QUESTIONS SUBMITTED BY THE SUBCOMMITTEE

HUMAN GENOME RESEARCH CENTERS

Question. Doctor, I understand that the Center funded four human genome research projects in FY 1990, will have nine under way this year, and has requested funding for a total of 11 in 1992. These are large centers by NIH standards with average funding at about $2.9 million apiece. How are you assigning responsibilities to each of these centers to help insure an efficient and coordinated mapping effort?

Answer. As of this date, the NCHGR has funded 6 human genome research centers. We have not assigned responsibilities to each human genome research center. Rather, each human genome research center applicant selected a goal for their project. NCHGR funded those that were considered to be of high scientific merit by the peer review committee and would make significant contributions towards accomplishing the mission of the Human Genome Program. The two goals of the human genome research centers funded so far are chromosomal mapping and technology development. Three centers (Washington University, University of California at San Francisco, and Baylor College of Medicine) have chosen the development of a physical and genetic map of one or more human chromosomes as their goal. The center at the Massachusetts Institute of Technology will develop the physical and genetic map of the mouse. The other two human genome research centers (University of Michigan and University of Utah) have chosen mapping, sequencing, and gene identification technology development as their goals.

Each human genome research center will provide overall coordination of its efforts with other projects with similar goals in order to avoid duplication of effort. Human genome research centers are required to provide outreach to the scientific community in terms of providing data and materials developed within the human genome research center. In practice, it is envisioned that the human genome research centers will accelerate progress in other laboratories by making available the resources developed in the human genome research center and by being responsible for coordination of data on chromosomal regions that are within their mission.

Question. The technology necessary to complete the Human Genome mapping project for $3 billion does not yet exist. In fact with current technology the price could reach $15 billion. To what extent are the centers focused on developing the necessary technology?

Answer. All of the funded human genome research centers are involved in technology development. While much new technology for genetic and physical mapping has been developed over the past few years, it has not been applied on the scale that is required to produce maps of entire human chromosomes. Several centers, for example the Washington University human genome research center, are continuing their efforts to develop improved methods for physical mapping. The University of Michigan human genome research center is concentrating on the development of new mapping technologies that will speed up the isolation of a disease gene once the gene has been mapped. The center at the Massachusetts Institute of Technology (MIT) has been automating the development of new genetic markers for a complete genetic map of the mouse. Both the MIT and Washington University human genome research centers are developing robotics to accommodate the scaled-up throughput that will be needed to develop complete chromosomal maps.

The greatest need for new technology necessary to finish the genome project is in DNA sequencing. The completion of the human DNA sequence will require the development of new technologies to both speed up the rate of sequencing and reduce its cost. Several technology development efforts within the human genome research centers are contributing to this area. At the University of Utah, investigators are exploring capillary gel electrophoresis, a method that could potentially increase the speed of sequencing 24-fold, as well as multiplex sequencing, another high throughput sequencing method. In the Baylor University human genome research center, scientists are using current sequencing technology coupled with new computer programs in an effort to identify genes in regions of DNA believed to contain disease genes. NCHGR

also supports research on sequencing technology through regular research grants and program projects.

SEQUENCING TECHNOLOGY

Question. Dr. Watson, from the Center's inception, the overall goal of this program was to complete the sequencing of 3 billion DNA base pairs within 15 years. However, to do this, we must have available to us technology that will reduce the cost of sequencing from the current $2 to $4 dollar range to approximately $.50 a pair. What is the likelihood for these kinds of

technological breakthroughs occurring any time soon?

Answer. It is difficult at this early stage to predict whether the program will attain the goal of reducing the cost of sequencing to $0.50 per base pair in the first 5 years. We are using a two-faceted strategy to approach this problem. We are supporting completely new technologies, that could dramatically improve efficiency and reduce costs, but may take 5 to 10 years before becoming available commercially. In addition, we support several sequencing projects that have the goal to sequence on a scale much larger than is currently possible by improving and pushing current technology to its limits. It is hoped that the increased efficiencies that result from this approach will reduce the costs of sequencing. These projects are attempting to sequence the genomes of important model organisms, the roundworm (C. elegans) and two bacteria (E. coli and Mycoplasma capricolum) as well as biologically important regions of the human genome (the T-cell receptor region). We expect that using these approaches we will be able to reduce the costs significantly over the next 5 years.

There is also promising new technology supported by NCHGR that I expect will decrease the cost of sequencing in the next 5 years. Using capillary gel electrophoresis, NCHGR-supported scientists have been able to increase the number of base pairs that can be determined in a given period of time about 10-fold. The use of mass spectroscopy to detect DNA during sequencing is also being developed. The advantage to such a scheme is that smaller amounts of DNA could be sequenced. There are also several other novel approaches (e.g., time of flight mass spectroscopy, tunneling electron microscopy) which, if successful, would significantly improve sequencing. However, these technologies may take more than 5 years to become useful.

COST OF MAPPING AND SEQUENCING

Question. Dr. Watson, the Committee has heard different estimates of the cost of sequencing an individual DNA base pair. Sometimes we hear a range of $2 to $4; sometimes it's $3 to $5; and sometimes it's reported to be $5. are the accurate figures for sequencing an individual base pair?

What

Answer. Determining the cost of DNA sequencing has turned out to be much more problematic than anticipated, for a variety of reasons. Most importantly, there has not been agreement among sequencing laboratories as to which cost elements should be included in the determination. NCHGR has therefore begun an effort to systematically calculate such costs and has, as the initial step, established a working definition. For purposes of cost estimation, NCHGR considers DNA sequencing to start with an isolated (cloned) large DNA fragment and end with a completed, verified sequence stored in a computer. The costs for determining this sequence include all expenses for personnel (salaries plus fringe benefits), supplies, equipment (amortized over its useful lifetime), alterations and renovations, other expenses, and indirect costs attributable to the sequencing project. The cost per base pair is this total expense divided by the number of base pairs determined.

At present, an additional complication in cost estimation is that technology development is a significant element in all NCHGR-supported sequencing projects. Since new DNA sequence is actually generated during the technology development work, the technology development component in these projects is very difficult to separate from the sequence generation component. Therefore, current cost estimates include a significant fraction of technology development expenses. As these new technologies mature, the developmental

costs will decrease and the project costs will more nearly reflect sequence production costs.

Having established these definitions, the NCHGR is now working closely with on-going efforts to estimate current costs and how these costs change over time. From the limited number of completed estimates so far, the current cost of sequencing in a laboratory whose major focus is DNA sequencing mixed with technology development, ranges from $2.50 to $4.00 per base pair. Such a broad range in our estimate is due to the differing amounts of technology development that are part of each sequencing effort. The NCHGR has also been able to evaluate a limited amount of cost data from sequencing projects completed 5 to 10 years ago. In 1981, the sequencing of the DNA of a bacterial virus cost about $16.00 (in 1991 dollars) per finished base pair, while in 1984, sequencing the mitochondrial DNA from the toad cost over $8.40 per finished base pair (in 1991 dollars). Thus, although costs have decreased 4 to 6-fold over the past 10 years, we need at least another 5 to 8-fold decrease in the next 5 years to reach $0.50 per base pair.

There are currently several biotechnology companies that offer DNA sequencing as a commercial service. They charge $2.50 to $3.50 per finished base pair for sequencing large contiguous DNA segments. Although the NCHGR has not been able to analyze these costs because of proprietary

considerations, it is assumed that the prices do not include the cost of significant amounts of technology development. Furthermore, these companies do not yet have enough experience with sequencing to know whether these prices will cover the costs in the long run.

COORDINATION WITH DEPARTMENT OF ENERGY

Question. I understand that the Department of Energy's FY 1992 request for its portion of the Human Genome Research Project is approximately $59.0 million, which makes the total Federal effort $169 million. Could you describe DOE's particular research emphasis and how it relates to NIH's research agenda. What mechanics are in place to make sure we have a

coordinated effort?

Answer. The Department of Energy's Human Genome Program emphasizes several areas: development of new methods for the construction of physical maps and for DNA sequence determination; construction of physical maps of human chromosomes; development of computational tools for acquiring, storing, retrieving, and analyzing map and sequence data; training students and postdoctoral scientists; and consideration of the ethical, legal, and social issues related to the use of genomic and genetic information, with a particular emphasis on educational opportunities.

The NIH program is similarly concerned with technology development; physical mapping; improving methods for and reducing the cost of DNA sequencing; informatics; training; and the questions of ethical, legal, and social implications with emphasis on the use of genetic information as it relates to the individual and to standards of medical practice. The missions of the two agencies in these areas are complementary; there is a high degree of interaction and coordination between us, including joint meetings of advisory groups, joint working groups that address issues in areas of common interest, and exchange of information between agency staffs on a frequent and on-going basis. The two agencies jointly developed a research plan for the first 5 years of the genome project, published in 1990.

In addition to the areas of common interest, the NCHGR program is distinguished by its emphasis on several additional aspects of genome research. Considerable emphasis is given to the production of a high resolution human genetic map. Such a map will be an invaluable resource to scientists and physicians investigating the genetic basis of human disease. The NCHGR program also includes the analysis of the genomes of a number of non-human species. Such model systems have repeatedly proven themselves to be invaluable as experimental sources for information that can be used to interpret data and test hypotheses about human biology. Model organisms are also important systems for the development and testing of new technology.

COORDINATION WITH THE EFFORTS OF OTHER NATIONS

Question. Dr. Watson, I understand that Britain, France, Italy, the Netherlands, Japan, as well as the European Community all have human genome efforts underway. While the figures are soft, I understand that perhaps another $60 million of genome research is underway worldwide. What mechanisms are in place to help coordinate this worldwide effort?

Answer. Because information about the human genome will be applicable to the entire human race, countries around the world have shown great interest in participating in the Human Genome Project. The importance, complexity and cost of the effort to map and sequence the human genome make international collaboration and coordination desirable. Human genome programs have been initiated in Japan, the United Kingdom, Italy, France, the Soviet Union and by the Commission of the European Community. Plans for dedicated genome research efforts are also being discussed in Sweden, Canada, Australia, and the People's Republic of China.

Staff from the National Center for Human Genome Research (NCHGR) meet frequently with representatives of these programs to exchange information and collaborate on new scientific initiatives. NCHGR staff attend a variety of international conferences, seminars and meetings to present information about genome research advances. Specifically:

(1) international workshops have been very effective in bringing together researchers from different countries to share information. These workshops also serve as a format to compare data and resolve ambiguities, to evaluate new technologies, to share resources, and to discuss gaps in research knowledge. The human chromosome-specific workshops are a model of collaboration and coordination. The NCHGR initiated these workshops and they are managed primarily by NCHGR staff. Workshops are held in the U.S. and other countries and are supported jointly by the participating countries;

(2) most funding agencies sponsor grantees' meetings in which investigators have an opportunity to discuss their research findings. Representatives from funding agencies in the U.S. and other countries are routinely invited to attend each others' meetings;

(3) the Genome Bulletin Board, a form of electronic communication, and the bimonthly newsletter, Human Genome News, also facilitate interactions between scientists in the U.S. and other countries by disseminating information about new initiatives, research findings and meetings in a timely manner;

(4) public databases for collecting and disseminating information on the human and mouse genomes are another form of international coordination; contributors to the database include primarily investigators from the U.S., the U.K., the European Community, and Japan. The database for the human genome is currently being restructured and is expected to be supported jointly by the U.S. and other countries;

(5) the Human Genome Organization (HUGO) is an international organization of scientists with the mission of assisting in the international coordination of research and training efforts in support of the Human Genome Initiative. It is currently headquartered in the U.K., with regional offices in the U.S. and Japan. HUGO is in the process of developing its infrastructure and acquiring the financial resources to carry out its mission. However, even when HUGO is fully operational, informal collaborations among scientists and funding organizations will continue and will represent a strength in facilitating research progress.

You are absolutely correct in stating that dollar estimates for international genome efforts are "soft." These science budgets, like our own, continue to change due to political decisions, internal scientific decisions, and fluctuations in international exchange rates. Each of the international genome programs have a different definition of "genome research" and salary costs are generally not included in international budgets. All of these

factors complicate an easy comparison of international funding. We estimate that in fiscal years 1990 and 1991, other countries will have invested at least $30 and $60 million respectively in genome research.

ETHICAL, LEGAL AND SOCIAL ISSUES

Question. As genetic research has advanced, there have been many questions raised about the appropriateness of genetic testing and the impact of such information in areas such as insurance coverage and employee discrimination. Last year, the Committee requested the Center to expand its efforts to address special concerns about the ethical and social issues of genome research. Could you briefly describe the NIH-DOE joint plan in this area and how the recommendations will be implemented?

Answer. One of the goals of the NCHGR is to anticipate and address the ethical, legal and social implications of the Human Genome Project through a program of public and professional education, research, and policy development. Three sets of professional and public policy issues have been identified as top priority for the program: (1) protecting the privacy of genetic information, including questions of clinical confidentiality and research data management; (2) insuring the responsible integration of new genetic tests into clinical medical practice, including questions of quality control and professional standards; (3) promoting fairness in the use of genetic information, including questions of insurance and employment screening.

In FY 1990, the NCHGR provided $1.6 million in support of 16 projects pursuing research, policy development and education on these issues. These include a major National Academy of Science/Institute of Medicine study of the policy issues raised by the clinical introduction of new genetic tests, studies of genetic privacy and discrimination, major conferences on the applicability of current law and regulations to employment and insurance issues, and public education initiatives on these issues through public television. In FY 1991, the Center expects to provide approximately 4 percent in support of projects in this area, rising to 5 percent in FY 1992.

The investigators leading these projects will produce their own reports and recommendations concerning the specific issues they are exploring. Meanwhile, in order to coordinate the work and catalyze results, the NCHGR will bring the investigators concerned with high priority issues together on a regular basis to assess progress and ascertain areas of consensus. The reports of these meetings will be analyzed by the NIH-DOE Ethical, Legal, and Social Implications (ELSI) Working Group, and recommendations for policy development by government agencies, legislators, professional groups or industries will be formulated and communicated directly to the relevant audience.

The first meeting of the ELSI Working Group, on September 10-11, 1990, addressed the clinical introduction of new genetic tests, and produced a recommendation for pilot studies to develop professional standards for the delivery of genetic tests for cystic fibrosis. This recommendation has since been adopted by the Director of NIH, and a plan for such studies is being developed. Subsequent workshops are focusing on regulatory and legal approaches to protecting access to and use of genetic information.

Sound public policy on these issues cannot be developed without the underlying knowledge base created by genome research. Without the insights of genome scientists into the real potential of emerging genetic technologies, our ability to accurately anticipate and develop policy on these issues would be seriously curtailed. The best way to approach these problems in a systematic and timely fashion is to combine the scientific research and social policy initiatives, so that each helps inform the other as they advance.

TIMING OF PROJECT

Question. Last year you indicated that we should start counting the fifteen years projected for the overall project. As you are well aware, the