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National Advisory Council for Human Genome Research
Summary of Meeting

Chevy Chase, Md.

February 12-13, 1998

The National Advisory Council for Human Genome Research was convened for its twenty-second meeting at 8:30 a.m. on February 12, 1998, at the Holiday Inn, Chevy Chase, Palladian Center and East conference rooms. Dr. Francis Collins, director of the National Human Genome Research Institute, called the meeting to order.

The meeting was open to the public from 8:30 a.m. to 5:30 p.m. on February 12. In accordance with the provisions of Public Law 92-463, the meeting was closed to the public from 5:30 p.m. on February 12 to adjournment February 13 for the review, discussion, and evaluation of grant applications.

Council members present:

Allen E. Buchanan
Aravinda Chakravarti
Ellen W. Clayton
David R. Cox
Troy Duster
Leroy Hood
H. Robert Horvitz
Jeanne Lawrence*
Richard Mathies
Joseph Nadeau
Diane Smith
David Valle
Alan R. Williamson
Barbara Wold

Ex officio members:

Joel N. Buxbaum
William M. Nelson

Liaisons from Professional Societies:

Rosalie Goldberg, National Society of Genetic Counselors
Kurt Hirschhorn, American College of Medical Genetics
Jeffrey Murray, American Society of Human Genetics

*Participated via telephone conference call

Staff from the National Human Genome Research Institute:

Jane Ades, OPC
Joy Boyer, DER
Lisa Brooks, DER
Erin Burgess, OAM
Jean Cahill, OAM
Francis Collins, OD
Elise Feingold, DER
Adam Felsenfeld, DER
Leslie Fink, OPC
Mary Glynn, OAM
Bettie Graham, DER
Mark Guyer, DER
Linda Hall, OAM
Kathy Hudson, OPC
Linda Jacobson, OAM
Elke Jordan, OD
Charles E. Leasure, OD
Tara Mowery, OAM
Kenji Nakamura, OSR
Diane Patterson, OAM
Carolyn Pomicter, DER
Rudy Pozzatti, OSR
Jerry Roberts, CIDR
Susan Saylor, DER
Jeffery Schloss, DER
Elizabeth Thomson, DER
Monika Yakovich, OAM
Sally York, OAM

Others present for all or a portion of the meeting:

Finley Austin, Merck Genome Research Institute
Robert Boyd, Knight Ritter
Bill Bunnag, CSR
April Burke, Association of Independent Research Institutes
Cheryl Corsaro, CSR
Lyle Dennis, The Genome Action Coalition
Machi Dilworth, NSF
Dan Drell, DOE
Susan Greenhut, NCI
Arthur Katz, DOE
Jean McKay, NCI
Richard Klausner, NCI
Annette Kornblum, The Washington Post
Ari Patrinos, DOE
Maria Persinos, Washington Insight
Lisa Putman, The Blue Sheet
Sara Radcliffe, Smith, Kline and Beecham
Latonya Rich, Lewis Burke Associates
Paul Scott, OD/OBSSR
Grace Shen, NCI
Michael Strazzella, American Society of Clinical Pathologists
Nancy Sung, Burroughs Wellcome Fund
Michael Teitelbaum, Sloan Foundation
Marina Volkov, OD/OBSSR
Meredith Wadman, Nature

Introduction of New Members, Liaisons and New Staff

Dr. Jordan introduced the new Council member: Dr. Allen E. Buchanan, University of Wisconsin; and the two new ex officio members: Dr. Joel N. Buxbaum, New York Department of Veteran Affairs Medical Center and Dr. William M. Nelson, Naval Medical Research Institute.

Dr. Jordan introduced the liaisons to the council from the professional societies: Dr. Kurt Hirschhorn, representing the American College of Medical Genetics; Ms. Rosalie Goldberg, representing the National Society of Genetic Counselors; and Dr. Jeffrey Murray, the new liaison representing the American Society of Human Genetics.

Approval of Minutes

The minutes from the September 11 - 12, 1997 NACHGR meeting were approved as submitted.

Future Meeting Dates

May 4-5, 1998, and September 14-15, 1998 were approved dates for NACHGR meetings. The following dates were proposed for future meetings: February 22-23, 1999; May 17-18, 1999; September 13-14, 1999; February 28-29, 2000; May 22-23, 2000; and September 11-12, 2000.

Director's Report
Recent Scientific Accomplishments

Dr. Collins indicated that there have been a number of significant research findings reported by scientists in the Division of Intramural Research, NHGRI since the last council:

Knockout of Mouse Gene Results in Unexpected Social and Behavioral Change. Dr. Anthony Wynshaw- Boris and Dr. Nardos Lijam at NHGRI, together with Dr. Richard Paylor at the National Institute of Mental Health (NIMH), have identified a gene, dishevelled-1, that disrupts normal social behavior among laboratory mice missing that gene. This research should prove useful in studies of human neuropsychiatric disorders.

Gene for Pendred Syndrome. Using the recently completed map of human chromosome 7, scientists have identified an altered gene thought to cause as much as ten percent of hereditary deafness. The work was performed in the laboratories of Dr. Eric Green at NHGRI, in collaboration with Dr. Val Sheffield at the University of Iowa and Dr. Benjamin Glaser at Hadassah University Hospital in Jerusalem. The normal gene makes a protein the researchers have named pendrin. When altered, the gene produces defective pendrin and causes Pendred syndrome, a disorder that typically produces deafness at birth.

New Gene for Hirschsprung Disease. Dr. William Pavan and colleagues at the NHGRI have identified another mutated gene that causes Hirschsprung disease in laboratory mice. The gene appears to be essential for the proper development of the nervous system. The scientists expect to find that the equivalent human gene, when mutated, may cause Hirschsprung disease in people.

DNA Chip to Sequence Breast Cancer Gene Region in Chimps, Gorillas, and Orangutans. Dr. Joseph Hacia and Dr. Collins, working with scientists at Affymetrix, have reported the use of new DNA micro chip technology to analyze the structure of BRCA1 in several species of animals, incuding the chimpanzee, the gorilla, and the orangutan.

Gene Therapy in AIDS Animal Model. Scientists in the laboratory of Dr. Richard Morgan, together with researchers at National Heart, Lung and Blood Institute (NHLBI) and the Johns Hopkins School of Medicine, have demonstrated for the first time in a non-human primate that gene therapy works against viruses that destroy the immune system. Their work may eventually benefit patients infected with HIV, the virus that causes AIDS.

Items of Interest

Tuscon Microarray Meeting The Second Workshop on Methods and Applications of DNA Microarray Technology was held on January 11-13, 1998 in Tucson, Arizona. The co-organizers of the workshop were Dr. Jeff Trent, scientific director of the NHGRI and Dr. Pat Brown of Stanford University. The size of the workshop was much larger than last year. This year there were 65 abstracts and 140 participants, including Dr. Harold Varmus, NIH director, and several institute directors. The meeting focused primarily on various formats of the microarray technology, and included presentations of work using the Affymetrix chip technology and reports about new array technologies. The proceedings of this meeting will be published in the March issue of Nature Genetics, and will also be posted on the NHGRI Home Page Web site.

CIDR: The Center for Inherited Disease Research (CIDR) has been a new initiative at NIH, led by NHGRI scientist Dr. Robert Nussbaum. CIDR is a centralized facility that provides genotyping and statistical genetics services for investigators seeking to identify genes that contribute to human disease. CIDR was established in 1996 as a joint effort by eight institutes at the NIH. The facility is supported through a contract to The Johns Hopkins University (JHU), with Dr. David Valle of the JHU Center for Medical Genetics as Principal Investigator (PI). Dr. Robert Nussbaum serves as the government Project Officer. Proposed projects are reviewed by the CIDR Access Committee, chaired by Anne Spence, and three cycles of review have now been completed. The first official project was a study of bipolar disease funded by NIMH and begun on September 8, 1997. The second project, a study of deafness, began on January 9, 1998.

In order to encourage scientists to use the CIDR facilities, the Board of Governors has decided that genotyping for PIs funded by the participating eight institutes will be free for the time being. The cost for other researchers is $1/genotype. Now that the production activities of CIDR have been established, more attention is being devoted to technology development, particularly in the use of chip technology. Scientists are encouraged to go to the CIDR website for further information.

Budget Issues

Fiscal year 1998 was a good year for NHGRI. In November 1997, Congress passed the Departments of Labor, Health and Human Services, Education and Related Agencies Act, which appropriated $13.6 billion to NIH, an increase of 7.1 percent over the FY 1997 level. Within the NIH level, NHGRI was appropriated $218 million, an increase of $28.7 million or 15.2 percent over the FY 1997 level.

Of the total increase for NIH, $443 million will be used to support research in six emphasis areas: Genetic Medicine, the Biology of Brain Disorders, New Approaches to Pathogenesis, New Preventive Strategies Against Disease, Therapeutics/Drug Development, and Developmental and Advanced Instrumentation. NHGRI has specific increases in three of these areas (Genetic Medicine, New Preventive Strategies Against Disease, and Developmental and Advanced Instrumentation).

The FY 1999 President's Budget includes a request for an increase of over $1 billion for the NIH, the largest ever in the history of NIH. Dr. Varmus, Secretary Shalala, and the President and Vice- President deserve enormous credit for making biomedical research such a high priority.

The NIH budget request for FY 1999 is $14.8 billion, an increase of $1.15 billion or 8.4 percent over the FY 1998 level. The NHGRI request is for $240.1 million, an increase of $22.4 million or 10.3% over the FY 1998 level. The next step in the FY 1999 appropriation process will be the Congressional Hearings on the President's Budget Request. The House Hearings are scheduled to begin on March 12, 1998 and the Senate Hearing will occur on April 2, 1998.

Legislative and Policy Update

State of the Union Address Dr. Collins pointed out that Dr. Varmus was strategically seated between Hillary Clinton and Tipper Gore at President Clinton's State of the Union Address. President Clinton emphasized the importance of genetics research in his speech; and Dr. Collins read the following quote from the address, "As important as all this scientific progress is, we must continue to see that science serves humanity, not the other way around. We must prevent the misuse of genetic tests to discriminate against any American."

Health Insurance Discrimintion The Health Insurance Portability and Accountability Act (HIPAA), enacted in 1996, provided some protection against genetic discrimination in health insurance, but does not guarantee coverage for uninsured individuals seeking individual health insurance policies, does not offer protections against exorbitant premiums in the individual market, and does not provide privacy/confidentiality protections. NHGRI and DHHS are working with Congress to encourage legislation to address the HIPAA loopholes.

Employment Discrimination On January 20, 1998, at the annual James Watson Lecture sponsored by The Genome Action Coalition, Vice President Al Gore released the report "Genetic Information and the Workplace," and announced that the Clinton Administration was calling for legislation to bar employers from discriminating against workers in hiring or promotion because of their genetic makeup. Dr. Kathy Hudson was instrumental in the development of this report, which was based on the ELSI and NAPBC recommendations on genetic discrimination and the workplace published in Science in March 1997.

In his speech, Vice President Gore referred to the Affymetrix chip as "a double-edged helix," and stated emphatically that, "Genetic discrimination is wrong-and it's time that we end it." He indicated that the report states that employers should be prohibited from requiring or requesting a genetic test or genetic information as a condition of employment or receiving benefits; and, that employers should be prohibited from using genetic information to limit job opportunities. However, genetic information and testing should be allowed in some situations to ensure workplace health and safety, and preserve research opportunities.

On a related note, in a decision released on February 4, 1998, the 9th Circuit Court of Appeals proposed constitutional limits on how employers may use genetic information. This decision was the result of a suit brought against the University of California and Lawrence Berkeley National Laboratory. The laboratory had tested employees for sickle cell, pregnancy and syphilis without their knowledge. The appeals court ruled that such tests may only be performed with the express permission of the individual or in circumstances that are directly related to the employee's ability to perform the job. The court felt there had been a significant invasion of privacy and that the employees' Constitutional rights had been violated.

Ellen Clayton indicated that this was a very signficant finding with far reaching consequences. For the first time a legal opinion stated that just obtaining medical information without permission was sufficient evidence of harm, even if the information was not used for adverse employment actions.

Recent and Upcoming Meetings

The National Coalition for Health Professional Education in Genetics (NCHPEG) NCHPEG is an organization comprised of leaders from health care professional organizations, consumer and voluntary groups, government agencies, industry, managed care organizations and genetics professional societies whose purpose is to provide an organized, systematic, and national approach for providing genetics education. The organization was established in 1996 by the American Medical Association, the American Nurses Association, and the NHGRI. Currently, there are three working groups: 1) The Information Center, that is developing a website; 2) the Core Competencies/Genetics Curriculum group, that is identifying a core curriculum for all health care professionals to integrate genetics into the prevention, diagnosis, and management of disease; and 3) the Education/Licensure/Certification group, that will facilitate the integration of genetics content and questions into continuing education programs, certification, and licensure exams.

Now that NCHPEG is established, there is concern regarding the long-term financial support of this organization. The NCHPEG Steering Committee has expressed a desire for a balanced public-private partnership, rather than being housed completely within one of its member organizations or becoming a free-standing non-profit organization. Steering committee members have also discussed the potential use of a foundation to serve as the NCHPEG fiscal manager under the public-private partnership model.

The new National Foundation for Biomedical Research (NFBR) is a congressionally-created foundation "dedicated to creating public-private partnerships to promote the mission of the National Institutes of Health." NFBR can raise and distribute funds in support of education programs that benefit medical research. The NFBR Board met in January 1998 and was overwhelmingly in favor of serving as the Coalition's fiscal manager. The Coalition's Steering Committee will consider using NFBR as its fiscal manager in the coming weeks.

David Cox asked about the NCHPEG Web site and expressed concern that many health care professionals either do not have access to information on the internet or do not seek information using that mechanism. In March 1998, the AMA will host a meeting in New Orleans in partnership with the NHGRI, the ASHG, and a number of professional medical groups, to reach out to physicians in the community who must deal with genetics issues when providing primary care and educate them on how to use the internet to obtain genetic information. However, Dr. Clayton indicated that large conferences may not be the best mechanism for educating physicians and that it is hard to reach those who really need this information. Dr. Collins indicated that the NCHPEG working group on education/licensure/certification would be working on this problem.

Follow-Up ACOG/ACMG Workshop on Cystic Fibrosis Consensus Conference Recommendations Since the cloning of the cystic fibrosis gene in 1989, there has been debate about who should be tested for this gene. An NIH Consensus Development Conference on Genetic Testing for Cystic Fibrosis was held on April 14-16, 1997. The consensus panel recommended that genetic testing should be offered to 1) adults with a positive family history of cystic fibrosis (CF), 2) to partners of people with CF, 3) to couples currently planning a pregnancy, and 4) to couples seeking prenatal testing. The panel did not recommend offering the test to the general population or to newborn infants at this time. The panel wanted the testing to be phased in to ensure that adequate education and counseling services were available to all persons being tested.

A Follow-Up Workshop on the Cystic Fibrosis Consensus Conference took place on October 15-16, 1997. This meeting brought together diverse professional and consumer representatives to further deliberate the issues surrounding genetic testing for CF. The group came out with a strong recommendation that interdisciplinary professional and consumer groups continue to work together to provide further clarification about protocols for CF genetic testing. In addition, the consensus of the participants was that an 18 to 36 month time line for further implementation of CF genetic testing was desirable; therefore, such testing is not considered to be the "standard of care" at this time.

The American College of Obstetrics and Gynecology (ACOG) and the American College of Genetics (ACMG) will be meeting with NHGRI representatives on February 20, 1998 to initiate the formation of a steering committee and working groups to develop guidelines to support the implementation of the Consensus recommendations.

Council members expressed concern over whether the participants in the Consensus Panel had sufficient information on which to base their recommendations and if there was too much pressure to put out a report within a specified timeframe. The appropriate allocation of resources with regard to the cost of genetic testing was also discussed. There is a whole array of possible options that can be delivered by the health care system. Decisions have to be made about what is most important, not just what people are interested in. There was debate about whether the consensus development process was the ideal way to proceed.

There was also concern that if you "offer" a test, it will inevitably happen. Elizabeth Thomson indicated that the Consensus Panel debated between making information "available" on CF genetic testing versus "offering" a test. However, the panel felt that just making the information available would limit access to the testing (i.e., to people who can read or are highly motivated). Dr. Collins believed that the procedures for introducing CF carrier testing had been done properly and should serve as a model for implementing genetic testing.

Dr. Kurt Hirschhorn asked if anything was happening with regard to life insurance and genetic testing. Dr. Collins indicated that discussions were ongoing in Great Britain regarding the minimum amount of life insurance a person can get despite any genetic test information. However, in the United States, the current battles have to do with health insurance, and underwriting for life insurance has received less attention.

Computational and Mathematical Biology Applications to Genomics and Genetics Research

The Human Genome Program (HGP) will produce vast amounts of genomic DNA sequence information within the next five to ten years. This information will be of little value to biologists if the tools to manage and interpret the information are not available and are not user friendly. There is concern regarding how to get scientists with backgrounds in mathematics, physics, informatics, statistics and computer science involved in genetics research. Consequently, NHGRI staff surveyed scientists in academia from departments of mathematics, physics, computer science, etc. to find out the barriers/opportunities that could be addressed by the NHGRI, acting individually or in collaboration with other components of NIH or the private sector. The following recommendations were presented by Dr. Bettie Graham.

Infrastructure. While, ideally, new departments should be set up to deal with the interface of mathematics and computational biology and genetics research, the current climate in academia probably would not be conducive to this because of financial considerations. Instead, individuals in authority (Provosts, Chancellors, Deans, and Department Heads) should be made aware of the broad range of opportunities that computational and mathematical biology present in biology and medicine. In addition, private and philanthropic organizations should be encouraged to support endowed chairs in departments of mathematics and computer sciences and related disciplines for those working on biological problems and vice versa.

Curriculum Development. Most scientists indicated the need for release time for themselves or other appropriate staff to develop courses or curricula at the interface of biology and the other non-biology disciplines relevant to the Human Genome Project. One solution was the use of the academic career award (K07) mechanism to develop curricula in computational and mathematical sciences as they related to genomics and genome analysis.

Career Development and Research Training. The need to have a cadre of individuals trained at the interface of biology and the non-biological sciences relevant to the Human Genome Project will become even more critical as the large-scale sequencing projects ramp up. The establishment of an institutional K01 program award would provide a critical mass of computational and mathematical biologists working in areas critical to genome research and analysis. It was recommended that the number of individual K01 awards be increased. Institutional training grants were also considered an important mechanism for increasing the number of computational and mathematical biologists. It was also recommended that: (1) the number of training grants in genomics that emphasize computational or mathematical biology be increased; (2) industry be encouraged to supplement the stipend levels of trainees and fellows; (3) that NHGRI pay full tuition cost on training grants rather than the current tuition policy of paying 100 percent of full tuition that is $2,000 or less and only 60 percent of tuition above $2000; (4)other components of NIH should be encouraged to initiate or increase the number of training grant programs that interface with mathematics, statistics and computer sciences; and (5) that the NIH institutes co-sponsor training grant programs.

Research Individuals interviewed expressed concern about how research projects in computational and/or mathematical biology are evaluated. They recommended that these types of projects should be funded for more than three years and that there be increased dialogue with the research community to increase awareness of the research opportunities in computational and mathematical biology.

Dr. Michael Teitelbaum of the Sloan Foundation indicated that his organization in collaboration with the Department of Energy (DOE) had developed a program that was successful in attracting researchers trained in computational and mathematical sciences into the biological sciences. NHGRI staff were encouraged to speak with the Sloan/DOE Fellows, which led to the following conclusions and recommendations:

  1. NHGRI was not doing a good job of communicating with the target audience. As an example, the Sloan/DOE fellows had not heard about NHGRI's career development programs.

  2. "Matches" for interdisciplinary training were usually achieved by serendipity. A better, more efficient process needs to be developed.

  3. Curriculum should be developed to spark an interest in interdisciplinary training at the undergraduate level.

  4. The eligibility requirements for the K01 program need to be expanded to include individuals who have had up to two years postdoctoral experience.

  5. Sloan/DOE fellows stated that they needed additional time in order to transition into independent careers.

It was suggested that annual meetings of professional associations would be a good venue to expose researchers in non-biological fields to the exciting research opportunities in genomic research and analysis. Also, information could be disseminated via a Web site and through bulletin boards of the various professional societies.

Dr. Teitelbaum said that since 1994 there has been a greater demand for computational sophisticated people in biological sciences, and at the same time there has been a surplus of Ph.Ds in the computational areas who are finding a limited job market.

Dr. Finley Austin of the Merck Genome Research Institute described her organization's program, founded in 1996, to fund functional genomics research activities. Bioinformatics is the target area. This program is committed to supporting individual investigators, and so far it has funded three researchers. However, the Merck Genome Research Institute is also interested in curriculum development and will partner with other institutions in Government.

Dr. Nancy Sung of the Burroughs Wellcome Fund described her organization's program, which is to train scientists at the interface. Each year, several awards of up to $500,000 per year for five years are made to institutions working at the interface between the physical/chemical/computa- tional sciences and the biological sciences. These funds can be used to support students and postgraduate fellows, faculty seed money and invited lectures.

Dr. Chakravarti indicated that he agreed that professional societies like the American Chemical Society were a good source for promoting interdisciplinary career opportunities. Dr. Graham indicated that this was an area that would be addressed in the future.

Dr. Mathies indicated that undergraduates realize that there are career opportunities for mathematical, physical and computational researchers in the biological sciences. However, post-doctoral programs are limited to 2 to 3 years, and this becomes a barrier to meaningful cross training. Institutional programs need to be developed to meet this need.

Dr. Horvitz said that there should be a comparable review of the trends in industry and the private sector as there has been for academia. Within academia, there are barriers to setting up new departments and funding limitations. However, the private sector could provide funding and training, and candidates should be able to move from the industrial sector to academia. Sometimes there may be reasons why researchers are reluctant to reveal connections between industry and academia, and these concerns need to be resolved.

Dr. Hood mentioned that when postdoctoral fellows from fields such as physics, computer science or mathematics are brought into biological research, they tend to be "used" as technicians, and learn biology in a narrow way. This is not a good career move for them. He felt the K01 grants should offer a two-phased program with lab rotations to learn biology for two years and a third year to work on actual research problem solving. Dr. Graham indicated that this is what the K01 program does.

Dr. Williamson also felt that it was important to get key people in industry involved in training programs using mechanisms such as internships and job rotations in industry. When graduate students and postdoctoral fellows intern in both industry and academia, it increases their career options. However, trainees need to be paid by industry when they are interning for industry, and mechanisms for co-funding need to be set up between industry and academia. The issues of proprietary information also need to be addressed.

Council agreed that a round-table should be set up to discuss these issues in greater detail. Dr. Williamson will work with NHGRI on this project. Dr. Hood stressed the importance of including smaller biotech companies in these discussions; and Dr. Duster wanted to be certain that curriculum issues were addressed.

Dr. Collins asked how professional societies such as the American Chemical Society and the American Physics Society could be involved in this project. Using society newsletters to disseminate information and having representatives at professional meetings to describe job opportunities were suggested. Dr. Graham offered that NHGRI staff and grantees could present a symposium at a professional society meeting on interdisciplinary career opportunities.

Dr. Collins was concerned that interdisciplinary training programs actually foster true mentoring relationships, so that trainees do not become mere technicians. Dr. Graham indicated that under the Sloan/DOE Fellowship Program, trainees seemed to work best in larger laboratories, where they could interact with many people. Dr. Wold felt one-to-one match-ups still had merit and suggested that trainees could serve 3- to 6-month rotations before deciding on a mentor.

Dr. Graham encouraged council members to share this report with their academic deans and department heads.

Concept Clearance for Three Career Awards

Dr. Graham presented three career awards for consideration by the Council. The K01 is a revision of a previous program announcement. The K12 and K07 are new career awards.

  1. The Individual Mentored Research Scientist Development Award in Genomic Research and Anaylsis (K01) is aimed at increasing the number of non-biologists trained in genomic research and analysis. The eligibility criteria will be expanded to include non-biologists who have had up to two years postdoctoral experience in the biological sciences. The program will also be opened up to non-biologists in related areas, such as, bioinformatics, computational biology, statistics, biomathematics and bioengineering. This is an award with a maximum of five years of support. The career development period is divided into two phases - didactic training and laboratory rotations and research. The salary cap remains at $75,000.

  2. The Institutional Mentored Research Scientist Development Award in Genomics Research and Analysis is the equivalent of an institutional K01 award and will give an institution the authority to fill up to three slots. The purpose and allowable costs for individual appointees is the same as for the individual K01 award. Applicants apply to the institution and the institution selects the individuals. This is a five year award.

  3. The Curriculum Development Award in Genomic Research and Analysis supports the development and implementation of new courses or curricula that combine knowledge and concepts of genomics and genetics with computer science, mathematics, chemistry, physics, engineering or closely related scientific disciplines. Provisions of the award include salary for release time to develop and implement courses and ancillary support for collaborators, consultants, supplies, equipment, etc.

Dr. Chakravarti questioned why these awards were not developed as part of training grants. Dr. Graham explained that a training grant only allows for very limited costs related to the research experience of graduate students and postdoctoral fellows. A discussion ensued regarding the need to combine the curriculum development award with training programs. It is essential that curricula not be developed in isolation. Grantees developing curricula should be able to test the program with trainees. It was suggested that this concept be combined with a training program, or perhaps the award should be made to individuals with training grants. Dr. Collins indicated that grantees would not want to apply for two separate grants, and that we need to explore better ways of bridging the two kinds of awards. In any event, training grant directors should be made aware of the new awards.

Dr. Cox indicated how important it is to pay salaries to individuals to free up their time to work on these kinds of projects.

The Council indicated approval of the three new initiatives.

Overview of NCI Activities

Dr. Richard Klausner, Director of the National Cancer Institute (NCI), made a brief presentation to the Council about planning and initiation of NCI research programs. Several of these programs have been undertaken in collaboration with the NHGRI. Dr. Klausner noted that the NCI uses the bypass budget as both a planning and budget document, which is submitted directly to the President. He specifically discussed the areas of cancer research referred to in the bypass budget as "extraordinary opportunities for investment" in cancer research. An extraordinary investment opportunity must meet the following criteria: 1) it must offer new scientific insights; 2) it must have implications for all cancers; and 3) it must involve the entire community. The areas identified as extraordinary opportunities are: preclinical models for human cancers; developmental diagnostics; cancer genetics; and imaging sciences. In order to identify robust research opportunities in these areas, the NCI has established several working groups to develop recommendations for infrastructures that will facilitate cancer research in these areas. Dr. Klausner briefly described some of the activities of these working groups, which function as ad hoc think tanks.

Cancer Genetics Working Group. The discussions of this group provided the general guidelines for the development of the National Cancer Genetics Network, which will soon be funded. The group is co-chaired by Drs. Kenneth Buetow, Alfred Knudson and Barbara Weber.

Preclinical Models for Human Cancers Working Group. This group, co-chaired by Drs. Douglas Hanahan and H. Robert Horvitz, is looking into animal models for cancer, and includes several subgroups: 1) Mouse Genomics and Genetics; 2) Mouse Models of Human Cancers; and 3) Non-mammalian Models of Human Cancers. The Mouse Genomics and Genetics Subgroup is collaborating with NHGRI to sponsor a workshop on March 19 - 21, 1998.

Developmental Diagnostics Working Group. This group, co-chaired by Drs. Eric Lander and Arnold Levine, provided the general recommendation for an infrastructure that would provide the molecular characterization of normal and malignant cells. This led the NCI to the development of the Cancer Genome Anatomy Project (CGAP) and the Tumor Gene Index (TGI). The goals of CGAP are: to enhance the discovery of acquired and inherited molecular changes involved in cancer; and to apply these discoveries in the clinical arena by creating and disseminating technologies required to read and interpret the molecular features relevant to cancer predisposition, development, prevention, detection, diagnosis, prognosis and treatment. Discussions of this group have led to improved methods of obtaining and analyzing tissues, including laser capture microdissection and an evaluation of approaches for preserving tissue for gene analysis.

The information obtained via CGAP is available on the Web at http://www.ncbi.nlm.nih.gov/ncicgap. Sixty to seventy percent of the new genes currently being discovered are coming from CGAP. To date, approximately, 200 libraries have been made and 68 have been sequenced. The website offers a great deal of additional information. For instance, there are 28,000 sequences on prostate cancer, and 30 to 40% of the genes of interest are tissue specific. Based on recommendations from the preclinical models for human cancers working group, the NCI plans to establish a mouse-CGAP, similar to the human CGAP. The NCI is involved in the development of new technologies for gene discovery and analysis, and has issued an RFA on technologies for high-throughput analysis.

Council members discussed with Dr. Klausner these and other activities of the NCI. Dr. Nadeau emphasized the need for other analytic tools to be developed parallel to the development of the website. Dr. Chakravarti wanted to know how cancer centers decided which cancers will be studied. Dr. Horvitz elaborated on the recommendations of the Preclinical Models for Human Cancers Working Group for using model organisms (yeast, worm, fly, fish, and mouse) to study the human. The Council raised issues about the use of the CEPH families as the basis for the identification of single nucleotide polymorphisms (SNPs). These issues included the lack of ethnic diversity of the CEPH registry and the potential for missed opportunities for determining the significance of SNPs in the development of cancer. Dr. Clayton also raised the issue about protecting the participants in the Cancer Genetics Network from discrimination. In response to the issue regarding the use of the CEPH families to detect SNPs, Dr. Klausner distinguished the technology assessment phase of the genetic annotation project from the SNP discovery phase. The technology assessment phase will rely on the already consented CEPH families in order to establish Mendelian transmission as part of SNP technology validation. The SNP discovery phase will utilize DNA from diverse populations, and common and standard DNA sets as they become available. In response to the issue of protecting the confidentiality of the participants in the cancer genetics network, Dr. Klausner recognized the complex nature of ensuring these protections and noted that the NCI is actively exploring potential encryption technologies and other methods to ensure confidentiality of patient information. Dr. Clayton stated that it will be important to include representatives of the participant community in these discussions. Dr. Klausner agreed, and cited the activities of the recently-established [NCI] Director's Consumer Liaison group.

Report from the Department of Energy

Dr. Ari Patrinos presented an update on activities at the Department of Energey (DOE). He began by discussing the report of the JASON group This committee, consisting mainly of physical and information scientists, was set up to review the DOE Human Genome Project. The group focused on three areas: technology, quality control and quality assurance, and informatics. The report warned that DOE must make significant improvements in the technology used to sequence the genome to reach the 2005 target goal. Despite concerns expressed about the adequacy of the report, Dr. Patrinos feels that eventually interaction with physicists and information scientists will pay off, and DOE wants to continue activities and support of training in the area of informatics.

Regarding the budget, DOE was not as fortunate as NIH this year. However, the Department did receive an additional $5 million for its Microbial Genome Program and a 7 percent increase for genomic efforts. Despite any budgetary concerns, DOE will continue to make funding the Human Genome Project (HGP) a high priority.

The DOE has been heavily involved in organizing the Joint Genome Institute (JGI). This project will be a community effort between the three National Laboratories involving collaboration with researchers at other sites contributing new sequencing technologies. The JGI will enable the DOE to support its fair share of the sequencing efforts of the HGP and to play a significant role in the international HGP. Dr. Patrinos recognized the efforts of those individuals who were instrumental in establishing a management system for the JGI, and indicated that approximately $16 million in awards over a three-year period had been made to enhance the success of the JGI. This included a three year, $11 million award to Dr. Eric Lander, and technology development awards to Dr. Ron Davis at Stanford University and Dr. Trevor Hawkins at the University of Florida.

Dr. Patrinos reported that the DOE is involved in efforts to reform and rehabilitate its long-term technology program and is reassessing its informatics program. The Genome DataBase (GDB) has ended, but for now, a "static" version will continue. A joint DOE-NHGRI workshop is planned for April 2-3, 1998 to look into informatics needs.

Dr. Chakravarti asked about DOE's approach to long-term technology issues. DOE should be concerned with how we will be sequencing in the future, as well as production sequencing.

Dr. Wold indicated that the JASON report highlighted the difficulty of getting the best physical scientists interested in the biological sciences.

Council members expressed concern about the demise of the GDB and the urgent need to develop a replacement database. Dr. Collins indicated that the NCBI is looking into how to fill the gap for now.

Dr. Patrinos indicated that DOE continues to be very interested in the development of the new 5-year plan for the Human Genome Project and is carrying on planning activities in parallel with the NHGRI.

Report on the Second Large-Scale Sequencing Quality Assessment Exercise

The results of the second Quality Assessment Exercise are currently being reviewed, and the excercise is still on-going. However, preliminary indications are that most of the centers are generating DNA sequence that meets or exceeds the accuracy standards. Based on these results, it appears that all centers are capable of sequencing at the required level of accuracy. Furthermore, this method of checking appears to be a useful way of assessing sequence quality, since there was a good consistency between the checkers' reports. The results may also provide insight into how errors arise.

Dr. Cox indicated that the exercise should be very useful, but raised concerns about the contig size of the regions being sequenced. There was a general agreement among Council members that we need to force investigators to sequence longer stretches, and that the standard for the sequencing centers should be raised. Dr. Jordan said this issue would be addressed in the new 5-year plan.

Upadte on 5-Year Planning Activities

Dr. Aravinda Chakravarti summarized the activties of his Council Planning Subcommittee, which is helping to develop a new strategic plan for NHGRI. The committee has met several times to discuss issues relating to sequencing, sequence-based variaton, sequence-based function, informatics and ELSI concerns. In addition, Dr. Chakravarti has been instrumental in organizing several workshops to discuss specific areas of interest for the 5-year plan.

A Resource for Discovering Human DNA Polymorphisms Dr. Lisa Brooks reported on an NHGRI project to establish a resource of DNA samples and cell lines that can be used to discover SNPs (single nucleotide polymorphisms) in the U.S. population. The resource design came out of a workshop held by NHGRI on December 8-9, 1997. SNPs are a useful tool for genetic researchers, and there is a great need to find SNPs and get them into the public domain. NHGRI has recently issued an RFA on SNP detection, which includes technology development and production of SNPs.

The SNPs to be found will include random SNPs, SNPs in particular regions, and SNPs that represent potential functional variants in known genes. The resource will include cell lines and DNA from 450 unrelated individuals. To maximize the chances of discovering the common DNA sequence polymorphisms, the individuals sampled will be U.S. residents with diverse ethnic backgrounds, including African-Americans, European-Americans, Mexican-Americans, Native Americans, and Asian-Americans. The cell lines will come from several sources, including the CDC NHANES III study, existing collections, and on-going collection studies. All samples will come from individuals who have provided informed consent to be part of this resource. Although information about geographic origin of ancestry and sex will be collected in order to ensure a diverse sample, all identifying and phenotypic information will be removed from the individual samples so that links to the individual donors will be irreversibly broken. The samples will be deposited with the Coriell Institute, which requires that all uses of the samples must have been approved by an IRB or designated as exempt.

All SNPs found under this RFA will be placed in a central database, which is under development.

Council debated the value of having samples from diverse populations, since most genetic variations are shared by populations throughout the world. Dr. Cox felt that since you can't accurately represent world samples, you are complicating issues unnecessarily by insisting upon a diverse population. It was felt that diversity was both a political issue and a scientific issue. However, some genetic variations do exist only in certain geographic regions around the world, and recently arising variants are more likely to be found in only some groups. Several council members indicated that they favored the diversity of the sample scheme. The starting point should be a diverse sample, even if it imperfectly reflects the exact distribution of global variation.

Functional Analysis of Genomic Sequences. Dr. Elise Feingold reported on the workshop on the Functional Analysis of Genomic Sequences, held December 2-3, 1997. The purpose of the workshop, which was attended by a small group of scientists from the research community representing a broad range of biological expertise, was 1) to define the biological questions which can be addressed using genomic approaches to gain insight into the function of genomic sequences; and 2) to explore what new technology and resource development will be required to facilitate genomic approaches to these questions. Dr. Feingold reported on the recommendations made by this group:

  1. Production Resources. The workshop participants endorsed the production of full-insert human cDNA sequences, and possibly mouse cDNA sequences. Sequencing the mouse genome in the near future was unanimously recommended. Since the cost of DNA sequencing is still relatively high, development of a strict set of criteria for determining what other genomes should be sequenced was recommended. Further support of technology development to reduce the cost of genomic sequencing was strongly endorsed.

  2. Technology Development. The group cited numerous opportunities for technology development, including technologies for determining the funtion of non-coding sequences, improving the generation of full-length cDNAs, determining the function of proteins from structure, and analysis of protein expression and protein interactions.

  3. Bioinformatics and Training. It was recommended that NHGRI support the development of new tools for data representation, visualization, and analysis to build the capability to handle complex sets of data arising from genomic analyses. There was also a strong endorsement for training in the area of computational biology.

Dr. Hood led a discussion on alternative strategies for mouse sequencing to get the information sooner rather than later. He felt the value of sequences with an accuracy lower than 1 error in 10,000 should not be underestimated. It was also noted that, while currently there is little effort to sequence the mouse genome, in the current RFA for production sequencing, the sequencing centers can propose to do up to 10 percent of their sequencing on the mouse.

Large-scale Sequencing Principal Investigators Meeting: Dr. Mark Guyer reported on the December 18, 1997 meeting in which the principal investigators (PI) of the NHGRI-funded large-scale DNA sequencing projects met with members of the Council Planning Subcommittee and NHGRI staff to discuss large scale sequencing in the new NHGRI 5-year plan. Critical issues discussed at the meeting included: 1) sequencing costs; 2) scale-up plans and sequencing capacity; 3) technology development; 4) the merits of centralized mapping; and 5) the role of mouse sequencing.

The PIs were optimistic that the goal of completing the human genome sequence by 2005 could be attained. However, there were concerns about costs. Although difficult to estimate, there was general agreement that current unit sequencing costs appear to be about $0.50 per base pair. At the same time, there was less optimism than in past discussions about the likelihood of significant cost reductions in the near term. However, there was also agreement that there is not a good generic approach to cost accounting for DNA sequencing and that one is very much needed. One proposal was presented in which costs are broken down according to process (i.e., per-lane accounting). This was considered to be more useful for assessing which parts of the process might be amenable to cost reduction. There was also concern that a cost model described by NHGRI staff that allowed $60 million per year for large-scale human sequence production would not be adequate.

The PIs emphasized the importance of maintaining high standards for sequence quality and adopting ambitious goals beyond the human genomic sequence to assure a long-term future for the sequencing centers. The council pointed out that having goals for high throughput sequence generation beyond the completion of the first human sequence would also help stimulate further technology development.

In the subsequent discussion, members of the Council planning subcommittee introduced the concept of framing the sequencing discussion in the next five-year plan in terms of developing "sustained sequencing capacity" of several hundred megabases per year. This approach would address several issues that were raised at the PI meeting:

  • Providing incentive to participants and institutions to look forward to being involved in large- scale sequencing after the completion of the first human sequence
  • Producing large amounts of DNA sequence at increasingly lower cost, while maintaining standards of sequence accuracy and continuity.
  • Developing the capacity for sequencing large genomes other than the human, e.g. mouse, other mammals, other vertebrates, etc.

Dr. Cox noted the critical importance of having an involved, proactive council. While advice from experts, such as the PIs in the case of sequencing, is critical, experts necessarily have their own agendas. It is ultimately the responsibility of council to listen to the advice of all interested parties, evaluate that advice, and offer its judgement to the institute. Similarly, Dr. Wold commented that it was important for council to help set realistic goals for accuracy and cost in the face of the ever-present temptation to create unrealistic expectations.

Dr. Cox also concluded that the recent sequence quality assessment exercise had been very important, and supported staff's proposal to continue such exercises. Dr. Hood indicated that the council should take another look at numbers and dynamics, and not be held to the "gold standard" of 1 in 10,000 accuracy. He pointed out that sequencing to an error level of 1 in 1,000 would save money and may be satisfactory. Other members were not ready to endorse a greater error level.

Dr. Horvitz reminded council that once the human genome sequence is complete, there will be great utility in sequencing the genome of another model organism because comparative analysis will give us a great deal more information that will be useful in identifying genes, alternative splice products, regulatory regions and regulatory hierarchies.

Dr. Valle felt the council should go on record as saying that there are enough funds to complete the human genome sequence, even if the cost of sequencing base pairs does not change.

Dr. Jordan and Dr. Collins pointed out that there are several upcoming meetings where these, and other, issues will be considered, including the mouse meeting in March, the DOE informatics meeting in April, and the Airlie House meeting in May to discuss feedback on the draft of the 5-year plan.

Report on ERPEG Activities

Dr. Ellen Clayton reported on the activities of the ERPEG Committee that has been evaluating the ELSI Research Program activities and its portfolio. The committee concluded that the portfolio has many strengths, particularly in the clinical integration part of the portfolio, (e.g. the Cystic Fibrosis Studies Consortium and the subsequent Consensus Development Conference on Genetic Testing for CF and the Cancer Genetics Studies Consortium).

The committee also identified some weaknesses, particularly in the areas of disciplined intellectual inquiry. There is underrepresentation of some research communities and types of applications. ERPEG has identified a need to explore alternative review and funding mechanisms in order to broaden the array of disciplines that may be successful in their applications and that can deal with some of the interdisciplinary issues that have arisen. ERPEG has also raised some concerns about grantee accountability and what can be done when a grant is awarded and no grant product is produced.

The ELSI portfolio is concentrated in two major areas: research and education. Genetic diversity and variation is an important topic in both these areas. The planned research on SNPs in diverse populations raises a whole host of questions that will need to be addressed.

There are 26 possible goals now under consideration for the ELSI Research Program, which now must be prioritized. With regard to the education part of the portfolio, ELSI needs to clarify who the audience should be and how best to reach them. ERPEG wants to encourage ELSI to think "outside the box" and look more explicitly at priorities, requirements for applications, and possible new funding mechanisms.

Dr. Clayton stated that an RFA on ELSI issues related to diversity would be appropriate. She also suggested that there could be changes in the Program Announcement to deal with diversity issues as well.

Dr. Buchanan commented on his experience as a reviewer of ELSI grants. It was his belief that there were too many social science proposals that were weak in ethics, and too many ethics proposals weak in methodologies or not relevant to the HGP. Many of the philosophical and analytic proposals were completely disconnected from empirical research.

Dr. Clayton acknowledged that interdisciplinary work is difficult to encourage. She said that it is hard to get people in medical schools to talk to people in law schools. In her view, projects that are truly interdisciplinary traditionally haven't fared well. She stated that the review process should be more open to interdisciplinary proposals and methodologies. This is one area where smaller "seed" grants should be considered.

Dr.Clayton expressed that the religous community should be encouraged to participate more in the deliberation and consideration of ELSI issues. While other council members agreed that the religious perspective was missing from the ELSI portfolio, there was concern about what kinds of religious projects were appropriate for ELSI funding. Some concluded that such projects should not espouse a particular religious view. Disciplined intellectual inquiry is desired. Religious views that cross cultures are also of more interest than those that have a more narrow view and are specific to particular groups.

Dr. Collins indicated that the AAAS was promoting a dialogue between scientists and religious spokesmen regarding issues of genetic discrimination. He felt, however, that many religious organizations would not apply for ELSI money for fear of being viewed as having been compromised by accepting federal money from the HGP.

Dr. Wold wanted further clarification regarding the concerns that had been raised by ERPEG about accountability. Apparently there have been some grants that have led to no discernible output. The reason for this is not always obvious. She asked if periodic detailed technical reports were required. ELSI grants are monitored in the same way that other NIH grants are, with review of annual progress reports and competitive renewals. Dr. Clayton suggested that may of these problems reflect "early" ELSI projects, and that these concerns do not apply to many current ELSI activities. A need was identified to monitor ELSI projects to see if the ratio of success to failure is any different than for other kinds of research grants. Ms. Elizabeth Thomson indicated that 125 ELSI grants were funded to date and that they had resulted in 250 publications. She also said that the NIH has no systematic tracking system for publications and other grant products. She reported that competitive renewals without evidence of products do not fare well in peer review.

Dr. Clayton expressed unhappiness with continued ad hoc review groups. Ad hoc groups do not build cohesiveness and trust and in her view are far less effective in their review of applications. She also reiterated that the review mechanism needs to be more respectful of very diverse methodologies.

Statment of Understanding

Ms. Jean Cahill presented changes in the Statement of Understanding Between the Staff of the National Human Genome Research Institute and the National Advisory Council for Human Geonome Research. These changes in the guidelines indicate when NHGRI staff can make supplemental awards which are above the level recommended by council without having to go back to council for approval. The new guidelines refer to total cost increases instead of direct cost increases, which is easier to track. In addition "the amount of increase (total costs) per project period will be limited to 25 percent or $150,000 total costs, whichever is greater, of the annual total cost level approved by council. A special exception to this 25 percent rule may be made in the case of one time equipment costs which will increase the speed and efficiency of mapping and sequencing projects". This change will be of benefit in dealing with smaller grants, where the 25 percent rule was too restrictive. Dr. Horvitz felt it was unclear whether the guidelines as written applied to a single year of the grant or the whole project period. With the understanding that the language will be clarified, council approved the changes.

Announcements and Items of Interest

Dr. Jordan noted the items of interest, which are listed on the agenda.

Council-Initiated Discussion

Dr. Clayton raised concern about an FDA and OPRR notice in the Federal Register, "Protection of Human Subjects: Suggested Revisions to the Institutional Review Board (IRB) Expedited Review List; Request for Comments." This notice was published November 10, 1997, without any fanfare, in fact, with few people even being aware that the revisions were being proposed. In her view, the proposed changes were worrisome, in that they expanded the list of research protocols that could have an expedited review. She felt that this was not the time for OPRR to be proposing rules to expand this list, particularly since the National Bioethics Advisory Committee was considering this issue and might come up with recommendations that were at odds with the proposed rules.

Dr. Clayton intends to make comments in response to this notice, which are due by March 10. She encouraged others to look the notice over and express any concerns that they have as well. Dr. Cox assured Dr. Clayton that NBAC was reviewing the notice and would make comments if needed.

Review of Applications

The council reviewed 49 applications, totaling $21,393,449. The applications included eight regular research grants, five pilot projects, 13 ethics grants, three grants in response to request for application, two center grants, one conference grant, two continuing education training programs, 13 small business innovative research awards-phase I, and one small business innovative research award-phase II. A total of 30 applications, requesting $8,278,352 were recommended.

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Last updated: March 01, 2006