Advisory Council Minutes, May 14-15, 1998

The National Advisory General Medical Sciences (NAGMS) Council was convened in closed session for its one-hundred and eighth meeting at 8:30 a.m. on Thursday, May 14, 1998, in Conference Rooms E1/E2, Natcher Conference Center, Building 45. Dr. Marvin Cassman, director of the National Institute of General Medical Sciences (NIGMS), presided as chairman. The meeting was open to the public on May 14 from 11:07 a.m. to 4:02 p.m., followed by the closed session for consideration of grant applications.

Council Members Present:

David A. Clayton, Ph.D.
Sarah C.R. Elgin, Ph.D.
Lila M. Gierasch, Ph.D.
Carlos G. Gutierrez, Ph.D.
Susan A. Henry, Ph.D.
Freeman A. Hrabowski, III, Ph.D.
Angeline A. Lazarus, M.D.
Eva J. Neer, M.D.
Steven M. Paul, M.D.
Christopher T. Walsh, Ph.D.

Members Absent:

Slayton A. Evans, Jr., Ph.D.
Wayne A. Hendrickson, Ph.D.
Daniel J. Kevles, Ph.D.
Neil S. Mandel, Ph.D.

Special Consultants Present:

David DeRosier, Ph.D.
Professor
Department of Biochemistry
Brandeis University
Waltham, MA 02254-9110

David E. Draper, Ph.D.
Professor and Chairman
Department of Chemistry
Johns Hopkins University
Baltimore, MD 21218-2608

Stephen F. Lowry, M.D.
Professor and Chairman
Surgery Department
University of Medicine and Dentistry of New Jersey
New Brunswick, NJ 08903-0019

Paul Wender, Ph.D.
Bergstrom Professor
Department of Chemistry
Stanford University
Stanford, CA 94305-5080

For the record, it is noted that to avoid a conflict of interest, Council members absent themselves from the meeting when the Council discusses applications from their respective institutions or in which a conflict of interest may occur. Members are asked to sign a statement to this effect. This does not apply to "en bloc" actions.

Council roster (available from NIGMS).

Members of the Public Present:

Dr. Sister Maria Cooper, Immaculata College
Dr. Elaine J. Davis, Bowie State University
Mr. Sunil Iyengar, The Blue Sheet
Ms. Pamela Moore, Capitol Publications
Dr. Georgia Persinos, Washington Insight

Federal Employees Present:

National Institute of General Medical Sciences Employees:

Please see sign-in sheet (available from NIGMS).

Other Federal Employees:

None

OPEN PORTION OF THE MEETING

I. Call to Order and Opening Remarks

Dr. Cassman called the meeting to order and introduced the guests present and the four ad hoc members of Council: Dr. David DeRosier, Abraham S. and Gertrude Berg Professor of Life Sciences, Brandeis University; Dr. David E. Draper, professor and chairman, Department of Chemistry, Johns Hopkins University; Dr. Stephen F. Lowry, professor and chairman, Department of Surgery, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey; and Dr. Paul Wender, Bergstrom Professor of Chemistry, Stanford University.

Dr. Cassman announced that Dr. Slayton Evans is still recovering from his quite serious illness. He also reported that Dr. Evans was recently married.

Two new NIGMS staff members were introduced: Dr. Alison Davis, a science writer in the Public Information Office, and Mr. Andre Smith, an equal opportunity specialist in the Equal Employment Opportunity Office.

Mr. Geoff Grant, director of the Office of Policy for Extramural Research Administration, NIH, will be leaving in early June to become associate vice president for research administration at Stanford University.

Dr. Eugene Vigil of the Division of Minority Opportunities in Research will be leaving NIGMS to take a position in the Center for Scientific Review at NIH.

Mr. Tom Boyce of NIGMS' Information Resources Management Branch will be leaving to take a position in the Center for Information Technology (formerly the Division of Computer Research and Technology), NIH.

Dr. Cassman congratulated a member of Council, Dr. Eva Neer, on her recent election to the National Academy of Sciences.

II. Consideration of Minutes

The minutes of January 29-30, 1998, incorrectly stated Dr. Lila M. Gierasch as being absent. She should have been listed among the members present. The minutes of the January 29-30, 1998, meeting of the National Advisory General Medical Sciences Council were approved with this correction noted.

III. Future Meeting Dates

The following dates for future Council meetings were confirmed:

September 10-11, 1998
January 28-29, 1999
May 13-14, 1999
September 23-24, 1999
January 27-28, 2000
Thursday-Friday
Thursday-Friday
Thursday-Friday
Thursday-Friday
Thursday-Friday

Dr. Cassman 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. Report From the Director, NIGMS: Status of Appropriations

Dr. Cassman discussed the President's budget for NIH for FY 1999. He noted that NIGMS received an increase of 7.5 percent--just under the 8.5 percent recommended for NIH overall. The NIGMS increase amounted to about $79.5 million. Almost all of the increase is in research project grants and training. He pointed out that there was an unusually large increase in the budget for training, almost entirely due to the 25 percent increase in stipends recommended by Dr. Varmus. This is considered by most people to be a much-needed correction to support levels that have been unacceptably low. There is also provision for a small increase in postdoctoral support for interdisciplinary training of mathematicians, physicists, and engineers; for the area of clinical pharmacology; and for a new career development program in the MORE Division that would combine research and teaching. Also in the budget is an accommodation for an increase of 10 percent in the average cost of a new research project grant, as recommended by Dr. Varmus. Finally, Dr. Cassman noted that the FY 1999 budget included only a 3 percent increase in the component called Research Management and Support, which pays for the internal operation of the Institute. He pointed out that the many initiatives that were discussed in the past and that were to be discussed later that day required informed management. He expressed his concern that the constraints on personnel arising from the small increases in this overhead budget would limit the Institute's ability to carry out its mission.

Dr. Cassman then turned to a consideration of various policies that had been instituted over the past 10 years, largely as a response to limited resources. Although cautioning that the future budget projections held a considerable degree of uncertainty, he said he felt that circumstances had changed sufficiently to warrant a reexamination of these policies.

  1. The $500,000 Trigger

    This required that applications from investigators having more than $500,000 in direct cost support from any source be examined particularly carefully. After discussion, a motion was made and accepted to retain the trigger, but at the higher level of $750,000 in FY 1999, to account for inflation and other increased costs of conducting research. The trigger will be increased by the Biomedical Research and Development Price Index in subsequent years.

  2. Facilities and Administrative (F&A) Cost Constraints on Interim Funding

    When the interim funding awards were initiated, the F&A costs were limited to 25 percent. It was moved and accepted to remove this limitation and provide full F&A reimbursement.

  3. Program Project and Center Caps on Support

    Currently, both program projects and centers are limited to a maximum of $4 million in direct costs over 5 years, exclusive of equipment. After considerable discussion, it was decided to defer action on this issue pending further consideration at September Council.

  4. Cap on the Initiative for Minority Student Development

    Applications to this program are currently capped at $500,000 direct costs per year. Council voted to remove the cap.

  5. Limitation of Tuition Reimbursement on Training Grants

    Tuition reimbursement is currently limited to 60 percent of costs above $2,000. This is an NIH-wide policy that NIGMS had worked hard to put in place, at a time when tuitions were rising rapidly while our training budget was constant. There was extensive discussion, resulting in a general consensus that although some constraints should be retained, the specific formula might be reconsidered. Further examination of the consequences of such an action is needed.

This part of the open session concluded with a correction to the language in the Operating Procedures permitting administrative increases in trainee positions in an award. There was a motion and approval to permit an administrative increase of one position on training grants with fewer than 15 trainees, and two positions on those with 15 or more trainees.

V. Reports from Council Working Groups

Division of Cell Biology and Biophysics

Dr. James Cassatt presented a summary of the discussions of the CBB advisory group. A recurring theme was the need for integrative approaches to understanding processes at the cellular level. To accomplish this, new technologies would be needed as well as an increased emphasis on collaborative research. Since the resulting "emergent properties" are impossible to predict, it was felt that the old paradigm of requiring hypothesis-driven research might not be adequate in all cases. A critical need to replace older laboratory instruments was discussed. The need for larger instruments, such as cryoelectron microscopes, on a shared basis was also considered. There was considerable discussion regarding the need to bring other disciplines, with a special emphasis on chemistry, into the study of biology and possible mechanisms for doing so. Discussions on training emphasized "better, not more." In this context, it was felt that there was a need to encourage highly motivated individuals to pursue creative projects during their postdoctoral careers. Finally, the need to have proprietary data--for example, EST tags--available to NIH grantees was discussed.

Following the presentation of the deliberations of the CBB advisory group, further Council discussion focused on a number of issues. There is a need to find a way of funding a cadre of people who are trained to run the facilities and instrumentation, such as NMRs and electron microscopes. In addition, the crumbling of basic infrastructure beyond the failing of older instruments is an issue. Finally the Council discussion returned to the issue of systems analysis contained in the CBB report, that is, we are going to have to put the parts back together in a "post-reductionist" period--an effort that will require collaborations among disciplines that have not necessarily collaborated in the past.

Division of Genetics and Developmental Biology

Dr. David Clayton provided an overview of the general and more specific issues raised by the GDB advisory group during their discussions on May 13, 1998. He first noted that the subcommittee reaffirmed the value of the investigator-initiated R01 grant. Specific initiatives included the development of research tools and resources, such as a hyper-recombinant mouse strain; a database for genomic sequences of tissue-specific control elements in the mouse; and centralized facilities for monoclonal antibodies, micro-array technology, and confocal microscopy. Access to such centralized resources was considered crucial for the smaller laboratories with limited funding. He also noted the need for improvement of the research infrastructure through replacement of outdated instrumentation. Longer-term endeavors included the development of new model systems that would require sustained and significant support.

Dr. Clayton emphasized several overarching themes. One was the management of the large volume of data that is being amassed for sequencing and structural information, and the training of scientists in bioinformatics to meet the needs of the pharmaceutical and biotechnology marketplace. Emerging areas of science will depend on interactions between disciplines that traditionally have not closely interacted. This integrative approach should lead to a rebirth of more traditional areas, such as physiology and intermediary metabolism.

Dr. Sarah Elgin presented overheads reflecting seven areas emphasized by the subcommittee:

  1. Bioinformatics--and more broadly, the establishment of--and access to--databases for genomic sequences and gene expression.
  2. Training--of research scientists at the interface between biology and computer sciences and other non-biological sciences.
  3. Integration of information--for the study of "concerted biology," such as cellular metabolism and physiology.
  4. Development of genetic resources--including new model organisms for the study of developmental principles and access to centralized resources, such as stock centers, databases, libraries of biological and genetic tools, and high-throughput sequencing facilities.
  5. Infrastructure--support for individual and multi-user equipment, small and large.
  6. Interdisciplinary research--complex biological systems and the interface between mathematics, the physical sciences, and biology.
  7. Funding mechanisms--for long-range, collaborative, and cross-disciplinary projects.

Dr. Susan Henry added that she was struck by the convergence of ideas expressed by all three subcommittees and those articulated at the November 1997 workshop on " New Approaches to the Study of Complex Biological Processes." Another unifying theme was recognition of the emergence of new and powerful research tools and the necessity of making these tools widely available to the research community. She emphasized the need to maintain research training activities in order to keep our universities at the forefront of biological research. In addition to protecting the basic R01 grant mechanism, new grant mechanisms are needed to support multi-user equipment and facilities and to support the training and re-training of young and mid-career scientists. Finally, Dr. Henry noted the need to reeducate our study sections and to develop new ones to deal with non-hypothesis-driven research, along with the more traditional hypothesis-based applications.

Division of Pharmacology, Physiology, and Biological Chemistry

Dr. Michael Rogers stated that the participants in the PPBC advisory group meeting represented a wide range of scientific backgrounds, but expressed a common theme of the need for scientists in different areas to work together. Drs. Christopher Walsh and Steven Paul were asked to present a summary of the advisory group discussion. They expressed the advisory group view that science may have advanced to the point where advances on major questions may require the coordinated effort of many investigators from many different disciplines. Mechanisms to promote these coordinated efforts should be considered. Furthermore, biology has become an "information science," such that the need for the generation of new technology and widely useful data from the application of new technology may require the scientific community to rethink the meaning of the term "hypothesis-driven" in evaluating these efforts. It may be worthwhile, for example, to catalog all the small molecules in a cell. Limited access to certain technologies and data was cited as a concern, as was the need for training biologists in informational science. The need for research in biomaterials and specific issues in the pharmacological sciences were also discussed, including molecular approaches to the study of pharmacokinetics and a new effort in pharmacogenetics. Chemistry issues included concern over an apparent shortage of chemists trained in synthesis and the need of biologists for directed combinatorial libraries. Discussion pointed out the important role that synthetic chemists can play in interdisciplinary research, including clinically relevant translational research. Discussion also centered on clinical issues that need to be addressed, especially the need to foster the development of a cadre of investigators skilled in patient-oriented research. This was of particular importance to the Institute's program in trauma and burn research.

VI. Meeting Report: Structural Biology Workshop

Drs. John Norvell and David Clayton summarized the NIGMS plans for a Protein Structure Initiative (PSI). The goal of this project is the study of protein structural families and structural folds. This research involves the determination of a large number of protein structures in a high-throughput mode. Data from the genome project has led to comparative protein sequence analyses and numerous efforts to develop methodologies for the identification of protein families. The success of this research and recent technological advances in protein structure determination have led to calls for the initiation of a federal support program for a large-scale structural project. In January 1998, the Department of Energy sponsored a meeting focused on the feasibility of this project. In April 1998, NIGMS sponsored a smaller, follow-up workshop on this topic in Bethesda, MD. The NIGMS workshop was co-chaired by Dr. Paul Bash, Northwestern University, and Dr. Ed Lattman, Johns Hopkins University, and included 19 scientists from the United States and England (including two NAGMSC members, Dr. David Clayton and Dr. Wayne Hendrickson). About 30 observers from various federal agencies and various NIH institutes also attended.

The workshop was organized into four sessions, with considerable discussion on recent progress and feasibility. These sessions were 1) the identification of protein families and target selection; 2) the generation of proteins for biophysical analyses; 3) the preparation of proteins for structural analyses (crystallizations for X-ray and isotopic labels for NMR); and 4) the methods for structure determination. The participants agreed that all of the necessary tasks for the PSI project are feasible and that the goal of this initiative was an important scientific endeavor. The resulting basis set of protein structures and structure folds would be crucial in studying protein structure and evolution, as well as the protein folding problem. The workshop participants recommended that NIGMS take three steps to support the PSI project: 1) organize a workshop to study protein target selection issues, 2) provide support for the development of related technologies and infrastructure (especially synchrotron facilities), and 3) establish pilot projects in genome-directed structural biology.

Council members discussed the PSI project and the expected scientific results from this directed-science project. It can be called an "educated" fishing expedition, but is likely to have major scientific impact. The staff was asked to continue this initiative and to examine ways of incorporating the biotechnology industry in this effort.

VII. MORE Division: Initiative for Infrastructure Enhancement at MBRS and MARC Institutions

The MORE Division discussed the need for access to contemporary tools of communication via the Internet and Intranet at MARC- and MBRS-supported institutions. Dr. Clifton Poodry, the director of the MORE Division, noted that there is quite a range of Internet and Intranet capability among MORE-supported schools, from minimal to superb. The Division proposed to allow institutions currently holding MARC or MBRS awards to compete for supplemental funding to support the development or upgrade of Internet and Intranet capability. Council members agreed with the assessment and the importance of addressing the need. Further, they urged that the institutions be allowed to ask for support personnel in addition to hardware and software. They also pointed out the importance of training for faculty and staff in the use of the new technology. There was general agreement that MORE should go forward with the initiative.

VIII. Council-Initiated Discussion

Dr. Cassman discussed the efforts the Institute is making to improve access and help provide stability to the operation of synchrotron facilities. Synchrotrons are devices that are operated by the National Science Foundation or the Department of Energy and are of great importance to a variety of biomedical research efforts. In particular, synchrotrons have become an essential resource in the area of structural biology, where they are indispensable for many aspects of X-ray crystallography. Since NIH is the major supporter of biological structure determination, and NIGMS provides about 50 percent of all the NIH support to investigators in this area, the Institute has a significant responsibility in ensuring that user access for biological crystallography, in particular, is maintained. NIGMS is currently involved in two efforts related to synchrotron use. The first is an attempt to provide additional support for existing installations that would result in improved user access for NIGMS grantees. The second is the participation in an Office of Science and Technology Policy Working Group that is examining the possibility of trans-agency efforts to provide long-term stability for the support of synchrotron facilities and to evaluate ongoing and long-term needs. Dr. Cassman is chair of this working group. The Council will be kept informed as matters progress.

CLOSED PORTION OF THE MEETING

IX. Procedure for Conduct of Meeting

Dr. Cassman brought to the attention of the 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 which was not readily apparent.

X. Review of Applications

A summary of applications reviewed by Council is available from NIGMS.

Appendix I: Research grant applications
Appendix II: SBIR applications
Appendix III: Institutional fellowship applications
Appendix IV: Minorities in biomedical research applications

These appendices are available upon request from Ms. Pam Haney 301-594-2172.

ADJOURNMENT

The meeting adjourned at 11:30 a.m. on Friday, May 15, 1998.

CERTIFICATION

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

Marvin Cassman, Ph.D.
Chairman
National Advisory General
Medical Sciences Council

W. Sue Shafer, Ph.D.
Executive Secretary
National Advisory General
Medical Sciences Council