Answer. In FY 1989 the NCNR awarded 25 percent of the approved competing applications, and expects to award 19 percent in FY 1990.

Question. Will this decline impact the Center's ability to carry-out the NCNR's Priority Research Agenda?

Answer. As each Priority Expert Panel completes the work of defining and prioritizing the topics of most urgency and scientific promise within each area, the results will be widely reported to the scientific community, to influence the choice of research plans by investigators. The Center will also issue direct invitations to the field, through program announcements and requests for applications.

However, the intent of the Center is to balance these priority areas with the need to allow the bulk of research proposals to remain investigator. initiated. The priority areas will not be protected as support is reduced. The decline in award rate will reduce the emphasis on priority areas, such as prevention and care of low birthweight infants, just as it will reduce the rest of the competing portfolio.

NATIONAL CENTER FOR HUMAN GENOME RESEARCH

STATEMENT OF DR. JAMES DEWEY WATSON, DIRECTOR

BUDGET REQUEST

Senator HARKIN. Dr. Watson, Director of the National Center for Human Genome Research, you are charged with managing the most aggressive and perhaps most important scientific project ever launched-that is my own view, as you can probably tell from what I have said earlier today.

We look forward to hearing your statement. You are asking next year for $108.03 million, for a modest 81.45-percent increasemodest, in light of the job ahead of you I might add. Please proceed.

Dr. WATSON. Mr. Chairman, with your permission, I will read my short statement. The mission of the newly established National Center for Human Genome Research is to lead the NIH component of the worldwide research effort now popularly called the Human Genome Project.

The goal of this endeavor is to determine the order or the sequence of the subunits of human DNA, the substance that makes up our genes. Doing so will allow us to identify and locate all the genes that comprise the human genome.

Deciphering genetic information encoded within our genes will provide important insights into the molecular roots of health and disease.

With rigorous planning and coordination with the Department of Energy we have now developed a broad and orderly approach to tackling the many and diverse challenges surrounding the genome project.

Briefly, the goals that we have established through fiscal year 1995 are to develop the genetic and physical maps of the human genome, including overlapping clone sets for several chromosomes; improve the cost and efficiency of DNA sequencing methods; map and begin to sequence the genomes of several model organisms; develop computer technology for handling genome data; examine the ethical, legal and social issues raised by the availability of genetic information and develop policy options; train researchers; support innovative technology development; and transfer genome project technology to United States industries for development.

To achieve our goals, genome scientists are finding ways to rapidly isolate, reproduce and analyze long segments of human DNA. Scientists have now used modified yeast chromosomes to isolate and clone human DNA segments spanning a length of 2 million nucleotides, the chemical subunits of DNA.

Finding new genetic markers on all the human chromosomes will streamline research efforts to map the human genome. Several

grantees have played a key role in finding new types that will fill in gaps and allow mapping to be done more easily, perhaps even by automation.

Recently, genome scientists developed a system which used markers called "sequence tag sites" that will help unify the various mapping techniques used today.

We have also made headway in developing methods to speed up sequencing the nucleotides in human DNA by improving current sequencing machines and automating additional steps in the proc

ess.

Foremost among our initiatives is the establishment of multidisciplinary genome research centers. Housing experts in complementary scientific fields, these centers will offer resources and collaboration and technology transfer opportunities to genome researchers in government, academia, and industry. In fiscal year 1990 we expect to fund 3 of these centers. In fiscal year 1991 we hope to raise that number to 9 and plan to fund up to 20 in the next few years.

The ethics working group chaired by Dr. Nancy Wexler of Columbia University has made significant progress in focusing on the social, ethical, and legal issues raised by the availability of genetic information. We have already received a number of ethics grant applications and plan to strengthen that program further. In fiscal year 1991 we hope to begin town meetings around the country to educate and seek public views about this program.

PREPARED STATEMENT

Mr. Chairman, if the short history of the National Center for Human Genome Research is an example, I have every confidence that our future will be productive and promising.

Our budget request for fiscal year 1991 is $108,029,000. I will be happy to answer your questions.

[The statement follows:]

STATEMENT OF DR. JAMES DEWEY WATSON

Mr. Chairman, and members of the subcommittee, it is my pleasure to appear before you today for the first time as director of the newly established National Center for Human Genome Research. Our mission is to lead the NIH component of the worldwide research effort now popularly called "the human genome project." Being before this subcommittee today is particularly significant because the budget for genome research has reached a level from which we can formally launch the 15-year human genome project. The goal of this endeavour is to determine the order, or sequence, of the subunits of human DNA, the substance that makes up our genes. Doing so will allow us to identify and locate all the genes that comprise the human genome. The task is both tremendously important and formidable.

Recognizing the growing role the National Institutes of Health has played in the human genome project, Secretary Sullivan formally established the NIH National Center for Human Genome Research in October of 1989. Before that time, our business was conducted as part of the NIH director's office, where we were called the Office for Human Genome Research.

We have watched the human genome project be transformed from an ambitious idea--some said overly ambitious--into a reality. In the past year, we have developed a broad and orderly approach to tackling the many and diverse challenges surrounding the genome project. Deciphering the genetic information encoded within our DNA will provide an important handbook to explain how we function as healthy human beings. It will also provide us with a new understanding of the genetic components of such widespread illnesses as heart disease, high blood pressure, diabetes, and many, if not all, cancers. As we enter the last decade of this century, we are ready to proceed with a project that will have a profound impact on the biological science of the next century.

Locating individual genes on a chromosome and then analyzing the DNA components that make up these genes is now possible for increasingly complex genomes. The National Institutes of Health has supported much of the basic research that has brought us to this threshold, particularly research emanating from the invention of recombinant DNA technology in the early 1970s. Because of the generous funding provided by the Congress to the National Institutes of Health, the United States is clearly a leader in the science of gene mapping and sequencing.

This past

How will we use this scientific leadership to achieve our goal? August, advisors to the National Institutes of Health and the Department of Energy met to plan our collective mission over the next 5 years of this project. The scientific experiences of our respective agencies dovetail remarkably and bring complementary strengths to the human genome project. After vigorous planning and coordination, our path is now well charted and A Five-Year Plan for the Human Genome Project was issued. Briefly, the goals we have established for fiscal years 1991 through 1995 are: 1) to map in detail the human genome, both genetically and physically; 2) to improve the efficiency of DNA sequencing methods to reduce the cost to an acceptable level; 3) to map and in some cases begin to sequence the genomes of selected model organisms; 4) to develop computer and other information technology for storing and analyzing map sequence data; 5) to identify and examine ahead of time the ethical, legal and social issues raised by the availability of genetic information and develop policy options to address them; 6) to train researchers in the combined areas of scientific expertise needed to map and sequence the human genome and to interpret the resulting information; 7) to support innovative technology development as well as improvements in current technology to meet the needs of the human genome project; and 8) to transfer technology invented as part of the human genome project to U.S. industries for development into useful commodities that will improve the quality of life for Americans and compete favorably in the international marketplace.

As part of the August planning meeting, we evaluated the state of the science of gene mapping and sequencing. We were excited by the rapid progress that has taken place over the past two years. In that time, many promising gains have been made in the technology of mapping and sequencing. Mapping

refers to identifying the location of genetic or physical landmarks on chromosomes. The so-called "physical" map of the human genome uses nucleotides, the chemical subunits of DNA, as its unit of measure. Over the years, many different, and often exclusive, methods have been developed for determining nucleotide distances between recognizable landmarks, such as genes. On the one hand, these diverse methods have allowed scientists to make great strides in fashioning physical maps. On the other, they have made comparing information in maps produced by different methods very difficult, if not impossible. This past summer, four genome scientists proposed a system that promises to be the "Rosetta Stone" for physical maps. This system uses markers called "sequence-tagged sites,' or STSS, that can be incorporated into any mapping technique used today. Scientists working in different laboratories, using different techniques, can now add their results to a common physical map that will be available to and usable by all genome researchers. The properties of STSS will allow scientists to use them to regenerate any desired piece of DNA in their own laboratories--an advantage that will reduce dependence on centrally stored DNA pieces.

Our

During fiscal year 1990 we are developing and refining the STS idea. advisory council has established a joint working group with the DOE to discuss the establishment of a pilot program for converting existing markers to the STS system and for a central computer database for STS information. We hope to begin this program in 1991.

Another hurdle physical mappers have faced is finding ways to isolate and reproduce long segments of human DNA for analysis. Recently, Dr. David Schlessinger, at Washington University in St. Louis, used modified yeast chromosomes to isolate and clone several overlapping segments of human DNA from the X chromosome, In all, these segments spanned a stretch 2 million nucleotides long. This achievement, which has produced the longest continuous region of human DNA ever cloned, greatly advances our efforts to produce a complete physical map because it demonstrates that our 5 year goals for physical mapping are indeed achievable.

Usually, genes located near each other are passed on together in a "linked" way to the next generation. Maps called genetic "linkage" maps, designed to track disease genes from one generation to the next, rely on knowing the location of easily identifiable genetic markers that are routinely passed along with specific disease genes. Finding enough of such markers on all the human chromosomes will streamline our research efforts and help other efforts to isolate and analyze disease genes. NCHGR grantees have played a key role in adding landmarks to the current genetic linkage map. Dr. Helen Donis-Keller of Washington University in St. Louis, has been working to narrow the gaps between markers. Dr. Raymond White, at the University of Utah, is focusing on regions of the map that contain few markers. As part of his project, Dr. White is also developing markers that can be translated usefully to the physical chromosome map.

Several grantees are looking for new types of linkage markers that will allow gaps to be filled and mapping to be done more easily, perhaps even by automation. One example is the "CA repeat,' a new type of marker developed by a number of scientists, including Dr. James Weber at the Marshfield Medical Research Foundation in Wisconsin. The number of CA repeats at a given site in DNA can be used as a genetic marker because it differs from person to person and can be analyzed using the powerful new polymerase chain reaction to trace its inheritance from one generation to the next.

Sequencing all of the 3 billion nucleotides in human DNA is the human genome project's ultimate goal. Recently, the NCHGR supported a major conference at Wolf Trap, Virginia, to bring biologists doing DNA sequencing together with technology experts to discuss the state of the science of sequencing large pieces of DNA. We are encouraged by the consensus of the many top-notch scientists at that first Genome Sequencing Conference: sequencing technology is improving; the automated DNA sequencers are reliable and useful for sequencing large DNA stretches.

However, these are first-generation machines. The time, labor, and expense even these machines now require dictate that significant improvements