Advisory Council Minutes, September 19-20, 1996

The National Advisory General Medical Sciences (NAGMS) Council was convened in closed session for its one-hundred and third meeting at 8:30 a.m. on Thursday, September 19, 1996, in Conference Room 6, Building 31C. 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 19 from 11:00 a.m. to 5:28 p.m., followed by the closed session for consideration of grant applications.

Members Present:

David A. Clayton, Ph.D.
Sarah C.R. Elgin, Ph.D.
Carlos G. Gutierrez, Ph.D.
Susan A. Henry, Ph.D.
Freeman A. Hrabowski, III, Ph.D.
Henry Lewis III, Pharm.D.
Alvin Manalaysay, M.D., Ph.D.
Thomas D. Pollard, M.D.
Christopher T. Walsh, Ph.D.
Mary Wiley, J.D.

Members Absent:

Steven M. Paul, M.D.
Franklyn Prendergast, M.D., Ph.D.
Franklin J. Zieve, M.D., Ph.D.

Special Consultants Present:

Lila M. Gierasch, Ph.D.
Head
Department of Chemistry
University of Massachusetts
Amherst, MA 01003-4510

Paul A. Insel, Ph.D.
Professor
Department of Pharmacology
University of California, San Diego
La Jolla, CA 92093-0636

Brian W. Matthews, Ph.D.
Professor
University of Oregon
Institute of Molecular Biology
Eugene, OR 97403

Lawrence Que, Jr., Ph.D.
Professor
Department of Chemistry
University of Minnesota
Minneapolis, MN 55455

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. Stan Ammons, Association of American Medical Colleges
Mr. Nielsen Hobbs, The Blue Sheet
Dr. Georgia Persinos, Washington Insight
Mr. Chris Peterson, GRI
Mr. Christopher Shafer, American Chemical Society

Federal Employees Present:

National Institute of General Medical Sciences Employees:

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

Other Federal Employees:

Dr. Neil Mandel, Medical College of Wisconsin, VA Medical Center, Milwaukee
Dr. Judith Plessot, National Science Foundation

OPEN PORTION OF THE MEETING

I. Call to Order and Opening Remarks

Dr. Cassman called the meeting to order and welcomed the guests present and the four special consultants. These were Dr. Lila M. Gierasch, Department of Chemistry, University of Massachusetts, Amherst, MA; Dr. Paul A. Insel, Department of Pharmacology, University of California, San Diego, La Jolla, CA; Dr. Brian W. Matthews, University of Oregon, Institute of Molecular Biology, Eugene, OR; and Dr. Lawrence Que, Jr., Department of Chemistry, University of Minnesota, Minneapolis, MN.

Dr. Henry Lewis completed his term of service at the September meeting. Dr. Elvera Ehrenfeld resigned after the May meeting so that she could be appointed Director, Division of Research Grants.

Dr. Cassman introduced and welcomed the two new members of Council: Dr. Sarah Elgin, Professor, Department of Biology, Washington University; and Dr. David Clayton, Senior Scientific Officer, Howard Hughes Medical Institute. Their appointments were announced in May, but they were not able to attend at that time. Dr. Cassman also introduced a soon-to-be member, Dr. Neil Mandel, who is affiliated with the VA Medical Center in Milwaukee and is a professor at the Medical College of Wisconsin. Dr. Franklin J. Zieve, who was the ex officio member from the Veterans Administration, was not able to continue and Dr. Mandel has been nominated for the position but not yet officially appointed. Dr. Mandel attended this Council as an observer.

New staff members were introduced who have come on board since the last Council. They are: Dr. John Schwab, Program Director, Division of Pharmacology, Physiology, and Biological Chemistry; and Ms. Judy Reeves, Council and Financial Assistant, Office of Administrative Management. Dr. Cassman reintroduced Dr. Irene Eckstrand, who is returning to the Division of Genetics and Developmental Biology after a 2-year detail.

Dr. Cassman announced that Dr. Donald Luecke, former Deputy Director, Division of Research Grants, is moving to the National Institute on Deafness and Other Communication Disorders as the Deputy Director. He also announced that Dr. Thomas Pollard has been appointed President of the Salk Institute in La Jolla, California. Finally, he noted his appointment as the NIGMS Director.

II. Consideration of Minutes

The minutes of the May 16-17, 1996 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:

IV. Legislative Update

Dr. Warren Jones, Special Assistant to the Director for Legislative Affairs, reported on efforts in the Senate to develop reauthorization legislation. Dr. Jones pointed out that authorization legislation is used to establish agencies in the Federal Government, define their missions, and give general direction about how they should go about their work. He pointed out that the authority for most of the programs and organizations within NIH resides in permanent legislation. Although there are a few exceptions, the legal basis for NIH and its programs does not expire. Nonetheless, the practice has grown up in the Congress to examine the mission and organization of NIH every 3 years, and 1996 is the year for this effort.

The focus of the NIH reauthorization legislation thus far has been in the Senate Committee on Labor and Human Resources, chaired by Senator Nancy Kassebaum (R-KS). While most of the provisions in the bill that was introduced (S. 1897) concern components of NIH other than NIGMS, there are two notable exceptions. First, the proposed legislation provides that grants that do not exceed $100,000 in direct costs may be funded without consideration by an institute's advisory council. The current limit is $50,000. The other provision having a direct bearing on NIGMS would affect the Institute's Medical Scientist Training Program. This provision would have the Director of NIH undertake efforts to expand the number of trainees in the program who pursue Ph.D. studies in patient-oriented research. The intent of the bill is to increase the number of M.D.-Ph.D. graduates who have expertise in biostatistics, epidemiology, medical economics, and bioethics.

Dr. Jones noted that while the bill might not be considered by the full Senate this year, it could well serve as the starting point for future reauthorization legislation, particularly if the Republican Party retained control of the Senate in the upcoming election.

V. Report on the Structural Biology of Membrane Proteins Program

Dr. Peter Preusch presented information about the status of membrane protein structural studies, the history of NIGMS involvement in this area, and the applications received in response to program announcement PA-95-035, which was issued in January 1995. He mentioned the success of an NIGMS workshop held in August 1993 and of additional efforts to increase interest in the scientific community, including the value of earlier Council discussions of the subject.

The review of solved membrane protein structures indicated significant progress since 1993; however, as was the case at that time, most of the work has been conducted by non-NIH-funded researchers. Furthermore, relative to the rapid rate of new structure generation for other classes of proteins, the field of membrane protein structure still lags far behind. As a result of investigator interest and NIGMS promotion of work in the area, the number of NIGMS grants to conduct structural studies of membrane proteins has increased modestly. Several new grants were funded following the 1993 workshop and before issuance of the program announcement. However, several ongoing efforts failed in their competitive renewals. Forty-three applications have been received during the past year in response to the program announcement. NIGMS expects to fund 11 of those proposals. However, not all of the proposals responding to the announcement have been given an NIGMS assignment by the Referral Office in DRG, and this has created some tracking problems. Most of the applications were reviewed by the Biophysical Chemistry Study Section (BBCB) or by the Physical Biochemistry Study Section (PB). The proposals that have been received in response to the program announcement have adequately covered the range of activities that were envisioned. However, the success rates for projects involving NMR and electron diffraction methods have been greater than those for attempts toward x-ray diffraction studies of 3-D crystals, despite the inherently higher potential resolution and completeness of the latter method. The continued operation of a "no crystal, no grant" rule of thumb within NIH study sections was cited as the major obstacle to x-ray diffraction studies. The NIH Shannon Award and the NIGMS Diversity (High Risk/High Impact) Award programs have been valuable tools for increasing NIGMS investment in this type of research.

Dr. Preusch concluded that significant progress had been made toward increasing NIH support for research on membrane protein structures, but that a continued special effort was needed in this research area. The significance of each new membrane protein structure remains extraordinarily high and the methods to approach the structures are becoming less risky. By way of specific example, Dr. Preusch presented a synopsis of the understanding of cytochrome oxidase, circa 1993 versus 1996, after solution of x-ray structures of the enzyme by German and Japanese research groups.

In discussion, Council members agreed that work on membrane protein structures is very important, but questioned whether increased investment in an area necessarily means that results will immediately follow, since advances depend on the willingness of truly committed investigators to undertake the work. The problems of supporting preliminary work and of providing long-term, stable support were mentioned. The importance of encouraging changes in the study section mindset was endorsed as much as the encouragement of applicants. The value of disseminating review of the proposals to additional study sections was suggested. Concern was expressed for investigators whose proposals are assigned to other NIH institutes that may not be stressing this research area. Difficulties in tracking research in this area that has not yet reached the point of public presentation were discussed.

VI. Office of Naval Research Program on Gene Regulation Networks

Dr. Eric Eisenstadt of the Office of Naval Research described a program announcement issued by his office that looks for collaborations between molecular biologists and computational scientists with the goal of understanding genetic regulatory mechanisms. He stated that 47 proposals in this area have been received. During the discussion, there was considerable concern about the availability of good data on which modeling can be done. However, there was interest in the potential of this program.

VII. Metabolic Engineering Program Announcement

Dr. Warren Jones discussed the background and status of a program announcement that solicited research grant application in the area of metabolic engineering. The program announcement (PA) was issued in September 1995 by NIGMS and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Dr. Jones pointed out that the PA grew out of a workshop that was held in March 1995, which brought together a number of investigators from academia and industry who work in this area. This group identified a number of broad topics where additional research was needed if metabolic engineering were to flourish; included among these topics were enhanced quantitative studies of metabolic flux and its determinants and the development of additional genetic tools, such as selective markers, reporter genes, regulatory molecules, and vectors, which might facilitate the introduction of targeted synthetic or regulatory capacity into host cells. The overarching purpose of the PA was to encourage investigator-initiated research that would expand the conceptual and experimental basis of metabolic engineering.

Dr. Jones reported that the first group of applications received in response to the PA was reviewed by study sections in the summer and was now being presented to the NIGMS and/or NIDDK Councils. A listing of the 17 applications and the review results was provided and discussed. The reviews, which were carried out by standing study sections from the Division of Research Grants, were felt to have gone smoothly, with little evidence of misapprehensions from reviewers about research that had a more applied orientation. Of the 17 applications received, 7 were scored and 10 were not. Three of the scored applications are expected to receive funding. Dr. Jones said the institutes considered these results to be solid and rather typical of a group of applications predominated by first-time submissions. He also added that the institutes will be continuing efforts to encourage research in this area.

VIII. Drug Bioavailability Program Announcement

Dr. Rochelle Long discussed the background and status of a program announcement that solicited research grant applications in the area of drug bioavailability. The program announcement was issued in late 1994.

A workshop was held in late 1993 with participants from industry, academia, and government. The group agreed that there are problems having enormous financial impact when drug candidates do not penetrate physiological barriers or do not arrive at or remain in active form at their sites of action. It was concluded that fundamental research is required in areas that determine the physiological, pharmacological, biological, and chemical processes that contribute to drug absorption, metabolism, transport, and clearance. The experts felt that these studies should be aimed at maximizing bioavailability at the drug design stage and predicting the bioavailability of drug candidates in humans. They recommended encouraging basic research into determining the mechanisms, developing and validating the models, and devising structure/activity relationships in the specific areas of transport processes, human drug metabolism, site-specific processes, interactions between organ systems, in vitro tests, integrated modeling, compound libraries, pro-drug strategies, formulation approaches, analytical techniques, genetic differences, and non-genetic factors.

In the 2 years since the program announcement was published in late 1994, 50 responses have been received. Of these, 21 grants have been awarded for direct costs funding of $2,368,329.

The plans for the future are to evaluate and disseminate the research findings, possibly by arranging a symposium in association with a national society meeting. Additionally, a small update meeting with a group of participants from the original workshop may be appropriate to assess what has been accomplished and what is still needed. The Council will be informed about these and any other follow-up activities. The cooperation of industrial participants with the insights they bring to identifying the practical research problems of designing drug oral bioavailability remains a unique aspect of this NIGMS program announcement. A complete copy of the workshop report that summarizes the original scientific meeting is available upon request to longr@nigms.nih.gov or by calling Dr. Long at (301) 594-3827.

IX. Report of the Committee on Rating Grant Applications

Council members were provided with the Executive Summary of the Report of the Committee on Rating Grant Applications, which has been available via the grants section of the NIH home page for reading and comment. In addition, they received an excerpt from the minutes of the July meeting of the Peer Review Oversight Group (PROG) that dealt with this topic. The PROG had recommended that experiments be tried before changes recommended in the report are implemented. Dr. Donna Dean of DRG gave an update on the proposed experiments on scoring using individual rating criteria. The results will be discussed at the PROG meeting on November 20 and 21. If any of the recommendations are to be implemented for reviews affecting FY 1998, decisions must be made by January 1997. Council members expressed some concern that this time frame was too fast and did not leave enough time to evaluate the effectiveness of the proposed changes.

X. NRSA Predoctoral Training in the Biomedical Sciences--Selected Outcomes

Dr. Georgine Pion, Senior Fellow at the Vanderbilt University Institute for Public Policy, presented a progress report on the results of studies of NIH research training programs. In addition to her duties at Vanderbilt, Dr. Pion is employed through a NIH contract to direct these studies. This work, which is overseen by the NIH Committee on Research Training Assessment, was initiated, in part, in response to calls from the National Academy of Sciences (NAS) for such evaluations. Others in the scientific community, as well as congressional committees, have asked for these studies. The first phase of this work examines the career outcomes of trainees and fellows using extant data sources and includes two relevant comparison groups. It extends an earlier study done by NAS in 1985.

Dr. Pion's work demonstrates that NIH predoctoral trainees are more successful than the comparison groups by several measures: degree completion, time-to-degree, postdoctoral support, and research grant support. She finds that about 15 percent of biomedical graduate students receive NIH research training grant support at any given time, and 30-40 percent of Ph.D. recipients in biomedical fields were appointed to training grants during some part of their graduate training. Dr. Pion is currently examining bibliometric data for sample groups of these predoctoral trainees and should have further analyses available soon. The Council members expressed the need for more detailed comparisons, including GRE scores. Future plans include a tracking system for trainees and possibly a sample survey.

XI. Support of Novel Research Projects Draft Announcement

Continuing a discussion from the May meeting, the Council returned to the issue of how to promote highly innovative research at a time of perceived increased conservatism on the part of both investigators and reviewers. The current practice of identifying high risk/high impact research during study section review, and the now terminated NIGMS High-Program Priority initiative, were cited as well-intentioned actions designed to retrospectively identify such research and send the message that such research was encouraged. These actions, however, fell short of Council expectations. Various reasons were offered to explain why, on the whole, Council was seeing less daring proposals, and what could be done to encourage their submission. Although opinion varied on both the magnitude of the perceived problem and the degree to which it could, or should, be proactively addressed, Council considered the alternative of directly soliciting applications that met its criteria. Staff provided a draft program announcement for this purpose that included research objectives, eligibility, term and funding, and review criteria for a program based on the R21 exploratory/developmental grant mechanism. Discussion focused on the importance of formulating clear criteria for both applicants and reviewers such that the purposes of the program--to foster innovative research of high potential impact but with substantial experimental risk--would be met. Members agreed that the desired applications should be directed at more than acquiring preliminary data for untested ideas; the plausible outcomes would have to be highly significant and the approach sufficiently untested such that a pilot project would be essential to determine its value.

One member noted that the proposed program attempts a short-term solution to a longer-term basic issue, that of the criteria used by reviewers, and hoped that the proposed program would not be viewed as permanent. This concern, and the experimental nature of the program, led to Council's decision to place a 2- to 3-year limit on its term. Some members expressed the wish that, if the program were to be adopted, Council retain the prerogative of encouraging funding for regular R01s that meet high risk/high impact criteria. In response to a question about how many R21 grants would be funded, staff responded that in FY 1995 the HPP program funded 51 awards, for $4.4 million in total costs; this figure was 0.6% of the RPG line. The proposed R21 program would be expected to be of similar magnitude.

Council voted approval of the proposed R21 program as broadly described in the draft program announcement. Dr. Cassman solicited suggestions for changes to the draft, allowing Council 6 weeks to respond. Staff will plan for a program announcement issuance date of mid-December, in time for the first applications to be submitted by February 1.

XII. Criteria for Review of Crystallography Research Projects

The Council continued its discussion of various aspects of the review and funding of crystallographic applications. The first of three issues involved the appropriate criteria for review and, in particular, the "no crystal, no grant" de facto policy of most study sections in this field. At the previous Council meeting, discussion centered on a policy statement asking for greater emphasis on the biological significance of the project, as well as a broader assessment of the project's feasibility than is often made by reviewers when they consider only the availability of diffraction-quality crystals (as is implied by this commonly quoted phrase). A few changes in the statement were suggested and Dr. Matthews offered to make these and return the document to NIGMS for distribution.

Dr. Walsh led discussion of the next issue, the need to disseminate crystallographic and other structural biology applications to a wider spectrum of study sections, in contrast to the current practice of assigning almost all of the applications to BBCA or BBCB. This is in response to concerns that the increasing number of high-quality applications in this field are saturating these two study sections, leading to a quota system in priority scoring and funding. In addition, the expertise on these two biophysical study sections is not always appropriate for examining biological significance. One concern with this recommended change is the lack of crystallographic expertise on other study sections. NIGMS staff will advise DRG of these recommendations and of the need to bring crystallographic expertise onto other study sections.

Dr. Pollard led the Council in a discussion of the third related issue, providing grant support for crystallization projects. Since macromolecular crystallographic techniques have progressed to the point that obtaining a suitable crystal is often the most difficult and time-consuming part of the project, a mechanism is needed to provide small grants for crystallization work when a full crystallographic project cannot be justified. After considerable discussion, the Council considered two possible mechanisms: 1) Applicants can apply for a small supplement to an ongoing grant. This supplement would provide up to $50,000 for personnel and supplies for crystallization efforts. 2) Applicants could receive an award with a two-stage budget. An initial, lower budget would provide support for the crystallization phase of the project. Once diffraction-quality crystals were obtained, a larger budget would support data collection and structure determination. Applicants could request this two-stage budget mechanism and/or reviewers could recommend it. Crucial to this mechanism is the decision to expand to stage two, which depends on the availability of diffraction-quality crystals. The Council members suggested that staff send applicants' requests and documentation to reviewers for advice before making such decisions. Dr. Cassman concluded that the staff would develop a statement on both mechanisms for consideration at the next Council meeting.

XIII. Council-Initiated Discussion

Dr. Pollard proposed a modification to the priority and percentile score reporting exercise that NIGMS undertook in FY 1996 and is continuing in FY 1997. He illustrated one of the effects that the rounding of both priority and percentile scores has had on the final distribution of percentile scores. He expressed a concern that the percentile score distributions of some study sections contain relatively large bins of applications that are widely spaced on the percentile scale, and that these distributions also are not uniform across study sections. Dr. Pollard noted that this lack of uniformity could be a problem particularly if it occurs near the payline. He proposed that the rounding of priority scores be performed after percentile scores are calculated, which will tend to produce a more uniform distribution of percentile scores within and across study sections.

Senior NIGMS staff reviewed the original intent of the exercise, which had been to create larger bins using fewer of the percentile score values in order to reduce reliance on percentile scores, which, prior to the exercise, were more uniformly distributed but which were seen as creating a false sense of precision. To compensate for the lack of uniformity across study sections in the percentile score distributions generated by the rounded scoring procedures, NIGMS program directors have been considering larger percentile score bands in making their paylist decisions so that no study section is disadvantaged. It was also noted that the lack of uniformity in the percentile score distributions is governed to some extent by the degree to which study section members spread their priority scores over a broad range.

Dr. Cassman indicated NIGMS would examine further the outcomes of the scoring exercise and the implications of Dr. Pollard's proposal, and that the scoring procedures could be modified, if necessary.

CLOSED PORTION OF THE MEETING

XIV. 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 that was not readily apparent.

XV. Review of Applications

Dr. Shafer called Council's attention to tables found under Tab V of the agenda book. These show the numbers and funds requested by applications reviewed for the September 1996 Council.

Council reviewed the following applications with primary NIGMS assignment: 598 applications that included new research grants, competing continuation grants, and supplemental grants; and 21 institutional training grant applications. In addition, Council considered 126 applications on which NIGMS had received secondary assignment. 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. Haney, 301-594-2172.

ADJOURNMENT

The meeting adjourned at 11:51 a.m. on Friday, September 20, 1996.

CERTIFICATION

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