Advisory Council Minutes, September 10-11, 1998

The National Advisory General Medical Sciences (NAGMS) Council was convened in closed session for its one-hundred and ninth meeting at 8:30 a.m. on Thursday, September 10, 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 September 10 from 11:10 a.m. to 5:25 p.m. and was followed by the closed session for consideration of grant applications.

Members Present:

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

Members Absent:

Slayton A. Evans, Jr., Ph.D.

Special Consultants Present:

William R. Roush, Ph.D.
Professor
Department of Chemistry
University of Michigan
Ann Arbor, MI 48109-1055

Shirley M. Tilghman, Ph.D.
Professor
Department of Molecular Biology
Princeton University
Princeton, NJ 08544-0001

Richard M. Weinshilboum, M.D.
Professor
Department of Pharmacology
Mayo Foundation
Rochester, MN 55905-0001

For the record, it is noted that to avoid a conflict of ineterst, 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. Al Lazen, National Research Council
Mr. Tim Leshan, American Society for Cell Biology
Ms. Pamela Moore, Capitol Publications
Dr. Georgia Persinos, Washington Insight
Ms. Haimi Shiferaw, The Blue Sheet
Ms. Jennifer Sutton, National Research Council

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, Dr. Shirley M. Tilghman, professor, Department of Molecular Biology, Princeton University; and Dr. Richard M. Weinshilboum, professor, Department of Pharmacology, Mayo Foundation; and the ad hoc member of Council, Dr. William R. Roush, professor, Department of Chemistry, University of Michigan.

Dr. Cassman thanked the three NAGMS Council members who completed their terms of service with the September meeting: Dr. Susan Henry, Dr. Freeman Hrabowski, and Dr. Carlos Gutierrez.

Dr. Cassman announced that Dr. Rochelle Long has been appointed chief of the Pharmacological and Physiological Sciences Branch of the NIGMS Division of Pharmacology, Physiology, and Biological Chemistry. He also noted that Ms. Martha Pine was recently promoted to the new NIGMS position of Associate Director for Administration and Operations.

Dr. Gerald D. Fischbach, chair of the Departments of Neurobiology at Harvard Medical School and the Massachusetts General Hospital, has been named director of the National Institute of Neurological Disorders and Stroke. Ricardo Martinez, M.D., M.P.H., has been named director of the Division of Extramural Research at the National Institute of Dental and Craniofacial Research. Dr. Martinez comes to the NIDCR from the University of Texas Health Science Center in San Antonio, where he served as deputy chairman for research and professor of pediatrics, physiology, and cellular and structural biology.

II. Consideration of Minutes

The minutes of the May 14-15, 1998, meeting of the National Advisory General Medical Sciences Council were approved as submitted.

III. Future Meeting Dates

The following dates for future Council meetings were confirmed:

January 28-29, 1999
May 13-14, 1999
September 23-24, 1999
January 27-28, 2000
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 prospects for the FY 1999 budget, pointing out that both the House and the Senate Appropriations Committees provided significant increases for NIH and NIGMS, although there was a considerable disparity between the two levels.

Dr. Cassman then turned to a discussion of a proposed effort by NIGMS to improve access to synchrotron facilities for X-ray crystallographers. Evidence was provided demonstrating that investigators in the life sciences are an increasingly large percentage of the synchrotron user community, and that an increasing percentage of new macromolecular crystal structures were done on synchrotrons. NIGMS has a major involvement in this issue since the Institute provides about one-half of the approximately $150 million in support by NIH for X-ray crystallography. Consequently, NIGMS has a responsibility to ensure that grantees have access to a major piece of equipment. The Institute plans to send letters to each of the six synchrotrons in this country asking for proposals that would ensure improved access to investigators in return for additional investments in personnel and equipment at the facilities. Dr. Cassman also reported that the Office of Science and Technology Policy Working Group, which he chairs, is attempting to coordinate interagency efforts in support of synchrotron facilities.

Next, Dr. Cassman reported on several initiatives that the Institute has recently begun. One, for high-risk/high-impact proposals, is intended to provide funding for novel and significant hypotheses that have limited preliminary information to support the concept. The first group of these proposals was funded after the January 1998 Council meeting; thus, the current total reflects about two-thirds of the number that can be expected over a full fiscal year. So far, there have been 266 applications, with 37 funded for a total of $3.75 million. Although the success rate is still low, the dollars awarded approximate the target of about $5 million over a full year that the Institute had planned.

The second initiative is structural biology supplements, which are made administratively in response to a program announcement, with a maximum award of $50,000 in direct costs. The first full year of funding was in FY 1997, with 16 applications received and 7 awarded, for a total of $452,000. In FY 1998, NIGMS received almost double the number of applications, and again funded about one-half of them--16 out of 29, for a total of $970,000.

V. Evolution of Infectious Diseases

Dr. Irene Eckstrand of the NIGMS Division of Genetics and Developmental Biology presented background information on a proposed NIGMS initiative on the evolution of infectious diseases. This initiative will require collaboration between NIAID and NIGMS. The first step was taken on June 15, 1998, when the two institutes co-sponsored a meeting of experts to identify research areas that need to be stimulated in order to make progress in this field. The goals of the initiative are to understand the characteristics of systems that produce infectious diseases and to create a predictive science of the evolution of infectious diseases. The initiative will also encourage collaborations among scientists representing different approaches, including clinicians, evolutionary and population biologists, molecular biologists, mathematicians, and computer scientists. The NAGMS Council discussed the proposed initiative and recommended that NIGMS proceed with a request for an application announcement.

VI. Pharmacogenetics

Dr. Richard Weinshilboum presented the recommendations of the NIH working group entitled "Understanding Individual Variations in Drug Responses: From Phenotype to Genotype," which met on June 9 and 10, 1998. The report can be found on the NIGMS Web-site at http://www.nigms.nih.gov/News/Meetings/pages/DrugResponses.aspx. He pointed out that pharmacogenetics can be considered the intersection of pharmacology and genetics, and that presently, there is a resurgence of interest given the dramatic opportunities being afforded by advances in the field of genomics. The scope of the report covered drug responses related to differences in drug absorption, distribution, and metabolism, as well as drug targets and receptors. The group agreed that fundamental research into identification of the mechanisms that determine drug response variations should be encouraged. Both pharmacologic and genetic approaches, including population studies, were recommended. The group urged consideration of drug response variations as a complex phenotype, rather than simply as single gene responses. Furthermore, the group recommended that appropriate model systems be developed. Finally, the working group advocated the development of a pharmacogenetic polymorphic variants resource database. Some limited kinds of databases are available privately, but proprietary collections are not currently being made available to researchers at academic centers. Dr. Weinshilboum stated that the development of such an information resource would be a tremendous service to the academic community, and would promote further creative, hypothesis-driven research. The group also recommended sample banks for patient materials and the need for training and cross-training of appropriate individuals.

Dr. Steven Paul noted that the working group was an interdisciplinary one. He said that the difficulties in phenotyping in particular could be rate-limiting; therefore, partnerships would be needed to access specific patient cohorts. He advocated the use of animal models amenable to genetic manipulation, particularly for sorting out the complex phenotypes.

Dr. Rochelle Long then presented the plan for a program announcement to stimulate research via traditional, investigator-initiated research grants, which closely paralleled the working group's recommendations. She also presented the conceptual basis for a pharmacogenetic database initiative, in which reference sequences, possible variants, functional information, and phenotype information would be stored for proteins/genes involved in pharmacogenetic variation. This database would ideally be fed by a network of basic scientists and informatics scientists. Dr. Mark Boguski of the National Center for Biotechnology Information, National Library of Medicine, gave a status report on the Human Genome Project and the search for variation through a trans-NIH Single Nucleotide Polymorphisms initiative. He recommended that the NIGMS initiative should capitalize on--and build from--data that are being produced elsewhere that have special relevance to this field in biology. He also mentioned that new collaborative structures are needed to bring the right kinds of scientists together in order to push this field forward.

VII. Presentation of the National Academy of Sciences Report: "Changing Career Paths in Biology"

Dr. Shirley Tilghman spoke to the NAGMS Council about a recent study by a committee of the National Research Council, a component of the National Academy of Sciences. The committee was chaired by Dr. Tilghman and was charged with developing a data profile on how career trends in biology have changed over the past 20 years. Her capsule conclusion of the committee's report was that the structure for the support of science that has served the United States well by intimately linking training and research is now under considerable stress. This is because the rate of Ph.D.s being trained is outstripping the increase in the number of jobs that are available.

Dr. Tilghman provided numerous details to illustrate this conclusion. The annual Ph.D. production in the biological sciences has increased by 40 percent since 1987, mostly due to the increase in women entering the biological sciences and the dramatic influx of foreign nationals into U.S. Ph.D. programs. Foreign nationals are also entering postdoctoral positions in record numbers. She pointed out that the time-to-degree has increased substantially, as have the length and number of postdoctoral positions held by young biomedical Ph.D. graduates. This is most evident in the dramatic increase in the number of Ph.D. graduates who are still in postdoctoral positions many years after receiving their Ph.D. degrees. She pointed out that although the industrial job sector has increased, it is not sufficient to provide jobs for such a high rate of Ph.D. production.

Dr. Tilghman summarized the recommendations of the NRC report:

(1) The life sciences community should restrain the rate of growth of Ph.D. production, with no further growth except in special circumstances.

(2) Life sciences academic departments should provide career path information to both prospective and current graduate students. It was pointed out that NIGMS strongly encourages the program directors of its training grants to do this.

(3) Graduate education should be supported by fellowships and training grants instead of by research assistantships. Dr. Tilghman noted that training grants, such as those at NIGMS, are pedagogically superior mechanisms for supporting graduate education.

(4) Postdoctoral fellows have tremendous energy, creativity, and originality, and should have enhanced positions in academic settings. The committee recommended the establishment of career transition grants as one solution to this problem.

(5) The alternate careers market has been oversold, and the number of employment positions in non-research fields is small. Master's degree programs should be encouraged, since they can provide the appropriate education for many careers other than research science. Universities should show restraint in recruiting foreign graduate students.

Dr. Tilghman discussed with the Council the ramifications of the NRC committee's recommendations. One possible avenue to improving career prospects might be to increase the number of stable, non-tenure-track research positions in academia. However, it was agreed that a shift from graduate students to technicians and academic research staff as the primary workers on research grants would be difficult to accomplish. Council members discussed the difficulty in persuading the academic community to employ fewer graduate students as research assistants. Growth of the NIGMS training grant programs was mentioned as one consequence of such a shift

VIII. Protein Structure Initiative

Dr. John Norvell of the NIGMS Division of Cell Biology and Biophysics presented an update on the Institute's plans for a Protein Structure Initiative (PSI), which has also been referred to as "structural genomics." He first identified the previous workshops at Argonne National Laboratory and at NIGMS that focused on this topic. A third, and larger, meeting in October 1998 has been organized by Rutgers University. This project involves the determination of protein structures in a high-throughput mode for studying protein structural families and protein structural folds. The PSI project is based on the success of the Human Genome Project, as well as on the ability to identify families of proteins from sequence homology analyses of genomic databases. At the previous NIGMS workshop, the experimental components of this project (protein expression, purification, crystallization and labeling, and structure determination) were discussed and thought to be feasible in a large-scale mode. Although the theoretical components (protein family identification and target selection) were seen as feasible, further discussions of the details of target selection were deemed necessary. As a first step in developing a program to determine the structures of all the characteristic protein motifs, the Institute will issue a program announcement calling for research grant applications for 1) program projects that will serve as pilots for subsequent large-scale efforts and will include all the required tasks of the PSI in an integrated project, and 2) research grants for methodology and technology development for the constituent components of the PSI.

The Institute is planning to sponsor further discussions of protein family classification and target selection through a second workshop that will be devoted to these issues. Dr. Chris Sander of Millenium Corporation and Dr. John Moult of the University of Maryland are organizing this workshop, which will be held in Bethesda on February 11-12, 1999. At least six groups (from the United States, Europe, and Asia) are actively involved in this research and will be invited to attend the workshop. A Web-site will be utilized to provide participants (and other interested scientists) with an opportunity to prepare for the workshop by posting and comparing their protein sequence analyses.

NIGMS staff will continue to provide updates to the Council on this program and the second workshop.

IX. Council-Initiated Discussion

At its May meeting, the Council encouraged NIGMS to consider ways in which the Institute could support summer research experiences for undergraduate students. In response to this recommendation, Ms. Annette Hanopole and Ms. Marcia Hahn, both of the NIGMS Division of Extramural Activities, developed four options for consideration. After reviewing the assumptions and allowable costs the program would provide, they noted that a basic premise was to minimize the administrative burden for both applicants and NIGMS staff.

Option 1: An automatic supplement to support an individual student in each competing and non-competing award would pose the least administrative burden and the highest cost, estimated at $15.7 million in FY 1999.

Option 2: A solicitation letter would be sent to all active principal investigators announcing the availability of support for one student per grant. The principal investigators would request the supplement when they submit their non-competing continuation applications. Anticipating a 30 to 50 percent response rate, this approach was estimated to cost $4.7 to $7.8 million in FY 1999.

Option 3: A separate program would be created in which an institutional official would submit an application on behalf of the institution to support up to 10 students per award. Costs were estimated at $3.5 million in FY 1999.

In Option 4: NIGMS could supplement or co-sponsor existing National Science Foundation Research Experiences for Undergraduates programs. Costs to support 200 to 500 students were estimated at $1.0 to 2.5 million in FY 1999.

Dr. Cassman clarified that while he is supportive of research experiences for undergraduates, he questions the cost in staff resources and the potential overlap with existing programs.

Council members favored Option 3, which they thought would get the most "bang for the buck" and would be the easiest to evaluate. Dr. Cassman stated that staff would develop Option 3 into a proposed program and he would consult with the other Institute Directors to see if there was interest in this as an NIH-wide program.

CLOSED PORTION OF THE MEETING

X. 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.

XI. 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 12:15 p.m. on Friday, September 11, 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