National Institute of
General Medical Sciences

The National Advisory General Medical Sciences (NAGMS) Council was convened in closed session for its one-hundred and eighteenth meeting at 8:30 a.m. on Thursday, January 24, 2002. Dr. Marvin Cassman, director of the National Institute of General Medical Sciences (NIGMS), presided as chairman of the meeting. The meeting was open to the public on January 24 from 10:35 a.m. to 3:00 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.
George C. Hill, Ph.D.
Corey Largman, Ph.D.
Eaton E. Lattman, Ph.D.
Douglas A. Lauffenburger, Ph.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.

Members Absent:

Angeline A. Lazarus, M.D.

Special Consultants Present:

George L. Kenyon, Ph.D.
Professor
College of Pharmacy
University of Michigan
Ann Arbor, MI

Council roster (available from NIGMS).

Members of the Public Present:

Mr. James Bernstein, American Society of Pharmacology and Experimental Therapeutics
Dr. Richard McGee, Mayo Clinic
Dr. Georgia Persinos, Washington Insight
Dr. Merna Villarejo, University of California, Davis

Federal Employees Present:

Dr. Karl Koehler, National Science Foundation
Dr. Kamal Shulka, National Science Foundation

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. Cassman called the meeting to order. He introduced and welcomed the guests and one ad hoc participant: Dr. George Kenyon, professor, College of Pharmacy, University of Michigan.

II. Consideration of Minutes

The minutes of the September 13, 2001 meeting were approved as submitted.

III. Future Meeting Dates

The following dates for future Council meetings were confirmed:

IV. Council Operating Procedures

Council unanimously approved the Council Operating Procedures for 2002.

V. Report from the Director, NIGMS: Status of Appropriations and Other Matters

Dr. Cassman reported on recent changes at NIH. These include the departures of the directors of the National Cancer Institute, National Institute on Drug Abuse, National Institute on Alcohol Abuse and Alcoholism, and National Institute of Mental Health. Dr. Cassman announced that Dr. Andrew von Eschenbach has been appointed director of the National Cancer Institute.

Dr. Cassman described the budget for FY 2002. He noted that the increase for NIGMS is a very healthy 12.4 percent, for a total budget of $1,725,263,000. The Institute will be able to increase the number of research grants awarded by 170 over the previous year and expects to fund a total of about 4,000 research grants--the largest number ever awarded by NIGMS. However, because the average costs requested by applicants have increased substantially, the Institute will need to reduce the budget levels recommended by study sections.

Dr. Cassman presented a proposal for stabilizing potential swings in the success rate of research grant applications as NIH adapts to a rate of growth in its budget that is likely to be less than that during the past 5 years. The plan is to increase first-year budgets of new and competing awards by 5-10 percent and to reduce the last year of awards by a comparable amount. The total amount of an award to an investigator would not change, and investigators would continue to have the flexibility to carry over funds from one year to the next. This proposal would effect a decrease in the success rate for the first year of awards and an increase in the success rate for the last year of awards (because of the decreased commitment base in the final year). By adopting this approach, NIGMS could "smooth out" the success rate over 4-5 years. Council expressed support for this approach.

Dr. Cassman asked for Council's approval to alter the terms of the administrative supplements for computational biology which Council approved at the previous meeting. He requested and received approval to increase the duration of these supplements from 2 years to the remaining length of the parent grant which, in most cases, is 2 years, but can sometimes be 3 years.

VI. Report on the Workshop on Studies of Large-Scale Genetic Variation

Dr. Irene Eckstrand of the NIGMS Division of Genetics and Developmental Biology presented the report of a working group titled "Studies of Large-Scale Variation" which met at NIH on June 20, 2001. NIGMS convened the meeting because the amount of variation in biological systems has exceeded many expectations. This variation, in nucleotide or protein sequence, developmental or metabolic pathway, physiological system, population, or ecosystem, is not random and, indeed, is a fundamental feature of biological organization. The working group identified six research areas that may prove fruitful:

1. Mid-level reality--the variation in form and process between the level of DNA and the level of phenotype.
2. Context dependence--the notion that biological systems behave differently depending on their milieu.
3. Evolution of genome properties--the evolution of properties such as methylation patterns, recombination patterns, and organization of genes on chromosomes.
4. Extensions to other organisms--the use of data from organisms that have been studied intensely in other fields, such as agriculture and ecology.
5. Bioinformatics--the management of biological information, including clinical data.
6. Modeling and statistical methods--the application of innovative modeling tools as well as rigorous tests of the assumptions underlying methods currently used.

The working group encouraged NIGMS to foster partnerships with minority-serving institutions and minority scientists.

VII. Report on the Upcoming Workshop on the Basic Biology of Mammalian Stem Cells

Dr. Judith Greenberg of the NIGMS Division of Genetics and Developmental Biology reported that NIGMS will convene a workshop titled "The Basic Biology of Mammalian Stem Cells" in Bethesda, MD, on June 9-11, 2002. This workshop is one of several NIH efforts in response to President Bush's announcement on August 9, 2001 to allow Federal funds to be used for research on existing human embryonic stem cell lines that meet several criteria. The criteria are: First, the derivation process (which begins with removal of the inner cell mass from the blastocyst) must have been initiated prior to August 9. Second, the stem cells must have been derived from an embryo created for reproductive purposes but no longer needed for these purposes. Third, informed consent must have been obtained for the donation of the embryo. Fourth, no financial inducements must have been provided for donation of the embryo.

Dr. Greenberg noted that NIH created a registry that lists approximately 70 cell lines which meet these eligibility requirements for Federal support. NIH is now anxious to support research on human embryonic stem cells and to expand research on adult stem cells.

Because research on human embryonic stem cells is a new area for most investigators, NIH is undertaking a number of efforts to promote and facilitate this research. NIH is awarding grants to eligible providers of stem cells, to enable them to scale up production so that cells can be more widely available for researchers; supporting training for potential stem cell investigators; helping to resolve issues pertaining to technology transfer and patents; and holding workshops on the use of stem cells to treat various diseases.

Another necessary goal is to stimulate research on the mechanisms that keep stem cells in an undifferentiated and pluripotent state. NIGMS plans to address this need by convening the workshop in June. This workshop will bring together investigators who study embryonic and adult mammalian stem cells with investigators who study basic genetic and cellular mechanisms and research problems, such as development, cell cycles, regulation of gene expression, transduction of signals, and the structure of chromatin. The goals of the workshop are twofold: (a) to promote interactions between the two groups of investigators, and (b) to engage in a discussion that will help NIGMS, and perhaps other NIH components, determine how to promote research to improve understanding of the basic biology of stem cells. The workshop will be divided into two parts: a symposium, with presenters and discussion; and a roundtable, for discussion of future research needs. Dr. Jamie Thomson of the University of Wisconsin and Dr. Ken Zaret of Fox Chase Cancer Center will co-chair the meeting.

VIII. Progress Report on the Gilman U54 Grant

Dr. Rochelle Long of the NIGMS Division of Pharmacology, Physiology, and Biological Chemistry summarized progress during the first year of funding grant U54GM62114. This grant, titled "The Alliance for Cellular Signaling," is awarded to Dr. Alfred G. Gilman of the University of Texas Southwestern Medical Center. The goal of the Alliance, which involves many laboratories and researchers, is to create a "virtual cell," as part of a large-scale effort to understand and model cellular signaling in two primary cell types, cardiac myocytes and B lymphocytes. The Alliance for Cellular Signaling is the first "Large Glue Grant" funded by NIGMS. The "glue grants" support collaborative research projects.

Dr. Long discussed the organization of the Alliance, the activities of individual laboratories, projects' milestones, and achievements. The Alliance maintains a public Web site, http://www.afcs.org​, which includes information on sponsors and members, proteins and molecules being studied, and preliminary signaling maps. The Alliance has a Steering Committee and two committees to provide oversight of experiments on specific cell types. The laboratory directors and chairs meet regularly.

Dr. Long noted that progress is on track and that the External Advisory Committee commended the Alliance for accomplishments in developing the infrastructure needed to support the research and in identifying and resolving scientific problems. She also noted that all data and the conditions under which they are obtained will be posted on the Web site immediately after validation, for use by the entire scientific community. The second annual meeting of the Alliance will be held May 5-8, 2002, in Dallas, TX.

IX. Examples of Evaluation in the MORE Program

Dr. Clifton Poodry, director of the NIGMS Division of Minority Opportunities in Research (MORE), introduced two presentations on evaluation, which were given by NIGMS grantees. He explained that, although NIGMS requires all MORE grantees to evaluate their programs, the kind and quality of information collected are highly variable and the analysis of data is even more so.

The two grantees presented very different approaches to evaluating their programs. One approach is to analyze outcomes and relevant factors for interventions, whereas the other is to conduct qualitative research to better understand students' choices. Dr. Poodry commented that both methodologies yield information that could be useful in planning interventions that might be proposed by the MORE programs.

Dr. Merna Villarejo of the University of California at Davis summarized a thorough analysis of data collected over a number of years in the university's Biomedical Undergraduate Scholars Program (BUSP). The data included comparison groups matched for high school and SAT background as well as other variables such as socioeconomic status. One of the conclusions emerging from the data, which is germane to the MORE programs for student development, was that participation in undergraduate research is a positive factor in improving retention and yielding high performance. Surprisingly, however, participation in research during a student's freshman year did not correlate with success. Also, although the BUSP is very successful for better-prepared students, the results of extending the program to a second tier of students were not positive. This finding demonstrates the importance of tailoring interventions to specific contexts and of not assuming that programs that work well in one place or with one group will be similarly effective everywhere.

Dr. Rick McGee of the Mayo Clinic described qualitative research that may yield a better understanding of whether a student is more likely to pursue research or clinical training. The study included a structured interview process and subsequent computer-aided analysis of themes that emerged from students' responses. Dr. McGee summarized a variety of questions and examples of responses from students who subsequently attended medical school, graduate school, or an M.D.-Ph.D. program. The study and analysis are continuing, but preliminary findings indicate that qualities such as curiosity and comfort with uncertainty, versus a desire to know "the" answer, correlate highly with subsequent application to Ph.D. programs, rather than medical school, and vice versa.

X. MORE Division: Concept Approval for Support of Minority Supplements at Minority-Serving Institutions with SCORE Grants

Dr. Clifton Poodry asked Council to approve a proposal from the MORE Division to extend minority supplements to grantees in the Minority Biomedical Research Support (MBRS) program, for Support of Continuous Research Excellence (SCORE) (S06) grants. The S06 version of minority supplements would support only eligible faculty from minority-serving institutions and minority postdoctoral scientists. The procedures currently in place for all other minority supplements would apply to the S06 supplements. Council approved the proposal.

XI. Report on the Workshop on Functional Studies of Targeted Proteins

Dr. Warren Jones of the NIGMS Division of Pharmacology, Physiology, and Biological Chemistry reported on an NIGMS workshop, held December 7, 2001, to discuss opportunities for multidisciplinary research on the possible biological or biochemical roles of selected proteins whose functions have not been clearly defined. NIGMS convened the workshop because experimentally based information on the function of many proteins being characterized by the nine centers of the NIGMS Protein Structure Initiative (PSI) is sparse. For the workshop, NIGMS convened 15 investigators who are actively studying the structure and function of proteins. The investigators discussed numerous experimental and computational approaches to elucidating the function of proteins, and they considered the rationale, scope, and organization of possible research in this area.

Dr. Jones said that the participants offered no specific recommendations, but were in general agreement on a number of points. These are as follows:

1. The PSI centers are generating significant opportunities for experimental research on protein function.
2. Determination of the structure of many proteins will not be fully useful without also characterizing their function.
3. Although any NIGMS effort to support the study of protein functions should not be limited to proteins targeted by the PSI centers, these proteins could be the central focus for such studies.
4. Researchers could profitably focus their studies of the function of proteins on molecular properties (i.e., features such as catalysis, specificity, regulation, and state of oligomerization).
5. Interdisciplinary groups of investigators could best pursue the study of protein function.
6. Studies of the function of proteins will critically depend on the planned NIGMS. centralized facility for collecting, storing, and distributing materials produced by the PSI centers.
7. Experimental techniques for determining the function of proteins need to be developed and refined.
8. NIGMS needs to define a clear and delimited scientific goal before undertaking support of focused research on the functions of proteins targeted by the PSI centers. Dr. Jones noted that the participants widely agreed, in particular, on the last two points. He commented that the idea of creating an initiative to support research on protein function is a work in progress, and he asked for Council's comments.

During the Council discussion, a participant noted that this type of research would not be underpinned by hypotheses and would be counter to the typical course of biological research, which begins with the characterization of function and ends with an understanding of the structural basis for the function. A number of members noted that research on the function of proteins would be very valuable. Others commented that this research would benefit significantly by including genetic approaches. Dr. Cassman noted that NIGMS does not fund research on the function of proteins, in its support of the PSI centers, but that NIGMS recognizes the potential value of this research and will continue, with Council assistance, to explore ways to approach this issue.

XII. Report and Follow-up on the 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 actions resulting from the NIGMS Workshop on Achieving Scientific Excellence Through Diversity, held May 6-7, 2001, and the subsequent Council meeting on May 17-18, 2001. She described the Web site that NIGMS has established, which includes the report of the workshop, a feedback form, and other useful resources for program directors of NIGMS training grants.

Dr. Zatz noted two modifications of NIGMS policy which are posted on the NIGMS Web page for Minority Recruitment and Retention Strategies. The first change allows NIGMS investigators to support multiple underrepresented minority students, in high school and college, with supplements to their research grants. This was fully described at /funding/pa/pages/minority_supp_multiple.aspx.

The second change is in the document titled "NIGMS Procedures for Implementation of the NIH Requirement for the Recruitment of Underrepresented Minority Individuals into NRSA Research Training Grants." The modified language in this document clarifies that the directors of training programs may identify not only minority students supported on a training grant, but also students who are full participants in training grant activities but have other sources of support. Dr. Zatz stated that the modified language is intended to strengthen the existing NIGMS requirements and to give more flexibility to the directors of training programs when they provide information on their recruitment and retention efforts. The modified language is consistent with current instructions to grant reviewers for assessing efforts to recruit and retain underrepresented minority students in training programs.

During the Council discussion, Dr. Hill asked for clarification of instances when minority students who are in NIGMS-supported training programs would not be supported by NIGMS training grants. Dr. Kenyon noted that this situation had arisen at the University of Michigan when students had other sources of support. He said that, although the Michigan campus has a very active program for recruiting minority students, this program had been criticized because students were not supported on the training grant and therefore were not "counted." Dr. Kenyon thought the modified document would alleviate this problem. Dr. Hill expressed concern that the directors of training grant programs could potentially neglect their responsibility to recruit minority students. Dr. Zatz and others emphasized that NIGMS drafted the modified language carefully to circumvent this possibility.

Dr. Warner commented that Louisiana State University, which has a very aggressive program for recruiting minority students, has many individual fellowships that attract minority students but would preclude their support on an NIGMS training grant. He suggested that not crediting these recruitment efforts would be punitive to the school, the program, and the students. He supported the modified language for providing greater flexibility and allowing aggressive recruitment practices to be rewarded. Dr. Taylor, who, during the Council discussion last May, asked for a mechanism that would provide greater flexibility in NIGMS guidelines, concurred and noted that the University of California at San Diego encourages minority students to apply for independent fellowships, yet fully involves them in its training grant program. The Council concluded the discussion by accepting the modified language in the document.

XIII. Summary of 2001 NIGMS Retreat

Dr. Cassman presented a brief history of previous NIGMS retreats and described the rationale for the Institute's most recent retreat, held October 29, 2001, at Rockwood Manor Park in Potomac, MD. Dr. Anthony Carter of the NIGMS Division of Genetics and Developmental Biology summarized the sessions.

The purpose of the retreat was to discuss the selection and implementation of 49 NIGMS initiatives developed from 1995 to the present. To facilitate discussion, a staff committee grouped the initiatives into five areas:

1. Consortia--Promotion of Collaborations
2. Complex Biomedical Systems
3. Minority Opportunities in Research
4. Access to Tools/Infrastructure/Resources
5. Initiatives in Other Categories

Departing from the format of previous retreats, the committee invited a small group of outside discussants to participate in the retreat. Members of Council who participated were Drs. Dunlap, Lattman, Pozos, and Weinshilboum.

At the retreat, an NIGMS program director provided a brief overview of the origin and status of one or more initiatives in each of the selected areas. The discussants, Council members, and NIGMS staff offered opinions and suggestions on: (a) the composition of current initiatives in each area; (b) problematic programs or potential, missed opportunities; (c) future needs of the research community; and (d) strategies for developing future initiatives.

Dr. Carter presented several examples of the opinions and suggestions offered during the retreat. For example, the participants noted that:

• The name "Small Glue Grant" is confusing, and the dollar incentives for Small Glue Grants are not high enough. Because these grants are not intended to be planning grants, awards ranging from $300,000 to $5,000,000 could stimulate a greater number of applications than awards for smaller amounts.
• Currently, funds are going to well-known, well-funded principal investigators. Some sort of "glue award" is needed for investigators who are not already "big names." Mechanisms of support are needed for newly independent, young investigators (including non-tenure-track principal investigators) to enable them to pursue promising, but "risky" research. Perhaps consortia should include mentoring components similar to those in K awards.
• NIGMS could support educational initiatives to facilitate changes in curricula to give greater emphasis to quantitative and computational approaches.
• Efforts are needed to encourage engineers to be proactive in approaching biologists, to help biologists address questions from an engineering perspective, rather than expecting biologists to always approach engineers first.
• NIGMS should strongly consider initiating a program to support minority faculty at non-minority schools.
• NIGMS should develop a program to engage and interest M.D.-degree minority students in research.
• NIGMS needs to be more proactive in advertising its initiatives. The GEMS system appears to be an effective way to communicate new initiatives. Staff should send program announcements and Requests for Applications as attachments to the e-mails. Staff should advertise initiatives at meetings, in Council minutes (as a "hint of what is coming from NIGMS"), and through increased institutional visits.
• NIGMS should judiciously use administrative supplements to support research on structural biology, protein preparation, and proteomics; microarrays (solicited more than once); and high-risk/high-impact portions of existing awards, by adding an additional year or additional funds, or both.
• NIGMS should extend the program of "Supplements for the Determination of High-Resolution Structures" to include preparation of samples.
• Staff needs to improve dissemination of information on NIGMS interests and funding mechanisms to the community and to reviewers.
• Bioengineering is still an emerging discipline that NIGMS previously supported strongly. Although NIGMS efforts may overlap with those of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), NIGMS should continue to foster research in bioengineering, particularly in relation to cell biology.

CLOSED PORTION OF THE MEETING

XIV. Review of Applications

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

ADJOURNMENT

The meeting adjourned at 3:00 p.m. on Friday, January 25, 2002.

CERTIFICATION

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