National Advisory Council for Human Genome Research
Summary of Meeting

Silver Spring, Md.

May 17-18, 1999

The open session of the National Advisory Council for Human Genome Research (NACHGR) was convened for its twenty-sixth meeting at 8:30 a.m. on May 17, 1999 at the Holiday Inn, 8777 Georgia Avenue, Silver Spring, Md. in the Lincoln Room. Dr. Francis Collins, director of the National Human Genome Research Institute (NHGRI) the meeting to order.

The meeting was open to the public from 8:30 a.m. until 1:00 p.m. on May 17. In accordance with the provisions of Public Law 92-463, the meeting was closed to the public from 1:00 p.m. on May 17 until adjournment on May 18 for the review, discussion and evaluation of grant applications. Dr. Jeffrey Trent, NHGRI Division of Intramural Research (DIR) scientific director, gave an update on activities within the DIR during the closed session.

Council members present:

Allen Buchanan
Wylie Burke*
Aravinda Chakravarti*
David R. Cox
H. Robert Horvitz
Raju Kucherlapati
Jeanne Lawrence
Richard Mathies
Joseph Nadeau
Maynard Olson
Colleen Scanlon
Alan R. Williamson
Barbara Wold

Ex officio members:

Joel N. Buxbaum
William M. Nelson

Ad hoc members:

Kim J. Nickerson

Council members absent:

Troy Duster
Robert Waterston

*Via teleconferencing

Staff from the National Human Genome Research:

Jane Ades, OPC
Carol Almeida, OAM
Joy Boyer, DER
Lisa Brooks, DER
Erin Burgess, OAM
Jean Cahill, DER
Monika Christman, DER
Francis Collins, OD
Elise Feingold, DER
Adam Felsenfeld, DER
Barbara Fuller, OPC
Bettie Graham, DER
Alan Guttmacher, OD
Mark Guyer, DER
Karen Hajos, OD
Craig Higgins, OPC
Kathy Hudson, OPC
Linda Jacobson, OAM
Elke Jordan, OD
Charles E. Leasure, OD
Emily Linde, DER
Jane Peterson, DER
Rudy Pozzatti, OSR
Charmaine Royal, DIR
Jeffery Schloss, DER
Elizabeth Thomson, DER
Benjamin Wilfond, DIR
Emma Williams, OAM
Sally York, DER

Others present for all or a portion of the meeting:

Gene Belt OFM/OD
Cheryl Corsaro, CSR
Rosalie Goldberg, National Society of Genetic Counselors
Kurt Hirschhorn, American College of Medical Genetics
Arthur Holden, The SNP Consortium Ltd.
Rachel Hunt, Analytical Sciences Inc.
Maureen Johnson, NCI
Elliot Marshall, Science Magazine
Susan Mattson, OBSSR/NIH
Usha McFarling, Knight Ridder
Michael Morgan, Wellcome Trust
Pamela Moore, Capitol Publications
Ari Patrinos, DOE
James Shreeve, National Geographic
Kelly VanKoughnet, OSP/NIH
David Wang, Bristol-Myers Squibb
Ron Worton, American Society of Human Genetics

INTRODUCTION OF AD HOC COUNCIL MEMBER

Dr. Jordan introduced ad hoc Council Member Dr. Kim J Nickerson, program officer with the Minority Fellowship Program of the American Psychological Association.

INTRODUCTION OF LIAISONS AND NEW EMPLOYEES

Dr. Jordan also welcomed the liaisons to the council from the professional societies: Dr. Kurt Hirschhorn, representing the American College of Medical Genetics, and Ms. Rosalie Goldberg, representing the National Society of Genetic Counselors. She also introduced Dr. Ronald Worton, of the Ottawa General Hospital Research Institute, who will represent the American Society of Human Genetics.

Dr. Alan Guttmacher was introduced to the council as the new senior advisor to the director for clinical affairs. His official start date will be June 14, 1999.

APPROVAL OF MINUTES

The minutes from the February 21 and 22, 1999 NACHGR meeting were approved as submitted, with a note that Dr. David Cox was incorrectly listed as being present.

FUTURE MEETING DATES

The following dates were proposed for future meetings: September 13-14, 1999; February 28-29, 2000; May 22-23, 2000; September 11-12, 2000; February 12-13, 2001; May 21-22, 2001; and September 17-18, 2001.

DIRECTOR'S REPORT

General Announcements

Dr. Collins reiterated that Dr. Alan Guttmacher would be joining the Office of the Director as senior advisor to the director for clinical affairs. In this position Dr. Guttmacher will provide advice and guidance on clinical issues, the NHGRI outreach program that targets health professionals, clinical genetics issues having ethical, legal and social implications (ELSI), and serve as a liaison to other NIH and DHHS components. Currently, Dr. Collins is the only physician in the NHGRI Office of the Director and he must spend a significant amount of time dealing with clinical issues and responding to Congress regarding potential misuse of genetics research findings. A search committee chaired by Dr. Robert Nussbaum conducted a nationwide search to identify a candidate who could assist Dr. Collins in these activities. Dr. Guttmacher emerged as a leading candidate. He is an Associate Professor of Pediatrics and Medicine at the University of Vermont College of Medicine. In addition, as director of the Vermont Human Genetics Initiative and director of the Vermont Regional Genetics Center and Pregnancy Risk Information Service, he has been involved in efforts to educate primary care physicians regarding genetic issues, and to determine the potential for misuse of genetic information in health and life insurance underwriting. He also served as associate cirector for clinical genetics in the Familial Cancer Program of the Vermont Cancer Center.

Dr. Collins announced that Dr. Michael Blaese has retired as chief of the Clinical Gene Therapy Branch to become chief scientific officer and president of the Molecular Pharamaceuticals Division of Kimeragen Inc. in Newtown, PA. Dr. Blaese first came to NIH in 1966 and during his distinguished career engaged in pioneer research on gene therapy. A special tribute was held for him in the Masur Auditorium at NIH on April 15, 1999. A search is currently being conducted to recruit a new chief of the Clinical Gene Therapy Branch.

Dr. Leonid Kruglyak, an NHGRI K01 grantee, was one of 10 individuals to receive the McDonnell Award for "Geniuses of the 21st Century" worth $1 million. Dr. Kruglyak was trained by Dr. Eric Lander, and has been involved with "analyzing biological states and their determining genetic factors." He has also carried out important work on the potential applications of SNPs.

Dr. Janet Rowley, former chair of the Board of Scientific Counselors for NHGRI, was awarded the National Medal of Science, the nation's highest science honor, by President Clinton. Last year Dr. Rowley was a Lasker Award winner.

NIH Initiatives

Dr. Collins reported on three NIH initiatives concerning the rat, the zebrafish, and other non-mammalian models.

A meeting on Rat Genomics was held on May 3, 1999. This trans-NIH meeting was sponsored by NHLBI and attended by rat genomicists and physiologists, as well as mouse and human genome researchers. Attendees discussed resources needed to develop the rat model to a state comparable to the mouse. Highest priority was given to the development of rat embryonic stem cell lines and the ability to do knockouts.

A meeting on Genomic and Genetic Tools for the Zebrafish was held on May 10-11, 1999. The zebrafish is a transparent fish that is ideal for studies on developmental genetics, and an expanding number of investigators are entering this field. The meeting in May, which was organized by the Trans-NIH Zebrafish Committee, was held to review progress in this field and study available resources. One of the more exciting presentations was made by Nancy Hopkins who presented advances in insertional mutagenesis. There were questions about when we should start genomic sequencing of the zebrafish, and whether it should follow the same strategy as sequencing of the human and mouse models.

The Non-Mammalian Models (NMM) Workshop was held February 16-17, 1999 and chaired by Drs. Raju Kucherlapati and David Valle. Organisms reviewed included yeast, C. elegans, D. melanogaster, zebrafish and Xenopus. Dr. Collins called attention to the summary of the meeting, especially Appendix C, which gives the recommendations of breakout groups for each of the main non-mammalian models.

Dr. Collins also announced the establishment of the Trans-NIH Coordinating Committee for Non-Mammalian Models (CCNMM), chaired by Drs. Elke Jordan and Marvin Cassman. The charge of this committee is to plan and coordinate development of genomic resources for non-mammalian model organisms, using the recommendations of the NMM workshop as a starting point. Each NIH institute is being asked to identify staff with appropriate expertise to serve on the CCNMM, since this is an area where resources are needed beyond what NHGRI can provide. Dr. Jordan is currently gathering names of institute representatives, and Dr. Bettie Graham is assembling a Web page for the CCNMM.

Dr. Horvitz expressed concern that the report of the NMM Workshop underplayed the significance of comparative genomics.

Dr. Lawrence asked about the status of the dog genome. Dr. Jordan indicated that we are not supporting research in this area to any great extent, and since the dog is a mammal, it is not under the purview of the CCNMM.

Council members agreed that difficult decisions needed to be made about allocating resources for sequencing additional genomes once the human genome is sequenced.

Report of Total Human Sequence in Genbank

As of Friday, May 14, 1999 GenBank is reporting the following numbers:

329,238 kb (10.2 percent) finished sequence

215,053 kb (6.7 percent) working draft sequence

544,291 kb (16.9 percent) TOTAL (including finished and working draft)

These figures are expected to increase dramatically in the months to come, particularly with regards to working draft sequence.

PROGRAM ITEMS OF INTEREST AND SCIENTIFIC ACCOMPLISHMENTS

Large-Scale Effort to Sequence the Human Genome

The pilot phase of sequencing the human genome has been successfully completed, and the full scale effort to sequence the total human genome has begun. An international consortium of the five largest sequencing groups, consisting of three U.S. laboratories funded by the NHGRI, the Joint Genome Institute of the U.S. Department of Energy, and the Sanger Centre supported by the Wellcome Trust predicts they will produce at least 90 percent of the human genome sequence in a working draft form by the spring of 2000. In support of this sequencing effort, the NHGRI has awarded new grants totaling $81.6 million to three U.S. academic sequencing groups at the Whitehead Institute, Washington University School of Medicine, and Baylor College of Medicine. There have been weekly conference calls between NHGRI staff and staff at the five largest sequencing centers to facilitate meeting this ambitious timetable. This effort will also be a topic for discussion at the upcoming meeting at Cold Spring Harbor.

In a related development, the new SNP Consortium (to be presented in more detail later in the council meeting) is also planning to speed up the process of cataloging SNPs. This innovative collaboration involving ten pharmaceutical companies, the Wellcome Trust, and several leading academic centers is unprecedented and will ensure that SNP discoveries move forward rapidly and remain freely accessible to the public. This effort complements the NIH SNP RFA that was reported at the February council meeting.

ELSI RFA

One of the mandates from the ELSI Research Planning and Evaluation Group (ERPEG) was that the NHGRI ELSI program look at the consequences of research studies on human DNA sequence variation. Consequently, NHGRI has released an RFA for "Studies of the Ethical, Legal and Social Implications of Research into Human Genetic Variation". The RFA was released on April 29, 1999; letters of intent are due June 15, 1999; and the application deadline is August 31, 1999.

NIH Animal Model Uncovers a Role of BRCA1-Associated Breast Tumor Formation

NHGRI scientists have collaborated on a study of an animal model of tumor formation that holds great potential for studying breast cancer in women. They have uncovered the role of two key genes implicated in the development of inherited forms of breast cancer. This research was published in the May issue of Nature Genetics.

Dr. Jeffrey Trent, DIR scientific director, will be addressing the council in closed session to give further updates on intramural research activities.

Congressional/Budget Issues

The President's Budget for FY 2000 has been submitted, proposing a 2.1 percent increase above the FY 1999 budget for NIH. On February 23, 1999, NIH Director Dr. Harold Varmus appeared before the Senate Appropriations Labor, Health and Human Services, Education and Related Agencies Subcommittee as spokesperson for the NIH. On February 25, 1999, Dr. Collins appeared before the House Appropriations Labor, Health and Human Services, Education and Related Agencies Subcommittee chaired by Congressman John Porter. This was Dr. Collins' first appearance before Congress since the new 5-year plan was adopted, and subcommittee members had questions about NHGRI collaboration with the private sector; different scientific methods used by NHGRI and others; and issues arising from genome research, such as genetic testing and counseling, genetic privacy and genetic discrimination.

Appropriations subcommittee members are in a difficult position because budget caps are still in place that make it impossible to meet program needs. The prospect of a $10 billion shortfall for the House Appropriations, Labor, Health and Human Services, Education and Related Agencies subcommittee is being discussed in Congress. In the Senate, the situation is expected to be equally bleak , where allocations reportedly would leave FY 2000 programs $8 billion below FY 1999 levels unless the budget caps are lifted. At this time it is impossible to predict the NIH budget for FY 2000.

Dr. Buxbaum asked if Congress was still concentrating on obtaining funding for research into specific illnesses, rather than obtaining funds for health research in general. Dr. Collins said this varied among the different legislators, but that Mr. Porter wants to see NIH benefit as a whole.

House Appropriations Subcommittee Visit to NIH

On April 20, Chairman Porter and House Appropriations Subcommittee members Miller, Dickey, Cunningham, Pelosi, and DeLauro were given a tour of NIH intramural programs. Dr. Collins was among the NIH staff who addressed the group. The visit was extremely positive.

Genetic Testing Hearing

On April 4, 1999 Dr. Collins gave a presentation before the House Subcommittee on Technology, Committee on Science as part of its hearing on genetic testing. This House subcommittee is chaired by Ms. Connie Morella, in whose Congressional district NIH resides. In a similar vein, HHS Secretary Donna Shalala is in the process of establishing an Advisory Committee on Genetic Testing, which was a major recommendation of the NIH-DOE Task Force on Genetic Testing.

Upcoming Meetings

International Sequencing Meeting, Cold Spring Harbor, May 19. This meeting will bring together NHGRI staff, representatives of the Wellcome Trust, the Department of Energy, and international partners in the HGP from France, Germany and Japan to coordinate human genome sequencing efforts and discuss intellectual property issues.

SNP Meeting, Bethesda, June 7-8. This meeting will bring together Principal Investigators from the NIH SNP RFA, NIH staff, and representatives from the SNP Consortium to coordinate large scale SNPs discovery and production. Attendees will discuss mutual concerns, including quality assessments, databases and ELSI issues.

The American Society of Gene Therapy is meeting in Washington, D.C. on June 9-11.

National Medical Association, August 9. NHGRI will present a symposium on genetics and minority populations, focusing on the NHGRI/Howard University collaboration to study disorders that disproportionately affect African Americans, including prostate cancer and diabetes.

REPORT FROM THE DEPARTMENT OF ENERGY

Dr. Ari Patrinos, Associate Director for Biological and Environmental Research, Department of Energy (DOE) Office of Science updated the council on genome-related activities at the Department of Energy (DOE). He indicated that DOE is concerned about the same budget caps that are affecting NIH. DOE has an ambitious science agenda, but a money shortfall.

DOE is also scaling up to participate in the international effort to meet the accelerated human sequencing goals set forth in the Five-Year Plan. The DOE Joint Genome Institute's (JGI) Production Sequencing Facility (PSF) in Walnut Creek, Calif. was dedicated on April 19, 1999, and will be responsible for producing approximately 10 percent of the human working draft sequence. Trevor Hawkins has been appointed as the new Sequencing Director. However, growing pains have resulted in significant changes in personnel for high-throughput sequencing efforts.

Major equipment purchases have been initiated. The JGI is switching to capillary sequencers and acquiring 18 more MegaBACE machines. They may have 100 such machines by the end of the year.

The JGI continues to focus on 5X coverage of human chromosomes 5, 16 and 19. JGI has completed 31 Mb of human sequence (to Bermuda standards) and hopes to have completed 52 Mb of Bermuda quality human sequence by next March.

Recent awards have included $2 million for ELSI activities, $4 million for instrumentation, $3 million for R&D infrastructure including the Bacterial Artificial Chromosome (BAC) end sequencing effort, and $2 million for informatics.

Dr. Patrinos was concerned about the how accelerated demand for human sequencing data may be affecting other potentially useful projects.

TRANSLATION OF ELSI RESEARCH INTO POLICY

Dr. Kathy Hudson initiated the presentation on the translation of ethical, legal and social implications (ELSI) research into policy by giving an overview of the ELSI programs within the NHGRI. The original organizational component within the institute was the ELSI Research Program, which is part of the Division of Extramural Research (DER). The DER ELSI program is responsible for soliciting and managing a portfolio of ELSI research projects that focus on the ethical, legal and social implications of genetics research. ELSI policy issues are dealt with primarily in the Office of Policy and Public Affairs in the Office of the Director. In addition, bioethics research and research involving special populations are a priority for the Office of Bioethics and Special Populations Research within the Division of Intramural Research.

There are four major priority areas of the overall ELSI program: 1) privacy and fair use of genetic information; 2) clinical integration of genetic technologies and information; 3) ethical principles in human genetics research; and 4) public and professional education. ELSI research is important for development of research policy, health policy and public policy. The process by which ELSI research is translated into policy is: 1) collection of data; 2) input from stakeholders; 3) development of policy options; 4) validation of policy recommendations; 5) dissemination of recommendations; and 6) implementation of recommendations.

Dr. Benjamin Wilfond, Co-Director of the Office of Bioethics and Special Populations Research, DIR, discussed the integration of ELSI research into research ethics policy. Dr. Wilfond cited four examples where ELSI research has had an impact on research policy: 1) pedigree research; 2) stored tissue research; 3) gene transfer research; and 4) issues surrounding community consent and group harms.

As an example of the way ELSI research can lead to research policy, he cited three articles published in professional journals and a book which deal with informed consent in stored tissue research. He also demonstrated the impact that these publications had on professional organizations which later issued their own policy statements regarding this topic (American College of Medical Genetics, the American Society of Human Genetics, the American Association of Medical Colleges, and the National Bioethics Advisory Commission).

Elizabeth Thomson, ELSI Program Director in the DER, discussed the translation of ELSI research into health policy. She listed examples in which ELSI research has influenced the development of health policy: 1) cystic fibrosis; 2) breast, ovarian, and colon cancer; and 3) Alzheimer's disease.

In the case of Alzheimer's disease, there were extremely diverse views about whether there should be predictive genetic testing using APOE testing. She cited the research project awarded to Stephen Post in which research was carried out, a policy group deliberated the findings and a number of publications resulted, including policy recomendations about such testing (in JAMA and NEJM). In the area of cancer genetic testing, Ms. Thomson outlined the work of the NIH Cancer Genetic Studies Consortium established in 1994. This consortium of 15 investigators was formed to conduct research examining the ethical, legal and social implications surrounding the use of cancer genetic tests. As a result of this group's deliberations, four significant publications resulted, including one on informed consent for cancer genetic testing and recommendations for follow up care for those found to have cancer genetic mutations. Another paper presented ethical and health policy issues related to cancer genetic testing. In addition, members of the consortium published another 30 papers in peer reviewed journals on the topic of genetic testing for cancer.

Finally, Ms. Thomson discussed the process that led to a consensus statement on genetic testing for cystic fibrosis (CF). The gene for CF was discovered in 1989. At that time although general population testing was anticipated in the near future, it was felt that genetic testing for CF would be premature because many unanswered questions remained and the test was not sensitive or specific enough. In 1991 NHGRI (along with NICHD, NINR, AND NIDDK) released an RFA to study the issue of CF testing and eleven research projects were funded. Between 1991 and 1995 research was conducted. Research results were reported in the literature from 1992-1997 and beginning in 1996, an NIH Consensus Conference was planned. Finally, in 1997 the Consensus Conference was held, which recommended that CF genetic testing be offered to pregnant women or couples planning a pregnancy.

Ms. Thomson made it clear that while NIH is not in the business of recommending health policy, it does have a formal process through which health policy recommendation can be made. For CF, this was the NIH consensus conference mechanism. The consensus conference process has been designed to pull together an expert, non-federal, unconflicted panel to examine all the available data and make recommendations regarding the issue under consideration. In the case of the CF Consensus Conference, panelists considered the results of ELSI-funded research that showed that there were a variety of ways to educate people, including individual genetic counseling, and the provision of brochures and videos. These studies further showed that when offered the test, the majority of pregnant women opt for the test. Based on the results of the research and the panel's deliberations, the panel concluded that such testing should be "offered" to pregnant women. That recommendation is now under consideration by the American College of Obstetrics and Gynecology.

Dr. Kathy Hudson discussed how research on the privacy and fair use of genetic information is translated into public policy, and pointed out that only 16 percent of the ELSI research budget is devoted to this priority area. She discussed a diagram of how -funded research follows a pathway to become policy recommendations that are disseminated or possibly implemented through legislation. Examples include legislation on health insurance passed by numerous states. On the federal level, the Health Insurance Portability and Accountability Act (HIPAA) was enacted by Congress in 1997 and four bills regarding fair use of genetic information have been introduced in the 106th Congress.

The concept of genetic justice encompasses privacy issues, involving research and medical records, and fair use, involving health insurance and workplace issues. These issues have been discussed in workshops set up with the stakeholders involved, and the resulting recommendations have been disseminated widely.

The Workshop on Privacy and Confidentiality in Genetics Research discussed how legislation could affect research, and whether participants in research studies should have access to their records if the results were unclear or unproven. The workshop participants wanted to make sure that experimental research data was not placed in a patient's medical record and developed guidelines about when experimental research data should be disclosed.

Dr. Hudson summed up her presentation by saying that, "ELSI research is necessary but not sufficient for good policy-making."

Council members expressed concern about research conducted by managed care systems and how to define and classify a medical record. There was also discussion about regulating companies that direct market genetic tests and how they can use the samples they collect. Dr. Collins questioned whether genetic tests should be directly marketed to the public.

Dr. Cox asked whether the people who make policy recommendations are actually basing their decisions on research results. He stated that the conclusions of the CF Consensus Conference were so surprising, some questioned whether they were really based on research findings. He also stated that while papers recommending policy published in professional journals may have great impact, they do not necessarily tell people what the actual research findings were.

Ms. Thomson explained that it is the responsibility of the Office of Medical Applications Research to gather the appropriate research data and make it available to the panelists selected for an NIH Consensus Conference. While panelists are supposed to have expertise in a particular area, they cannot be directly involved in the research related to the topic being deliberated. In addition, in the case of CF genetic testing, outside sources were invited to give presentations to panelists giving different points of view.

Council members expressed a desire for assurances that recommendations of consensus panels would clearly follow from research data. They also questioned what constituted consensus. Was unanimity required? Dr. Horvitz pointed out that consensus may be influenced by different societal views -- "what you see depends upon where you stand." There is a need to bring other stakeholders into policy decisions, including consumers, the insurance industry, managed care personnel, etc.

Dr. Hirschhorn of the American College of Medical Genetics (ACMG) mentioned that one of the complicating features of CF testing is that minority groups have different sets of mutations. These groups may not benefit from genetic testing for CF since there may be a large number of missed carriers. He suggested that there can be a problem with offering genetic testing when there are many populations with differing genetic alleles.

Dr. Mathies said that concerns over ELSI issues will accelerate as the gene discovery process is scaled up and more genetic tests become available. He questioned whether the current process of setting up consensus panels will work as the volume of candidate genes increases. Dr. Collins suggested that guidelines be established for representative genes with recommendations about interventions and available testing. Dr. Mathies also suggested that this issue be handled in a trans-NIH manner. Dr. Hudson pointed out that the CDC and the FDA are also involved in policy decisions.

Two new advisory groups have been established to look at ELSI issues. A trans-NIH Bioethics Committee is dealing with a number of issues that affect all of NIH. At this time it is dealing with privacy and confidentiality of research records. This committee was established as the result of a recommendation of the ELSI Evaluation Committee chaired by Dr. Spence and Dr. Rothstein. The second committee, established by HHS Secretary Donna Shalala, is an Advisory Committee on Genetic Testing. Its members should be named soon. Council members questioned how the NHGRI ELSI program will work with the Secretary's advisory committee. There were concerns about how much data should be collected, what should be done with it, and what oversight was needed?

Dr. Williamson pointed out that consensus is not always possible. We can only bring investigators together to see if it is possible. Dr. Olson felt that NHGRI needs an exit strategy in dealing with disease-related genetic tests. Other IC's need to take responsibility for genetic testing for diseases in their research areas of interest. However, he stated that increased research emphasis on human variation will soon dwarf disease specific issues. At the same time, the need for public education will greatly increase.

Dr. Lawrence felt NHGRI through its ELSI program should lead the way in developing processes to translate research data into policy. Dr. Collins pointed out that we have made substantial progress towards drawing stakeholders and consumers into policy debates and have made ourselves readily available to help inform the legislative process.

THE SNP CONSORTIUM LTD.

Mr. Arthur Holden, Chairman and CEO, began the presentation on The SNP Consortium (TSC). He thanked council members Alan Williamson, David Cox and Robert Waterston for their roles in initiating and developing the project. He also acknowledged the support of the Wellcome Trust, represented at the council meeting by Dr. Michael Morgan, in establishing the TSC.

Following a presentation of the mission statement, Mr. Holden described the consortium as a non-profit organization made up of diverse participants and funded exclusively by member contributions, whose purpose was the development of "pre-competitive genomic platforms."

The organization will "establish a strong, focused alliance to collaborate and complement ongoing public efforts."

The TSC was set up because there was strong support within the pharmaceutical industry to develop an industry standard SNP map with universal access. It was felt that a consortium would maximize the total data available, and there were economic benefits to be gained from cost and risk sharing.

Founding members include the Wellcome Trust and ten pharmaceutical companies (AstraZeneca, Bayer, Bristol Myers Squibb, Glaxo Wellcome, Hoechst Marion Roussel, Hoffman LaRoche, Novartis, Pfizer, Searle, and SmithKline Beecham). These members will be working with leading academic centers, including the Whitehead Institute for Biomedical Research, Washington University School of Medicine, Stanford Human Genome Center, Cold Spring Harbor Laboratory, and the Wellcome Trust's Sanger Centre. Member commitments go beyond money and include collaborative management. Underperformance is the only reason members can withdraw from the consortium.

The TSC is run by a Board of Directors, and there are three task forces. The Scientific Task Force is headed by David Wang. The IP Legal Task Force is headed by John Keller, and is dealing with intellectual property issues. The Public Relations Task Force is headed by Mary Prescott.

The key objectives of the TSC will be to create the highest quality SNP map. The goal is to identify a minimum of 300,000 SNPs in the next two years, and map at least 150,000 SNPs. A database will also be created with on-going support from Cold Spring Harbor Laboratory. A budget of $45 million has been established for the initial phase of the project.

Mr. Holden concluded by summarizing progress to date. The TSC has been established and management processes put in place. Eleven funding agreements and five research agreements have been completed. An intellectual property program is in place and the public relations program has been launched. Pilot studies have been successfully completed and production scale-up has begun.

Dr. David Wang of Bristol-Myers Squibb gave a scientific overview of the TSC project. SNP identification will be done at the Whitehead Institute, Washington University, and the Sanger Centre. During the first year of the project approximately 97,500 SNPs will be identified, and 202,500 during the second year, for a total of 300,000 SNPs identified by the year 2002.

SNP mapping will be performed by radiation hybrid (RH) mapping at Stanford University and the Sanger Centre, and by in silico mapping at Cold Spring Harbor.

Approximately 18,000 SNPs will be mapped by RH analysis in 2000 and in 2001 respectively, for a total of 36,000; and 24,000 and 90,000 will be mapped in silico in 2000 and in 2001 respectively, for a total of 114,000.

The number of SNPs needed for whole-genome studies is estimated to be 60,000 to 600,000. The TSC target is 300,000 SNPs. SNPs will be obtained using the NIH DNA Polymorphism Discovery Resource set of 24 unrelated individuals of diverse origins.

Cold Spring Harbor (CSH) will serve as the Data Coordinating Center. CSH will be responsible for collecting SNP and mapping data from the genome centers into a central, highly usable database, facilitating management of the overall project's progress, and ensuring systematic and uniform data release to NCBI's dbSNP, a public database of SNPs. The data format should be compatible with public databases and there have been discussions with NCBI.

As for program management, the Board of Directors will meet quarterly, the TSC Operating Committee will meet monthly, and the Scientific Management Committee will meet monthly.

A "protective" strategy has been developed for Intellectual Property (IP). Provisional patents will be filed to protect novel information until it can be put in the public domain. Provisional patents will be converted to Continuation in Part (CIP) applications, and these will be converted to Statutory Invention Registrations (SIRs) as SNPs are mapped and ready for release. Intellectual property will be managed by the consortium, and all parties will have equal data access. There will be no early access to SNP data by participating companies.

Dr. Chakravarti wanted to be certain that the TSC patents would not preclude organizations from filing functional use patents. He was assured that groups could request a patent on the use of a SNP, but not on the SNP itself.

Current available funding for phase 1 of the TSC project includes $14 million from the Wellcome Trust and $30 million from the pharmaceutical companies ($3 million from each of the 10 pharmaceutical partners). Most of these funds will be used for R&D, with only a small amount to be used for administrative purposes. However membership in the TSC is open, and hopefully new members will join and contribute additional funding. Once the core focus of developing the SNP map is completed, the project can concentrate on other areas such as verification studies, informatics, education, and ethical issues.

Dr. Olson noted that the presentation on the TSC did not contain information about the technical processes that would be used to identify and map SNPs. He indicated that this was a change from the past and wondered if there was reason for the secrecy. Mr. Holden responded that this was an inappropriate forum for discussing technical processes. A provisional patent has been filed regarding the process to be used, and the information will eventually be made available to the public. Dr. Morgan of the Wellcome Trust assured Council that there was no hidden agenda.

Dr. Morgan also pointed out that a SNP must be validated before it can be released into the public domain. Dr. Collins indicated that Maria Freire from the NIH Office of Technology Transfer had reviewed the consortium's plans for handling intellectual property and given assurances that they were legal and well conceived, and an excellent way to place intellectual property in the public domain.

Dr. Collins also mentioned that NIH had issued a SNP RFA that resulted in 16 awards. Of the SNPs found under this RFA, about half will be in coding regions and half will not be. The DNA Polymorphism Discovery Resource of DNA samples and cell lines that has been deposited with the Coriell Institute will be used by most of the investigators under this RFA. These samples are representative of the diversity found in the U.S. population, which includes people of European, Asian, Native American, and African descent. This same resource is being used by the SNP Consortium.

Dr. Horvitz offered his congratulations and indicated he realized how difficult it was to establish a consortium of this nature and get everyone to agree on how to proceed. He then asked how an academic research center's resources would be diverted if, upon review it was felt that the center was not producing adequately. Would there be competition for the resources?

Mr. Holden indicated that a performance standard would be established. A center would need to meet basic baseline objectives that had previously been agreed to by all. Significant underperformance would be the only reason to reallocate resources, and there was no reason for centers to actually compete with each other. Also, the research centers participating in the project have an established track record.

Council members also questioned why some pharmaceutical companies agreed to join the consortium and others did not. Mr. Holden indicated that some pharmaceutical companies elected not to join the TSC since the SNP information will be made available to the public. Therefore, they could get the information for free and not pay the $3 million dollar contribution made by the companies who joined the consortium.

Dr. Hirschhorn asked how the TSC would deal with a 5 percent failure rate if the goal was 95 percent accuracy. There was discussion regarding how to confirm the accuracy rate. There was also a question about how the FDA would become involved as SNPs were discovered. Dr. Collins pointed out that the consortium has focused on getting started and other issues will be considered later.

Dr. Nickerson asked if there was a mechanism for integrating diverse groups into the consortium. He also questioned the consortium's long-term goals and asked if there was a Web site. Mr. Holden responded that the membership of the consortium is open and that they are proactively trying to get information out to various groups. Long-term goals will depend upon how quickly short-term goals are met. As to the third question, the consortium will be using the Cold Spring Harbor Web site.

Dr. Collins indicated that a meeting has been scheduled for June 7 and 8 so NIH grantees and members of the SNP Consortium can meet and discuss SNP research, including ELSI issues. It is expected that the social consequences of SNPs research will soon dwarf other ELSI research issues.

Dr. Collins invited Dr. Michael Morgan from the Wellcome Trust, and NHGRI's long-term partner in the HGP, to address the Council. Dr. Morgan indicated that the Wellcome Trust is prepared to challenge any patents that deny public access to information on SNP identification. He also reported that the Sanger Centre is committed to sequencing one-third of the human genome sequence by 2003, and the sequence production rate is proceeding on schedule and new equipment will be acquired. The Sanger Centre was also involved in sequencing C. elegans and is looking into other pathogen genomes. Other interests of the Sanger Centre include functional genomics and family collections. In support of the HGP, the Wellcome Trust is currently trying to expand the U.K. genome campus.

ANNOUNCEMENTS AND ITEMS OF INTEREST

Dr. Jordan noted the items of interest in the council folders, and referred council to the material in Tabs "K through W." She mentioned that issues arising from the recently enacted law requiring public access to all federally funded research data under the Freedom of Information Act (FOIA) have not been resolved, but it is possible that Congress will take action to block the law.

COUNCIL-INITIATED DISCUSSION

Dr. Collins announced that Dr. Gerald Rubin of the University of California, Berkeley and Dr. Craig Venter would be invited to the September Council meeting to give an update on the partnership of Celera and the Berkeley Drosophila Genome Project and their effort to decode the sequence of the fruit fly. Dr. Wold indicated that it would also be useful to have a presentation by Dr. Venter on his efforts in sequencing the human genome.

REVIEW OF APPLICATIONS

In closed session, the Council reviewed 80 applications, totaling $123,073,955. The applications included 44 regular research grants, six other research grants, one training grant, and 29 small business program grants. A total of 56 applications requesting $116,231,397 were recommended.

I hereby certify that, to the best of my knowledge, the foregoing minutes are accurate and complete.



Date Elke Jordan, Ph.D.
Executive Secretary
National Advisory Council for Human Genome Research


Date Francis S. Collins, M.D., Ph.D.
Chairman
National Advisory Council for Human Genome Research

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Last Reviewed: March 2006