The National Advisory General Medical Sciences (NAGMS) Council was convened in closed session for its one-hundred and sixteenth meeting at 8:30 a.m. on Thursday, May 17, 2001, in Conference Rooms E1/E2, Natcher Conference Center, Building 45. Dr. Norka Ruiz Bravo, associate director for extramural activities of the National Institute of General Medical Sciences (NIGMS), presided as chairman in NIGMS director Dr. Marvin Cassman's absence. Dr. Cassman was at a Congressional hearing and joined the group in the afternoon. The meeting was open to the public on May 17 from 11:00 a.m. to 4:30 p.m. and was followed by the closed session for consideration of grant applications.
Council Members Present:
John N. Abelson, Ph.D.
Jay C. Dunlap, Ph.D.
Lila M. Gierasch, Ph.D.
Eaton E. Lattman, Ph.D.
Douglas A. Lauffenburger, Ph.D. (participated via telephone conference)
Angeline A. Lazarus, M.D.
Leslie A. Leinwand, Ph.D.
Robert S. Pozos, Ph.D.
Debra A. Schwinn, M.D.
Susan S. Taylor, Ph.D.
D. Amy Trainor, Ph.D.
Isiah M. Warner, Ph.D.
Richard M. Weinshilboum, M.D.
George C. Hill, Ph.D.
Daniel J. Kevles, Ph.D.
Special Consultants Present:
John Newport, Ph.D.
Division of Biology
University of California, San Diego
La Jolla, CA
Basil Pruitt, M.D.
Department of Surgery
University of Texas Health Science Center at San Antonio
San Antonio, TX
Vern Lee Schramm, Ph.D.
Department of Biochemistry
Albert Einstein College of Medicine
Council roster (available from NIGMS).
Members of the Public Present:
Ms. Nura Shehzad, The Blue Sheet
Dr. John Moult, University of Maryland Biotechnology Institute
Ms. Nancy Moy, SRI International
Federal Employees Present:
National Institute of General Medical Sciences employees and other NIH employees:
Please see the sign-in sheet (available from NIGMS).
OPEN PORTION OF THE MEETING
I. Call to Order and Opening Remarks
Dr. Ruiz Bravo called the meeting to order and noted that Dr. Cassman was at a Congressional hearing and would be joining the group in the afternoon. Dr. Ruiz Bravo welcomed returning Council members and welcomed and introduced the guests and three ad hoc Council participants. The ad hoc participants were: Dr. John Newport, professor of biology, University of California, San Diego; Dr. Basil Pruitt, professor of surgery, University of Texas Health Science Center at San Antonio; and Dr. Vern Lee Schramm, professor of biochemistry at Albert Einstein College of Medicine.
II. Consideration of Minutes
The minutes of the January 25-26, 2001 meeting were approved as submitted.
III. Future Meeting Dates
The following dates for future Council meetings were confirmed:
|September 13-14, 2001||Thursday-Friday|
|January 24-25, 2002||Thursday-Friday|
|May 9-10, 2002||Thursday-Friday|
|September 12-13, 2002||Thursday-Friday|
Dr. Ruiz Bravo reminded the members of their responsibility and commitment and asked that they not schedule any other meetings, etc., for the dates that they had just confirmed, and that they inform their secretaries of these dates so that other commitments would not be made for them.
IV. Update on Minority Recruitment on Institutional Research Training Grants
Dr. Janna Wehrle of the NIGMS Division of Cell Biology and Biophysics gave an update on the Institutional National Research Service Award (NRSA) training grants requirement to recruit, matriculate, and graduate students and postdoctoral fellows from groups traditionally underrepresented in science. All NIH institutes are required to evaluate the acceptability of recruitment activities, plans, and progress for each research training grant. In addition to the assessments by initial review groups and Council, NIGMS uses review by a standing staff committee charged with reviewing minority recruitment programs for all of the applications in each Council round. This Committee on Minority Recruitment (CMR) provides the director, NIGMS, with a detailed evaluation of the programs and provides feedback to training grant principal investigators (PIs) about the strengths and weaknesses of their programs.
Several years ago NIGMS put in place a program designed to increase oversight on programs that are worthy of funding but have had deficiencies in minority recruitment. The committee works with the PI to develop a revised plan. If the revised plan is considered acceptable, an award is issued in which the funding in the last 2 years of the 5-year award period are contingent on a clear demonstration of both effort and progress. A similar oversight requirement is placed on awards to programs that are only marginally acceptable at two consecutive competing reviews.
Data from the first evaluation of this enhanced oversight program are encouraging. Of programs that have already recompeted, four of seven now have satisfactory recruitment programs. Three are still marginal, and one of those has been given a 3-year award to allow for early re-evaluation of both minority recruitment and other issues. The others remain in the close monitoring program. Of the training programs that have only reached their mid-term re-evaluations, eight showed clear improvement, not only in terms of activities, but in enrollment of minority students or fellows. Those programs had their last 2 years of funding released. Four more programs are still completing their evaluations, so awards for their last 2 years are still pending. In addition, a new system of computer flags has been designed to remind program directors and grants management officials of which programs need more attention. NIGMS will continue to evaluate the effectiveness of its current system and work for improvement.
V. Report from "NIGMS Workshop on Achieving Scientific Excellence through Diversity"
Dr. Marion Zatz of the NIGMS Division of Genetics and Developmental Biology reported to the Council on a workshop that took place May 6-7, 2001, in Bethesda, MD, titled "NIGMS Workshop on Achieving Scientific Excellence Through Diversity." The workshop was organized by Dr. Zatz and chaired by Dr. Richard I. Morimoto (Northwestern University), who serves on the NIGMS Biomedical Research and Research Training (BRT) review committee. The goal of the workshop was to explore strategies for improved recruitment and retention of underrepresented minorities in predoctoral graduate training programs and biomedical research careers. There were approximately 175 participants, representing program directors and administrative officials from most of the 75 institutions receiving NIGMS predoctoral training grants, as well as minority students and NIH staff. The workshop agenda was designed to maximize discussion and participant interaction and included a keynote address by former Council member Dr. Freeman A. Hrabowski, III, (University of Maryland, Baltimore County) and a concluding address by Dr. David R. Burgess (Boston College), past president of the Society for Advancement of Chicanos and Native Americans in Science and former BRT committee member. Two council members, Drs. Lila M. Gierasch and Isiah M. Warner, attended the workshop and conveyed their impressions to the Council.
Dr. Gierasch commended NIGMS for its proactive focus on minority recruitment and retention efforts. She noted the frustration and challenge that academician's face in trying to enhance the pool of underrepresented minority scientists choosing biomedical research careers. The workshop addressed that frustration by providing a successful venue to exchange experiences and successful strategies. Dr. Gierasch's highlights included:
- The keynote address, which made the point, as demonstrated by the highly successful Meyerhoff program, that pragmatic approaches and careful mentoring can increase the number of minority students who pursue research careers. The issue is not the pool of students, but the choices they make.
- The poster session, which displayed successful recruitment and retention strategies.
- Practical ideas for student recruitment, such as evaluating minority graduate applicants by emphasizing their commitment, research experience, and letters of recommendation, rather than their grades and GRE scores.
- Practical ideas for student retention, such as faculty involvement in individual mentoring, group study practices, and flexible curricula.
- The personal student accounts, which described pressures to pursue a M.D. degree and how choices were influenced by individual encounters and family situations.
Dr. Gierasch concluded that it takes time and dedication to make effective recruitment and retention strategies work. She also noted the tension in deciding whether to support minority students on training grants versus other mechanisms, such as supplements to research grants. Dr. Gierasch recommended that the workshop be repeated.
Dr. Warner focused his comments on Dr. Hrabowski's keynote address. While some participants perceived Dr. Hrabowski's approach as paternalistic, he is putting in place the self confidence and "I-can-do-it" attitude that cannot be taken for granted. Minority students must be actively encouraged to pursue an academic career and may need mentoring that is not readily available--at every stage of their careers. Dr. Warner was struck by the importance of one key person, not necessarily a scientist, who serves as a sympathetic ear and mentor to students at many stages throughout their careers.
During the Council discussion, Dr. Zatz said that the Institute would create a Web site with workshop details and other information, including successful strategies for minority recruitment and retention (Minority Recruitment & Retention Strategies). Drs. Gierasch and Lattman suggested that the Institute find a way to provide compensation on training grants for staff who devote substantial time to recruitment and retention efforts, noting that scientific staff may need release time from research and teaching commitments. Dr. Taylor suggested that a category of "associate trainee" be considered for students who fully participate in training grant activities but are supported by other mechanisms. This approach would alleviate the tension that Dr. Gierasch noted when students have options for support that may be preferable to training grant support. It was agreed that these suggestions will be further considered and discussed.
VI. Pharmacogenetics Research Network and Knowledge Base: Update on Activities
Dr. Rochelle Long of the NIGMS Division of Pharmacology, Physiology, and Biological Chemistry reported on three separate but related activities of the NIH Pharmacogenetics Research Network and Knowledge Base. On April 24, 2001, the third meeting of the NIGMS Populations Advisory Group on Pharmacogenetics Research took place. The members discussed principles of the community consultation process as related to pharmacogenetics research, and they reviewed the Network's policies, which are posted at http://www.pharmgkb.org . Among their conclusions were: community involvement in research is important for pharmacogenetics; communities may want to share in intellectual property rights; it is valuable to communicate the purpose of research; the Populations Advisory Group should continue as an independent body; and the group should review Network polices as they are developed.
On April 25, 2001, an open scientific meeting was held to introduce the scientific public to the Pharmacogenetics Research Network. The meeting included presentations of research results and panel discussions on ethics and industrial interactions. There was a discussion of the scientific approaches being taken and the experimental designs. Varying opinions were expressed about the levels of polymorphism detection and significance, about the candidate gene choices, the analysis, and the types of data being readied for posting at PharmGKB. The ethics panel discussed the results of pharmacogenetics testing and achieving the balance between patient confidentiality and sharing research results. Finally, the industry panel stressed their common goals for pharmacogenetics research, including standardizing definitions and nomenclature, as well as the value of education.
On April 26, 2001, the Pharmacogenetics Research Network held a Steering Committee meeting. At that meeting, the committee heard presentations on tracking the distribution of single-nucleotide polymorphisms (SNP) within populations and strategic approaches to identifying important targets for pharmacological action across populations. The committee created a new shared resources working group in order to identify common Network scientific needs. A letter was drafted in which journal editors are being invited to indicate interest in forming a relationship with PharmGKB to publicize network data postings. Content of the Web site was discussed, including the genes list, links to publications, a new SNP surveillance tool, and opportunities for interactions with groups outside of the Network. An overview of the Pharmacogenetics Research Network and the funded investigators is available on the NIGMS Web site. NIGMS expects to announce additional cooperative agreement awards in the summer of 2001.
VII. Clinical Research Enhancement Program at NIH
Dr. Stephen I. Katz, director of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, presented a number of NIH initiatives designed to ensure the development of clinical researchers and clinical research. One set of initiatives involves providing loan repayment for physician-scientists in specific areas. This is particularly important since the heavy debt burden incurred by many physicians during their medical training is a strong dis-incentive to becoming research scientists. There are four loan repayment programs that have become available in the last year through new legislation. These are: the Children's Health Act, which provides for loan repayments for physicians doing research in pediatrics; the Public Health Improvement Act, which, among other things, will provide loan repayment for physicians doing clinical research; the Minority Health and Health Disparities Research and Education Act, involving loan repayment for individuals working in areas related to health disparities; and a bill that allows for loan forgiveness for scientists from disadvantaged backgrounds. A second concern is the nature of peer review of clinical research applications. Changes are now being made to ensure that these applications go to review groups where there are a significant number of such clinical applications being considered. This has been identified as a critical factor in obtaining an appropriate review.
Finally, Dr. Katz mentioned some other efforts NIH is undertaking related to clinical research, such as the development of a public Web site for clinical trials and the construction of the new Clinical Center on the NIH campus.
The Council then addressed a number of questions to Dr. Katz, including those on such issues as the training of clinical researchers who are not U.S. citizens, the application of loan repayment programs to physician-scientists who are not doing clinical research, and the pressures of managed care on the careers of new faculty who are required to establish a research program and also be responsible for clinical services.
VIII. Demonstration of the Electronic Council Book
Dr. Thor Fjellstedt, deputy director of the Division of Extramural Research and Training at the National Institute of Environmental Health Sciences, demonstrated the improved capabilities of the Electronic Council Book (ECB). New features include enhanced searching functions for text and application concerns (e.g., animal welfare), the ability to download summary statements individually or as a group into PDF format, and the option of retrieving the "Resume and Summary of Discussion" for summary statements. Coupled with existing functions, the ECB should allow Council members to retrieve and review summary statements in an expedient manner. In the ensuing discussion, members offered several good suggestions for improvements, such as being able to adjust the length of the session before the system closed, to approve summaries online as part of the expedited review process and to automatically bring up the next summary, and to retrieve assigned summary statements not yet reviewed or available since one's previous session.
IX. Microarray Supplements: a Progress Report
Dr. Laurie Tompkins of the NIGMS Division of Genetics and Developmental Biology reported on a FY 2001 initiative to provide administrative supplements for microarray analysis to NIGMS-funded investigators. Investigators could request up to $50,000 in direct costs for equipment and supplies. In addition, they could request funds for part-time personnel with expertise in data analysis. The Microarray Review Committee received 187 requests for supplements. The requests were reviewed by the investigators' program directors for eligibility, the relationship of the proposed experiments to the parent grant, and the probability that doing the proposed experiments would enhance the progress of the parent grant. Eligible requests were then reviewed by two members of the Microarray Review Committee for the logic of the proposed experiments, the adequacy of plans for quality control and data analysis, and the availability of resources to do the proposed experiments. Of the 187 supplement requests that were received, 87 were funded. The funded supplement requests were diverse, representing a wide range of experimental systems and problems to be addressed by doing the proposed microarray analyses. Since the supplements were awarded just a few months before the Council presentation, there were relatively few success stories to report. However, some of the investigators who were awarded microarray supplements have already done the proposed experiments and obtained useful data. It is also clear that the microarray supplement initiative has stimulated collaborative research. Encouraged by NIGMS to do so, eight groups of investigators coordinated their supplement requests, enabling the members of each group to purchase equipment and reagents that they could share. In some cases, the microarray initiative had more far-reaching effects on collaborative research than anticipated. For example, NIGMS awarded microarray supplements to two investigators at one university, which then decided to upgrade its biotechnology center. Because of the upgrade, investigators from three different departments began to use the facilities at the center, forming groups and interacting with each other. Another example involves the Myxococcus community, three members of which submitted microarray supplement requests to do a global analysis of gene expression. After NIGMS funded two of the three requests, eight investigators in the Myxococcus community joined forces to determine how to do the proposed global analysis and develop other genomics resources for the community.
In response to a question, Dr. Tompkins reiterated that the microarray supplement program was a one-time-only initiative, the purpose of which was to enable NIGMS-funded investigators who were not anticipating submission of a grant application in the near future to utilize a new, expensive technology. Discussion among Council members focused on the idea that providing relatively low-cost administrative supplements to groups of investigators could foster collaborations and stimulate cost-sharing by universities.
X. Report on the Second International Structural Genomics Meeting
Dr. John Norvell of the NIGMS Division of Cell Biology and Biophysics and Dr. John Moult of the University of Maryland Biotechnology Institute jointly described the recent Second International Structural Genomics Meeting. Dr. Norvell summarized structural genomics and the earlier efforts to develop an international policy agreement in this field. Structural genomics is an effort to determine the 3-D shapes of proteins, building on information from genome sequencing projects and recent advances in both structural biology and computational model building. It aims at high-throughput operations and complete coverage of the universe of protein structures. The NIGMS Protein Structure Initiative (PSI) is a national support program in this emerging field; other countries have or are developing their own structural genomics programs. Background information on the PSI can be found on the NIGMS Web site at Protein Structure Initiative.
In April 2000, NIGMS and the Wellcome Trust, an UK-based medical research charity, cosponsored the First International Structural Genomics Meeting near Cambridge, UK, to discuss policy and worldwide cooperation in structural genomics. Heading the list of issues discussed by the participants were: goals of the effort; necessary resources and infrastructure; cooperation with industry; and policies on data release and deposition, publication, and intellectual property. A Structural Genomics Informatics Task Force with five subgroups was formed to examine these various issues and to prepare reports. NIGMS organized the Second International Structural Genomics Meeting on April 4-6, 2001, at the Airlie Center near Washington, DC, to continue this effort. Drs. Moult and Norvell and Dr. Chris Sander, MIT, organized the meeting. It was cosponsored by NIGMS, the Wellcome Trust/UK, and RIKEN/MEXT/Japan. At this meeting, the Task Force discussed the subgroup reports, as well as other scientific issues facing this field. The structural genomics community, with participants from four continents, approved an international collaborative agreement at the conclusion of the meeting.
Dr. Moult summarized the "Airlie Agreement," which provides for open sharing of scientific data and technological expertise. The agreed conditions for the sharing of data reflect the balance between two different goals: timely release of all structural genomics data to the public and consideration for intellectual property regulations that vary significantly in different countries. In addition, the agreement recognizes the potential for collaboration between structural genomics researchers in academia and in industry. The Airlie Agreement extends and refines an earlier agreement reached the previous year in Cambridge.
Highlights of the Airlie Agreement include:
- Rapid release of data and wide availability to the international public.
- Deposition of atomic coordinates of 3-D structures of biological macromolecules and associated experimental data into the Protein Data Bank (PDB) (http://www.rcsb.org/pdb/ ) immediately after their determination.
- In most cases, release to the public soon thereafter.
- In some cases, allowing a holding period for release of data of up to 6 months to facilitate patent filing where deemed appropriate.
- In no cases, permitting withholding of data from the public for more than 6 months.
- The importance of high quality structures. Projects must not compromise quality for high-throughput operation.
- The responsibility of the investigator to ensure sufficient quality.
- Development of public Web sites listing target information and status of work by structural genomics laboratories with public funding.
- Establishment of procedures for capturing data and experimental results, including deposition of coordinates in the PDB.
- Encouragement of short, peer reviewed electronic publications.
- Encouragement of patent offices and courts to harmonize the laws, since patent laws vary between different countries and are unclear regarding the products of structural genomics. Asked for strengthened utility conditions for inventions based on these structures.
- Election of an executive committee to establish an international organization for structural genomics and to plan the next international meeting.
The meeting participants also shared their experiences and bottlenecks in setting up large-scale, high-throughput structural genomics operations. Many of the groups gave brief presentations on the highlights and status of their projects.
During Council discussion of this topic, Dr. Lattman pointed out that the position some participants took on delay of data release was motivated both by intellectual property considerations, as well as the possibility of follow-up studies that could lead to major publications. Dr. Cassman said that NIGMS will have more stringent requirements on coordinate deposition, namely 4-6 weeks following completion.
Dr. Gierasch pointed out that one expected benefit of the structures coming out of structural genomics projects was an understanding of the relationship of function to sequence. Dr. Norvell pointed out that most of the international structural genomics projects are not genome-driven in target selection, in contrast to the NIGMS projects. Dr. Taylor noted the expanded role of the PDB in structural genomics, with the need to acquire information on experimental details, as well as the coordinates. Dr. Norvell pointed out that he discusses these issues with Dr. Helen Berman (the director of the PDB) often, and NIGMS has asked her to develop the PSI target registration Web site.
XI. NIGMS AIDS PO1s
Dr. James Cassatt of the NIGMS Division of Cell Biology and Biology reported on an NIGMS program, initiated in 1987, designed to use principles of structure-based drug design to develop new pharmaceuticals that would be effective anti-virals against HIV, the virus that causes AIDS. The idea behind the program was to fund collaborations of crystallographers, synthetic chemists, theoreticians, and virologists to determine the structures of key enzymes and design chemical compounds that, based on these structures, would inhibit the action of these enzymes. At that time, few proteins encoded by the HIV genome had been purified. Only the crystal structure of the HIV protease was on the horizon.
Since 1987, the program has had a number of successes, including:
- Research that led to the development of one new drug.
- The determination of the structures of several HIV-related proteins.
- New methodologies, including DOCK from Kuntz's laboratory and AUTODOCK from Olson's laboratory.
- Legitimizing the structure-based drug design paradigm.
- Bringing almost 100 basic scientists into the field of AIDS research.
In preparation for the reannouncement of this program, a committee of outside experts was assembled and met on April 30, 2001, to evaluate past progress and make suggestions for future directions. Overall, the committee felt that the program had been quite successful citing the progress made above. The committee suggested:
- A continued emphasis on high-payoff, high-risk research.
- A continued emphasis on synthetic chemistry, both for the synthesis of new compounds and proof of concept.
- A new emphasis on treating virus host-cell interactions as molecular machines using structural techniques appropriate for that scale.
The request for applications is expected to be published in summer 2001, with a receipt date sometime in December 2001 and an earliest possible funding date of August 1, 2002.
XII. Report From the Director, NIGMS: Status of Appropriations and Other Matters
Dr. Cassman reported on the recent budget hearings. He noted that the Appropriation Hearing in the House of Representatives did not follow the pattern of hearings in previous years. Rather than have each institute director testify, there was a single hearing where the director of NIH, Dr. Ruth Kirschstein, formally provided testimony, and the institute directors were available to respond on selected issues that arose. The only question directed to NIGMS was on support of behavioral science research and training. This was a concern of Congressman Kennedy from Rhode Island.
In addition to the budget hearing, another novelty was the establishment of "theme" hearings, which focussed on NIH efforts in a variety of areas, such as chronic diseases, health disparities, etc. Dr. Cassman described his involvement in presenting the NIH approach to research training. This was part of a hearing on infrastructure, which included, as well peer review, buildings and facilities, instrumentation, and the Library of Medicine.
Dr. Cassman then described the process of establishing a new institute at NIH, the National Institute of Bioimaging and Bioengineering, and a new center in NIGMS, the Center for Bioinformatics and Computational Biology. The Center will have the primary function of centralizing activities in complex systems, computational biology, and bioinformatics within NIGMS. It will manage grants from the existing complex systems initiative, training programs in computational biology, and will develop new initiatives in both computational biology and bioinformatics. It will also act as the contact point with other agencies and institutes and with the extramural community. Finally, the Center will assume responsibility for the Biomedical Information Science and Technology Initiative Coordinating Committee. This is a Committee that has been operated out of the Office of the Director, NIH. In conclusion, Dr. Cassman discussed the NIH response to the National Academy of Sciences report on research training at NIH. He noted that the main elements of the NIH response were a proposed increase in both pre-and postdoctoral stipends; a potential restriction on the length of time that NIH would support either pre- or postdoctoral students; and the establishment of a tracking system to determine the number of students supported on research grants.
In the subsequent Council-initiated discussion, there were several concerns related to bringing underrepresented minorities into the biomedical sciences. One suggestion was to provide funds in training grants to allow support for an individual who would dedicate their activities to issues of recruitment and retention. This will be considered by the Institute together with the recommendations that emerged from a recent meeting on approaches to more effectively bring underrepresented minorities onto training grants.
CLOSED PORTION OF THE MEETING
XIII. Procedure for Conduct of Meeting
Dr. Cassman brought to the attention of Council members the procedures for the conduct of the meeting. Council members were reminded that all of the review materials furnished are privileged information. Although most conflicts of interest involving institutional affiliation already had been identified, members were asked to absent themselves during discussion of any application in which there was a personal conflict that was not readily apparent.
XIV. Review of Applications
A summary of applications reviewed by Council is available from NIGMS.
The meeting adjourned at 12:00 p.m. on Friday, May 18, 2001.
I hereby certify that the foregoing minutes are accurate and complete to my knowledge.
|Marvin Cassman, Ph.D.|
National Advisory General
Medical Sciences Council
|Norka Ruiz Bravo, Ph.D.|
National Advisory General
Medical Sciences Council