Last updated: March 23, 2013
National Advisory Council for Human Genome Research
Summary of Meeting
Fishers Lane Conference Center
September 12, 2005
The open session of the National Advisory Council for Human Genome Research was convened for its forty-fifth meeting at 8:40 A.M. on September 12, 2005 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 8:40 a.m. until 5:10 p.m. on September 12, 2005. In accordance with the provisions of Public Law 92-463, the meeting was closed to the public from 5:10 P.M. on September 12, 2005 until adjournment for the review, discussion, and evaluation of grant applications.
Council members present:
William Gelbart, ad hoc
Deidre Meldrum, ad hoc
Richard Myers, by teleconference
Stephen Prescott, ad hoc
David Valle, ad hoc
Alan Williamson, ad hoc
Barbara Wold, ad hoc
Council members absent:
Vicki Yates Brown
Ex officio member absent:
Joann Boughman, American Society of Human Genetics
R. Rodney Howell, American College of Medical Genetics
Sharon Olsen, International Society of Nurses in Genetics
Sharon Terry, Genetic Alliance
Wendy Uhlmann, National Society of Genetic Counselors
Staff from the National Human Genome Research Institute:
Maggie Bartlett, OD
Saveri Bhattacharya, DER
Christianne Bird, DER
Vence Bonham, OD
Joy Boyer, DER
Lisa Brooks, DER
Comfort Browne, DER
Sudeshna Chatterjee, DER
Cheryl Chick, DER
Monika Christman, DER
Francis Collins, OD
Chris Davis, DER
Karen DeLeon, OD
Tanya Dougans, DER
Elise Feingold, DER
Adam Felsenfeld, DER
Phyllis Frost, OD
Peter Good, DER
Bettie Graham, DER
Eric Green, DIR
Alan Guttmacher, OD
Mark Guyer, DER
John Hodges-Howell, DER
M.K. Holohan, OD
Rebecca Kolberg, OD
Tim Leshan, OD
Laura Liefer, DER
Carson Loomis, DER
Jessica Melone, DER
Jean McEwen, DER
Keith McKenney, DER
James McWilliams, DER
Patrick Nailer, DER
Ken Nakamura, DER
Vivian Ota Wang, DER
Brad Ozenberger, DER
Allison Peck, DER
Rudy Pozzatti, DER
Jerry Roberts, DER
Laura Rodriguez, OD
Jeff Schloss, DER
Derek Scholes, OD
Geoff Spencer, OD
Shundel Stephenson, DER
Gary Temple, DER
Larry Thompson, OD
Susan Vasquez, OD
Melinda Weiss, DER
Kris Wetterstrand, DER
Lynn Zacharia, DER
Others present for all or a portion of the meeting:
Diane Baker, Genetic Alliance
Rachel Diaz, Families of Untreated Mentally Ill Persons
Steve Evangelista, SRI International
Daniela Gerhard, National Cancer Institute
Andrew Hawkins, Research Policy Alert
Eric Lander, Broad Institute
Liz Pennisi, Science
Jonathan Pollack, NIDA
Margaret Snyder, OD/ OER/OSA
Introduction of Liaisons and New Employees
Mark Guyer introduced six ad hoc Council members: Deidre Meldrum, University of Washington; Stephen Prescott, University of Utah; William Gelbart, Harvard University; David Valle, The Johns Hopkins University School of Medicine; Alan Williamson, private consultant; and Barbara Wold, California Institute of Technology.
Dr. Guyer introduced new NHGRI staff: Keith McKenney, Scientific Review Administrator; Chris Davis, Grants Management Specialist; Christianne Bird, Saveri Bhattacharya, Sudeshna Chatterjee, and Melinda Weiss, Program Analysts; Gail Allen, Executive Assistant to Francis Collins; and Derek Scholes, ASHG/NHGRI Policy Fellow. Additionally, Dr. Guyer introduced Dale Lea, a health educator on sabbatical with Vence Bonham, and Teri Manolio, who will be at NHGRI on a sabbatical from NHLBI starting October 1.
Dr. Guyer welcomed liaisons from professional societies and members of the press: Joann Boughman, American Society of Human Genetics; Rod Howell, American College of Medical Genetics; Wendy Uhlmann, National Society of Genetic Counselors; Sharon Olsen, International Society of Nurses in Genetics; Sharon Terry, Genetic Alliance; and Liz Pennisi, Science. Information about liaison organizations is provided in the Council folders.
Dr. Collins presented certificates of appreciation and thanked Bill Gelbart, Bob Tepper, and Eric Juengst, who have all completed their terms as Council members.
Approval of Minutes
The minutes from the May 2005 Council meeting were approved as submitted.
Future Meeting Dates
The following dates were proposed for future meetings: February 13-14, 2006, May 22-23, 2006, September 11-12, 2006, February 12-13, 2007, May 21-22, 2007, and September 10-11, 2007.
A number of scientists who have been connected with NHGRI in one capacity or another over the past several years were affected by the Hurricane Katrina disaster along the Gulf Coast. Council member Bronya Keats and her family are safe but were displaced by the hurricane. Paula Gregory and Bruce Bunnell experienced extensive flood damage to their research facilities. Dr. Collins expressed sympathy on behalf of NHGRI and the intention to help them in whatever way is possible for the Institute. Along with the rest of NIH, NHGRI has been working to find suitable places for displaced faculty, post-docs and students to continue their research work.
Bob Waterston, a long-time NHGRI grantee and former member of the NACHGR, was selected by an international panel of experts to receive the 2005 Genetics Prize of the Peter Gruber Foundation. The $200,000 unrestricted cash award will be presented to him on October 26 at the meeting of the American Society of Human Genetics in Salt Lake City, Utah. Previous winners of the Genetics Prize include former NACHGR members H. Robert Horvitz (2002) and David Botstein (2003).
The Howard Hughes Medical Institute has announced the selection of two genome researchers as new HHMI investigators - Joseph deRisi from UCSF, and Stephen Quake at Stanford University, who has an NHGRI sequencing technology grant.
On August 25, the Department of Health and Human Services announced a revision of the interim supplemental standards of ethical conduct for employees of NIH. Several aspects of the interim regulations which had been of serious concern, such as the prohibition on outside activities with professional societies and trade organizations, were not included in the revised regulations. The final rule prohibits NIH staff from consulting for Substantially Affected Organizations (SAOs), such as pharmaceutical, biotechnology or medical device manufacturing companies, health care providers or insurers, and NIH-supported research institutions, except as an official duty. Mandatory divestiture of holdings in SAOs in excess of $15,000 per company is limited to about 200 senior NIH employees, not the 6,000 employees as originally proposed. Monetary awards from outside sources can be accepted if certain specific criteria are met and the award is approved in advance by DHHS. Dr. Zerhouni, NIH Director, and Dr. Kington, NIH Deputy Director, deserve credit for ensuring that the final ethics rules are a reasonable set of regulations that do not threaten the recruitment or retention of the best employees at NIH.
Currently, only one Principal Investigator (PI) is associated with and given credit for NIH-funded grants, contracts, and cooperative agreements. With the increasing number of interdisciplinary teams involved in biomedical research and the incentive and reward structure for academic investigators, consideration is being given to the possibility, in some cases, of allowing more than one PI to be associated with an application and award of federal research support. The Office of Science and Technology Policy (OSTP) has released a Request for Information (RFI) to seek both general and specific input and advice from the broader scientific community about the issue of permitting multiple PIs to be associated with NIH applications and awards. The deadline for submitting comments is September 16, 2005.
NIH Roadmap for Biomedical Research
Many of the NIH Roadmap initiatives have reached the point at which grant awards are being made. NHGRI is particularly involved in the Molecular Libraries and Imaging Initiative, which will be funding seven new grant programs in September 2005. One of the centers in the Molecular Libraries Screening Center Network (MLSCN), the NIH Chemical Genomics Center (NCGC) in the NHGRI Intramural Program, ran its first full screen in May and has since completed 10 more screens on assays submitted by the research community, generating over 100,000 data points in each. The NCGC has 20 staff and has multiple robotic screening platforms operational, including an ultra-high throughput screening system. Data produced by the NCGC are available in the PubChem database.
NHGRI has released an RFI on the "Identification of Mendelian Disorders by Genomic Sequencing." The RFI is requesting input from the human genetics community about investigators' interest in having access to targeted sequence data for Mendelian disorders. The deadline for comments is November 4, 2005.
Knockout Mouse Project (KOMP)
A trans-NIH effort is underway to make a null mutation in every gene in the mouse genome by trapping and targeting. Two RFAs soliciting applications for research projects to participate in generating the mouse resource have been released (see below).
NHGRI - Extramural Program
A table showing the current status of the sequencing and assembly pipeline, and a press release about the next set of target organisms for large-scale sequencing are included in the Council members' table folders.
On June 13, the NHGRI held a workshop to discuss the future of the NHGRI large-scale sequencing program, including sequencing technology, potential applications, and the appropriate focus of scientific attention. The executive summary from the workshop is included in the Council members' table folders.
The chimpanzee genome sequence and analysis were published in the September 1 issue of Nature. Several NHGRI staff members attended a news conference at the National Press Club in Washington, D.C. on August 31 at which the publication, which is the first comprehensive comparison of the human and chimp genomes, was announced. The sequencing of the chimp genome was done at the Washington University Genome Sequencing Center and the Broad Institute, and the analysis effort was led by Bob Waterston.
Sequencing Technology Development
A second round of grants for research on the $1,000 and $100,000 genomes program was awarded (see below). Two papers detailing new, rapid sequencing approaches were recently published. The new technologies were developed by 454 Life Sciences Corp. and George Church, respectively, each with NHGRI support, and each has the potential to significantly reduce sequencing costs.
Human Cancer Genome Project
On July 20-22, the NCI and NHGRI held a joint meeting to discuss the Human Cancer Genome Project (HCGP). During the meeting, participants addressed many of the issues that were raised in the NCAB report released in February, and discussed approaches for large-scale genomic analysis of tumors. The meeting proposed that the pilot phase of the HCGP be implemented with a strategy that includes the in-depth analysis of a few (two or three) tumor types and a less exhaustive examination of the genomes of a broader set of tumor types. At present, the working model for the pilot phase includes several components -- sample collection, high-throughput genome characterization, large-scale sequencing of genes of interest, technology development, bioinformatics, and ethics, law and policy (ELP). NHGRI and NCI will share the cost of the pilot project equally. Some NACHGR members are participating in the External Steering Committee (ESC) that has been established for the project. Solicitations for grants, cooperative agreements and contracts to implement the effort will be released in time to allow funding in FY2006.
Mammalian Gene Collection
The Mammalian Gene Collection project, the effort to generate a complete set of human and mouse full-length cDNAs, is pursuing targeted approaches to finish the effort. The per based recovery effort is well underway and the project is also undertaking a pilot to examine the feasibility of using gene synthesis acquire cDNAs that cannot be captured by other means. (See below)
Mouse acquisition. $11 million from 20 NIH Institutes and $6 million from the Wellcome Trust have been committed to acquire an initial set of mouse knockouts, from private sector vendors, which include detailed phenotypic data. The mice will be stored in public repositories and the phenotypic data will be incorporated into existing mouse resource databases. Both the mice and their phenotypic data will be available to all academic researchers.
NHGRI Intramural Program
Researchers from DIR were involved in a multi-investigator study on multi-species genome comparisons that was recently published in Science. The study found that genomic translocations are not random events, and that the same regions tend to undergo repeated rearrangements.
NHGRI Intramural investigators have recently published a study in the Proceedings of the National Academy of Sciences (PNAS) that indicates that an anti-cancer drug may have promised to treat progeria, a genetic disorder characterized by premature aging. The findings were discovered using cell culture and will be tested in an animal model.
NHGRI Office of the Director
During the week of July 31, NHGRI held its annual Short Course, "Current Topics in Genomic Research," for faculty and students from institutions with substantial minority enrollment and rural institutions. The Short Course was organized by Vence Bonham and included lectures from NHGRI investigators, lab tours, student lab shadowing, and curricula development for the faculty participants. Additional back-up and support for participating faculty will be provided by NHGRI as needed. 19 faculty and 15 students from 19 different colleges and universities across the country participated.
Family History Initiative
The U.S. Surgeon General's Family History Initiative seeks to encourage individuals to collect their family medical history. Individuals are encouraged to construct pedigrees using the online family history tool and to give copies of their pedigrees to their health care providers to be included in their medical files. Online version 2.0 will be available before National Family History Day on Thanksgiving Day 2005. The improved tool will be available in a web-based and downloadable format. To date, the Family History Initiative has been highlighted in more than 1,000 media stories and the initial version of the family history tool has been downloaded more than 250,000 times.
The Administration's FY06 request for the NIH was $28.7 billion, an increase of less than one percent. On June 24, the House passed its version of the Labor-HHS Appropriations bill with slightly less funding for the NIH. The Senate Appropriations committee passed a bill containing a $1 billion, or 3.7%, increase for the NIH, but the full Senate had yet to take action on the bill at the time of the Council meeting. It is unclear what the final budget of NIH will be after the bills enter conference committee, especially in the context of the funds that are required for the Hurricane Katrina recovery effort. There is little chance that the fiscal environment will improve within the next 2-3 years. It is probable that a budget will not be passed by the start of the new fiscal year and that the NIH will operate according to a continuing resolution. A budget is expected around Thanksgiving time.
NIH Reauthorization bills are being considered by the House since the NIH has not been formally authorized by Congress since 1993, even though reauthorization theoretically is supposed to happen every 3 years. After Dr. Zerhouni testified before the House Committee on Energy and Commerce on July 19, the House version of the bill was redrafted to address some of his concerns about the original version. Many controversial issues remain unresolved. These include the proposed organization of NIH institutes into 2 clusters, "mission-specific" and "science-enabling" (NHGRI is currently proposed for inclusion in the "science-enabling" cluster), the process for making appropriations to individual institutes, and the establishment of a Roadmap-like "common fund" which could ultimately grow to 5% of the NIH budget. If a reauthorization bill is not passed, individual parts of it could be included in other bills.
Genetic Discrimination Legislation
In February, the Senate unanimously passed the Genetic Information Nondiscrimination Act of 2005 (S. 306) which prohibits genetic discrimination by employers and insurance companies. An identical version of the bill (HR 1227) was introduced into House and referred to the Committee on Education and the Workforce, the Committee on Energy and Commerce, and the Committee on Ways and Means. No hearings have been scheduled. The bill is encountering opposition from some parts of the business community. On September 28, Dr. Collins will participate in a briefing on Capitol Hill with former Speaker Newt Gingrich on the subject of Personalized Medicine and Genetic Discrimination. The Secretary's Advisory Committee on Genetics, Health and Society has been working to get the Secretary's support to help move this legislation.
The NIH's PubChem database is a free public-access database containing data on small molecules from public sources and from the Roadmap's Molecular Library Screening Centers. The American Chemical Society (ACS) has expressed concern that PubChem will threaten the financial survival of the Chemical Abstracts Service (CAS) database, which charges a fee for researchers to access. The NIH believes that PubChem does not threaten CAS because the databases contain different and complementary information and serve different research communities. Dr. Zerhouni and other NIH representatives met with staff of the ACS and offered a 6-point proposal to solve the situation, but no resolution has yet been reached. Language in reports from the House and Senate Labor Health & Human Services Appropriations bills has urged the NIH to work with the private sector on this matter.
NAS IP studyThe National Academy of Sciences has been conducting a study on intellectual property funded by the NHGRI, NIGMS, NCI, NIDCR and the NIH OD. The results of the study will be released in a report to the NIH in early October. The results of the study will have implications for NHGRI's ELSI and large-scale research programs.
Report from the Division of Intramural Research (DIR)
Eric Green, Scientific Director of the NHGRI Division of Intramural Research (DIR), presented his annual report to the NACHGR on the intramural program. DIR is the focal point for genetics and genomics research at the NIH and is known for its enthusiasm for participating in inter-institute collaborations, its willingness to challenge the status quo when necessary to perform the best science, and its vision and leadership for large, strategic initiatives. DIR works with the NHGRI Division of Extramural Research on several large projects, such as ENCODE and MGC, and has participated in partnership programs with universities including Johns Hopkins. Between 200 and 250 peer-reviewed research papers are published by NHGRI DIR researchers each year.
The DIR's budget comprises about 20% of the total NHGRI budget. The Division is organized in 7 branches -- the Cancer Genetics Branch, the Genetic Disease Research Branch, the Genetics and Molecular Biology Branch, the Genome Technology Branch, the Inherited Disease Research Branch, the Medical Genetics Branch, and the Social and Behavioral Research Branch. It also includes 3 support centers - the NIH Intramural Sequencing Center (NISC), the NIH Chemical Genomics Center (NCGC), and the Center for Inherited Disease Research (CIDR). The components of DIR are dispersed among 9 buildings at the NIH campus in Bethesda, MD and off-campus in Rockville, Gaithersburg, and Baltimore.
DIR has around 500 staff total, 49 of whom are investigators with appointments similar to faculty appointments at academic institutions. DIR is expected to expand by about 10% in the coming years; most of the expansion will occur in the Social and Behavioral Research Branch, the Cancer Genetics Branch, the Computational Genomics Program, and the NIH Chemical Genomics Center. Every four years, each branch undergoes an extensive review process by the Board of Scientific Counselors, which is a chartered committee that provides advice to the Scientific Director and the Institute Director.
Council members asked several questions concerning the external scientific review process, resource allocation, opportunities for performing high-risk research, the availability of outside funding sources, and the process for forming outside collaborations.
At the lunch break, Council members were given a tour of the facilities of NISC and the Computational Genomics Program, which are located on the fourth floor of the neighboring building at 5625 Fishers Lane.
Scientific Talk on Large-Scale DNA Sequencing
Dr. Eric Lander spoke about the scientific benefits that large-scale sequencing has already enabled and the process for building upon past successes to set and reach new biomedical goals. Sequencing is the only general-basis tool for unbiased and comprehensive biological discovery currently available, and large amounts of sequence data can be used to address a range of important biomedical research questions, including cross-species comparisons, characterization of organisms used in research, and as the basis for developing an understanding of cellular and organismal function, medical genetics, tissue-specific variation, and evolutionary processes. At our present state of knowledge, genomic sequences from a large number of different mammals are particularly important in interpreting the human genome sequence. Selecting species as targets for large-scale genomic sequencing should be a reasoned process with the overall aim of contributing knowledge that will lead to improvements in health and medicine.
With the human genome sequence in hand, additional specific long-term scientific goals for the acquisition and use of sequence information and technological targets need to be developed and clearly articulated. Continued technological developments are needed to improve our capability for sequencing and assembling new genomes and for sequencing large chromosomal regions and large sets of coding regions from human genomes for medical purposes. New technologies that have the potential to increase efficiency are emerging but many issues related to read length and quality control still need to be addressed. For these reasons, investments should be made in improving both the current technologies and the new ones.
Council members commented on the need to expand the number of stakeholders in large-scale sequencing, noting that the larger scientific community has been unexpectedly slow in learning how to use genomic data and resources. The benefits of sequencing need to be touted in the context of larger ideas such as the transformation and personalization of modern medicine, the redefinition of human disease, and the rising costs of health care. Emphasis should be placed on efficiencies and productivity of technologies and on the education of and communication with the public and medical community. Sequencing is a necessary component of the emerging medical-industrial complex. New ways of interacting with and visualizing sequence data are needed.
Concept Clearance for the Renewal of the NHGRI Large-Scale Sequencing Program
Adam Felsenfeld presented the Council with a concept document for the renewal of the NHGRI large-scale sequencing program. Important elements of the proposal included the following:
Sequencing centers funded under the new program:
- should have a core competency in state-of-the-art, efficient production of sequence data
- should be able to adopt new technologies readily
- should place an emphasis on the dissemination of knowledge to the community.
Capabilities that should be available across the program as a whole include:
- the ability to provide a range of sequence products
- to match pipelines with inputs and outputs
The proposed format for the renewed sequencing program is based upon the experience with the current program, rapid changes in sequencing technologies, the emergence of new scientific opportunities, community input, and the notion that sequence data are not just a commodity.
Under the proposal, sequencing centers would be funded for 3-year terms using the U54 cooperative agreement mechanism. There is a planned reduction of 10% of funding per year for the program; since sequencing costs have historically been going down, even as production is increasing, this reduction in funding is not expected to significantly reduce production capacity. The sequencing program would continue to be managed by NHGRI staff in consultation with Scientific Advisory Panel. Centers would continue to be required to submit formal quarterly reports describing all aspects of production and other activities. Individual centers would be able to propose to use up to 10% of their budgets on projects of interest to them. These self-identified projects would be reviewed and approved by the Coordinating Committee.
Comments from Council members included:
- NHGRI should provide a clear definition of the program and its goals to guide applicants and reviewers. The program should have short- and long-term scientific visions of what sequencing centers should be. These visions should fit into a broader genomic vision. Communicating these visions to potential applicants will help them decide on appropriate foci for their efforts.
- The flexibility of the proposed program should be great in order to allow the centers to achieve visions once they have been developed. The more difficult problem is in creating such visions.
- Sequencing centers should be allowed to place some focus on topics besides production, including informatics and computational analysis, sequencing difficult regions, driving down the costs of finishing, improving assembly software, and genotyping. They should also be encouraged to define the biology that they want to study and to motivate community input.
- Center representatives should participate in the process of setting goals for the program, but should not be charged with establishing goals themselves.
- Potential new centers will, in all likelihood, not be able to compete with existing centers because of the high cost and time required to start a competitive new center. However, new centers are not necessary as long as competition exists between the current centers. NHGRI should consider the possibility of funding one or more pilot centers sometime in the future, when the new sequencing technologies have matured.
- It would be useful to integrate larger biological interests with the interests of the sequencing centers. The whitepaper and data dissemination processes have already begun to achieve this integration. NHGRI staff should continue to encourage communication between the centers and the community.
- The sequencing grants should be made for four years instead of three this time, to encourage investment in the new technologies and equipment.
The Council unanimously voted to approve the concept for a renewed large-scale sequencing program.
Lisa Brooks gave an update on the HapMap Project which has produced a major new tool for investigators to use in studying human variation to find genes that contribute to complex disease and drug responses, as well as other purposes. In Phase I of the HapMap Project, a 5kb map was generated, consisting of 1 million SNPs genotyped in 269 samples from 4 populations. The results of this analysis will be published in October [note: the paper was subsequently published in Nature 437, 1299-1320 (October 2005). As part of Phase I, in-depth genotyping has been done in ten of the ENCODE regions to provide complete information about sequence variation in specific parts of the genome. Data collection for Phase II, which involved genotyping an additional 4 million SNPs in the same samples, has been completed and the data will be available in October, with detailed analysis to follow.
The first two phases of the HapMap Project have identified patterns of linkage disequilibrium and recombination, tag SNPs needed to capture most variation information, polymorphic insertions and deletions, and regions under selection. A planned additional component of the project will examine variation in 7 additional populations to assess the generality of the HapMap. The project will stimulate additional study of human genetic variation, including the discovery of rare SNPs, insertions and deletions, and other structural variants. Other continuing efforts at NHGRI will be aimed at improving analytical methods, reducing the costs of genotyping, and gathering phenotype information on samples.
Council members asked about the HapMap Project plans to study additional populations and its interactions with other NHGRI projects.
Elise Feingold gave an update on the progress of the ENCODE Project. The goal of ENCODE is to compile a comprehensive encyclopedia of all sequence features in the human genome. The pilot and technology development phases of the Project are currently ongoing and a plan to scale the project to the whole genome is being developed.
Analyses of the ENCODE datasets are being conducted by the several Analysis Working Groups. In July, ENCODE held a Data Analysis Workshop which brought together bioinformaticians from the various ENCODE labs to collaboratively analyze the data being produced by the project. The Workshop was followed by a Consortium meeting where results from the analyses were presented to all ENCODE participants and the ENCODE advisors. In addition, several experts on specific loci in the ENCODE regions were invited to the meeting to provide biological reality checks on the Consortium's findings. The meeting agenda also addressed gaps in current technologies and strategies to characterize all functional elements and considered how to scale the Project to the whole genome.
An ENCODE data freeze is planned for October 15. The Analysis Working Groups will meet again in late October and early November and will prepare both summary reports and manuscripts for submission in early 2006. The ENCODE Scientific Advisory Panel will meet in January to review the reports and use them in considering options for scaling the Project. Factors to consider when deciding the readiness of research projects to scale include the robustness of the technologies and their costs, and the biological utility of the data. The current plan is to present a concept clearance for the next phase of ENCODE to the NACHGR at the February 2006 meeting and, assuming clearance is obtained, to issue an RFA in March 2006. Funding is anticipated to occur in March of 2007.
Council members indicated that NHGRI staff should consider the possibility that ENCODE may not be ready to scale as soon as originally thought and that intermediate steps between the pilot phase and the scaling may be warranted.
Mammalian Gene Collection (MGC)
Gary Temple made a presentation on the Mammalian Gene Collection (MGC) Project, the goal of which is to generate one full-length open reading frame clone for every well-defined gene locus in the human and mouse genomes (18,544 for human; 18,112 for mouse). Goals have also been established for cloning full-length open reading frames from the rat, Xenopus laevis and Xenopus tropicalis, and Danio rerio. The MGC Project has so far achieved 70% of its goal for human and 65% of its goal for mouse. Technological approaches being used by the Project include ORF discovery (random 5' EST screening), ORF recovery (PCR rescue), ORF prediction, and ORF DNA synthesis.
It is estimated that the combined approaches of ORF discovery, recovery, and prediction will fall short of the combined goal by about 5,000 genes. An RFP for a small pilot for ORF DNA synthesis of 21 sequences representative of the missing genes has been released to determine if that approach would be a viable option for capturing these 5,000 genes. A full-scale RFP could be released in 2006 if the pilot were successful.
The MGC Project has a preliminary collaborative agreement with scientists at the Sanger Institute and elsewhere to create a complete public collection of expression-ready human full-length ORFs in Gateway format. The collaboration, termed the ORFeome Project, will coordinate to minimize duplication of efforts.
Council members were pleased with the progress of the MGC project but noted that it is likely that the MGC collection will never be entirely complete. Council also expressed a concern that DNA synthesis could produce transcripts that never exist in vivo, and staff indicated that it was aware of that possibility.
Knockout Mouse Project (KOMP)
Jane Peterson gave an update on the Knock-Out Mouse Project (KOMP). The Project seeks to create a comprehensive collection of null mice that will be available to the public. This null knockout resource will complement a conditional knockout resource being created by European sources. Dr. Peterson estimated that KOMP will reduce redundancy in making knock-out mice by at least 25% and will realize at least a ten-fold cost savings and one to two year time savings by centralizing efforts that are currently being funded by various NIH ICs and other sources and a large number of laboratories around the country and around the world. A survey of the literature and repository inventory information indicates that about 6,550 genes have been knocked out in mice or ES cells, though not all of these will be available. Therefore, 10,000-15,000 null ES cells will need to be created by the KOMP Project to have complete coverage over the mouse genome. Sixteen NIH institutes have committed to contribute funds to the project.
NHGRI recently released two RFAs, one to solicit applications for participation in the KOMP Research Network and one to solicit applications to develop and maintain a KOMP Data Coordination Center (DCC). A third RFA will be published by NIDA to improve the efficiency of germline transmission in C57BL/6 ES lines. NCRR will release an RFA in FY06 to provide funds to repatriate 1,000 existing mouse mutants and to support the storage and distribution of resources produced by KOMP.
The RFA for the KOMP Research Network calls for the use of gene trapping, gene targeting, or transposon mutagenesis to knockout genes in mice for which null mutations have not already been made. It indicates a strong preference for making the knockout mice in the C57BL/6 strain background. One to four cooperative agreement awards will be made for a total cost of up to $10 million per year for 5 years. The DCC will develop, house, and maintain databases to track the progress of the KOMP pipeline and deliver information to members of the KOMP Research Network, NIH, staff, and the public. One award will be made for up to $0.5 million per year for 5 years. Applications are due on November 22 and will be discussed by the NACHGR in May 2006. Funding is anticipated in July 2006.
Council members asked about the prioritization of genes for repatriation or creating knockouts and emphasized the need for capable distribution networks.
DNA Sequencing Technology Development
Jeff Schloss gave an update on the DNA sequencing technology development portfolio. A second round of grant awards were made in August for the $100,000 and $1,000 genome efforts which are supporting research to reduce the cost of DNA sequencing by two and four orders of magnitude, respectively. Examples of technologies being used by grantees include microfluidics, pyrosequencing, and single-molecule sequencing. A grantee meeting was held in June at Harvard University and a second meeting is scheduled for February 2006. The DNA sequencing technology development portfolio also includes unsolicited grants.
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 is a consortium of ten screening centers, nine extramural centers that have been funded using the U54 collaborative agreement mechanism plus the intramural NIH Chemical Genomics Center. Together, the extramural centers will receive $89 million over the three year award period. Most of the centers use a variety of biochemical, cell-based, and test-tube assays and some of the centers specialize in specific assays.
The MLSCN program also includes a Small Molecule Repository (SMR) of compounds (in the first year of the SMR contract, the repository is supposed to acquire 100,000 compounds). Another component of the program solicits assays from the larger scientific community. There will be 3 solicitations a year for assay recruitment, using a new mechanism (X01) for requesting access to an NIH resource. Assay submission can be done electronically and submitters will be required to submit a validation assay with their screening assay. No funds will be awarded for assay submission since submitters receive the benefit of their assay going through high-throughput screening. Data generated by the screening centers are being stored in the PubChem database. MLSCN's goal is to be able to screen between 300,000 and 500,000 compounds within 3 years.
The MLSCN is overseen by the Molecular Libraries and Imaging Implementation Group and the MLSCN Project Team, which is made up of representatives from all interested NIH institutes. The Project Team is to be advised by an external scientific panel. There is also a Steering Committee, which is made up of representatives from the centers and from the NIH. Program managers oversee the individual centers, with additional contributions from NIH science officers who have specific expertise in assay development. The MLSCN Steering Committee met in July and has monthly meetings by teleconference. Five working groups have been convened to address policy and technical issues. These working groups make recommendations to the Steering Committee, which develops the final policy recommendations and procedures for the Network.
Council members asked about the criteria for compounds to be described in PubChem, strategies for targeting specific classes of compounds, and how the community will be informed about the availability of the MLSCN.
The ENCODE Project scale up and Intellectual Property RFA will be discussed during the February 2006 council meeting. Council members suggested inviting a member of the Duke CEER to attend and participate in the discussion of the National Academies of Science intellectual property report. Council members indicated that they would like negotiations between NHGRI and NCI about the Cancer Genome Project to proceed.
Announcements and Items of Interest
Dr. Guyer reminded council members to review and comment on the RFI on the proposal to recognize multiple PIs on NIH applications and awards. He called attention to the reports from NHGRI's liaison organizations in the Council folders.
Conflict of Interest
Dr. Guyer read the Conflict of Interest policy to Council and asked them to sign the forms provided.
Consideration of NHGRI Applications
In closed session, the Council reviewed 138 applications, requesting $42,809,683. The applications included 48 regular research grants, 7 pilot projects, 18 ELSI grants, 9 responses to RFAs, 13 center grants, 4 conference grants, 21 SBIR Phase I grants, 8 SBIR Phase II grants, 5 fellowship grants, 2 STTR Phase I grants and 3 others. A total of 74 applications totaling $28,449,267 were recommended.
I hereby certify that, to the best of my knowledge, the foregoing minutes are accurate and complete.
Date Mark Guyer, Ph.D.
National Advisory Council for Human Genome Research
Date Francis S. Collins, M.D., Ph.D.
National Advisory Council for Human Genome Research