of a few visionary scientists to the recent completion of
the human sequence under the skillful leadership of Dr. Collins, Dr. Patrinos
and others. Over a dozen years, the St. Louis Center grew from a team of just
half a dozen staff producing about 10,000 bases of DNA sequence a day to a staff
of over 150 producing more than 50 million bases of DNA sequence daily. The St.
Louis Center was one of the three large NIH-sponsored centers in the human
genome project and produced more than 20% of both the draft and finished human
sequence. It also played leadership roles in the completion of the genomes from
the baker's yeast, Saccharomyces cerevisiae, the round worm, Caenorhabditis
elegans, and the mustard weed Arabidopsis thaliana. Today its efforts are
directed at completing the mouse genome sequence, as well as producing draft
sequences of both the chimpanzee and chicken genomes.
ORGANIZATION AND FUNDING OF THE HUMAN GENOME PROJECT AND THE GENOME
SEQUENCING CENTER
The Genome Sequencing Center received most of its funding from the NIH
through what is now the NHGRI. But at critical junctures it has also received
funding from Merck and two different consortia of pharmaceutical companies, as
well as NSF. In 1990 we were one of several laboratories funded to begin the
effort of adapting and improving sequencing methods to the task of sequencing
whole genomes. This was an exploratory period, in which the NHGRI set clearly
defined overall goals and invited proposals from scientists with their many
different ideas about how to realize these goals. James Watson, the first head
of the NHGRI, played a critical role in fashioning this as an exciting project
that would draw in the top scientists of the day. Many groups responded, and the
proposals were rigorously evaluated, following the tradition of
investigator-initiated, peer-reviewed research that has made US NIH-sponsored
biomedical research the envy of the world.
Out of that process came several pilot projects exploring a variety of ways
to sequence DNA at an ever-increasing scale. Some worked while others didn't,
and as these grants came up for renewal, winnowing occurred, through rigorous
evaluation of results -- and costs -- by panels of peers. By 1997, the community
coalesced around the most effective DNA sequencing technology and reached a
broad consensus that the technology was now up to the task of sequencing the
human genome. While peer review of proposals continued to be the means of
evaluating applications, collaborative discussions among all players - both NIH
staff and scientists in the labs - became the instrument for establishing
direction and policy in the project as a whole.
As the major partner in the international public project, which included some
20 laboratories from 6 countries, the NHGRI and Dr. Collins in particular played
a central role in coordinating the effort. Through weekly conference calls,
quarterly meetings and many emails, Dr. Collins and his staff kept the group
focused on the task at hand and at the same time never lost sight of the long
term goal of complete, highly accurate human sequence.
Of the various decisions made by the group, perhaps none was more important
than the decision at one of the first gatherings of the international human
sequencing community to release all the sequence data immediately upon
generation for all the world to use without constraint. No patents would be
filed. The sequence was held to be of fundamental importance, like the atoms of
the periodic table, and all recognized the many steps between discovery of a
sequence and its application to improving human health. This decision gained the
confidence of the wider scientific community, but more importantly it meant that
the sequence stimulated research in labs both public and private throughout the
world from the day the project was begun.
ACCOMPLISHMENTS AND OPPORTUNITIES
The patience and persistence of Dr. Collins and his staff have paid off.
After the joint announcement with our colleagues from Celera Genomics of the
draft sequence in June 2000, the public scientists continued to refine the
sequence. As a result, we have before us today the effectively complete sequence
of a reference human genome. About 99% of the sequence is represented. We have
closed more than 99.5% of the gaps that existed in the draft sequence. The error
rate has been pushed to below 1 per 100,000 bases. This highly accurate,
complete sequence speeds the work of researchers trying to find the genes behind
genetic diseases. It enhances the ability of computational biologists to
interpret the sequence. And most importantly it provides a solid foundation for
scientists to build upon.
But of course the sequence is a beginning, not an end in itself. While we
know that the genome contains all the genetic instructions handed down in the
form of DNA from one generation to the next, we can only read those instructions
poorly. It is likely to take decades to understand this instruction set
thoroughly, but the effort will be worth it. As we unravel the complexity and as
we learn what happens when some part of the code is disrupted by mutation, we
will uncover opportunities for improving human health and well-being.
The plans for the future developed over the past year by the NHGRI and DOE
and described by my colleagues Dr. Collins and Dr. Patrinos in their testimony
outline some of the important next steps. The HapMap that Dr. Collins described
begins to explore human diversity. And the Centers of Excellence in Genome
Science program that NHGRI began in 2001 seeks to foster innovative approaches
toward understanding and integrating genomic information. The University of
Washington was the recipient of two of the first three awards.
One important ongoing activity I'd like to highlight is the sequencing of
additional genomes. We have learned an enormous amount by comparing the
sequences of the mouse and human. We are reading evolution's notebook, the
results of 75 million years of mutation and selection. The functional parts of
the genome begin to stand out in these comparisons and to tell us important
things about how the human genome came to be and how it works. Additional
sequences from animals like the cow, dog, pig and chimpanzee will yield still
more insights into our genome, while at the same time bringing the power of
genomic approaches to the study of these important animals.
But the impact of the genome sequence extends beyond the purview of the NHGRI
and even that of the whole NIH. Virtually all areas of biomedical research, in
both the public and private sectors, are deeply affected by its availability.
Opportunities abound. The doubling of the NIH budget came at an essential time,
as researchers scramble to exploit this new knowledge. The broad approach
advocated in the NHGRI plan and likely to be reflected in any road map for the
NIH will ensure steady progress in our understanding of disease and in
developing novel therapies.
But in addition to these initiatives, the NIH should continue to search for
new goals analogous to the Human Genome Project of 15 years ago, goals that
catch the imagination, that are of obvious relevance to medicine and that focus
research for years to come. One example would be the sequencing of a large
cohort of carefully characterized individual humans. We would uncover our
evolutionary roots and begin to understand at a profound level how sequence
variation leads to variation in the population, variation in susceptibility to
disease and variation in many different traits. A project such as this would
push science and society closer to the goal of using the genome for the benefit
of all.
The Human Genome Project required significant adaptations in the time-tested
procedures of the NIH. But the NIH responded by taking on this big, novel
effort, initially defining the goals and later assuming the oversight role
needed to bring the project to fruition. The peer-review system served us well
throughout, allowing many avenues to be explored and providing time for the
successful technologies to mature. Building on its success the NIH is well
positioned to take on this next complex stage of translating this knowledge for
practical benefit.
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