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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

conference funding level for your Center was under your request last year. Are we still on schedule for completing the project in fifteen years?

Answer. As you noted, the 15-year clock began ticking on October 1, 1990, at the start of FY 1991. As we are only 6 months into the first year, it is really very early for me to give a firm answer to your question. The goals that we have set for ourselves are very challenging ones. To meet them, we will have to improve our capabilities for producing genomic maps and generating DNA sequence many-fold compared to what we can do today. I believe that we can do this, and I look at the improvements that have occurred just within the past few years, from before the genome program was even organized and during its very earliest phase, to justify my confidence. I think that with the level of funding that we have currently, and with the projected increases that we hope will be appropriated over the next 2 to 3 years, the likelihood is high that the necessary technological improvements will be developed and utilized within the predicted 15-year timeframe.

ETHICAL, LEGAL AND SOCIAL IMPLICATIONS PROGRAM

Question. Dr. Watson, you have told us that you plan to devote 3 percent of the funding of the National Center for Human Genome Research to study the ethical, legal and social issues arising out of the uses of genetic information. What are the major issues in this area? What progress have you

made?

Answer. Three major sets of questions have been identified by the Program on the Ethical, Legal and Social Implications of Human Genome Research as particularly important to pursue as the genome initiative proceeds.

First, issues involved in the integration of new genetic tests into health care. Human genome research is expected to greatly increase the number of gene-based diagnostic and prognostic tests available to health professionals. The social policy problems involved in integrating those tests effectively into medical practice include developing standards for a number of components of genetic health care. These include standards for: (1) insuring the accuracy and quality control of genetic tests; (2) defining the indications for testing and the design of testing protocols; (3) establishing the professional responsibilities of clinicians who perform tests; (4) protecting the confidentiality of information obtained from testing; (5) controlling access to and use of test results by third parties like health insurers; and (6) providing reimbursement for testing and test-related counseling. To help develop these standards, the NCHGR has commissioned a 2-year study by the National Academy of Sciences/Institute of Medicine, designed to assess and propose professional guidelines for the clinical introduction of new genetic

tests.

The current focus of much of the discussion of these issues is a test for the DNA mutations involved in cystic fibrosis (CF), which now makes widespread testing for CF carrier status conceivable. The professional practices and policies developed with respect to CF carrier testing are expected, to establish important precedents for the development of subsequent tests, like the genetic predictors of breast and colon cancer risk now on the horizon. a result, the Center is developing an initiative to evaluate and establish sound policies before the test for CF carrier status becomes diffused into practice.

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Second, issues involved in educating and counseling individuals about genetic test results. The primary risk that the diffusion of genetic tests poses is the misinterpretation of their findings and the resulting potential for psychological trauma, stigmatization and discrimination against those availing themselves of the tests. This risk broadens as the genetic elements of more health problems are uncovered and gene-based tests for susceptibilities and carrier states are developed.

To protect against these risks, NCHGR is soliciting and supporting projects aimed at improving professional and public understanding of these tests and their implications. For example, the NCHGR is already supporting a 10-part television series, "The Future of Medicine," which will explore the

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clinical impact of genome research for a public audience. In addition, the NCHGR will be involved in over 15 open meetings, in 11 states and the District, devoted to the public discussion of the social implications of genome research during the 1990-91 academic season. Other projects involve studies of genetic risk perceptions, stigmatization and discrimination. conclusions of these studies, and the continuing involvement of those at risk for genetic stigmatization in the program's projects, will help inform the professional deliberations of the medical community, and help give substance to educational projects seeking to improve public understanding.

Third, issues of access to and use of genetic test results by third parties, including insurance providers, researchers and employers. One way to combat the unfair use of genetic information is to protect its privacy. Because genetic information pertains to the most personal aspects of individual's lives-- their health problems and reproductive plans--most wish to ensure its confidentiality. But genetic information almost always has implications for other people's welfare as well: spouses, children and extended family members. The interests of insurers, employers and biomedical researchers can also be affected. As a result, the ethical and legal bases (and limits) of such protections are still unclear. Thus, the program is supporting research projects addressing the legal status of genetic information, the information-sharing practices of biomedical researchers, and the clinical ethical issues involved in maintaining confidentiality within families.

At a January 10-11, 1991 program workshop on these issues, grantees and consultants identified two profitable avenues for the development of public protections against the unfair use of genetic information. First, the recently enacted Americans with Disabilities Act has the potential to prevent the abuse of genetic information in the context of employment. The language and intent of the Act apparently extends its protections to persons at risk for genetic disorders. ELSI researchers are currently developing specific

recommendations to the E.E.O.C. about how best to make these protections against genetic discrimination explicit in the implementation of the Act. Second, the Health Insurance Association of America, which is in the process of establishing its own policies with respect to genetic testing, has invited the NIH to work with them in developing their policy, and an interdisciplinary Insurance Task Force has been established by the program to develop recommendations for industry policy. Meanwhile, ELSI researchers are also working with state governments towards the development of model legislation in this area.

In summary, these activities have allowed the NCHGR to accomplish four important preliminary goals: (1) inaugurating open discussions of ELSI issues by the public, the scholarly community, and policy makers; (2) initiating a program of research on priority areas of concern; (3) facilitating the development of professional and social policy key issues; and (4) fostering public education about genome research and its implications.

COST OF HUMAN GENOME RESEARCH CENTERS

Question. Originally you projected that the average cost of the human genome research centers would be $4 million per year. Your current estimate is $2.9 million. Why has this estimate changed?

Answer. As you know, in the course of peer review, the cost of the research along with its scientific merit is critically evaluated. The initial human genome research center grant applications we received requested budgets averaging $4 million. As a result of very stringent peer review, the recommended budgets were reduced and we now estimate about $2.9 million per human genome research center in FY 1991 dollars. The resulting human genome research centers are of outstanding quality and operate on very lean budgets. It should be understood, however, that even the awarded levels are only current best estimates of the cost of large-scale mapping, since mapping on this scale has not been attempted before now.

I would also like to anticipate another issue related to the cost of an average human genome research center. We expect to initiate a program of

developmental grants (P20) to provide support for institutions where investigators would like to establish a human genome research center or program project, but must establish a track record in genome research, develop interdisciplinary collaborations, or generate additional preliminary data and/or resources before submitting an application. These grants will be limited in size to $750,000 total cost and will be funded according to NIH budget protocol through the center budget line. Each developmental grant will be counted as an entity within the center budget, which will greatly reduce the average cost of each entity. In the future it will be necessary for us to differentiate between human genome research centers and human genome developmental grants for purposes of discussing average cost as well as overall progress of the center program.

MAPPING CHROMOSOMES

How many

Question. I know there are 24 chromosomes in the human genome. of these chromosomes have you started to map? What plans do you have for those chromosomes that you have not started mapping?

Answer. In terms of genetic or linkage mapping, the NCHGR has started to develop "framework linkage maps" for all of the human chromosomes. Framework linkage maps, which are composed of only the most informative markers, are designed to be an important first step towards the final goal of "high resolution" maps and, at the same time, to be an early product of the Human Genome Project for use by the larger scientific community. With respect to high resolution linkage maps, those for chromosomes 1, 4, 5, 7, 10, 16, 17, 21, 22, and X, are currently being developed, representing about half the chromosomes.

With respect to physical maps, major projects designed to produce maps of the entire chromosome have been initiated in the NCHGR Human Genome Program Centers for five chromosomes chromosomes 4, 7, 11, 17, and X. Smaller scale physical mapping projects have begun for seven others chromosomes 3, 5, 9, 18, 21, 22, and Y. If successful, many of these latter can be expected to grow and/or stimulate larger projects that address the entire chromosome. Together with the three chromosomes (16, 19, and 21) being tackled at the DOE Genome Centers, we have already begun to map 14 of the 23 human chromosomes.

We do not anticipate problems in finding research groups interested in mapping the remaining chromosomes. We have grants pending award or have had inquiries and/or applications about mapping most of the remaining chromosomes. However, to further stimulate interest and to attract outstanding investigators into the genome field, we are preparing to initiate a program of developmental grants that will support planning and feasibility studies toward the development of the interdisciplinary research programs required to improve mapping technology and produce the high quality maps, which are two of the 5year goals of the Human Genome Project.

MAJOR ACCOMPLISHMENTS OF THE NCHGR

Question. What do you consider to be your major accomplishments in the first year of the National Center for Human Genome Research?

Answer. As you can imagine, there has been an enormous amount of activity during our first year and I believe we have accomplished a great deal. Administratively, we have successfully organized and staffed the National Center for Human Genome Research. I am particularly pleased that we have rapidly and successfully initiated two NCHGR programs that I believe are crucial to the success of our mission, the Human Genome Research Centers program and the Ethical, Legal, and Social Implications (ELSI) program. have also recruited outstanding individuals to serve on the newly chartered Genome Research Review Committee study section and the National Advisory Council for Human Genome Research that will be responsible for the review of grant applications assigned to the NCHGR.

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Scientifically, the most important developments have been in the area of physical mapping. The 5-year physical mapping goal is to "generate sets of overlapping cloned DNA that are continuous over lengths of 2 million base

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