NINDS Advisory Council Meeting Minutes, September 17-18, 1998
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I. CALL TO ORDER AND OPENING REMARKS |
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VI. BEHAVIORAL AND SOCIAL SCIENCE REVIEW REORGANIZATION | |
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II. REPORT OF THE DIRECTOR, DIVISION OF EXTRAMURAL ACTIVITIES |
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VII. JOIN DISCUSSION WITH THE NATIONAL ADVISORY MENTAL HEALTH COUNCIL: "THE NIMH/NINDS/ CONNECTION" | |
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III. REPORT OF THE DIRECTOR, NINDS |
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VIII. COUNCIL CONSIDERATION OF PENDING APPLICATIONS | |
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IV. MOLECULAR GENETICS OF THE NERVOUS SYSTEM |
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IX. ADJOURNMENT |
DEPARTMENT OF HEALTH AND HUMAN SERVICES Summary of Meeting1 In accordance with Public Law 92-463, the meeting was:
for the review and discussion of program development, needs, and policy; and
for discussion and consideration of individual grant applications. Council members present were:
Council members absent were:
Council Roster (Attachment 1) Ex Officio Members present: Dr. John Booss, Department of Veterans Affairs Members of the public present for portions of the open meeting included: Ms. Melinda Kelley, Paralyzed Veterans of America NINDS employees present for portions of the meeting included:
Other Federal employees present for portions of the meeting included:
I. CALL TO ORDER AND OPENING REMARKS Dr. Fischbach welcomed the Council members, guests, and staff to the 143rd Council meeting. He announced that the slate of new Council members had been approved by the Secretary, Department of Health and Human Services (DHHS). One of the five new Council members was introduced: Mr. Morton Kondracke, Executive Editor and Columnist of Roll Call. The four new members who were unable to attend this meeting were: Dr. Uta Francke, Professor of Genetics, Howard Hughes Medical Institute and Stanford University School of Medicine; Ms. Kathleen Hunter, Chief Executive Officer, International Rett Syndrome Association; Dr. Julian Hoff, Professor and Head, Section of Neurosurgery, Department of Surgery, University of Michigan; and Dr. Richard Tsien, George D. Smith Professor, Department of Molecular and Cellular Physiology, Stanford University School of Medicine. Due to the Council absenteeism for this meeting, Mr. Arthur Ullian's term as a Council member was extended. II. REPORT OF THE DIRECTOR, DIVISION OF EXTRAMURAL ACTIVITIES Dr. Constance Atwell, Director, Division of Extramural Activities, NINDS, reported on the following topics:
Government in the Sunshine Act and Federal Advisory Committee Act: These Acts require the DHHS to open to public observation as many advisory committee meetings as possible, including the meetings of the National Advisory Councils. The Council meeting, therefore, was open to public observation except when grant applications were being reviewed, at the times previously specified in these minutes. Notice of the date and place of the Council meeting was published in the Federal Register thirty days prior to the meeting. Conflict of Interest: The regulations concerning conflict of interest were reviewed, and Council members were reminded that materials furnished for review purposes and discussion during the closed portions of the meeting are considered privileged information. All Council members present signed a statement certifying that they did not participate in the discussion of, or vote on, an application from any organization, institution, or any part of a university system, except for those which have multi-campus institution waivers or are specifically designated as separate organizations under 18 U.S.C. 208(a), of which they are an employee, consultant, officer, director or trustee, or in which they have a financial interest.
The minutes of the Council meeting of May 28-29, 1998, were considered and accepted as written.
Dr. Atwell reminded Council of the Program Announcements and Requests for Applications that had been published since the last meeting.
Dr. Atwell called Council's attention to the Reports Book, which lists the funding and interim actions (the category of actions authorized by the General Council Recommendations) since the previous Council meeting.
Dr. Atwell asked the members of the Council to consider what information they would need to feel comfortable about approving the award of grants to applications with percentile scores within the pay line before seeing the summary statements. How close to the pay line would feel comfortable? If Council favored these procedures, awards clearly within the pay line and with no administrative concerns could be made up to two months earlier than they are now. This would be particularly helpful to amended competing continuation (Type 2) awardees, to ensure continuity of funding for ongoing research. Dr. Atwell assured Council members that this process would not increase the burden on staff, but would change the time of the burden in a desired direction. A motion to adopt this process was made and passed. III. REPORT OF THE DIRECTOR, NINDS A. Perspectives on Neuroscience, NIH, and NINDS Dr. Fischbach summarized his career, including how the work that was being done in the 1960s and early 1970s motivated him to pursue a research career, part of which was spent in the intramural laboratories of the NIH. Dr. Fischbach said that he would not have come to NIH now if he did not feel that he could make a difference. Even if there were not other reasons for initiating a planning process, he would have wanted to do so, because there is so much opportunity for advancement, from molecules to memory. He wants to facilitate more research that integrates the various levels of analysis. This is also a propitious time for a planning endeavor because of the real possibility that there will be more funds with which to support research. The question of how to spend more money wisely is becoming more real than rhetorical. The 80 percent pay line will be at the 21 percentile, closest to the highest that it has been for several years. In addition, rather that reducing the recommended budgets of new awards by an average of 10 percent as it has for several years, the NINDS will reduce recommended budgets by only 5 percent. Ms. Mary Miers, Chief, Science Policy and Analysis Branch, NINDS, described the recommendations of the report, "Scientific Opportunities and Public Needs," from the Institute of Medicine. The report urges the NIH to be open to more contributions from external sources to the research priority planning process. Concerns were raised by Council members about the earmarking of the NIH appropriation that can result from successful lobbying efforts by groups who believe that they can buy a cure. Because lobbying is unlikely to disappear, it is important to increase the public understanding of how research actually does lead to cures, so that the lobbying can be wise. B. NINDS Planning Process Dr. Fischbach introduced his discussion of the NINDS planning activity with a slide of the anticipated FY 99 budget for the NINDS. He emphasized that not all types of science are "Manhattan Projects." The science policy of the United States has fostered a healthy environment for "curiosity-driven" research, in which discoveries are (to quote Oppenheimer) " . . . not found because they are useful, but because they can be found." It is a difficult challenge to develop a plan that would both facilitate the orderly accomplishment of the public health components of the NINDS mission and nurture the sources of vitality for curiosity-driven research. Yet, such a plan must be found. It is the bounty of "useless" discoveries from curiosity-driven research that sustains the development of clinical applications. The mission of NINDS is to reduce the burden of neurological disease by supporting and conducting research on the normal and diseased nervous system. The vision of NINDS is:
Dr. Fischbach described the start of the planning process. NINDS staff, members of the Council, and representatives of other organizations will participate. Seven panels, 10 to 15 members each, will meet to generate ideas. The seven topics to be addressed are the following:
Several members of the Council expressed support for using the term "nervous system diseases" rather than "neurological disorders" for the vision statement. They praised the vision statement responding to public concerns by setting a positive platform for the consideration of decentralized sources of input to the process of establishing priorities. Some Council members described the topics for the planning committees as "appropriately vague," that is, the framework defined by the topics would be inclusive enough to foster broad and creative consideration of issues. A planning venture of such depth and breadth could reinforce and renew the preeminence of the NINDS as a leader of research in neuroscience and diseases of the nervous system. It was recommended that the topic 'GLIA' should include other non-neuronal cell types that affect the nervous system. The discussion among Council members reflected the importance with which they regard the research training component of the vision. The disincentives of a career in research, especially but not only for medically trained scientists, must be identified and addressed. The NIH, including NINDS, receives the authority to support research training from the National Research Service Award (NRSA), separate from the authority to support research. Therefore, the funds appropriated under each authority cannot be intermixed freely. However, we must not let that preclude a creative approach to the challenge. Dr. Fischbach mentioned additional issues, e.g., international research, disparities in health care, bioethics and ethical conduct, that are relevant to all of the topics of the planning groups. C. Discretionary Funding Sources in the NIH Budget Process The NINDS planning activities take place in the context of NINDS and NIH budgetary processes. To encourage the institutes to look ahead with a critical and creative eye, Dr. Varmus uses the discretionary budget authorities that have been delegated to him. These include the Directors' "one percent transfer" authority and the Director's Discretionary Fund (the original source of funding for Shannon Awards). The development of the NIH's areas of emphasis provides further encouragement and a forum for identifying priority areas of research. Members of the Council wanted to know more about what tangible outcomes of the planning process are expected. Ms. Miers clarified the general process: the ideas that emerged from the planning groups would be used in the budgetary processes to obtain resources for the programmatic implementation of the ideas. Dr. Penn pointed out that the NINDS budget requests for NIH discretionary funds fare better when justified by clearly articulated priorities formulated by a rational assessment of need and opportunity. Dr. Atwell emphasized that the ideas developed by the planning groups are of foremost importance. Many different types of documents and information resources, for several different audiences, can be developed to promulgate those ideas. All customary programmatic "tools" (e.g., interdisciplinary conferences, requests for applications for support of research in a priority area) would be considered when devising the best way to implement each idea. New means of programmatic implementation can be devised. Care will be taken, Dr. Fischbach assured the Council members, that the planning activity will be used to inspire, not impede or distort, the natural momentum of research and discovery. Copies of the slides used in Dr. Fischbach's presentation are attached as Appendix 1. IV. Molecular Genetics of the Nervous System
Dr. Robert Baughman, Director, Division of Fundamental Neuroscience and Developmental Disorders, reported that during FY 1998 NINDS continued its activity in the genomics and molecular biology of the nervous system. The Brain Molecular Anatomy Project (BMAP) and Brain Tumor Genome Anatomy Project (BTGAP) have made new major steps. The following two presentations provide a report on the progress achieved in these areas. As we expand our efforts in genomics and molecular biology through BMAP, BTGAP, the Human, Mouse, Rat and Zebrafish genome projects and other related projects, a number of terms and methods have been introduced that may not be understood by everyone. The following is a brief explanation of some of the basic terms that will come up repeatedly. The foundation of genomic data is the NIH Genetic Sequence Database, called GenBank, which is maintained by the National Library of Medicine's National Center for Biotechnology Information (NCBI). GenBank is a repository of about 2.5M genetic nucleotide sequences. A single gene may be represented by many partial sequences in GenBank. To make this enormous pool of data more useful and manageable, it has been organized so that all sequences derived from a single gene are combined into UniGene clusters. The UniGene clusters include all sequences derived from a gene, such as alternatively spliced mRNA, mRNA-edited sequences and multiple clones of the same mRNA. There are about 53,000 human UniGene clusters and about 10,000 mouse UniGene clusters. The cDNA libraries used to obtain many of the sequences in GenBank contain "clones" of pieces of DNA from expressed genes. These cDNA clones must be expressed sequences since they are directly prepared from mRNA that can only be synthesized by gene expression. Even partial sequences can be "tags" for genes, hence the term Expressed Sequence Tags or ESTs. There can be many ESTs per gene. The longer the length of the cDNA clones, the more information is available for each gene. This is the source of the current emphasis on the development of new methods that will permit the construction of "full length" clones that contain an entire mRNA sequence. In the usual protocol for preparing a Standard Library of cDNAs from mRNA, more common mRNAs are represented by many cDNA clones and rare mRNAs are represented by few or no cDNA clones. In a Normalized Library the frequency of rare cDNA clones is brought up to a normalized level by biochemical manipulation; some rare mRNAs, however, still are not represented. In a Subtracted Library, the clones in an existing standard library are used to remove or "subtract" mRNAs that have already been cloned; the remaining, rare mRNAs now can be more readily cloned. If normalization and subtraction are combined in a Normalized-SubtractedLibrary, then even the rarest mRNAs can be characterized. In the nervous system, where many genes are expressed only at limited times in development or in very restricted cell populations, the use of these new techniques is critical to advancing gene discovery. When a large number of gene sequences is available, it is possible to use Array Technologymake arrays of clones or sequences such that thousands of genes can be assayed at the same time. This can be done either by blotting small amounts of actual clones onto a matrix, or by using a variation of microchip technology to synthesize known sequences de novo on a surface. Miniaturization has greatly increased the efficiency of the array approaches, but costs are still high. As a final point, the rapid accumulation of genomic sequence data creates serious information management problems, which are exacerbated when there is a requirement for the genomic data to be related to complex anatomic, developmental and functional properties of tissue like the brain and nervous system. This has produced tremendous demands for development of improved Bioinformaticsmethodology. Copies of the slides used in Dr. Baughman's presentation are attached as Appendix 2.
Dr. Judy Small, Health Scientist Administrator, Division of Fundamental Neuroscience and Developmental Disorders,reported on the Brain Molecular Anatomy Project (BMAP). The long-term goals of BMAP are to identify and localize all of the genes expressed in the nervous system and to study gene expression patterns under different conditions. New technologies and bioinformatics tools must also be developed for this project to succeed. Ultimately, BMAP will provide important resources for future studies in the nervous system. In FY1997, NIMH and NINDS issued an RFP for Gene Discovery. The contract would be to produce high quality cDNA libraries from 10 mouse brain regions, including the prefrontal cortex, hypothalamus, amygdala, striatum, basal ganglia, brain stem, cerebellum, olfactory bulb, and pineal gland. From these libraries, 100,000 3' ESTs would be sequenced. A mouse brain UniGene set of approximately 20,000 genes would be assembled from these sequences. In addition, it will be necessary to begin to develop informatics tools for disseminating information in a user-friendly way. An electronic, digitized Mouse Brain Atlas that can map gene expression data onto a 3-D anatomical base would be needed. The Atlas should be able to map anatomy, gene expression, and neurotransmitters, and be able to incorporate single cell biology, developmental stages and aging, and effects of disease and environmental agents. A possible first step would be to provide in situ mapping of genes using EST probes derived from known databases, or as a result of the Gene Discovery contract. Ten standardized planes of reference would be produced, and the data could be digitized for database entry and access on the Internet. Each investigator would have access to the data and would provide his own interpretation on location and level of expression. Ultimately, the data could be incorporated into the Mouse Brain Atlas.
Dr. Thomas Jacobs, Health Scientist Administrator, Division of Stroke, Trauma,, and Neurodegenerative Disorders, reported that the NINDS has initiated a partnership with the National Cancer Institute's (NCI) Cancer Genome Anatomy Project (CGAP) to advance genomic research for brain tumors. Our initial effort, BTGAP, is focused on malignant gliomas in adults, which are the most prevalent and malignant primary brain tumors. The majority of patients with high grade glioma and who are given our best conventional therapies die within one year of diagnosis. Clearly, new approaches to diagnosis and treatment are needed and developing a comprehensive gene expression profile for brain tumor patients through the BTGAP is one promising avenue of investigation. Knowledge of the expressed genes at progressive stages of glioma development could provide clinically relevant genetic fingerprints that would lead to specialized treatment strategies. To move us in this direction, several brain tumor cDNA libraries were generated and sequenced this year. A major goal of the BTGAP/CGAP is to discover new human genes that may be useful in understanding the process of cancer. There are approximately 83 CGAP cDNA libraries generated from many different cancer tissues that are included in the gene discovery project. This month, the first glioblastoma library submitted through the BTGAP was the top producing library for discovering new genes. Over 150 novel genes were identified in this library (genes that are specifically expressed in human brain and are not found elsewhere in the genome). These early results establish the technical feasibility of finding new genes in the brain through the BTGAP and encourage us to pursue these productive genomic investigations. Libraries for anaplastic oligodendroglioma that are in the sequencing pipeline, also appear promising for human brain gene discovery. One of the unique aspects of CGAP is that the sequence data processed through UniGene to identify novel genes, is immediately available to the public through the CGAP web site. It is anticipated that the wealth of genomic data being generated through the BTGAP will stimulate investigator-initiated research and move us closer to our goal of providing clinically relevant genetic fingerprints that would lead to specialized treatment strategies for one of our deadliest neurologic diseases, malignant gliomas. The following issues about the anatomy projects were raised by members of the Council:
VI. BEHAVIORAL AND SOCIAL SCIENCE REVIEW REORGANIZATION Dr. Virginia Cain, Special Assistant to the Director of the Office of Behavioral and Social Science Research (OBSSR), Office of the Director, NIH, gave a status report about the reorganization of the scientific review groups (SRGs) in the Center for Scientific Review (CSR). The reorganization of the SRGs that review applications for the support of behavioral and social science research began with a meeting held by Dr. Ellie Ehrenfeld, the Director of the CSR. Thirteen IC Directors and representatives of CSR and OBSSR attended. The objective of the reorganization was to develop a set of SRGs having these characteristics:
The proposed structure of the SRGs was tested by examining the results of a 'mock' referral process of about 1000 abstracts. NIH staff and non-NIH scientists participated. Revisions were made before forwarding the plan to the IC directors and posting it on the NIH web site for comment. The plan now consists of seven SRGs grouped as "Basic Behavioral Science," and eight SRGs as "Risk, Health, and Social Sciences." Approximately fifty organizations have submitted comments. After finishing some work regarding overlap with the neuroscience SRGs, the plan will be sent to CSR for implementation. Applications submitted for the February 1999 receipt dates will be assigned and consequently reviewed by the newly constituted SRGs. Dr. Cain's presentation led members of the Council to raise general concerns about the quality of review. Recruiting highly competent SRAs and facilitating and rewarding service on SRGs were mentioned as ways of ensuring quality review. VII. JOINT DISCUSSION WITH THE NATIONAL ADVISORY MENTAL HEALTH COUNCIL: "THE NIMH/NINDS CONNECTION" Dr. Fischbach and Dr. Hyman, Director, National Institute of Mental Health (NIMH), welcomed the members of the NANDS Council and the National Advisory Mental Health Council to the first combined meeting of these groups. The meeting was evidence of the increasing cooperation between the NIMH and NINDS, e.g., collaborative projects such as BMAP, neuroAIDS, and the support of research on the effect of genetic mutations on behavioral phenotypes. The cooperation between NIMH and NINDS (and cooperation with the National Institute on Drug Abuse) will be facilitated by the move of extramural staff to the 'neuroscience' building, which is under construction, and shared laboratory space in Building 36. Increased budgets for support of both extramural and intramural research are resources for developing excellence, but alone, do not ensure excellence. It is the responsibility of and opportunity for the institutes to determine how to use the money so that excellence does ensue. In the discussion that followed, Council members expressed support for the ongoing and planned cooperation between the NIMH and the NINDS. However, some of the comments tempered a general optimism about the progress of neuroscience. Many members expressed concern about being able to recruit and retain the most talented new researchers. Although it was noted that it is very difficult to get good data about who chooses research for a career and why or why not, the consensus seemed to be that it was a serious issue that deserves more attention. VIII. COUNCIL CONSIDERATION OF PENDING APPLICATIONS This portion of the meeting, involving specific grant review, was closed to the public. The Council gave special attention to applications from foreign institutions and applications for which there were concerns about human subjects, including appropriate representation of women and minority subjects, or laboratory animals.
The Council reviewed a total of 17 research career development grant applications; of this total, 14 applications had primary assignment to NINDS, and 10 of them (71.4 percent) were recommended for support in the amount of $1.0 million first-year direct costs. It is anticipated that, of the research career development grants competing at this Council, NINDS will be able to pay first-year direct costs of approximately $1.0 million.
The Council reviewed a total of 1,198 research grant applications; of this total, 709 applications had primary assignment to NINDS, and 472 of them (66.6 percent), were recommended for support in the amount of $112,075 million first-year direct costs. It is anticipated that, of the research grants competing at this Council, NINDS will be able to pay first-year direct costs of approximately $59.5 million. Senator Jacob Javits Neuroscience Investigator Awards The Senator Jacob Javits Neuroscience Investigator Awards are made to distinguished investigators who have a record of scientific excellence and productivity, who are actively pursuing an area of research of strategic importance, and who can be expected to continue to be highly productive for a seven-year period. Candidates are nominated at each Council meeting during the fiscal year, and from these nominations the awardees are selected at the June Council. At this meeting, the Council nominated two investigators as potential recipients of this award.
The Council reviewed a total of 124 Small Business Innovation Research (SBIR) and Small Technology Transfer Award (STTR) grant applications; of this total, 53 applications had primary assignment to NINDS and 36 of them (67.9 percent) were recommended for support in the amount of $4.0 million first-year direct costs. It is anticipated that, of the SBIR and STTR applications competing at this Council, NINDS will be able to pay first-year direct costs of approximately $2.0 million. The Council reviewed a total of 11 Academic Research Enhancement Awards (AREA) applications; of this total, 6 applications had primary assignment to NINDS, and 5 of them (83.3 percent) were recommended for support in the amount of $0.2 million direct costs. It is not anticipated that NINDS will be able to pay any of these applications. The meeting was adjourned at 10:10 a.m. on Friday, September 18, 1998. We certify that, to the best of our knowledge, the foregoing minutes and attachments are accurate and complete.
Ruth Linn These minutes will be formally considered by the Council at its next meeting. Corrections or notations will be incorporated in the minutes of that meeting.
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