in DNA sequencing methods are still required before we can completely sequence human DNA. Dr. Leroy Hood, at the California Institute of Technology, for example, has used machines to sequence a stretch of human DNA 70,000 nucleotides long, in about 7 months. With continued improvements in these machines, in the associated computer programs and in automation of other steps in the sequencing process, Dr. Hood expects to increase the capability of automated sequencing to about 50,000 nucleotides per week. We are also supporting research and development of entirely new approaches to sequencing, realizing that the best technology for this job may not yet have been invented. To assure that mapping and sequencing technology development moves as rapidly as possible, we plan to continue sponsoring a variety of conferences and workshops. The next sequencing conference, for example, is set for the end of this year in South Carolina. Mapping and sequencing the human genome demands the coordinated, laborintensive efforts of specialists in a variety of scientific fields. Foremost among our initiatives is the establishment of multidisciplinary genome research centers. Housing experts in genetics, molecular biology, as well as in computer science and even physics, these centers will serve as the centerpiece of the genome project and will offer resources and collaboration and technology transfer opportunities to all genome researchers. In fiscal year 1990, we expect to fund three of these centers. and plan to fund up to 20 in the next few years. In 1991, we hope to fund 9 While the knowledge gained from genome information will undoubtedly lead to many health benefits, we recognize the many concerns that possession of such information may pose. The joint NIH-DOE ethics working group, chaired by Dr. Nancy Wexler at Columbia University, has made significant progress in focusing our program on the social, ethical, and legal issues raised by the availability of genetic information. About 3 percent of the NCHGR budget will go toward this research. We have already received a number of grant applications to study these very important issues, and hope to fund many more grants in fiscal year 1991. In 1991, we also plan to begin "town meetings" around the country to educate the public about this program and to seek their input on these matters. Mr. Chairman, I have been enthusiastic about the human genome project from the time the idea was born. But I could not have predicted then that it would take such positive shape as quickly as it has in these past 2 years. If our short history is an example, I have every confidence that our future will be productive and promising. The budget request for the National Center for Human Genome Research for fiscal year 1991 is $108,029,000. I will be happy to answer your questions. 1950-51 1951-52 1953-55 1955-56 1958-61 1961-76 Research at the University of Copenhagen with Research at Cambridge University in the Cavendish Laboratory Research at Cambridge University in the Cavendish Laboratory Director of the Cold Spring Harbor Laboratory 1988-89 Awards: Honorary Degrees: Associate Director for Human Genome Research, NIH The John Collins Warren Prize of the Massachusetts General Eli Lilly Award in Biochemistry, 1960 Albert Lasker Prize (awarded by the American Public Health Research Corporation Prize (with F.H.C. Crick), 1962 M.H.F. Wilkins), 1962 John J. Carty Gold Medal of the National Academy of The Presidential Medal of Freedom, 1977 D.Sc., University of Chicago, 1961 D.Sc., Indiana University, 1963 L.L.D., Notre Dame University, 1965 D.Sc., Long Island University (C.W. Post), 1970 D.Sc., Albert Einstein College of Medicine, 1974 D. Sc., Hofstra University, 1976 D.Sc., Clarkson College, 1981 D.Sc., State Univ. of New York, Farmingdale 1983 Professional Affiliations: American Society of Biological Chemists Honorary Affiliations: American Academy of Arts and Sciences (1958) National Academy of Sciences (1962) Danish Academy of Arts and Sciences (1963) Honorary Fellow, Clare College, Cambridge University (1968) Atheneum (London) (1980) Royal Society (London) (1981) QUESTIONS SUBMITTED BY THE SUBCOMMITTEE Senator HARKIN. Dr. Watson, thank you very much. I followed that with interest. I appreciate that. I will have some more questions in a second here. [The following questions were not asked at the hearing, but were submitted to the Center for response subsequent to the hearing:] Question. QUESTIONS SUBMITTED BY THE SUBCOMMITTEE COORDINATION OF FEDERAL EFFORTS Dr. Watson, of course you know the Department of Energy also has a human genome effort underway. Could you describe, for the Committee, the mechanisms in place to ensure that the NIH and the Department of Energy efforts are well coordinated? Answer. The NIH and the DOE have had an excellent working relationship with respect to the Human Genome Project in the past and we expect that this relationship will become even better as the program develops. The basic mechanisms for coordination of human genome activities between the two agencies are specified in a 1988 Memorandum of Understanding. As called for in this document, a joint advisory subcommittee was established to monitor and coordinate programs. The membership of this joint subcommittee comprises members of the NIH Program Advisory Committee on the Human Genome and the DOE Health and Environmental Research Advisory Committee. Additional joint working groups have been established to address a number of programmatic issues. These include a joint informatics working group, a joint ethics working group, and a joint mapping working group. This approach has worked successfully to date in helping the agencies coordinate their development of program plans and policies and we expect that additional joint working groups will be established as needed. In August 1989, a group of NIH and DOE advisors and staff met, together with selected other experts, to jointly develop a 5 year plan for the Human Genome Project. Because of the success with which we regard the joint planning exercise and the need for frequent updates of the plan in light of the rapid advances occurring in the area of genomic research, the two agencies will repeat this process at regular intervals. This will help to ensure continued close coordination. Finally, there is extensive formal and informal contact between the two agencies at the staff level. Question. Also, what mechanism do you have in place in insure that the projects funded by NIH will not duplicate each other and cover the same sections of the sequence. Answer. All applications to the NCHGR for support of genome-related research are peer reviewed for technical merit by an initial review group. They are also individually considered for program relevance by a National Advisory Council. The Council makes recommendations to the NCHGR staff with respect to program balance, opportunities for new advances, and other factors. Information on currently supported projects is provided to reviewers, so that they can take this into account. GOALS OF THE HUMAN GENOME PROJECT Question. I understand that there is a 15-year target for having the basic map and sequence finished. Of course with approximately 100,000 genes and 3 billion sub-units which make up those genes, this is an enormous task. How optimistic are you that we will be able to meet the 15-year time table? Answer. I am quite optimistic that we will be able to do so. The way in which interest in the project has increased within the scientific community over the past 2 to 3 years and the rate at which scientific advances have been made during this time has only increased my conviction that the goals that we have set for ourselves can be met. Of course, it is also true that this is still an ambitious task. Further scientific progress and new technology will be needed to meet these goals. If we had to rely completely on the techniques and strategies available to us today, it is unlikely that we would finish the job in 15 years. That is why the strategy we have outlined in the 5-year plan emphasizes the development of new technology for both mapping and sequencing during the initial phases of the project. I would also like to emphasize that we will not have to wait for 15 years to reap benefits from this program. Certainly, the technological advances that will be forthcoming in the next few years will have immediate applications in other areas of biomedical research, such as the identification and analysis of genes associated with diseases. However, what does not seem to be widely appreciated is that map construction and sequence accumulation are incremental processes. Each time a new marker is added to the map or a new region of a genome is sequenced, the maps and sequences become more useful tools. Thus, I believe that we will be able to point to successes of this program starting in the very near future and continuing for the next 15 years and beyond. FUNDING PLAN Question. When the original consensus conference completed its work and recommended the establishment of the Human Genome project, it was recommended that your budget would build and be maintained at a $200 million level over a 3 to 5 year period. Is this still what you consider to be a reasonable funding scenario for this project? Answer. Yes. I believe that it is important for the budget for the Human Genome Project to reach the $200 million level rapidly. This level, in constant dollars, should allow us to achieve our outlined goals in about 15 years. ROLE OF THE HUMAN GENOME RESEARCH CENTERS Question. You have stated that you see the Human Genome Centers as being the center piece of the genome program. Specifically what role do you imagine these centers playing in the community beyond being centers of research? Answer. Each genome center will have a specific research goal related to one of the major goals of the human genome program, as identified in our national plan. This will naturally lead to each center becoming the focus for collaboration with other scientists working on related research efforts. All of the centers will be expected to have an outreach component through which they will facilitate the distribution of resources and information from the center to the rest of the interested scientific and industrial community. In addition, the centers are expected to serve as a means of coordination for information and resources for the field. TECHNOLOGICAL BREAKTHROUGHS Question. What are the technological breakthroughs of the past year and what further developments are needed for the program to be on track 5 years from now? Answer. In mapping, our 5 year goal is the creation of physical maps covering continuous stretches of DNA of between one to two million base pairs in size. Until recently, the length of continuous DNA that could readily be mapped was about one-tenth of that size. In the past year, work in the laboratory of Dr. David Schlessinger at the Washington University in St. Louis has led to maps of continuous regions of the human X chromosome of the desired size, thus demonstrating that our 5 year mapping goals are achievable. In the sequencing field, important advances have also been made in the past year. The existing automated sequencers have now been perfected so that a number of laboratories report that they can produce 8,000 base pairs of raw sequence per day. With improvements in the capacity of the machines and their software, it is expected that this rate can be increased several fold in the near future. There is also promising research under way on projects that are novel, such as separation of bases by capillary gel electrophoresis and detection by mass spectroscopy. The results of this research will not be available for a few more years, but it is possible that one of these methods will be superior to the current machines. REASSESSING THE 1 CM MAP GOAL Question. Recent reports in the press have indicated that the program has already backed off from its initial goal of accomplishing a 1 centimorgan map in the next 5 years. Is this the case, and if so what is the new plan and will it mean the project will not be finished in the projected 15 years? Answer. The human genome program has not changed its genetic mapping goal in any substantive way. All along, the genetic map has been seen as playing a dual role in the Human Genome Project. The first is as a tool for the identification and location of genes that can only be recognized by their effects, such as those that are associated with certain diseases. For this purpose, a three to five centimorgan map is generally considered to be of sufficient resolution. The second is as a tool to help assemble the physical Two years ago, a one centimorgan map was considered to be important to help order physically mapped units. Recently, however, physical mapping techniques have improved and it is now believed a two centimorgan genetic map may be adequate for physical mapping. map. This refinement in the goal was based on the assessment of recent technical improvements in mapping. In the same way, we intend to frequently reassess and update the goals of the program in the light of technological improvements in order to keep the cost of the effort as low as possible. It would be a mistake to consider each redefinition of the goals as a failure of the program or a delay in finishing it. THE NEED FOR MAPPING AND SEQUENCING MODEL ORGANISMS Question. The mapping and sequencing of several model organisms is included in the goals of the NIH genome program. Why do you believe that the study of such model systems is needed to accomplish this project in humans? Answer. The study of model organisms has been an integral part of the NIH research program for many years. The use of model organisms has allowed us to gain important insights into human biology by providing systems that can be easily manipulated experimentally and compared to the human, as well as by providing a test bed for methods and techniques that are later applied to the study of humans. A In the Human Genome Project, the mouse will be a particularly valuable model because the genetic crosses that are needed for detailed mapping, but which cannot be done with humans, can readily be accomplished in the mouse. number of studies have already shown that there is considerable conservation of gene sequence and gene clustering between mouse and man. Therefore the mouse map will be used to help scientists predict what human genes map together and to predict the function of newly identified human genes. In other model systems, such as bacteria, yeast, worm, and fruit fly, where the genomes are much smaller and more easily analyzed, scientists will not only gain knowledge about the function of individual genes and the structure of the genome of an important microorganism but will also test strategies they will need to use for mapping and sequencing the human genome. THE NEED FOR A MULTIDISCIPLINARY APPROACH Question. Achieving the goals of the genome project will require input from many different scientific disciplines. How does the program intend to address the need for a multidisciplinary approach? Answer. There are two ways in which the multidisciplinary research needs of this program will be met. The first is through the Human Genome Research Centers, where a group of 5 to 15 scientists from a variety of research fields will work together to address a major research goal of the program. The second method will be the training program which will emphasize multidisciplinary training, both at the predoctoral and postdoctoral levels. |