National Advisory Council for Human Genome Research
Summary of Meeting

Fishers Lane Conference Center
Rockville, Md.

February 13, 2006

The open session of the National Advisory Council for Human Genome Research was convened for its forty-sixth meeting at 8:35 a.m. on February 13, 2006 at the Fishers Lane Conference Center, Rockville, MD. Francis Collins, Director of the National Human Genome Research Institute, called the meeting to order.

The meeting was open to the public from 8:35 a.m. until 2:45 p.m. on February 13, 2006. In accordance with the provisions of Public Law 92-463, the meeting was closed to the public from 2:45 p.m. on September 13, 2006 until adjournment for the review, discussion, and evaluation of grant applications.

Council members present:

Andrew Clark, ad hoc, by teleconference
Marilyn Coors, by teleconference
Geoffrey Duyk, by teleconference
Sean Eddy, by teleconference
Vanessa Gamble, ad hoc
Deirdre Meldrum, ad hoc
Jeffrey Murray, by teleconference
Richard Myers
Stephen Prescott, ad hoc
George Weinstock

Council members absent:

Beverly Gaines
Mary Hendrix

Ex officio member absent:

Gerard Schellenberg

Staff from the National Human Genome Research Institute:

Saveri Bhattacharya, DER
Christianne Bird, DER
Vence Bonham, OD
Joy Boyer, DER
Lisa Brooks, DER
Zena Breeden, OD
Comfort Browne, DER
Cheryl Chick, DER
Francis Collins, Director
Chris Davis, DER
Elise Feingold, DER
Adam Felsenfeld, DER
Colin Fletcher, DER
Phyllis Frosst, OD
Peter Good, DER
Bettie Graham, DER
Alan Guttmacher, OD
Mark Guyer, DER
John Hodges-Howell, DER
Michael Lacy, OD
Tim Leshan, OD
Laura Liefer, DER
Leslie Linden, OD
Carson Loomis, DER
Kathleen Maguire, OD
Teri Manolio, DER
Jessica Melone, DER
Jean McEwen, DER
Keith McKenney, DER
James McWilliams, DER
James Mullikin, DIR
Patrick Nailer, DER
Ken Nakamura, DER
Vivian Ota Wang, DER
Brad Ozenberger, DER
Kenneth Ow, OD
Betsy Parker, OD
Diane Patterson, DER
Allison Peck, DER
Jane Peterson, DER
Rudy Pozzatti, DER
Eddie Rivera, OD
Jerry Roberts, DER
Laura Rodriguez, OD
Jeffery Schloss, DER
Shundel Stephenson, DER
Gary Temple, DER
Larry Thompson, OD
Elizabeth Thomson, DER
Susan Vasquez, OD
Lu Wang, DER
Elsa Weinstein, DER
Melinda Weiss, DER
Kris Wetterstrand, DER

Others present for all or a portion of the meeting:

Joann Boughman, American Society of Human Genetics
Camilla Day, Center for Scientific Review
Debbie Dietz, SSS
Mike Gilbreath, SSS
Susanne Haga, Duke University
Molly Laas, Research Policy Alert
Sharon Olsen, International Society of Nurses in Genetics
Dina Paltoo, National Heart, Lung, and Blood Institute
Ari Patrinos, Synthetic Genomics, Inc.
Michelle Rodriguez, SRI
Sharon Terry, Genetic Alliance
Jose Velasquez, National Institute on Alcohol Abuse and Alcoholism

Introduction of Liaisons and New Employees

Dr. Guyer introduced new council members Stephen Prescott, Andy Clark, and Vanessa Gamble.

Dr. Guyer introduced new NHGRI staff: Colin Fletcher, Program Director for the Knockout Mouse Program; Lu Wang, Program Director for the Sequencing Program; Kathleen Maguire, Administrative Officer; and Leslie Linden, staff member in the Office of the Director.

Dr. Guyer welcomed liaisons from professional societies: Joann Boughman from the American Society of Human Genetics; Sharon Olsen from the International Society of Nurses in Genetics; and Sharon Terry from the Genetic Alliance;

Dr. Guyer welcomed members of the press: Debbie Dietz and Mike Gilbreath from SSS; and Molly Lass from Research Policy Alert.

Approval of Minutes

The minutes from the September 2005 meeting of the National Advisory Council for Human Genome Research were approved as submitted.

Future Meeting Dates

The following dates were proposed and approved for future meetings: May 22-23, 2006, September 11-12, 2006, February 12-13, 2007, May 21-22, 2007, September 10-11, 2007, and February 11-12, 2008.

Director's Report

General Announcements

Deirdre Meldrum, who has been appointed to be a member of the National Advisory Council for Human Genome Research, has been appointed to a new position as Dean of the Fulton School of Engineering, Arizona State University.

The Bill & Melinda Gates Foundation announced on February 6th that Dr. Tadataka (Tachi) Yamada has been named Executive Director of the Foundation's Global Health program. Dr. Yamada is a former member of the NACHGR and is currently Chairman of Research and Development at GlaxoSmithKline (GSK).

The NIH announced thirteen recipients of the 2005 NIH Director's Pioneer Award. Awardees will receive $500,000 over 4-5 years. The Pioneer Award is an NIH Roadmap initiative that supports exceptionally creative scientists to take innovative approaches to major challenges in biomedical research. The recipients included Titia de Lange, Ph.D., who is the Leon Hess professor and head of the Laboratory of Cell Biology and Genetics at The Rockefeller University in New York City. Dr. de Lange investigates how the human telomeric complex executes its two main functions: to protect chromosome ends and mediate their replication. Dr. de Lange's Pioneer Award will be supported by NHGRI after its initial year.

The John D. and Catherine T. MacArthur Foundation named Olufunmilayo Olopade, M.D. as a 2005 MacArthur Fellow. Dr. Olopade is Professor of Medicine and Human Genetics, and Director of the Center for Clinical Cancer Genetics at the University of Chicago Medical Center. She has been studying the genetics of breast cancer in African and African-American women.

The American Society of Human Genetics has recognized Joe McInerney, the Executive Director of the National Coalition for Health Professional Education in Genetics, and awarded him the ASHG Award for Excellence in Human Genetics Education.

Joann Boughman noted that Dr. Collins received the Allan Award from the American Society of Human Genetics for his lifetime achievements in science.

In the December 23rd, 2005 issue of Science, "Evolution in Action" was identified as the breakthrough of the year for 2005, and several NHGRI-funded research projects were cited in the article as having made major contributions to developments in the field. These included the sequencing of the chimp genome, the HapMap Project, and work on the evolution of the three-spined stickleback genome that was done in the Center for Excellence in Genomic Science (CEGS) at Stanford (W. Talbot, P.I.).

The American Society of Human Genetics has a new president, Stephen Warren, Ph.D. Dr. Warren is the Chairman of the Department of Human Genetics at Emory University and has done seminal work in the genetics of Fragile X Syndrome.

Dr. Collins attended the World Economic Forum, which was held at the end of January 2006, in Davos, Switzerland, and for which he was a member of the Organizing Committee. This agenda for this year's meeting included a greater emphasis on scientific issues, such as global warming and stem cells, than in previous years. During the Forum, Dr. Collins helped to lead a discussion related to the use of genetics in human enhancement, and partook in a vigorous discussion about science education.

The NIH is starting a new funding program for young investigators, called the "NIH Pathway to Independence Award." The award (which will be termed K99/R00) is designed to support the transition of young scientists to their first independent positions. It will provide support for their final post-doctoral years (up to three) and for their initial independent research position (also up to three years, the award is a total of five years). Dr. Zerhouni strongly supports this new program, which is part of NIH's continuing interest in encouraging promising young investigators at the beginning of their independent research careers. The program is similar to the K22 program that NHGRI has supported for the past several years. The NIH expects to fund 150-200 K99/R00 awards in the next year and NHGRI plans to fund three of those. The first deadline for responses to the program announcement is April 7, 2006.

NHGRI Extramural Program

Sequencing Program

The Council members were provided with a written update of the status of the large-scale sequencing program that summarized the current projects, including the organisms whose genomes are being sequenced and the number of Q20 base pairs per organism that have been sequenced. All of the targets currently being sequenced were identified by the working group/Coordinating Committee process, and had approved by Council. The data from these targets are intended to address the goals of annotating the human genome and illuminating comparative genome evolution.

The mouse genome sequence was finished in January 2005, after a final, rigorous finishing effort by the Mouse Genome Sequencing Consortium (an international collaboration involving the sequencing centers at Washington University, Baylor College of Medicine, the Broad Institute, and the Sanger Institute, as well as scientists from the European Bioinformatics Institute). The quality of the final product is very high. The Mouse Genome Sequencing Consortium met on February 9th to discuss analysis of the finished genome sequence and publication plans.

Last September, Council approved three medical sequencing projects:
  1. Sequencing regions of the human genome implicated in Mendelian disease. Seven pilot projects have now been assigned to sequencing centers.
  2. X-linked disorders. Members of the X-linked mental retardation community have submitted a plan for re-sequencing all exons on the X chromosome of affected individuals.
  3. Allelic spectrum of common diseases.

These medical sequencing projects raise a number of ELSI (ethical, legal, and social implication) issues, including how to protect privacy and confidentiality of donors, return of results, and intellectual property. To ensure that these issues are addressed in a coordinated way, NHGRI has established an umbrella group within the ELSI program to discuss them and make recommendations to the Institute.

The receipt date for responses to the Genome Sequencing Centers RFA, which is the vehicle for the renewal of the large-scale sequencing program, is April 11, 2006. For the next phase of this critically important part of the NHGRI research portfolio, the cooperative agreements will be awarded for a four-year term. The initial review of the applications will be held in July 2006 and will include site visits. The applications will be presented for second-level review to the National Advisory Council for Human Genome Research at its September 2006 meeting.

The Cancer Genome Atlas, or TCGA

The Cancer Genome Atlas, or TCGA program was announced at a press conference in December 2005. The program will begin with a pilot project phase, in which a small number of tumors will be analyzed to evaluate the feasibility of this approach to the study of cancer. The NCI has requested community input into the selection of the first few tumor types through the issuance of an RFI to get information about existing tumor collections that might meet the pilot-project criteria of tumors with a high degree of homogeneity, large amounts of tissue, a large number of samples, and the availability of corresponding normal tissue. The initial tumor types to be analyzed will be chosen within the next two to three months, and at least 250-300 samples per tumor type will be analyzed so that the major issue of tumor heterogeneity can adequately be explored on the molecular level. Staff from the NHGRI and the National Cancer Institute (NCI) have been meeting weekly as a staff management team to coordinate the different elements of the project, which is in its beginning stages.

The project will comprise several components:

  • A centralized tissue collection and sample preparation center (Biospecimen Core Repository); an RFP has been issued to solicit proposals for this facility.
  • Cancer Genome Characterization Centers (CGCCs), which will be supported by NCI as cooperative agreements to characterize tumors using such methods for genomic analysis as copy number determination, transcriptome analysis, and perhaps epigenetic analysis, although only well-proven, high-throughput, comprehensive technologies will be supported. An RFA to solicit applications for the CGCCs will be released, for funding in FY2006.
  • Sequencing for the TCGA will be provided by the next round of NHGRI-supported large-scale sequencing centers. The $50M that NHGRI has committed to the TCGA project will be provided as an in-kind contribution of sequencing capacity.
  • An informatics and database effort, which will be managed in large part via NCI's caBIG platform.
  • Technology development, which will be supported by both institutes and for which an RFA is being developed.

As part of the developing NHGRI medical sequencing program, three of the sequencing centers (those at Washington University, Baylor College of Medicine, and the Broad Institute) are using their Council-approved 10% set-aside of funds to collaborate on a project known as the Tumor Sequencing Project (TSP). Additional collaborators on the TSP, which will study lung adenocarcinomas, include the Memorial Sloan-Kettering Cancer Center, the Dana Farber Cancer Center, the M.D. Anderson Cancer Center, and the University of Michigan, all of which will supply the tumor samples. The TSP, which will have obvious relevance to the TCGA, is in the process of collecting and confirming the pathological analysis of the samples, and sequencing should start by late Spring, 2006.

The final individual human chromosome manuscript has now been submitted for publication. To address the issue of keeping the reference sequence up to date, NHGRI held a workshop almost two years ago to discuss the long-term maintenance of the reference human genome sequence. That workshop concluded that long-term curation of the sequence (an activity distinct from annotation) should be carried out centrally by one, or perhaps two, organizations who would be to take ownership responsibility for updating the reference sequence in the database (for example in response to error reports), resolving the few yet-incomplete regions as that becomes possible, and dealing with the issue of alternate common haplotypes, particularly in highly variable regions. NHGRI will convene a meeting in May among the seven centers that currently have responsibility for individual chromosomes in order to implement this consolidation of responsibility.

Sequencing Technology

RFAs have also been (re-)issued for the NHGRI Sequencing Technology Development Program. One is for Near-Term Technology Development for Genome Sequencing (the $100,000 Genome) and the other is for Revolutionary Genome Sequencing Technology Development (the $1000 Genome).

The second annual meeting of the grantees of the DNA sequencing technology development program (both the $1000 and $100,000 genome programs) was held at Marco Island, Florida on Feb. 7-8, just prior to Council, in conjunction with the annual ABGT meeting.

Centers of Excellence in Genomic Science

The CEGS program held its third annual grantee meeting last autumn. This meeting was held at Yale and was hosted by Mike Snyder and his center team. The great progress that has been so striking at each of the CEGS grantee meetings since the first was again notable, with each of the groups reporting exciting advances, including the discoveries noted earlier related to the potential of the stickleback as an evolutionary "supermodel." A meeting of the Minority Action Program (MAP) participants was again held in conjunction with the CEGS meeting. At the MAP meeting also, progress was noted by the MAP program advisors in the ability of the CEGS and other large NHGRI grantees to attract and train scientists from underrepresented minority groups.


Phase I of the International HapMap Project was successfully completed in October of 2005 with the publication of a paper in the October 27, 2005 issue of the journal Nature (data collection had been completed several months earlier). In the paper, more than 200 researchers from Canada, China, Japan, Nigeria, the United Kingdom and the United States reported the initial results from this public-private effort to chart the patterns of genetic variation common in the human population. The Nature paper marked the attainment of that goal, with a detailed description of the Phase I HapMap containing of more than 1 million SNPs.

Data collection for Phase II of the HapMap Project was completed at the end of August 2005; these data were obtained by Perlegen Sciences with NHGRI support. The data were deposited in the Project's Data Coordination Center at Cold Spring Harbor. The Phase II dataset contains nearly three times as many markers as the Phase I dataset. Analysis of Phase II data is currently underway.

The HapMap has been a tremendous success. As noted earlier, it was highlighted by Science as one of the major achievements of 2005 and it is being widely used as a powerful new tool for research to identify genetic polymorphisms in alleles associated with complex diseases. A recent example is use of the HapMap in the identification of the involvement of a gene called TCF7L2 in diabetes. It is expected that many other genes involved in common diseases will be successfully identified by applying the HapMap.

However, in spite of the success of HapMap, and the incredible reduction in the unit cost of genotyping that it fostered, genotyping projects are still large and therefore their total costs remain high. It currently costs $2-$3 million to genotype 300,000 SNPs in 1000 cases and 1000 controls, and $3 million per disease is still a big challenge for medical research. To help resolve this concern, a pair of new programs has been developed at NIH.

" The first is a public-private partnership, called the Genetic Association Information Network (GAIN). Two companies, Pfizer and Affymetrix, constitute the public sector participants, and they will support the large-scale genotyping of case-control cohorts for seven diseases. The NIH will participate by supplying the patient samples to be analyzed, and the Foundation for NIH (FNIH) will assume the private-sector management role by conducting the peer review and program management. GAIN was announced in a press conference at the National Press Club in the week before the Council meeting. The press conference and other relevant information can be found at the project's website, It is hoped that additional parties from the private sector will contribute support so that additional projects can be undertaken.

GAIN will begin immediately. While the strategy has not been finalized by the Executive Committee, at present it is expected that the project will be set up as follows: The FNIH will issue a call for appropriate case-control sample collections. Investigators can nominate their collections for the free genotyping that will be provided by GAIN by submitting a proposal in response to that call. The proposals will be peer reviewed by a panel organized by the Foundation. The most highly rated studies will undergo a second-level review process by the GAIN Steering Committee, which will include extramural experts and private sector representatives. The criteria for selection will include scientific merit and a reasonable range of diseases. The selected studies will then send DNA samples from the cases and controls to a genotyping lab identified by the private sector donors. In the case of the studies that will be funded by Pfizer, the genotyping will be performed by Perlegen, using that company's high-density genotyping platform. Studies that use the Affymetrix platform will be conducted at the Broad Institute. As soon as the genotype data have been validated, they will be deposited into a new database that is being constructed by NCBI. The data will be available to the entire scientific community at the same time; the GAIN sponsors will not have advance access. The GAIN database will hold both genotypic and phenotypic information. All of the data in the NCBI database will be de-identified and, therefore, according to recent rulings from the Office of Human Research Protections (OHRP), DHHS, users will not need IRB approval to gain access. Access to the data will be available to any approved user; to gain approval a user will have to submit a request that will be assessed by a Data Access Committee as an appropriate use. An approved user and his/her institution will also have to agree to the GAIN principles, policies and procedures for the use of GAIN data. In particular, a user will have to agree that s/he will not submit a manuscript analyzing the data until 9 months have elapsed since the data were first posted to the database.

" The Genes and Environment Initiative (GEI). This program is included in the FY07 budget request for NIH as a new initiative. Its purpose is to study the relationships between genes, environment, and health and it includes $26M per year to support whole genome analyses of the genetic contributions to disease. In addition, a portion of the GEI program will be devoted to developing novel technologies aimed at assessing environmental exposure. It will be managed by a Coordinating Committee co-chaired by Drs. David Schwartz (NIEHS) and Francis Collins. It is likely that RFAs to detect toxins, measure body burden, assess biological implications, evaluate dietary intake, and monitor physical activity, will be released."

On Wednesday December 7th, 2005, an international team, led by researchers at the Broad Institute of MIT and Harvard, announced the publication of the genome sequence of the dog. Elaine Ostrander was essential in getting the project underway and completed.

The rhesus macaque genome was sequenced and assembled by Baylor, the University of Washington, and the J. Craig Venter Institute. Granger Sutton was responsible leading the team that produced the final assembly of 5x coverage.

The NHGRI is currently supporting the sequencing of the genomes of 100 bacteria from the human intestinal tract, a project that was recommended by the Coordinating Committee and approved by Council last September. Council approved sequencing 100 human gastrointestinal tract bacteria.

NIH announced the procurement of 251 lines of KO mice and extensive phenotypic data on them from Deltagen and Lexicon. The list of mouse lines available was made available on the websites of the NIH, the Mutant Mouse Regional Resource Centers, and The Jackson Laboratory. Since then virtually all available mice have been requested at least once. Since the contract remains open, additional mouse lines could be obtained in the future.

The goal of the Knockout Mouse Project (KOMP) is to ensure that a knockout mouse resource with a null mutation in every gene in the mouse genome is available to the mouse research community. 17 Institutes and Centers have committed nearly $55 million over the next five years to support 1) generation of the resource, 2) technology development to ensure that the resource can be made in C57BL/6, the most commonly used mouse strain, 3) a data coordination center and 4) a repository for the resources generated by the project. Grant applications in response to KOMP RFAs have been received for all but the repository effort. The applications will be reviewed in the spring and funded during the summer.

NHGRI Intramural Program

Intramural branch chiefs Bob Nussbaum and Jennifer Puck are leaving to take senior faculty positions at the University of California, San Francisco. DIR is has undertaken a search for two new branch chiefs, the closing date for this position is March 1, 2006.

On the 10th of January, NHGRI announced the appointment of Joan E. Bailey-Wilson, and Alexander F. Wilson as the new co-chiefs of its Inherited Disease Research Branch.

Senior intramural investigator Larry Brody has been named as the new Scientific Officer of the Center for Inherited Disease Research (CIDR). Larry will replace Bob Nussbaum who will be leaving in April 2006.

Drs. Leslie Biesecker and Joan Bailey-Wilson led the effort to identify missing persons from the September 11th attacks on the World Trade Center. On November 17th, 2005, in an article published in the journal Science, it was reported that DNA-based efforts led to the identification of more than one-quarter of those reported missing. The article also made recommendations to improve DNA identification in event of future terrorist attacks or mass disasters.

Now Drs. Biesecker and Bailey-Wilson are leading an advisory committee to conduct DNA sampling of missing persons following Hurricane Katrina, NHGRI volunteers constructed pedigrees, identified relatives on whom DNA collection would be helpful for identification and, perhaps most importantly, found many "missing" persons alive.

NHGRI Office of the Director

The Ninth Annual National Coalition for Health Professional Education in Genetics (NCHPEG) meeting was held February 2-3, 2006 in Bethesda, MD. The focus of this meeting was on risk assessment and risk communication in health care.

The U.S. Surgeon General's Family History Initiative celebrated the second Annual National Family History Day on Thanksgiving 2005. A press conference to announce the celebration, launch the new web-based "My Family Health Portrait" tool, and unveil the Brigham and Women's Hospital Family History project was held in Boston on November 15, 2005. The NIH and the American Society of Human Genetics were highly involved in the initiative. In the past year, more than 360,000 copies of the original "My Family Health Portrait" computer tool, which is available in English and in Spanish, have been downloaded from the HHS Web site.

On November 16th, 2005, the Policy and Program Analysis Branch (PPAB) of the National Human Genome Research Institute (NHGRI) convened a roundtable to examine further what core policy issues the NHGRI must work on to help ensure that our greatly expanding knowledge of human genomics is translated into improved health care.

The second Community Genetics Forum will be held on September 15-16, 2006. The goal of the forum is to engage community groups in genetics. NHGRI chose to focus this 2nd Community Genetics Forum in the DHHS Regions IV and VI (southern U.S.). Proposals were received following the release of a RFP and NHGRI selected the University of North Carolina/Duke University to host the 2006 forum. Last year's forum took place in May 2005 in Seattle.

The DNA Day 2006 Ambassadors Program is underway. The goal is to involve 60 ambassadors, with a focus on minority communities in the New England region. Serving as two online components to the program, a live chatroom will be setup for April 25th from 8 a.m. - 6 p.m., and Barbara Biesecker will be featured in a webcast. The program has partnerships with the Koshland Science Museum (part of the National Academies of Sciences), as well as with the American Society of Human Genetics Mentor Network, which includes the Genetic Alliance, the National Society of Genetic Counselors, the Genetic Society of America, and the NHGRI.

NHGRI Policy

The FY2006 NIH appropriation was $28.617 billion, a 0.9 percent increase. At the same time Congress passed the Department of Defense Appropriations bill, which included a 1% across the board cut to all domestic discretionary spending. This resulted in a slight cut in NIH funding for the first time since 1970. The passage of these two bills resulted in a -0.5% decrease below FY 2005 levels for NHGRI before any Roadmap transfers, or $486.0 million. The President's budget for FY 2007 included the same level of funding for NIH as was in the FY 2006 appropriations passed by Congress, but due to shifts in NIH priorities, particularly for biodefense, NHGRI's FY 2007 level before Roadmap decreases another -0.6%, for a total of $482.9 million.

Due to pending cuts in the NIH budget, last autumn the NIH IC Directors discussed how to spread those cuts across the portfolio. There was a major concern regarding young investigators, and to try to prevent the number of new and competing grants from being cut significantly in FY06 and FY07, the amount of money spent on noncompeting awards had to be reduced. Consequently, noncompeting commitments for every RPG will be reduced by -2.35% from the FY06 commitment of record. Competing RPGs will receive no average cost increase over FY 2005, with the expectation that the number of competing RPGs will be reduced slightly from the FY 2006 Conference. Hearings in the House of Representatives and in the Senate are scheduled to take place in mid-March 2006.

On February 17, 2005, the U.S. Senate unanimously passed S. 306, the Genetic Information Nondiscrimination Act of 2005, by a vote of 98-0. On March 10, a bipartisan group of House members also introduced the "Genetic Information Non-Discrimination Act of 2005," HR 1227, which is identical to S. 306. The bill was referred to the Committee on Education and the Workforce, the Committee on Energy and Commerce, and the Committee on Ways and Means. The Coalition for Genetic Fairness, headed by Sharon Terry has been working closely with those offices that introduced the bill and they believe there will be action this year. The Secretary's Advisory Committee on Genetics, Health and Society has also been working to bring the new Secretary up to speed on this matter. Secretary Leavitt has indicated his support and the President has indicated that he will sign this bill.

As was reported last year, the American Chemical Society (ACS) had expressed concern that a new NIH database called PubChem, which continues to flourish, may be a threat to the financial survival of the Chemical Abstracts Service (CAS). PubChem provides free access to its database; CAS charges a fee for researchers to use its database. A special working group of the Board of Scientific Counselors of NLM's National Center for Biotechnology Information has been formed with the specific purpose "to advise on interactions with private sector information providers in the development of PubChem."

Report from the U.S. Department of Energy

The Genomes to Life Program has been successful thus far. Biological research in the U.S. Department of Energy has been subject to a reduction in priority in favor of the physical sciences. However, the Genomes to Life Program bridges the gap between the two sciences by focusing on three efforts: clean sources of renewable energy, bioremediation, and carbon sequestration to deal with the increased atmospheric carbon dioxide and global warming. In the FY07 budget request, the Biological and Environmental Research Program received a $54.6M increase over the FY2006 level, and within this the Genomics GTL program increase was $49M. The first RFP will call for proposals to establish a protein production facility, with applications due in a couple of months. The National Academy of Sciences plans to endorse the program strongly, as well as the program's facilities plans.

Dr. Ari Patrinos announced his retirement from DOE and that he is now President of Synthetic Genomics. NHGRI gave Dr. Ari Patrinos a certificate in recognition of his accomplishments in promoting DOE-NHGRI collaboration on the Human Genome Project. He was also given some additional tokens of appreciation.

Report on the Office of Portfolio Analysis and Strategic Initiatives (OPASI)

Dr. Collins' presentation was put together in large part with the help of Dr. Kington and his staff.

In general, the NIH does a good job of setting priorities at the Institute and Center levels. However, there are problems with trans-NIH research that does not fit neatly into only one Institute's portfolio. Examples of such trans-NIH projects include the mouse and rat sequencing efforts, the HapMap, and the Mammalian Gene Collection (MGC). Collecting funding from different institute donors for such trans-NIH initiatives is a difficult and inefficient process that will only increase in difficulty in the face of pending budget cuts.

The Roadmap was a trans-NIH effort that funded 27 initiatives and has had some notable initial successes. But, the Roadmap is a one-time program. Thus, the NIH needed a n on-going process for handling trans-NIH initiatives. An alternative, long-term solution has been developed that will be overseen by a new office, the Office of Portfolio Analysis and Strategic Initiatives (OPASI). The role of OPASI will involve coordinating the management of the overall portfolio of NIH-funded research, developing better methods to assess the different programs throughout the NIH, and improving the evaluation of the effectiveness of the NIH programs. In particular, OPASI is designed to provide a more standardized pathway for getting trans-NIH initiatives considered for common funding. Programs that come out of OPASI will be supported from a common fund to which all Institutes contribute. The existing Roadmap funds will serve as a starting point, but it is anticipated that the common find will be able to increase to as much as 5% of the NIH budget.

The structure of the OPASI program will involve several components. The Division of Resource Development and Analysis (DRDA) will be responsible for knowledge management and assessing the public health need/burden of illness. The Division of Evaluation and Systematic Assessments (DESA) will evaluate the different NIH programs and the Division of Strategic Coordination (DSC) will process the trans-NIH initiative ideas. In addition, there will be a tiered process for the review of submitted trans-NIH proposals.

Council members commented on the problems of having a trans-NIH project eventually adopted by one NIH institute.

Concept Clearance of RFA for "Public Consultation to Inform the Design of a Large-Scale study of Genes and Environment in Common Disease"

The American Genes and Environment Study (AGES) has been under discussion for two years at NHGRI, as an American large longitudinal cohort study. As a first step, NHGRI proposes to release an RFA aimed at taking the "pulse" of the public to get a sense of the general attitude and receptivity to such studies. The RFA would support a preliminary, pre-pilot, study focused on assessing public opinion about topics including, but not limited, to privacy concerns (de-identified information posted online), recruitment strategies, medical follow-up preferences, and incentives/compensation. The knowledge gained from such a pilot project survey could inform the design of the future cohort studies.

NHGRI proposes to set aside $1,500,000 for a two-year period for this RFA. The Centers for Disease Control (CDC) is interested in also providing some support. It is anticipated that one award will be made, as a cooperative agreement, and that would provide support to survey several communities. Periodic reports would be required of the grantee, along with a final report summarizing the findings.

Council members approved the concept clearance.

Report on the National Academy of Science Study of Intellectual Property in Genomics and Proteomics

The NHGRI has helped to fund a National Academy of Sciences (NAS) study on intellectual property (IP) issues in genomics and proteomics. Since the goal of the NIH is to support research that advances public health, there is concern about the potential use of patents in a way that would slow biomedical research in genomics and proteomics.

The committee established for the NAS study was given the charge of determining: USPTO standards in granting patents, effects of patenting/licensing on research and innovation, trends in U.S. genomic/proteomic patents, and steps the NIH should take to protect research and innovation.

The committee's findings included: patenting varies greatly within the biotechnology industry; patenting has leveled off but, since there is a large backlog of patents pending approval, this plateau-effect may, in large part, be deceptive; U.S. inventors dominate patenting activity, but the bar is higher in Europe and Japan; most other countries have a research exemption (whereby an investigator can perform non-commercial research on particular patented inventions), but the U.S. does not; the number of research projects that have been abandoned or delayed due to IP concerns appears to be smaller than anticipated; most investigators do not revise their protocols to take into account IP issues because they do not think that IP is a concern; patent holders are asserting their rights, especially in the clinical lab arena; the burden on biomedical research could get much worse, especially considering the fact that academic institutions are becoming aware of IP issues and policies.

The NAS committee made thirteen recommendations, a number of which addressed the NIH. The committee recommended that NIH should:

  1. Encourage the free exchange of materials and data and should monitor grantee actions regarding data and material sharing, if necessary requiring grantees and contractors to comply with their approved intellectual property and data sharing plans.
  2. Adapt and extend the "Bermuda Rules" to structural biology data generated with NIH support for large-scale structural genomics efforts, making all information rapidly released to the public via the Protein Data Bank (PDB).
  3. Ensure that the protein database (PDB) works with the USPTO, JPO, and EPO to efficiently share structural biology data in published patents and to encourage investigators to share sequence data.
  4. Require that all recipients of NIH funds adhere to and comply with the NIH Principles and Guidelines for Recipients of NIH Research Grants and Contracts on Obtaining and Disseminating Biomedical Research Resources and Best Practices for the Licensing of Genomic Inventions.
  5. Encourage the use of the Simple Letter of Agreement for the Transfer of Materials or the Uniform Biological Material Transfer Agreement (UBMTA). Adapt the UBMTA to create a similar standardized agreement for data exchange.
  6. Assist the U.S. PTO in identifying experts who can serve on advisory committees or participate in forums to inform examiners about new developments and research directions in their field.
  7. Explore the possibilities of patent pooling and cross-licensing agreements with industry, university, and government.

The committee also addressed the USPTO, Congress, and inventors and their institutions with recommendations designed to encourage all participants to use intellectual property in a way that will not inhibit further research.

The NIH has formed an IP committee in part to respond to the NAS and the NHGRI is actively involved in this process.

A summary of the NAS study report was included in council members' folders and additional information is posted online at Intellectual Property Rights, Innovation and Public Health PDF file.

To view the PDF document(s) on this page, you will need Adobe Reader. Download Adobe Reader

Survey of Licensing of DNA Patents

Dr. LeRoy Walters presented the results from an empirical survey on the licensing of DNA patents by large U.S. academic institutions. The overall results of the survey revealed that, although one or two issues may need to be addressed in the future, there is no crisis in the arena of patenting and licensing DNA-based inventions. The survey was based on the initial thesis that licensing policies and practices may be as important as the patenting policies and practices themselves in determining the effect of intellectual property practices.

Using a combination of algorithms, the patents of interest were identified in the U.S. Patent Trade Office (PTO) databases. DNA- and RNA-based patents, not only DNA- or RNA-sequence patents, were selected. Based on national data, 2001 was the peak year for issuing DNA patents by the U.S. PTO. Since that year, there has been a reduction in the number of new DNA patents. Several explanations may account for the patent decrease: (1) institutions might be less likely to seek patents, (2) the U.S. PTO might be more stringent in granting patents, and/or (3) the backlog of patents pending approval might have gotten worse.

Thirty entities hold the largest number of U.S. DNA-based patents. The University of California holds the largest number, 1032. The U.S. government is the second largest holder of DNA-based patents, with 929. Other patent holders include groups of companies and academic institutions.

The government has an interest in ~1.18% of all patents, ~13.61% of all DNA-based patents, and ~50.29% of all DNA-based patents owned by the top 30 academic institutions.

Regarding licensing, 775 patents were never licensed, 45 were broadly licensed, and 1301 were licensed once. Exclusive licenses are in the interest of startup companies. However, there is a difference between "exclusive for all fields of use" and "exclusive for a particular field of use." If several parties are interested in an invention, it is less likely that exclusive licensing will be used.

Overall, the conclusions from the study indicated that there was a high degree of patent and license flexibility and pragmatism, and there tends to be protection of research-use rights among academic institutions (and at times all nonprofits). Furthermore, there is general awareness of and adherence to the NIH guidelines, which are perceived more as regulations than as guidelines.

In the future, a comparison of issued patents with corresponding publications by named inventors may be in the government's interest. More information about the income generated through the licensing of DNA-based inventions also may be advantageous.
Further exploration of iEdison files would be beneficial as well, as iEdison is a database that gathers information on all patents and licenses pursued by grantees and contractors of the federal government. Currently, the NIH does not have access to the iEdison database.

Council members discussed the debate over exclusive versus nonexclusive licensing with respect to diagnostics, the submission of IP infringement letters from the private sector to academic institutions and the Office of Technology Transfer, the difficulty in discerning pre-commercial research from academic research, the difficulty in surmounting IP obstacles to release mouse knockout genes to the public, and the challenge in agreeing to IP conditions that restrict future actions.

Project Updates

ENCODE Project

Elise Feingold reported on the ENCODE project. The Encyclopedia of DNA Elements, or ENCODE, project is based on a phased research approach and has been using the Human Genome Project as a model. One component is a pilot project using existing technologies to focus on the identification of transcription units, transcriptional regulatory sequences, DNase hypersensitive sites, chromatin modifications, and origins of replication within a carefully selected 1% of the human genome. Another phase focuses on technology development, including the identification of less well-studied functional elements and novel technological platforms. Two RFAs for technology development were issued. Grants in response to the first RFA were funded in September 2003 and those responding to the second RFA were funded in September 2004. The next phase for ENCODE will involve expansion of production activity to the entire genome.

The ENCODE pilot project awards were issued as cooperative agreements and the awardees were organized as a Research Network. The ENCODE consortium has gelled effectively and has been very active, participating in multiple teleconferences and establishing several working groups and five analysis groups. A two-day meeting of the Consortium followed a three-day Data Analysis Workshop in July 2005. That meeting highlighted the need for more data on common cell lines and factors as well as relevant tissues for specific loci to enhance ENCODE data analysis. Additional transcription factors and methods to detect chromatin marks also were recommended. Furthermore, meeting concluded that the scaling up of the ENCODE project to the whole genome must take into consideration robustness of the technology, the biological utility of the data, and the costs.

A second ENCODE data freeze occurred in October 2005. Following the data freeze, the ENCODE working groups were reconvened and the resulting meetings of the ENCODE analysis working groups in late October/early November 2005 further stressed the need to focus on the robustness of the technology. The Fall 2005 working group meetings also led to the compilation of individual working group reports.

An ENCODE Scaling Meeting took place on January 12-13, 2006, during which members of the project's External Scientific Committee, along with outside experts, discussed a number of issues relevant to implementing the next steps of the project. Specific topics discussed included the degree of scale-up for the next phase of the project and the "readiness" of the technologies for such a scale-up. Overall, it was noted that the ENCODE pilot project is going well, with a large amount of data, innovative data analysis methods, and interesting scientific conclusions generated. Preliminary findings from the working groups were presented. A few highlights include:

A. From the Genes and Transcripts working group:

  1. Only a fraction of processed RNA transcripts correspond to known annotated transcripts.
  2. A substantial fraction of transcription appears to be cell-type specific.
  3. The structure and organization of protein-coding and non-coding transcripts is composed of short and long distance lattice networks of RNAs. The same genomic sequence may be processed into multiple RNA sequences, with different fates. 5' RACE studies provide evidence of a large number of unannotated distal 5' transcriptional start sites (TSS) of protein coding genes; more than half of these are >250kb from the annotated 5' TSS.
  4. Based on 5' and 3' end analysis, nearly the entire genome (at least 80%) is transcribed into primary nuclear transcripts in at least one direction.

B. From the Transcriptional Regulatory Elements working group:

  1. Histone modification correlates with gene expression, which will allow the identification of potential new promoters.
  2. Many factors are co-associated (e.g., E2F1, Sp3, cMyc and STAT1 tend to bind at H3K4 dimethylated regions)
  3. Regulatory elements are often conserved.

C. From the Chromatin and Replication working group:

  1. For a given tissue, chromatin accessibility and histone methylation (H3lys4) and acetylation patterns are tightly linked.
  2. There is a general lack of correlation between chromatin/replication domains and strong evolutionary non-coding conservation.
  3. Chromatin architecture and replication timing are correlated. There is evidence for the existence of discrete large-scale functional domains in the human genome. Domains cannot be predicted using gene annotation, transcription, and/or conservation alone.

The attendees at the January 2006 ENCODE Scaling Meeting recognized the challenges of the project and, on the basis of the discussion at the meeting, NHGRI staff recommends that the project delay initiating a full scale-up for up to a year. This delay should give the technologies time to mature further by using the lessons learned from the pilot project thus far. Prior to the meeting, the NHGRI had already planned a six-month extension of the ENCODE pilot project. NHGRI is in the process of evaluating other conclusions based on the discussions at the meeting and will present a plan at the May 2006 Council.

Council members indicated a high degree of enthusiasm for the success of the ENCODE pilot project and for the potential publications that will result.

Mammalian Gene Collection Project

Gary Temple reported on the Mammalian Gene Collection project. The goal of the MGC project is to obtain a single full-length open-reading frame cDNA clone representing the complete set of well-defined human and mouse genes. Thus far, 75% of this goal has been attained for the human and 66% has been attained for the mouse. MGC has also taken on, or participated, in the isolation of full-length open reading frame cDNA clones from three other organisms, and 77% of the goals for the rat project, 71% of the Xenopus project (both X. laevis and X. tropicalis; project implemented and managed by NICHD), and 72% of the goals of the Danio rubio project (project implemented and managed by NIDDK) also have been achieved.

For the human and mouse efforts, the MGC project is currently employing a targeted recovery strategy based on RT-PCR synthesis of annotated genes. More than 12,400 annotated genes have been assigned to the two groups involved in this phase of the project and almost that full number has already been introduced into the production pipeline. Approximately 5600 of those genes have been cloned to date. Approximately 4600 additional genes have been sequence-validated and approximately another 2600 genes are still in the sequencing pipeline awaiting full-length (FL) sequencing. On the basis of the results to date, it is expected that the majority of the candidates awaiting FL-sequencing will turn out to be the correct genes. A realistic goal is to obtain 55%-60% of the previously unrecovered genes in the first round of PCR rescue. By the end of 2006, it is expected that 92% of the total 36,984 human and mouse genes will be cloned.

In anticipation of the need to implement a third strategy to obtain cDNA clones for those genes that have been missed to date, the MGC carried out a pilot study for synthesizing cDNA clones de novo. In this pilot, contracts were issued to four companies (Genscript, Picoscript, Codon Devices, and Blue Heron) on the basis of a competitive review. Each was assigned a unique set of 18 ORFs and a common set of 3 ORFs that were larger genes; in each case, a range of cDNA sizes was represented by the 21 assignments. The results obtained by the end of the 90 day-contract period, indicated that DNA synthesis is a very promising approach to obtain cDNAs that were not recovered from random cDNA libraries or by RT-PCR.

Council members discussed the possibility of working on single exon genes, the relationship between the ENCODE project and gene prediction work, the breadth of the genome involved in transcription, and potential organisms that could be added to future MGC pipelines.

Molecular Libraries Screening Center Network (MLSCN)

Carson Loomis reported on the Molecular Libraries Screening Center Network (MLSCN), one component of the Molecular Libraries Roadmap Initiative. The MLSCN comprises nine extramural high-throughput screening (HTS) centers, which were funded in July 2005 and the intramural NIH Chemical Genomics Center, funded in 2004. The MLSCN is designed to stimulate the development of new, small molecule research probes by providing access to high-throughput screening capacity for the public research sector and developing a database of HTS results. The MLSCN program is currently in a three-year pilot phase.

Investigators can interact with the MLSCN program in several ways, through submission of assays via the new X01 mechanism, by providing new compounds to the MLSCN Small Molecule Repository or by obtaining MLSCN data from the PubChem database at the National Center for Biotechnology Information. All data generated by the MLSCN is deposited into PubChem for public access.

Assay recruitment has been underway since last fall using the X01 resource access mechanism. Investigators do not receive funding through the X01; rather, the X01 provides a defined process for the peer review of requests from investigators to obtain access to the MLSCN HTS capacity. The first X01 solicitation yielded 64 applications, with 50% of the applications originating from the MLSCN centers; 28 assays were approved for entrance to the MLSCN. The second X01 solicitation yielded 42 applications, with 60% of the applications from the centers; 24 assays were approved. Finally, the third X01 solicitation resulted in 29 applications, 60% of which came from the centers. Awards for this last solicitation are pending. All of the approved assays have been assigned to the centers. All of the centers have signed the MLSCN Material Transfers Agreement and the Confidential Disclosure Agreement and are in the process of contacting the assay providers to begin to import the assays into the HTS centers. Three of the centers have already deposited data into PubChem. Thus far, PubChem has >200 bioassays, >5.3 million unique compounds, and 1.5 million logins/day.

The MLSCN is actively engaged in making itself known to the academic research community. Its outreach program has taken several approaches, including conference presentations, printed handouts, publications in Science and in the Journal of Biomolecular Screening, advertisements in journals regarding how to submit assays to MLSCN, providing supplemental funds to the MLSCN centers for local outreach activities, and invitations to assay PIs to present at quarterly Steering Committee meetings. An MLSCN website will go live soon.

Council members raised questions as to the allocation of MLSCN projects across the different NIH institutes.

Council-Initiated Discusssion

Two RFAs for the Knockout Mouse project, a review of the CEGS program, and the medical sequencing initiatives will be discussed during the May 2006 Council closed-session meeting. For the May 2006 Council open-session meeting, NHGRI staff suggested several options, including inviting Dr. Evan Eichler to give a presentation on the structural variation in the human genome, having a presentation on the CEERS program, and inviting Dr. Sean Carol to give an update on the field of evolutionary and developmental biology.

Council members also suggested providing an update on the new sequencing technologies, perhaps with the input of one or more Principal Investigators. Council members also indicated that they would like to have a presentation on the developments within the ELSI program for the medical sequencing initiatives. It was agreed that a presentation on the discovery and distribution of small molecules for therapeutics should be reserved for the September 2006 Council meeting.

Council members also expressed interest in fostering the progress of the Human-Base project.

Announcements and Items of Interest

There were no announcements or items of interest to report.

Conflict of Interest

Dr. Guyer read the Conflict of Interest policy to Council and reminded members to sign the forms provided.

Consideration of NHGRI Applications

In closed session, the Council reviewed 101 applications, requesting $29,762,995. The applications included 35 regular research grants, 9 pilot projects, 18 ELSI grants, 9 responses to RFAs, 2 area grants, 2 center grants, 2 conference grants, 12 SBIR Phase I grants, 6 SBIR Phase II grants, 3 fellowship grants, 1 STTR Phase I grant, and 2 others. A total of 74 applications totaling $24,688,656 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

Top of page

Last Reviewed: May 22, 2012