On Wednesday, September 13, 2000, the National Institute of General Medical Sciences (NIGMS) held a special open session to discuss a series of initiatives proposed for FY 2001 and FY 2002. The agenda, list of discussants, and initiatives proposed are available from NIGMS.

Summary of Council Discussion on Research Initiatives

Dr. Cassman began with an overview of recent programs initiated by NIGMS. As a result of 1998 discussions with groups of investigators in research fields related to the Institute's mission, several areas of special interest were developed:

• study of complex systems
• promotion of collaborations
• development of and access to research tools
• new approaches to training
• development of minority programs

NIGMS defines complex systems as systems in which the behavior or expressed characteristic of a biological system is determined by the contributions of multiple interacting components with quantitative expressions that may vary in time and space. Quantitative analysis and modeling of these systems should result in an increased understanding of the global control and integration of biological processes. This will require the involvement of cross-disciplinary groups of scientists, including mathematicians, engineers, and computer scientists. A variety of initiatives were established in this area, all of which are summarized on the NIGMS Web site. Dr. Cassman noted that the Institute has had only moderate success in stimulating applications through these announcements.

The 1998 discussion groups also encouraged NIGMS to think about new ways to stimulate collaborations. This resulted in the "glue grants" initiative. These are programs to support collaborative efforts between groups of investigators. "Glue grants" do not support the underlying research--only the resources required for the collaboration to effectively function. The intent is to permit investigators to pool their efforts in order to reach goals that are not accessible through their own laboratories. Only one such program has been funded thus far--the Alliance for Cellular Signaling, headed by Dr. Alfred Gilman of the University of Texas Southwestern Medical Center in Dallas. Dr. Cassman noted that many of the "glue grant" applications have had a significant contribution from modeling and computational biology.

There are a number of diverse NIGMS initiatives in the area of research tools. These include technology development and instrument support for high-resolution electron microscopy, synchrotron facilities, and supplements for microarray analysis, to name a few.

The most prominent new NIGMS training program is a predoctoral program in bioinformatics and computational biology. Additionally, NIGMS has begun a new program in summer research experiences for undergraduates, aimed at placing individuals with quantitative backgrounds in biology labs.

Finally, a number of initiatives have emerged over the past few years from the NIGMS Division of Minority Opportunities in Research. Most recently, these include the Native American Research Centers for Health program and a post-baccalaureate training program.

Dr. Cassman noted that not all of the programs that the Institute has initiated fall neatly into the above categories. (It should also be noted that although the initiatives presented at this meeting largely could be seen to fall in the categories already mentioned, this was not uniformly true. As an example, NIGMS recently initiated a program announcement involving single-molecule studies.) Dr. Cassman pointed out that the described categories and the presented initiatives do not reflect the totality of the science that the Institute finds important or interesting; however, they do reflect areas of science that need stimulation. As important as is most of the science that NIGMS supports, most of it does not require additional stimulation. For most of the fields of science supported by NIGMS, there is a large body of investigators engaged in research, and the value of the research is well understood. Most of the initiatives presented are targeted to emerging areas where this is often not the case.

Many of the recent initiatives involve quantitative approaches to biology, and they can also be very large scale, involving well high-throughput data collection and analysis. Dr. Cassman indicated that this reflected a new research paradigm, which is best expressed by an anthropological metaphor--the change from hunter-gatherer to harvester societies. (This metaphor was first stated by Dr. William Gelbart of Harvard University.) The distinction is between approaches that involve small groups that are interactive but not highly collaborative, operating in a data-poor environment (hunter-gatherer) and those that involve highly collaborative, large groupings in a data-rich environment, often dealing with high-throughput collection and analysis of large bodies of data (harvester). Further, the hunter-gatherer researchers distribute information primarily through publications, while the harvester does this primarily through databases. The harvester approach is visible in many of the initiatives described by NIGMS staff, and the initiatives are intended to facilitate the requirements of science as these changes continue.

Dr. Shirley Tilghman of Princeton University pointed out that it is difficult for universities to adapt to the harvester environment, in part because it is not clear how people participating in large-scale collaborations will be rewarded. This is especially true for young people. Dr. John Kozarich of Merck Research Laboratories noted that industry has had to deal with this issue for some time, and it might be of value to discuss the problem with companies that have had such experiences. Dr. Cassman suggested that this might be an issue for future discussion.

The first initiative discussed was in the broad area of biophysical tools, involving the development of collaborations to test the capabilities of 900 MHz Nuclear Magnetic Resonances (NMR). Dr. Janna Wehrle of the NIGMS Division of Cell Biology and Biophysics described some of the potential contributions arising from the availability of these instruments. They included structure determination of proteins in the 100,000 to 150,000 Da range; better assessment of macromolecular motions; the study of partially and fully unfolded proteins; and the structures of carbohydrates. Additionally, there is the ability to partially orient molecules, improve chemical shift dispersion, and improve signal-to-noise.

The proposal is to create scientifically based user groups, focused on NIGMS grantees, that will be largely applications-oriented. NIGMS anticipates perhaps two awards in the first year, for about $10 million total. The awards will include funds for staff support.

During the discussion, it was pointed out that the use of NMR in determining structural and dynamic characteristics of proteins is about 15 years old, and the ability to examine larger proteins has been increasing rapidly, especially over the past 3 years. These advances are partly due to advances in technology. It was felt that at this juncture, the new opportunities provided by the 900 MHz instrument should be integrated with other technologies through extended cross-disciplinary collaborations.

Another NMR technology that will have a major impact on the sensitivity of existing instruments was identified--cryoprobes. These are considerably cheaper than the 900 MHz instrument--about $200,000--and might be a good target for competitive supplements. However, it was also noted that the demand for these might be overwhelming. Dr. Cassman said that the possibility of issuing an announcement for a competitive supplement for cryoprobes would be considered.

The next set of topics addressed the chemistry/biology interface, with the first initiative "Metals in Medicine," presented by Dr. Peter Preusch of the NIGMS Division of Pharmacology, Physiology, and Biological Chemistry. This initiative emerged from an analysis that showed that, although NIGMS supports a great deal of research on metalloenzymes, it supports rather little work on metal metabolism and regulation or on the use of metals or metal complexes as probes in examining cell behavior. A June 28-29, 2000, meeting, titled " Metals in Medicine," was organized by NIGMS to consider this area. The intent was to look at obstacles and opportunities in developing pharmaceuticals using the tools and concepts of metallobiochemistry and to look at emerging areas of metal metabolism and the role of metals in regulating cell processes.

The Council discussion suggested a strong interest in developing the understanding of metals in cell biology and in bringing inorganic chemists into collaborations with biologists; however, there was considerably less interest in developing metallopharmaceuticals. A broad discussion ensued on the best way to encourage applications from the research community in areas of particular interest to the Institute. Additionally, there was encouragement for bringing in other institutes and agencies on initiatives with common interests.

A second initiative in the area chemistry/biology interface, "Centers of Excellence in Chemical Methodology and Library Development," was presented by Dr. John Schwab of the NIGMS Division of Pharmacology, Physiology, and Biological Chemistry.

The proposal is to support the development of chemical methodologies for creating, analyzing, and ensuring the quality of chemical diversity (i.e., combinatorial chemistry) libraries. This would extend the ability to do high-throughput functional screening, which has become a common approach for drug discovery and for the discovery of biological effector molecules. The development of these libraries involves a process whereby multiple compounds can be generated simultaneously by techniques that involve parallel chemical transformations. Effective library development requires the interaction of synthetic organic chemistry, polymer science, analytical chemistry, and perhaps even engineering, through approaches such as robotics. The intent is to support method development in diversity-oriented synthesis. The process would involve the establishment of centers, to provide focal points for the development of the collaborations noted above, as well as interactions with biologists. The estimated costs in the first year would be $4 million.

There was considerable disagreement and debate about the value of this proposal. Some of the participants felt that this approach would be better suited to industry, and that, in fact, industry was already heavily involved. Others felt that the effort would be entirely appropriate--that industry is not making any effort to develop the chemical methodologies required for the synthesis of complex compounds by high-throughput or combinatorial approaches. However, it was also believed that more funds are needed in this area and that closer linkages with biologists are required. Yet, others felt that the role of biologists in the centers was not particularly clear, while some members were not enthusiastic about the use of centers at all. There was also a sense that the end product of this effort was not clearly delineated.

The conclusion was that the proposal should be reformulated to focus on the basic research component, to clarify the role of biologists in a program targeted to developing chemical methodologies, and to reassess the mechanism by which this program should be supported.

The next initiative discussed was the development of a generic model organism database. Dr. Judith Greenberg of the NIGMS Division of Genetics and Developmental Biology began by reminding the Council members that NIGMS is the primary supporter of research with non-mammalian model organisms at NIH, and that the Institute has a significant responsibility to consider the genomic requirements of these communities. The existing databases appear to be meeting most of the needs of their respective communities. Nevertheless, some improvements are still needed, especially to make it easier for investigators to go back and forth between the databases. In addition, other model organism communities have been approaching NIH about wanting to develop their own databases, and it would be very inefficient for each of these groups to create a database de novo.

Recently, NIGMS and the National Human Genome Research Institute (NHGRI) convened a small meeting of the leaders of the existing databases to suggest ways for improving model-organism databases. The group described the existing databases as being constructed of several layers (a data storage layer, an exchange or middleware layer, a query and display layer, and an annotation layer), each comprised of modules. They felt that the most important things that NIH could do would be to support the improvement of existing modules and to create new and better modules. As better modules would be developed, the existing databases would adopt them, which would result in the eventual convergence of the different databases on an optimum structure. More importantly, groups wanting to create new model-organism databases would not have to start from scratch, but instead, could create one by picking and choosing among modules that would be available off the shelf. They would be able to concentrate on the biology and not on the software engineering of their databases. NIGMS is therefore proposing efforts to improve the modules used in the existing databases and to develop new modules. The idea is to make the modules more robust, with written documentation and consistent formats to facilitate searches and open source. The modules could be used to create new, generic model-organism databases.

Achieving these goals would involve two separate mechanisms. First, in cooperation with NHGRI, NIGMS proposes to fund competitive supplements to the existing databases. This would enable them to make the existing modules more robust and to write the documentation for them so they could be shared. Second, NIGMS proposes to issue an RFA (request for applications) to solicit competitive research project grants. The applicants for these grants would have to demonstrate a collaboration with one or more of the existing databases so that the project would really lead to the development of a useful module that could interact with and enhance an existing database, or that would lead to the creation of a generic database.

There was a great deal of enthusiasm for this initiative, particularly for its attempt to ensure that new databases would be structured on a well-tested and consistent model. There was also discussion on the need to develop and make accessible ontologies and on the need to generate databases that can capture data on interacting systems.

The next discussion was on a set of initiatives related to BISTI, the NIH Biomedical Information Science and Technology Initiative. Dr. James Cassatt of the NIGMS Division of Cell Biology and Biophysics began by presenting background on the development of BISTI, which emerged out of a report promoted by Dr. Harold Varmus, former NIH director. The recommendations of the report were considered by an internal NIH implementation committee. NIGMS is a participant in two NIH-wide announcements that emerged from this committee's work. The first is for planning grants to establish centers, and the other is for phased innovation grants in computational biology, which allow a small starter award to phase into a larger award without additional peer review, if milestones are met. Additionally, NIGMS has established individual postdoctoral training grants, as well as institutional predoctoral training programs in computational biology and bioinformatics. NIGMS now proposes to add to these an institutional postdoctoral training program. This would bring in Ph.D.s with either a biology or a computational science background and provide some didactic cross training together with lab work before committing to the research effort in computational biology. There was general agreement that this approach would be useful. There was some concern that higher salaries than the norm for NIH postdoctoral fellows would be needed to attract the right applicants

A second initiative discussed by Dr. Cassatt was a proposal for a joint announcement with the National Science Foundation Division of Mathematical Sciences to increase the involvement of mathematicians in research to address biological problems. Dr. Cassatt noted that NIGMS' previous efforts to encourage applications from mathematicians have not been very successful. Some of the discussants were skeptical that academic mathematicians would have a significant interest in biology, and that computer scientists, engineers, and applied mathematicians might be more likely targets. Nevertheless, there was general agreement about the value of this proposal and its potential to reach investigators with backgrounds in mathematics.

Dr. James Anderson of the NIGMS Division of Genetics and Developmental Biology presented the next two initiatives. The first would encourage the development of centers in computational biology and bioinformatics. Dr. Anderson gave a brief background on existing efforts to develop the areas of computational biology. He discussed the R01/P01 program, "Quantitative Approaches to the Analysis of Complex Biological Systems." Over the past 2 years, NIGMS received 27 applications and made 14 awards, for a current year total of about $3.5 million. A supplements program has generated 18 applications with seven awards, and a program to develop short courses yielded 10 applications and six awards.

The general objectives of the centers would be to encourage institutions to lower the barriers to interdisciplinary research in computational biology; to foster recruitment and training in biology of investigators with quantitative backgrounds; to act as a focus for disseminating knowledge in this area of science; and to stimulate undergraduate training in quantitative biology. The research goals are to discover the fundamental principles that govern the behavior of complex dynamical biological systems; to insure that theory is linked with experiment; and to develop tools for analysis of complex systems. Targets for research would include developmental programming, metabolic flux, signal transduction circuitry, and organ system networks, to name a few.

There was some concern that very few institutions would be prepared to respond in a mature way to such a proposal, and that money for recruitment and for construction of appropriate facilities would first be required. Dr. Cassman noted that planning grants were available, although probably not for construction and recruitment, and that a number of institutions had already expressed an interest in applying for such centers. It was also pointed out that NHGRI already issued an announcement requesting applications for centers in genomics and bioinformatics.

The final proposal in this group of BISTI-related initiative was an RFA to promote the development and analysis of model biological systems that would be amenable to quantitative modeling. An example is bacterial chemotaxis, where a great deal of information is available to begin in-depth modeling. Dr. Cassman pointed out that this initiative is a variant on existing NIGMS announcements and could be accomplished without a new program. However, it was being presented as yet another way to encourage proposals. There was general enthusiasm for all the BISTI-related initiatives.

The final group of initiatives related to health disparities. The first, "Differences in Response to Injury," was presented by Dr. Scott Somers of the NIGMS Division of Pharmacology, Physiology, and Biological Chemistry. Injury, in this context, is injury to he organism, and it is linked to the NIGMS program in trauma and burn injury. Dr. Somers gave a summary of the phases following injury, i.e., seconds to minutes, minutes to hours, and days following the event, and the problems attendant to each of these. A major consequence of trauma is the induction of inflammation. Although this is necessary for healing, it can also emerge as a systemic response, systemic inflammatory response syndrome (SIRS), which may be fatal. There are multiple regulatory points for SIRS and a number of known inflammatory mediators, some of which are known to exist as genetic polymorphisms. For example, an allele for tumor necrosis factor, a pro-inflammatory mediator, has been correlated with a relatively negative outcome following sepsis. Are there comparable genetic factors involved in response to injury, and can they be found to vary among populations or by gender? This initiative is focused on encouraging studies on the genetic regulation of the inflammatory response or other parts of the injury response. Although model systems are the most likely starting point, human studies are not ruled out.

Council discussion included concerns about the validity of animal studies for application to humans and some questions about the difficulty of dealing with human populations. These concerns will be considered before proceeding with this announcement.

The final initiative discussed involved supplements to the pharmacogenetics research network, to identify the genetic polymorphisms that can lead to variations in the response to medication, and to learn how these polymorphisms are distributed in different racial, ethnic, and geographic groups. This will be done in close collaboration with other efforts at NIGMS to establish appropriate interactions with populations that may be studied. The discussion raised the possibility of linking this effort to programs other than the pharmacogenetics program.

Dr. Cassman then asked for an en bloc concurrence with a motion to approve the initiatives presented. He noted that in the case of the "Metals in Medicine" and "Centers in Chemical Methodology" initiatives, there was significant disagreement among the discussants, and that these initiatives would be reformulated to address the concerns expressed. The motion for approval was moved, seconded, and concurred on by vote.

A general discussion followed. Topics included issues related to peer review, the need for stable support of technical personnel, the problems of obtaining data for in vivo analysis and modeling, and training of physicians in basic research. The latter topic raised many concerns, particularly about the career paths of clinician investigators. Dr. Cassman promised to raise the issue again at a later date.

Summary

• The initiative on "Metals in Medicine" will be reformulated based on the comments of Council. It will emphasize the need to understand the roles of metals in cellular regulation, the mechanisms by which organisms control metal ions, and the interactions of synthetic inorganic complexes with living systems. The results will be relevant to understanding the mechanisms of metal toxicity and the basic cellular roles underlying the nutritional requirement for essential metals. It is expected that this research will also contribute to the identification of new drug development targets, diagnostics, and future therapeutic approaches.
• The initiative on "Centers of Excellence in Chemical Methodology and Library Development" will be reconsidered in light of Council concerns. It will be presented at the next Council meeting in January 2001.
• The Institute will consider issuing a call for applications for competitive supplements for NMR cryoprobes.
• The Institute will consider initiating a discussion, together with representatives from academia and industry, to examine the problems of rewarding those who participate in large-scale research programs.
• The Institute will look into the question of career paths for physician-investigators. Since this has been a much-discussed topic within NIH, the first step will be to report on the discussions already held.

The National Advisory General Medical Sciences (NAGMS) Council was convened in closed session for its one-hundred and fourteenth meeting at 8:30 a.m. on Thursday, September 14, 2000, in Conference Rooms E1/E2, Natcher Conference Center, Building 45. Dr. Marvin Cassman, director of the National Institute of General Medical Sciences, presided as chairman. The meeting was open to the public on September 14 from 11:05 a.m. to 4:30 p.m. and was followed by the closed session for consideration of grant applications.

Council Members Present:

John N. Abelson, Ph.D.
Jay C. Dunlap, Ph.D.
Slayton A. Evans, Jr., Ph.D.
Lila M. Gierasch, Ph.D.
Wayne A. Hendrickson, Ph.D.
Leslie A. Leinwand, Ph.D.
Robert S. Pozos, Ph.D.
D. Amy Trainor, Ph.D.
Isiah M. Warner, Ph.D.
Richard M. Weinshilboum, M.D.

Members Absent:

Daniel J. Kevles, Ph.D.--not present September 13-15
Angeline A. Lazarus, M.D.--not present September 13-15
Leslie A. Leinwand, Ph.D.--not present on September 13
Neil S. Mandel, Ph.D.--not present September 13-15

Special Consultants Present on September 13:

Adam Arkin, Ph.D.
Professor
Lawrence Berkeley National Laboratory
Berkeley, CA

William Gelbart, Ph.D.
Professor
Department of Molecular Cellular Biology
Harvard University
Cambridge, MA

Hobart Harris, Ph.D.
Professor
Department of Surgery
San Francisco General Hospital
San Francisco, CA

Neville Kallenbach, Ph.D.
Professor
Department of Chemistry
New York University
New York, NY

John Kozarich, Ph.D.
Professor
Merck Research Laboratories
Rahway, NJ

Eaton Lattman, Ph.D.
Professor
Department of Biophysics
The Johns Hopkins University
Baltimore, MD

Douglas Lauffenburger, Ph.D.
Professor
Division of Bioengineering and Environmental Health
Massachusetts Institute of Technology
Boston, MA

James H. Prestegard, Ph.D.
Professor
Department of Chemistry and Biochemistry and Molecular Biology
University of Georgia
Athens, GA

Shirley Tilghman, Ph.D.
Professor
Department of Molecular Biology
Princeton University
Princeton, NJ

Thomas Tullius, Ph.D.
Professor
Department of Chemistry
Boston University
Boston, MA

Debra Schwinn, M.D.
Professor
Departments of Anesthesiology, Pharmacology/Cancer Biology, and Surgery
Duke University Medical Center
Durham, NC

Special Consultants Present on September 14:

Daniel Hartl, Ph.D.
Professor
Department of Organismic and Evolutionary Biology
Harvard University
Cambridge, MA

John W. Kozarich, Ph.D.
Professor
Merck & Company
Merck Research Labs
Rahway, NJ

Terry Orr-Weaver, Ph.D.
Professor
Massachusetts Institute of Technology
Department of Biology
Whitehead Institute
Cambridge, MA

Joel L. Sussman, Ph.D.
Professor
Department of Structural Biology
Weizmann Institute of Science
Rehovot, ISRAEL

Keith D. Watenpaugh, Ph.D.
Scientist
Retired
Coupeville, WA

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. Brigid Hogan, Vanderbilt Medical School
Dr. Howard Hiatt, Harvard Medical School
Dr. Charlotte Kuh, National Research Council
Ms. Luciana Lopez, FDC Reports
Ms. Pamela Moore, Capitol Publications
Dr. Georgia Persinos, Washington Insight
Mr. Brad Smith, American Chemical Society
Ms. Meredith Wadman, Nature

Federal Employees Present:

Dr. Dan Drell, Department of Energy
Dr. Janice Hicks, National Science Foundation
Dr. Debbie Stine, National Academy of Sciences
 

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 and introduced and welcomed the guests and the five ad hoc members: Dr. Daniel Hartl, professor, Department of Organismic and Evolutionary Biology, Harvard University; Dr. John Kozarich, professor, Merck and Company; Dr. Terry Orr-Weaver, professor, Department of Biology, Massachusetts Institute of Technology; Dr. Joel Sussman, professor, Department of Structural Biology, Weizmann Institute of Science; and Dr. Keith Watenpaugh, recently retired from his position as a distinguished scientist, Pharmacia and Upjohn Incorporated.

Dr. Cassman thanked two NAGMS Council members who completed their terms of service with the September meeting: Dr. Slayton Evans and Dr. Wayne Hendrickson. Dr. Cassman announced that the new Council slate was approved, and that in January, the Council would be welcoming five new members. They are: Dr. Eaton Lattman, professor and chair of the Department of Biophysics, Johns Hopkins University; Dr. Susan Taylor, professor, University of California, San Diego, and Howard Hughes investigator; Dr. Douglas Lauffenburger, professor, Massachusetts Institute of Technology, and co-Director of the Division of Bioengineering; Dr. Debra Schwinn, professor of Anesthesiology and Pharmacology, Duke Medical School; and Dr. George Hill, professor of microbiology, Meharry Medical College. Dr. Cassman noted that NIGMS would be adding two new positions to Council, one to cover bioengineering and bioinformatics, and one in clinical research related to the Institute's primary programs in anesthesiology and trauma and burn research.

Dr. Larry Tabak, from the University of Rochester, is the new director of the National Institute of Dental and Craniofacial Research, replacing Dr. Harold Slavkin.

Dr. Carl Kupfer, who was director of the National Eye Institute for the past 30 years, has retired.

Ms. Naomi Churchill, who was the director of the NIH Office of Equal Opportunity, has left NIH. Dr. Cassman encouraged attendees to consider colleagues and others who might assume this role at NIH.

Dr. Cassman introduced Joe Ellis, the new grants management officer, who comes to NIGMS from the National Institute on Aging.

Dr. Cassman then mentioned some awards NIGMS Council members have recently received:

• Dr. Richard Weinshilboum received the 2000 Henry W. Elliot Award for Distinguished Service from the American Society for Clinical Pharmacology and Therapeutics.
• Dr. Isiah Warner received the Louisiana State University Distinguished Faculty Award and was named the Boyd Professor at Louisiana State University.

II. Consideration of Minutes

The minutes of the May 18-19, 2000 meeting were approved as submitted.

The minutes of the January 27-28, 2000 meeting were approved as submitted.

III. Future Meeting Dates

The following dates for future Council meetings were confirmed: