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National Advisory Council for Human Genome Research
Summary of Meeting

Bethesda Hyatt
Bethesda, Md.

February 9, 2004

The open session of the National Advisory Council for Human Genome Research was convened for its fortieth meeting at 8:37 a.m. on February 9, 2004 at the Bethesda Hyatt, Bethesda, Md. Francis Collins, Director of the National Human Genome Research Institute, called the meeting to order.

The meeting was open to the public from 8:37 a.m. until 4:17 p.m. on February 9, 2004. In accordance with the provisions of Public Law 92-463, the meeting was closed to the public from 4:17 p.m. on February 9, 2004 until adjournment for the review, discussion, and evaluation of grant applications.

Council members present:

David Burgess
Ronald Davis
William Gelbart
Mary Hendrix
Eric Juengst
Bronya Keats
Richard Lifton
Richard Myers
Kim Nickerson
George Weinstock
Tadataka Yamada
Vickie Yates Brown

Council members absent:

Beverly Gaines
Janet Rowley
Robert Tepper

Ad hoc members present:

Sean Eddy

Ex Officio member present:

Gerry Schellenberg

Staff from the National Human Genome Research Institute:

Christopher Austin, OD
Maggie Bartlett, OD
Joy Boyer, DER
Lisa Brooks, DER
Comfort Browne, DER
Jean Cahill, DER
Monika Christman, DER
Francis Collins, OD
Karen DeLeon, OD
Kathleen Deloach, OD
Tanya Dougans, DER
Elise Feingold, DER
Adam Felsenfeld, DER
Peter Good, DER
Bettie Graham, DER
Alan Guttmacher, OD
Mark Guyer, DER
Linda Hall, DER
Rabiah Hendricks, DER
Sandra Kamholz, DER
Tim Leshan, OD
Jean McEwen, DER
James McWilliams, DER
Ken Nakamura, DER
Vivian Ota Wang, DER
Ken Ow, OD
Bradley Ozenberger, DER
Allison Peck, DER
Jane Peterson, DER
Rudy Pozzatti, DER
Eddie Rivera, OD
Jerry Roberts, DER
Laura Rodriguez, OD
Jeff Schloss, DER
Pam Sellman, DER
Geof Sisk, DER
Geoff Spencer, OD
Shundel Stephenson, DER
Larry Thompson, OD
Elizabeth Thomson, DER
Susan Vasquez, OD
Kris Wetterstrand, DER
Jon Witonsky, DER
Lynn Zacharia, DER

Others present for all or a portion of the meeting:

Joann Boughman, American Society of Human Genetics
Jennifer Couzin, Science magazine
Peter Chrosthwaite, Office of the Director, NIH
Sean Eddy, Washington University
Joann Howanna, Blue Sheet
Rodney Howell, American College of Medical Genetics
Manolis Kellis, Broad Institute/MIT
Edward Kloza, NSGC
Pat Kobor, American Psychological Association
Dierdre Meldrum, University of Washington
Ari Patrinos, Department of Energy
Asha Pathak, Office of the Secretary, DHHS
Michelle Russell-Einhorn, Office of Prevention from Research Risks, NIH
Margaret Snyder, Office of the Director, DER, NIH
William Talbot, Stanford University

Introduction of Liaisons and New Employees:

Mark Guyer welcomed members of the press and liaisons from professional societies: Rodney Howell from the American College of Medical Genetics, Joann Boughman of the American Society of Human Genetics, Joann Howanna from Blue Sheet, Jennifer Couzin from Science. Dr. Guyer introduced new NHGRI staff members: Bradley Ozenberger, Program Director for Technology Development, Vivian Ota Wang, Program Director for ELSI, and Eddie Rivera, NHGRI Chief Budget Officer. Dr. Guyer also introduced speakers for the open session: Deirdre Meldrum (U Wash), Will Talbot (Stanford), Manolis Kellis (Broad), and Sean Eddy (Wash U).

Approval of Minutes

The minutes from the September 15, 2003 Council meeting were approved as submitted.

Future Meeting Dates:

The following dates were proposed for future meetings: May 10-11, 2004, September 13-14, 2004, February 7-8, 2005, May 23-24, 2005, September 12-13, 2005, and February 13-14, 2006.

Director's Report

General Announcements

Francis Collins attended the World Economic Forum in Davos, Switzerland, and led several sessions. He reported that genomics and its impact on biomedical research figured prominently in the scientific proceedings.

Two former members of NACHGR, Leroy Hood and Bob Horvitz, were elected to the Institute of Medicine this past October. Michael Gottesman (former Acting Director of NCHGR) and Oliver Smithies (former member of the NHGRI Board of Scientific Counselors) were also elected.

On December 5, 2003, the NHGRI Intramural program held a daylong scientific symposium to commemorate its 10th anniversary. The symposium, "From Base Pairs to Bedside," featured a number of scientific talks. The first chair of the Board of Scientific Counselors (and current Council member), Janet Rowley, M.D., presented the first annual Jeffrey Trent Lecture in Cancer Research at the NIH.

Dr. Zerhouni has designated Dr. Collins to serve as the NIH liaison to the Department of Energy. His role will be to facilitate effective coordination of joint NIH-DOE activities, and to help explore areas of shared interest between NIH and DOE.

The NIH Steering Committee has been formed as a primary mechanism for NIH governance, specifically to oversee and develop common policies across the NIH, with the goal of increasing the efficiency of trans-NIH coordination. The Committee consists of 10 Institute Directors. The Directors of the three largest Institutes (NCI, NHLBI, and NIAID) have permanent seats, while the other seven seats will be filled on a rotating basis, with the members having 3-year staggered terms. The initial membership includes the Directors of NHGRI, NIA, NIAMS, NLM, NCCAM, NIDCR, and NIA. The Steering Committee has established five working groups, and Dr. Collins will co-chair the Intramural Working Group with Dr. Michael Gottesman, NIH Deputy Director of Intramural Research.

In August 2003, Dr. Zerhouni convened a panel on the Future of Intramural Clinical Research, looking for recommendations on: ways to energize the NIH clinical research enterprise, strategies for integrating clinical research throughout NIH, guiding principles for the intramural clinical research program, and measures for assessing the success of these activities. The committee made six recommendations: 1) Revise the NIH intramural clinical research oversight structure; 2) Develop new training and career pathways in patient-oriented research; 3) Continue to emphasize the study of rare diseases, and promote a strong emphasis on pathophysiology and novel therapeutics; 4) Create translational, multidisciplinary intramural and extramural partnerships; 5) Intramural clinical research should be excellent and distinctive, and distinguishable from research conducted at academic health centers; 6) Regulatory barriers and impediments to clinical research should be reduced. Council member Rick Lifton participated as a member of the committee, which met three times in 2003. Dr. Lifton reported that many of the issues that have been addressed nationally in regards to clinical research are also being addressed at NIH. He expressed confidence that NIH has strong clinical research infrastructure, which can further be harnessed by the individual NIH institutes.

NIH Management Issues

Following an article in the Los Angeles Times that alleged possible conflicts of interest on the part of certain NIH senior leadership, Senator Specter convened a Senate hearing on January 22, 2004. At that hearing, Dr. Zerhouni announced the establishment of a Blue Ribbon Panel on Conflict of Interest Policies to examine the guidelines governing consulting activities at NIH. The Panel is co-chaired by Bruce Alberts, Ph.D., and Norman R. Augustine, and will consist of selected members of the Advisory Council to the Director, the Council of Public Representatives, and outside experts. The Panel will examine the way the NIH addresses conflicts of interest and how decisions are made regarding such conflicts. Dr. Zerhouni has also established an NIH Ethics Advisory Committee to provide advice to the NIH Deputy Ethics Counselors on specific conflict of interest activities. Dr. Eric Green, NHGRI Scientific Director, will serve on this committee.

Leadership Changes at NIH

On October 31, 2003, Norka Ruiz-Bravo was named the NIH Deputy Director for Extramural Research. Dr. Ruiz-Bravo received her Ph.D. in biology from Yale University and came to the NIH in 1990. She has served as a scientific review administrator at NIGMS and a program director at NCI.

On October 9, 2003, Richard Turman was named Associate Director for Budget, filling the position previously held by Donald Poppke, who retired in September. Mr. Turman received his Masters in Public Policy degree from the University of California, Berkeley and came to the NIH from the Association of American Universities, where he was the Director of Federal Relations.

On November 12, 2003, Gerald Keusch, stepped down as Director, FIC and NIH Associate Director for International Research to become Assistant Provost for Global Health at Boston University Medical Campus and Associate Dean for Global Health at Boston University School of Public Health. Dr. Keusch had held his position at the NIH for the past five years. Sharon Hrynkow, Ph.D., who has served as FIC Deputy Director since 2000, is serving as Acting Director for the Fogarty Center.

On February 2, 2004, Charles Leasure, Deputy Director for Management, NIH, retired after serving more than 40 years at the NIH. Before serving as the Deputy Director for Management, NIH, Mr. Leasure held the position of Executive Officer for NHGRI for four years. He then became the Acting Executive Officer for the NIH and then Deputy Director for Management.

Jeremy Berg began his appointment as Director, NIGMS, in November 2003. Dr. Berg was formerly the Director of the Institute for Basic Biomedical Sciences and Professor and director of the Department of Biophysics and Biophysical Chemistry at The Johns Hopkins University.

As of April 2, 2004, Jean Cahill, Chief, Grants Administration Branch will be retiring after over 32 years of service at the NIH, the past 11 years of which were at NHGRI. A search for her replacement is underway.

Recent Scientific Accomplishments and Issues

NHGRI - Extramural Program

On November 7, 2003, NHGRI announced five awards under the NHGRI Large-Scale Sequencing Research Network. The five centers represent academia, private industry, and the non-profit sector.

On December 10, 2003, NHGRI announced the first draft of the chimpanzee genome sequence assembled by a team led by Richard Wilson at Washington University and Eric Lander at the Broad Institute. The initial assembly was based on four-fold sequence coverage and was deposited in GenBank.

On December 12, 2003, USDA announced the launch of the Bovine Genome Sequencing Project. The sequencing of the bovine genome will be done by the Baylor College of Medicine Genome Sequencing Center, while the isolation and sequencing of bovine full-length cDNAs will be done at the University of British Columbia. The BGSP is being jointly funded by NHGRI, USDA, the state of Texas, Genome Canada, The Commonwealth Scientific and Industrial Research Organization of Australia, Agritech Investments Ltd, Dairy Insight Inc. and AgResearch Ltd of New Zealand.

On January 7, 2004, NHGRI announced the first draft of the honeybee genome sequence, which was determined and assembled by a team co-led by Richard Gibbs and Council member George Weinstock at Baylor College of Medicine. The initial assembly was based on six-fold sequence coverage and was deposited in GenBank.

On December 15, 2003, EMBL-European Bioinformatics Institute, the Swiss Institute of Bioinformatics, and Georgetown University Medical Center's Protein Information Resource announced the launch of UniProt, a central resource of information about protein sequence, function, and classification.

On October 9, 2003, NHGRI announced the first grant awards for the pilot phase of the ENCODE Project, which will be carried out by a consortium of researchers in government, industry, and academia. In one phase of the project, researchers will pilot the large-scale application of existing technologies for determining functional elements in the human genome; a set of target regions comprising 1% of the human genome has been selected for the pilot project. Awards were also made for the second component of the ENCODE Project, which is to develop new or improved technologies for finding functional elements in genomic DNA.

The International HapMap Consortium published a paper in the December 18, 2003, issue of Nature describing the scientific strategy and rationale behind the effort to create a haplotype map of the human genome and to determine the patterns of human genetic variation. An important component of the paper outlined how the samples were collected in China, Japan and Nigeria. Dr. Collins also reported that the Consortium held its third strategy meeting on December 8-9, 2003, in Montreal, Canada.

Proposals submitted in response to a recent RFP for the Mammalian Gene Collection Project have been evaluated. Applicants proposed methods for full-length cDNA sequencing and directed strategies to find clones representing genes that are currently missing from the collection. A funding plan for these proposals is currently being formulated. As of January 23, 2004, approximately 28,700 full-ORF sequences have been submitted to GenBank (roughly 15,300 human, 12,700 mouse, 650 rat). This collapses to a non-redundant set of approximately 21,900 clones (roughly 11,100 human, 10,200 mouse, 630 rat). Additionally, several thousand candidate clones are in the pipeline. The MGC effort has been expanded to include cooperation with the full-length cDNA clone isolation and sequencing endeavors for Xenopus and zebrafish.

The essential completion of the human genome sequence will be summarized in a manuscript that is expected to be submitted for publication soon. The paper will report the finishing of the human sequence, and describe the differences between the draft version published in 2001 and the essentially finished version announced in 2003.

The Research Training Advisory Committee, responsible for overseeing the NHGRI's Minority Action Plan and other Institute research training programs, held a satellite meeting with the grantees and training coordinators in conjunction with the first annual meeting of CEGS grantees in Seattle on the afternoon of October 21, 2003.

NHGRI - ELSI Program

A substantial number of applications were received in response to the RFA inviting applications for the development of Centers of Excellence in ELSI Research (CEERs). The purpose of these centers is to bring together investigators from multiple disciplines to address new ELSI issues resulting from the advances in genetics and genomics. These applications will be reviewed this Spring and will be brought to May Council.

Two Program Announcements, describing the Regular ELSI Research Grant Program (R01) and the Small Grant Program (R03), were revised based on the NHGRI's 2003 Vision document and were released on February 1, 2004.

NHGRI - Intramural Program

NHGRI announced the formation of a new branch within the Division of Intramural Research. The Social and Behavioral Research Branch will be headed by Colleen McBride, Ph.D., a behavioral epidemiologist formerly of Duke University. The new branch will be organized around four main areas of research: testing communication strategies aimed at effectively communicating an individual's risk for developing a genetic condition; developing and evaluating interventions aimed at reducing genetically susceptible individuals' risk of acquiring a disease; translating genomic discoveries to clinical practice; and understanding the social, ethical, and policy implications of genomic research. Dr. McBride will also lead the development of a trans-NIH Social & Behavioral Science Center that will co-locate behavioral sciences from a number of different institutes.

Eric Green, Scientific Director, NHGRI will provide an update on the Division of Intramural Research at the May Council meeting.

NHGRI - Office of the Director

The NIH is one of several Institutes contributing to the support of an Institute of Medicine study of intellectual property in genomic and protein research and innovation. The other Institutes co-funding this initiative include NCI, NIGMS, and NIDCD, as well as the NIH Office of the Director, with NHGRI providing leadership. Shirley Tilghman has been appointed as the Committee Chair and the first committee meeting will be held February 27-28, 2004 in Washington, D.C.

NHGRI is working with the American Society of Human Genetics and the Genetic Alliance to hold the second annual DNA Day on April 30th. Building upon last year's successful effort, NHGRI will send out "ambassadors" (from all three of the Institute's Divisions) to high schools around the country (including the hometown schools of many of the ambassadors) to speak to students about genomics and genetics. All genetic scientists are urged to participate in DNA Day by offering to give a talk at their local high school. NHGRI is producing a new video that could be web cast to any school, including those that the DNA Day ambassadors cannot visit. If DNA Day continues to be successful, it is possible that it will become an annual event.

On December 1-3, 2003, NHGRI, in collaboration with NICHD, NHLBI, NIEHS, the CDC, and the EPA, convened a workshop to consider the scientific merit of developing a large-scale American family study of gene-environment interactions relating to common diseases. Similar efforts are already underway elsewhere around the world, in particular the Biobank project in the United Kingdom. The meeting attendees agreed that the objectives of such a study should be to identify major susceptibility factors (genetic and environmental) for common diseases; to determine the true population risk of genetic variants; to elucidate the effects of environmental factors, and to identify gene-environment interactions of major consequence. A potential model for the study would be to enroll the parents and grandparents of children participating in the National Children's Study.

On November 19-21, 2003, NHGRI co-hosted a 2-½ day conference on sickle cell disease with NHLBI, NIDDK, FIC, and ORD to discuss how the tools of genomics could be used to improve the treatment of sickle cell disease. The conference was co-chaired by Francis Collins and Sir David Weatherall. As a result of the meeting, a Trans-NIH Sickle Cell Disease Therapies Working Group was formed and includes members from NHGRI, NHLBI, NINDS, NICHD, NIDDK, FIC, and ORD. Alan Guttmacher, NHGRI, and Greg Evans, NHLBI, co-chair the Working Group, which will evelop ways to implement the conference's recommendations.

NHGRI, in collaboration with the Office of Rare Diseases, NIH, Redes En Acción National Network Center at Baylor University, the National Hispanic Medical Association, and the National Council of LaRaza, hosted a roundtable entitled, "Engaging Latino Communities in the Future of Genomic Science," on February 3, 2004, at the NIH. There was significant discussion about training initiatives to diversify the genomics research community, developing education programs, and translating research to improve the health of Latino communities. Vence Bonham of NHGRI organized this meeting.

NHGRI will host a roundtable on race, ethnicity, and genetics on March 8-10, 2004. Approximately 25 leading scholars in the fields of genetics, clinical medicine, genome science, anthropology, sociology, history and law have been invited to discuss the complex issues surrounding race and genetics and to provide guidance to NHGRI in its endeavors regarding these complex issues. Steven Olson, author of Mapping Human History, is serving as a consultant to NHGRI for this effort.

NHGRI and NIGMS are hosting a symposium on chemical genomics March 15-16, 2004 to highlight the scientific insights that can result from applying modern chemical approaches to studies of important, and often complex, biological processes. Chris Austin of NHGRI has taken a leadership role in these efforts.

NHGRI will be hosting a workshop on March 23, 2004 to explore the issue of direct-to-consumer marketing of genetic tests and to discuss potential policy options regarding this issue. The American College of Medical Genetics (ACMG) has recently issued a policy statement on direct-to-consumer marketing of genetic tests that stresses that genetic testing should only be provided through health care professionals and expressing concern that proliferation of this approach to marketing tests could feed a public misimpression that genetics is "junk science." The ACMG has concluded that some oversight of direct-to-consumer marketing of genetic tests is needed.

The American Association of Family Physicians (AAFP), an organization with 93,000 members, has chosen genomics as the focal topic for its 2005 Annual Clinical Focus gathering. NHGRI staff are working with the AAFP to develop the curriculum. NHGRI considers this to be an important opportunity to educate primary physicians about genomics and its potential implications for medical care.

NHGRI - Policy

On January 22, the Senate passed the fiscal year 2004 budget. The NIH will receive $27.729 billion, a net increase of $763 million (2.8%), and NHGRI will receive $479 million (an increase of 3%). The President has just released his FY2005 budget, which includes $28 billion, a 2.6% increase, for the NIH, and $493 million for the NHGRI (2.8% over FY 04).

On October 14, 2004, the U.S. Senate passed the Genetic Information Nondiscrimination Act of 2003 (S. 1053) by a vote of 95-0. This is the first time the Senate has passed a bipartisan genetic non-discrimination bill. The Senate bill would outlaw genetic discrimination in the areas of health insurance and employment. Upon passage of the bill, President Bush issued a statement of support and urged its passage by the House where S. 1053 awaits assignment to committee. It is likely that three committees in the House, Ways & Means, Energy & Commerce, and Education & the Workforce, will be given jurisdiction over the bill. The Energy & Commerce and the Education & the Workforce committees have expressed interest in having hearings on the issue, but it is not clear yet what action they will take on the bill.

The Secretary's Advisory Committee on Genetics, Health and Society continues to meet to discuss a number of topics. The next meeting will be March 1-2, 2004.

Council member Mary Hendrix raised the question of how the A-76 government restructuring is affecting the ability of NHGRI staff to carry out their many duties. Dr. Collins reminded Council that under A-76, the government is required to compete with the private sector for a variety of work functions. The activities that have been identified for competition include grants management support functions. The NIH put in a proposal for administering grants management more efficiently, by centralizing many of the necessary support functions. The government won this competition with its MEO (Most Efficient Organization) proposal. Dr. Collins noted the possibility that the centralization of grants management staff, and the subsequent loss of direct control over grants management activities by the Institute, might affect the way NHGRI prepares for future Council meetings. He also expressed concern about the MEO's effect on employee morale.

Council member Rick Myers asked if NHGRI had concerns about new interests in Translational Research diverting the focus away from basic science. Dr. Collins stated that he does not have such concerns. He pointed out that the first section of the new NIH Roadmap (New Pathways to Discovery) is heavily focused on basic science, as is the NHGRI vision for the future of genomics. He also stated that, to be successful, Translational Research will always need a strong basic science foundation upon which to build.

Report from the Department of Energy

Ari Patrinos provided a report on recent activities at the U.S. Department of Energy (DOE). The DOE Joint Genome Institute (JGI) expects to have a 6X sequence of Xenopus tropicalis by the end of May, and intends to proceed quickly with the assembly. The JGI is also working with colleagues at Stanford University and potentially NHGRI to do a quality assessment of their whole genome assembled sequences. Dr. Patrinos reported that the assembly of the poplar genome is going well. Having the genome sequence of this plant will have important implications for biomass and energy research. He also noted that the transformation of the JGI production-sequencing center into a "scientific user facility" is going extremely well.

Dr. Patrinos expressed his excitement that Dr. Zerhouni has named Dr. Collins to be the NIH liaison to the DOE. On March 3rd, DOE representatives will meet with Dr. Collins and other NIH representatives for an initial discussion of the DOE's Genomes to Life program, the light source program, which will focus on the structures of extremely complicated biomolecules, and the DOE investment in high power computing.

Dr. Patrinos also expressed his enthusiasm for the recent ecogenomics work that Dr. Craig Venter has been doing in the Sargasso Sea and around the Galapagos Islands. This work involves shotgun sequencing material extracted directly from soil or ocean water to catalog the many organisms in such complex environments that cannot be cultured.

Dr. Hendrix inquired whether DOE has concerns about the security of the information that is generated by the work of DOE-funded investigators. Dr. Patrinos agreed that this is a very important issue that extends beyond the work that DOE supports. He noted, for example, that it is relevant to the NIAID's genomics program. Much of Dr. Patrinos' work focuses on ensuring that proper safeguards are in place for sensitive types of scientific information.

Report on the HumanBASE Workshop

Drs. Peter Good and Sean Eddy (one of the co-chairs of the workshop) presented a report from the Workshop on Informatics Resources for the Human Genome (HumanBase) that was held in September 2003, co-sponsored by the NHGRI and the Wellcome Trust. The workshop participants embodied a broad range of scientific expertise, including model organism databases, data providers (NCBI, EBI, UCSC, etc) and bioinformatics database users. The objective of the workshop was to address the question of the need for a large, centralized informatics resource for the human genome. Dr. Eddy reported that the workshop addressed many complicated issues, stemming from the fact that while many informatics resources for the human genome already exist, the human genome sequence is still under-used and that many biomedical researchers have yet to take full advantage of the available resources. At the meeting, Dr. Eddy summarized that the major conclusions reached included the need for more general access to human genomics resources and the idea of providing such access through data hubs, which would promote communication and availability of data from both existing and data sources.

Dr. Eddy illustrated what he thinks are the key informatics resources needed for further study of the human genome:

  • Ability to see structured/free text reviews of each gene that point to the supporting literature, reviews, etc. He noted that OMIM currently does this well for disease genes, and argued that a similar resource is needed for all human genes.
  • Centralized views of gene models, transcripts, and intron/exon structure. These views are currently curated at three sites, each with their own view. Dr. Eddy informed Council that, as a direct outcome of the workshop, UCSC, NCBI and Ensembl have begun to self-organize to address this need.
  • Homology with genes from other organisms.
  • Coordination with clinicians to create controlled vocabularies for clinical data, phenotypic data, etc.
  • Full-text access to literature. The integration of full text literature with informatics is needed.
  • User-education. The informatics community needs to better educate users on where databases are located, and how to use them.

The concept for a HumanBase resource that emerged from this workshop was only partially defined, as a core infrastructure to link genome sequence to data in other "hubs" and to integrate a variety of human genome informatics resources for the benefit of the average, "non-power" user.

In the Council discussion that followed the presentation, a number of questions were raised, including whether the NHGRI has the funds available for supporting these complex informatics resources for the human genome, who would have authority over the resource, and how a HumanBase could build upon and utilize some of the features of the existing model organism databases in its own design. Council also discussed the possibility of having HumanBase run by a private sector organization; NHGRI staff and Council thought that this would be possible as long as the database were openly accessible to all.

Dr. Collins summarized the discussion by concluding that we still do not know the precise steps necessary for NHGRI to take to improve the situation. Staff will continue to work on the problem in an attempt to develop a solution that will address the needs identified while avoiding the duplication of existing resources that already function well and serve important needs. Dr. Collins also noted that NHGRI must remain cognizant of the cost of anything we propose to do. When Staff is ready with a proposal, the subject of the informatics needs of human genomics will be brought back to Council for further discussion.

Report on the CEGS Program

Jeffery Schloss presented a status report on the Centers of Excellence in Genomic Sciences (CEGS) program. The CEGS program is designed to provide sustained support for cross-disciplinary, multi-investigator, highly innovative genomics research projects designed to develop new capabilities and applications for genomics-based approaches to important biological problems. Innovation can fall into a number of categories, including concepts, methods, technologies, or data analysis. The CEGS program is intended to encourage risk, while balancing it with an outstanding scientific and management plan and very high potential payoff. NHGRI thinks that synergy and integration are key elements in these projects, which also must offer innovative, substantive training opportunities across disciplines. The CEGS program currently supports seven awards. The FY03 investment in the CEGS program was $23 million, including a $1.6 million investment in the Minority Action Plan. The final receipt date under the current PA is in June 2004.

Dr. Schloss' status report included a description of the first CEGS grantees meeting, which was held in October 2003 in Seattle. Each group presented an overview of its activities and an example of emerging scientific or technical achievements. The meeting also included a poster session and local lab tours. Discussion topics included data sharing, training, collaborations, and ways in which to strengthen the CEGS program.

An additional component of the CEGS presentation to Council involved progress reports from two of the CEGS grantees. William Talbot described the Stanford University CEGS project, The Genomic Basis of Vertebrate Diversity. This project takes genomic approaches to studies of major development and evolutionary questions, using the stickleback and zebrafish model systems. The project addresses several major questions: How many genetic changes underlie different traits? What specific genes are involved? What is the molecular basis of evolutionary change? What are the emerging morphologies? Dr. Talbot's talk focused on one of the goals of the Stanford CEGS, developing the genomics of the three-spined stickleback, a new model system to study the molecular basis of evolutionary change in vertebrates. He also described one of his center's approaches to training, the Stickleback Genomics and Molecular Genetics Course. Students who have participated in the course ranged from graduate students through principal investigators. The course includes intensive, hands-on laboratory exercises in stickleback and zebrafish genomics and genetics. The Stanford CEGS also participates in the Stanford Summer Research Program as part of the project's Minority Action Plan activities.

Dr. Hendrix asked whether this work could potentially lead to new insights regarding environmental effects on epigenetics. Dr. Talbot responded that he does think that environmental effects do have an epigenetic component, but he noted that this is a controversial viewpoint. Dr. Gelbart inquired whether there are new stickleback biologists as a result of the summer course. Dr. Talbot noted that some of the students were stickleback field biologists who now have a better understanding of the genetics of the species, while others were zebrafish or C. elegans biologists who are now more familiar with the kind of research that can be done using the stickleback.

Deirdre Meldrum then presented her University of Washington CEGS project: Microscale Life Sciences Center - "Life-on-a-Chip." The goal of this project is to develop new methods to analyze cells and cellular processes in real-time on micro-system devices. This project brings investigators focused on biological and medical applications together with technology developers. The collaborations are designed to enable the applications to drive technological innovations, and technology development to push new frontiers in the applications. Among the current efforts being pursued in this CEGS are a cellular-level understanding of programmed cell death, and study of the heterogeneity of pathogen and host interactions, employing fluorescent reporter technology to reveal the infection process in single cells. Other participants in this CEGS are taking a chemical genomics approach to inhibit both up and downstream events, in a fashion whereby multiple targets can be addressed simultaneously. The MLSC CEGS project includes minority-training opportunities through the Genomics Outreach for Minorities (GenOM) program. Dr. Hendrix suggested that the MLSC expand the GenOM program to bring in representatives from industry to educate students about opportunities in industry.

Council agreed that all of the CEGS projects would benefit from extensive interactions and collaborations where appropriate, and were pleased with the NHGRI's efforts to bring the different projects together, starting with the October CEGS grantee meeting. Council also strongly endorsed collaborations between CEGS programs on training and the recruitment of underrepresented minorities (URM) to genomics research. The CEGS program is currently a major component of NHGRI efforts to recruit URM to genomics. If the CEGS program is changed significantly, NHGRI needs to develop an alternative plan for recruiting URM to genomics.

Council members also expressed several concerns:

  • Whether the proposed third-year site visits will be useful or is it too early to judge the extent to which these projects have changed the nature of genomic research.
  • Whether the size of individual CEGS projects are appropriate. Members raised the possibility that the $2M direct cost ceiling is too often taken as the norm and, as a result, some centers may be operating at too large a scale, one which is either inappropriate or unnecessary for the project.
  • Whether the review panels that evaluate applications to the CEGS program need more education as to the goals of the program, so that they are fully able to evaluate all of the components required of a CEGS.
  • Whether the rest of the biomedical research and clinical communities are not using the tools and technologies being generated by genomics research. Members noted that the NHGRI devotes significant time and resources to developing tools which are, in some cases, not being adapted by the communities for which they are intended as rapidly as would have been hoped. The Council recommended that NHGRI take a more proactive role in ensuring that not only are these tools used and adapted by other research groups, but also that research in other communities inspire new innovations in tool and technology development by genomics researchers. Council thought that a valuable opportunity would be missed if closer coordination and interaction between these communities were not achieved. The Council was not sure, however, if the CEGS program is the right mechanism to achieve this interaction and coordination.

The last receipt date under the current CEGS program announcement is June 1, 2004. The Council will revisit the CEGS program after the data from the third-year site visits have been gathered to better inform the discussion of whether any reshaping and restructuring of the program is needed. To the extent that the shape of the program will change in any way, NHGRI and Council will need to determine what to do with the existing centers. At a subsequent Council meeting, NHGRI staff will present a proposal for the future of the CEGS program.

Report on Comparative Genomic Sequencing

At its September meeting, a workshop report that recommended a new process for the selection of sequencing targets was presented to Council. The initial phase of the new process was to be the formation of working groups that would develop recommendations for new genomics sequences that would be useful in addressing specific areas of biomedical research. Jane Peterson provided Council with an update on the progress of the two working groups that were convened, one on "Annotating the Human Genome" and the other on "Comparative Genome Evolution." Both working groups have been meeting every two weeks by phone to develop proposals. These proposals will be presented in April to a Coordinating Committee, which will use them as the basis for a plan that will be presented to Council for consideration at its May meeting.

To discuss the issue of comparative genomics, NHGRI invited two speakers from the workshop that recommended this new process to talk to Council.

Dr. Sean Eddy of Washington University described his lab's use of comparative genome sequence analysis for detecting RNA coding genes. He emphasized the additional statistical power that is gained by having sequence data from additional organisms; his simulations show that comparative sequence analysis will continue to gain statistical power even with large numbers (10-100s) of genomes. Dr. Eddy's main message is that single base resolution requires many genomes.

Council members discussed the difficulty that computational biologists currently have in dealing with rapidly evolving genomic regions. Different types of genomic regions need to be approached with different algorithms and may require more comparative genomic sequence. For example, some genomic features may be better annotated using light coverage sequence data from many genomes, while others might be better annotated using sequence data of higher quality from fewer genomes.

In a second talk, Dr. Manolis Kellis of MIT and the Broad Institute presented his work on extracting functional information from comparison of the genome sequences of four Saccharomyces species (total branch length of 0.83 substitutions per site). His analysis indicated that orthologous regions in yeast show conservation of local order and gene spacing. This allowed genome-wide alignments of both coding and non-coding regions, which revealed distinct patterns of nucleotide change. Based on these patterns, he was able to build a test for gene identification with great sensitivity and specificity, and use it to revisit the yeast genome. This led to the largest reannotation of the yeast genome so far, with changes affecting as much as 15% of all genes. Analysis of regulatory motifs presented a greater challenge, but Dr. Kellis found that analytical power can be increased by testing conservation in multiple regions, comparing intergenic versus genome-wide conservation. His results indicated that, while most conserved regions are found in coding regions, there is a class of sequence patterns that have higher conservation rates in intergenic regions than in coding sequences, allowing the direct identification of regulatory motifs. These contained nearly all previously known regulatory motifs, and a number of newly discovered candidate regulatory motifs. One can utilize systematic functional information data of related sets of genes to infer the function of these newly discovered regulatory motifs. The emerging picture of gene regulation in yeast is that versatility comes from motif combinations. The combinatorial code can be studied looking at non-random co-occurrence of conserved motifs, and the work showed that motif combinations indeed affect regulatory motif functions. Dr. Kellis indicated that this type of motif discovery is currently very challenging in humans, due to the much larger intergenic regions. The genomics community will need to co-examine gene expression data with comparative sequence data. The increased power in conserved features allows one to identify candidate target genes where motifs are conserved, and infer the circuitry of interconnected genetic network components. Comparative genomics can help us systematically identify genes, and also allows for systematic regulatory motif discovery. Integrative genomics using multiple data sources will identify network motifs thereby increasing the discovery power with potential applications to disease.

Updates on On-Going NHGRI Projects


Lisa Brooks presented a status report on the HapMap project. The HapMap project "marker paper" was published in December 2003, and a publication on the ELSI aspects of the project is currently being written. At the time of the Council meeting, dbSNP had approximately 7.2 million SNPs, approximately 3 million of which were double-hit SNPs, i.e. SNPs that have been discovered at least twice in different DNA samples. The project is preferentially using the double-hit SNPs. All blood samples collected for the project have now been received by the Coriell Institute for Medical Research repository, and DNA should be available for genotyping of all of the samples by May or June.

At the time of the Council meeting, approximately 324,000 SNPs had been genotyped, and the data for approximately 140,000 of those had been analyzed. The average extent of linkage disequilibrium (LD) is on the order of 8 kb, with large regions of LD in the genome. The project has also undertaken quality control analysis of the genotype data, with each group genotyping 1,500 identical SNPs. The average quality was 99.2% complete and greater than 99.5% accurate. Further efforts at data analysis will address the following questions: Where are more SNPs needed, based on LD? How many more SNPs are needed? How should regions of high LD be defined? And, finally, how should tag SNPs be chosen? There will be a meeting in April of the HapMap analysis group, which will also be open to other investigators who want to work on the HapMap data but are not official project participants.

The Analysis Group has also stimulated a HapMap sub-project to determine the density of SNPs needed for the HapMap project. This project entails re-sequencing across ten of the ENCODE regions (5Mb total genomic sequence) in 48 of the HapMap samples to identify all of the moderate frequency and many of the rare SNPs in those regions. All known SNPs in these regions will then be genotyped in all 270 HapMap samples to generate as complete a description as possible of the patterns of genetic variation in those regions. The data can then be analyzed to determine the minimal subset that will provide an accurate description of the variation patterns.

Dr. Brooks concluded that HapMap is moving along at a gratifying pace; is collaboratively rewarding, as the centers are working together effectively; and that the ELSI component has been interesting and challenging.


Elise Feingold presented Council with a status report on the ENCODE project. The project participants have formed a Consortium, as planned, to test and compare existing and new methods for the exhaustive identification and verification of functional elements in human genomic DNA, with the aim of compiling a comprehensive encyclopedia of all sequence features in the human genome. The ENCODE consortium is open to anyone who wants to participate and who will agree to abide by the consortium criteria for participation. Eight groups funded under the pilot project phase, and they are investigating a number of sequence elements using a variety of platforms.

The ENCODE consortium met for the first time as a group in December. Three working groups were formed at the meeting to address issues of Common Resources (chaired by Eric Green); Data Management (chaired by Ian Dunham) and Data Sharing/Release (chaired by Rick Myers). NHGRI considers the ENCODE project to be a "community resource project," in the sense described at the 2003 Fort Lauderdale meeting on sequence data release, and has proposed a data release policy for the ENCODE project that mirrors that meeting's recommendations. ENCODE project data will be stored at one of two databases for the project: sequence-based data will be housed at UCSC, and other data types will be housed in a database run by the NHGRI Intramural program.

In January, NHGRI re-issued an RFA for technology development for ENCODE. This new RFA has an added emphasis on using model organisms for technology development, and encourages high risk/high payoff grants. The funding for grants arising from this RFA is planned for the end of FY2004.

Status Report on the NIH Roadmap

Dr. Collins provided Council with a status on the NIH Roadmap for Biomedical Research. There are three themes of the NIH Roadmap: New Pathways to Discovery, Research Teams of the Future, and Re-engineering the Clinical Research Enterprise. A total of $135 million is set aside for Roadmap activities in FY2004. These funds are derived from the NIH Director's Discretionary Fund, plus contributions of each NIH IC based on the size of the institute.

Each of the themes has a number of initiatives. For New Pathways to Discovery, which is notably genome-relevant, the initiatives include Building Blocks for Biology, Pathways and Networks, Molecular Libraries and Molecular Imaging, Structural Biology, Bioinformatics and Computational Biology, and Nanomedicine. RFAs have already been issued for some of these initiatives, and applications are being received. Other components of the Roadmap are aimed at reducing roadblocks between bench and bedside and between bedside and clinical practice.

The NIH Roadmap web site, http://nihroadmap.nih.gov, is updated regularly with new grants and funding opportunities. Each Roadmap RFA will have a designated lead institute; however, every IC Council will see the applications received for each of the RFAs. This Council will be asked to particularly focus on those RFAs that are of relevance to NHGRI.

Council discussed the intersections between the NHGRI Vision Statement, the recent Institute of Medicine report and the NIH Roadmap. Council noted that the Roadmap agenda is highly ambitious, but that limited resources have been set aside for implentation. The Council discussed whether NHGRI in particular and NIH on the whole would end up focusing on particular projects at the expense of other endeavors. Dr. Collins said that it was his opinion that it would take a few years to assess the Roadmap effort. Initially, a modest amount of money is being put to Roadmap projects, but this could certainly climb over the course of time as the Roadmap demonstrates its value.

Memorandum of Understanding Between NACHGR and NHGRI Staff

Once a year, NHGRI staff is required to bring the Memorandum of Understanding between NACHGR and NHGRI, which describes the agreement between NACHGR and NHGRI Staff regarding operating procedures, to Council's attention. The MOU has not been changed since last year. Council expressed concern that a 25% increase in total grant award can occur without Council approval (via staff's discretionary authority); they felt this percentage was too high. More information will be provided to the Council explaining the Staff reasoning behind the few very large administrative increases, and Council will reconsider the MOU.

Announcements and Items of Interest

Dr. Guyer noted the items of interest in the Council folders, which included the FY2004 operating budget and the President's proposed FY2005 budget.

Council-Initiated Discussion

At its May 2004 meeting, the major agenda items for Council will be the applications received in response to the CEER RFA and the plan for new large-scale sequencing targets that will be proposed by the Coordinating Committee. Dr. Eric Green, the Scientific Director of NHGRI, will present an update on the NHGRI's intramural program.

Dr. Myers suggested that the Council consider the overall NHGRI budget scenario. Dr. Hendrix asked that Council discuss trans-NIH initiatives and projects in which NHGRI leads, participates and/or figures prominently. Dr. Burgess suggested that Council discuss the recommendation from a recent meeting, which was convened to address the advancing age of new principal investigators on NIH grants, and the status of post-doctoral fellows in the U.S. The report from this meeting will be published, and is also reported in Science magazine.

Conflict of Interest

Dr. Guyer read the Conflict of Interest policy to Council and asked them to sign the forms provided.

Review of Applications

In closed session, the Council reviewed 131 applications, totaling $341,526,533. The applications included 42 regular research grants, 17 pilot projects, one program project, 30 ELSI grants, seven center grants, four conference grants, two training grants, one research career development award, 15 SBIR Phase I, six SBIR Phase II, three STTR Phase I and one other. A total of 90 applications requesting $32,234,605 were recommended.

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

Date Mark Guyer, Ph.D.
Executive Secretary
National Advisory Council for Human Genome Research

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

Last updated: March 23, 2012