The National Advisory General Medical Sciences (NAGMS) Council was convened in closed session for its one-hundred and fifteenth meeting at 8:30 a.m. on Thursday, January 25, 2001, 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 January 25 from 11:00 a.m. to 4:30 p.m. and was followed by the closed session for consideration of grant applications.
John N. Abelson, Ph.D.Jay C. Dunlap, Ph.D.Lila M. Gierasch, Ph.D.George C. Hill, Ph.D.Daniel J. Kevles, 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.
Angeline A. Lazarus, M.D.Neil S. Mandel, Ph.D.
Michael P. Doyle, Ph.D.Vice PresidentResearch CorporationTucson, AZ
M. Anne Spence, Ph.D.ProfessorDepartment of PediatricsDivision of Human GeneticsUniversity of California, IrvineMedical CenterOrange, CA
Virginia A. Zakian, Ph.D.ProfessorDepartment of Molecular BiologyPrinceton UniversityLewis Thomas LabsPrinceton, NJ
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).
T.S. Dunlap, JT x CODr. Rachel Lindsey, Chicago State UniversityMs. Pamela Moore, Capitol PublicationsMr. Brad Smith, American Chemical SocietyDr. Sylvia Smith, Florida International UniversityDr. Reuben Wright, Prairie View A&M University
Dr. Philip Harriman, National Science FoundationDr. Linda Hyman, National Science FoundationDr. Sylvia Spengler, National Science Foundation
National Institute of General Medical Sciences employees and other NIH employees:
Please see the sign-in sheet (available from NIGMS).
Dr. Cassman called the meeting to order and introduced and welcomed the five new members of Council: Dr. George Hill, professor of microbiology, Meharry Medical College; Dr. Eaton Lattman, professor and chair, Department of Biophysics, The Johns Hopkins University; Dr. Douglas Lauffenburger, professor and co-director, Division of Bioengineering, Massachusetts Institute of Technology; Dr. Debra Schwinn, professor of anesthesiology and pharmacology, Duke University Medical School; and Dr. Susan Taylor, professor, University of California, San Diego, and Howard Hughes Medical Institute investigator. Dr. Cassman also introduced the guests and three ad hoc members: Dr. Michael Doyle, vice president, Research Corporation; Dr. M. Anne Spence, professor, Department of Pediatrics, Division of Human Genetics, University of California, Irvine, Medical Center; and Dr. Virginia Zakian, professor, Department of Molecular Biology, Princeton University.
Dr. Cassman then mentioned some awards NIGMS Council members had recently received:
The minutes of the September 13-15, 2000 meeting were approved as submitted.
The following dates for future Council meetings were confirmed:
May 17-18, 2001
September 13-14, 2001
January 24-25, 2002
May 9-10, 2002
September 12-13, 2002
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.
Dr. Cassman asked for approval of a change in the Council operating procedures. He suggested that NIGMS staff be allowed, without Council concurrence, to increase the length of funding for new investigators by 1 year beyond the study section recommendations to a maximum of 5 years beyond the study section recommendations. This is consistent with other Institute policies and would save time for both NIGMS staff and Council members. He also requested approval to raise the limit of direct costs on P01 and Center grants from $4.5 million over 5 years to $5.5 million over 5 years. The limit had not been raised in 4 to 5 years, warranting an increase. Both recommendations were approved by Council.
Dr. Cassman then described the budget for FY 01. He pointed out that NIGMS received an increase of $182 million (13.5 percent), for a total budget of $1.54 billion. Of the increase, approximately $100 million is required to support commitments and $10 million pays for increases in predoctoral training, including increases that will bring stipend levels to $16,500. There are also significant increases in support for the minority programs, as well as for research centers. The latter is due to the funding of structural genomics and "glue grant" proposals.
Dr. Cassman warned that, although the success rate will remain at a level well over 30 percent, there will be significant reductions below requested costs. This is because new applications have asked for amounts averaging 30 percent over last year's levels, and competing renewals have asked for increases averaging 20 percent. These cannot be accommodated without severely affecting NIGMS' ability to support an adequate number of outstanding proposals. The Institute plans to provide increases in the range of 5 to 7 percent. The result will be an overall increase in average costs of over 25 percent since 1998.
Dr. Cassman provided an analysis of the recently released NAS report, "Addressing the Nation's Changing Needs for Biomedical and Behavioral Scientists." He began by noting that the recommendations of the report addressing the needs in the clinical sciences and the need to recruit more underrepresented minorities were essentially identical with NIH initiatives and needed no further discussion, as were most of the recommendations regarding training in the behavioral sciences. The recommendations in the remainder of the report reflect from the assumption that "the number of new Ph.D.s awarded annually in the basic biomedical sciences is well above that needed." The report then continues by stating that "NIH and other Federal sponsors of research training should consider options to assist graduate departments in restricting overall expansion of Ph.D. programs," and that NIH should "consolidate its oversight of research training and training-related activities."
This somewhat ambiguous statement simply means that NIH should control the numbers of graduate students on research grants just as it now controls the numbers on training grants. The NAS report points out that between 1975 (the initiation of the National Research Service Awards) and 1997, the percentage of graduate students on training grants went from about 60 percent of the graduate students in biomedical Ph.D. programs to about 30 percent, while the percentage receiving funds through NIH research grants had almost doubled.
The difficulty is that this change, which is described as "inadvertent," has, in the NAS' opinion, led to an outcome contrary to that intended by Congress, i.e., "the number of students and postdoctorates provided research training through NRSA training grants and fellowships has been deliberately limited over much of the last 25 years to ensure that the supply of investigators trained through the program would not exceed what the research enterprise could absorb."
The NAS report's argument then is as follows:
The report then makes two recommendations:
The report does acknowledge that "Given the central role that graduate students and postdoctorates play in the conduct of basic biomedical research, however, a decrease in Ph.D. production could delay or disrupt research progress." NAS suggests that NIH address this by considering other ways to meet the ongoing demand for research support staff.
In short, the report recommends that NIH actively control the numbers of Ph.D.s through limiting the numbers on research grants--something NIH has never done.
There is a second set of linked but separate issues related to training of foreign students. The concerns still relate to issues of employment, stemming from the observation that "In the basic biomedical sciences, temporary visa holders account for more than 40 percent of the increase in the total number of Ph.D.s awarded since 1975. Moreover, many of these temporary visa holders who earn Ph.D.s in the United States remain in the country after completing their studies."
The NAS report's argument again seems to be that the reason for supporting foreign students is just for research staff, rather than to train principal investigators. From these concerns, the NAS report offered the following recommendation: NIH and other Federal science agencies that support research training should articulate clear goals regarding the education of foreign scientists and should modify their grants policies where necessary."
Again, the NAS argument can be read:
Dr. Cassman pointed out that there are several problems with this assessment. First, there is the question of how well one can project workforce needs in the future. A second issue is how deeply NIH should be involved in actively controlling the workforce. Additionally, the report assumes that NIH funding alone, or lack of it, can redress the situation. All of the statistics indicate that NIH supports, at any point in time, less than half of the graduate students in the biomedical sciences. But perhaps more importantly, the report implies, and sometimes directly states, that the primary goal for recruiting students on a grant is as labor, and that if alternative labor were provided, there would be a diminishing demand for graduate students. This ignores the culture of science in the United States. States want more graduate students trained because it is seen as ultimately contributing to local economies. (As witness, see the recent statement by the provost of the University of California system that they plan an increase of 11,000 graduate students in the next decade.) Universities want graduate students because their mission is not only the production of knowledge, but the production of education. Faculties want graduate students because they are energetic and enthusiastic, and they bring new ideas to the laboratory. Just providing an alternative workforce to the research environment will not do away with these driving forces for recruiting students.
With regard to foreign students, there are many reasons why they are recruited, including the fact that in certain areas of science, particularly those that are mathematically oriented, as a group, foreign nationals seem to be better trained. Finally, the issue is not and should not be education, but employment. We as a nation derive many benefits from training foreign nationals, and they and their nations derive many benefits from the training. If there is a problem with employment, this is a broader issue and should not be an NIH responsibility.
Finally, training grants and research grants have different goals, and the oversight and responsibilities attached to each are quite different. Further, the argument for training grants has changed since their initiation. They are no longer primarily for the purpose of addressing a shortage in numbers, but rather for increasing the quality of the training and the trainees. Consequently, the idea of using training grants to control numbers does not reflect reality. NIH does not support the majority of graduate students in the research system through training grants, nor would it if it could. The low numbers of trainees in these programs is not to control the production of Ph.D.s, but to reward and stimulate certain kinds of behavior, primarily interdisciplinary training, by funding only the best.
Additionally, research grants are not designed as training vehicles, but as research support. As a result, NIH does not make any demands as to how the labor force is constructed on these grants. The investigators get money sufficient to provide for their needs (more or less) with little restrictions on how it is to be used. Changing this to control numbers of graduate personnel would require major changes in the way the grants are reviewed, awarded, and tracked.
In summary, the support of students on research grants is a byproduct of the fact that most of the research, certainly the basic research, conducted in this country is located in universities. This research is tightly coupled to the educational mission of the universities, and student involvement in the research is considered an essential part of the apprenticeship that is central to research training. Since NIH is the primary funder of this research, student involvement is common on the grants that provide support for the research. However, these grants have always been flexible in the way the money can be used, and in recent years have become more so. To control the numbers of graduate students on research grants would require a degree of micromanagement that has been avoided by NIH. It is possible, of course, but not feasible without a major change in the way NIH interacts with its grantees.
Dr. Rochelle Long of the NIGMS Division of Pharmacology, Physiology, and Biological Chemistry reported on a meeting of the NIGMS Industry Liaison Group. This group will promote a dialogue between the recently formed Pharmacogenetics Research Network and Knowledge Base (PharmGKB) and members of the pharmaceutical industry. On January 11, 2001, the Industry Liaison Group met with the Pharmacogenetics Research Network Executive Committee to identify current and future areas of shared interest and complementary goals. The attendees concluded that the pharmaceutical industry will likely have an interest in using the PharmGKB. However, depositing data into the PharmGKB immediately is not compatible with industry goals, thus demonstrating the need for a public database. Nevertheless, the meeting participants identified common areas of high priority. These areas included: 1) educating the public about the potential value of pharmacogenetics research; 2) sharing expertise in pre-competitive areas (e.g., nomenclature, analytic tools, ethics); and 3) continuing individual research collaborations in areas of mutual scientific interest. Specific topics discussed and identified for follow-up were sharing common standards for terminology used in protocol designs, exchanging language used in informed consents, and emphasizing the protection of patient confidentiality. The meeting participants recommended further coordination and exchange. A roster of the group members and a summary of the meeting are posted on the NIGMS Web site at Pharmacogenetics Research Network.
Dr. Judith Greenberg of the NIGMS Division of Genetics and Developmental Biology reported on a meeting that took place on September 25-26, 2000. NIGMS, with support from several others components of NIH and other Federal agencies, sponsored a meeting called the First Community Consultation on the Responsible Collection and Use of Samples for Genetic Research. Dr. Greenberg briefly described the meeting, particularly the recommendations that came out of it, and presented a number of activities that are under way as a result of these recommendations.
The impetus for the meeting was an issue raised in relation to the NIGMS Human Genetic Cell Repository. Among the samples in the repository are some that are there, not because they are from individuals with genetic disorders, but because they are from essentially normal individuals who are members of identified populations. Even though the identity of the individuals is not known, these samples raise concerns because of the possibility of stigmatization, discrimination, and other kinds of group harm to the population from whom these samples came. On the other hand, samples from identified communities are very valuable for studying genetic variation. In fact, researchers have been asking the repository to make samples available from more populations. In July 1999, NIGMS held a small meeting--co-chaired by Dr. M. Anne Spence -- that endorsed the scientific importance of collecting samples from identified populations, but recommended that further discussions take place with communities. The September community consultation was designed to do just this.
The community consultation brought together lay people from diverse ethnic and racial communities, as well as some scientists and NIH staff. Discussions very quickly moved beyond issues of tissue samples to more general issues having to do with participation in genetic research, as well as in research in general. The participants expressed considerable frustration and skepticism about the research process and about NIH. In general, they expressed a large number of concerns, but it also became clear they often don't have a good understanding about genetic research. To distill the ten recommendations that are in the report to their most basic form, communities want three things:
The meeting ended with the participants feeling that indeed NIH had listened to them. The expectations of the participants were very high that NIH would begin to address their concerns. Dr. Greenberg then presented some of the activities that NIH has undertaken to follow up on their recommendations.
First, NIGMS has developed a very detailed policy that has been adopted by the repository for the responsible collection, storage, and research use of samples from identified populations. This policy is posted both on the repository's Web site and on the NIGMS Web site at http://www.nigms.nih.gov/Research/SpecificAreas/HGCR/Reports/Pages/default.aspx.
Second, as a result of the community consultation, members of the Native American community approached the Institute about the possibility of sponsoring a workshop. The goal is for them to begin to develop standard approaches to be used by researchers who wish to involve Native American and Alaska Native tribes in genetic research projects. These approaches would appropriately recognize the sovereign status of the tribes. NIGMS and the National Human Genome Research Institute, with the help of the Indian Health Service, are co-funding a small workshop that will be held in February. This is a very important outcome of the community consultation meeting because it reflects a certain level of trust by Native Americans in NIH.
Third, at the community consultation meeting, some of the Hispanic participants felt that they could not adequately represent the views of the very diverse Hispanic and Latino communities. In response, NIGMS is working with them to organize a national meeting to address a wide range of genetic issues of particular concern to the Hispanic community.
And finally, perhaps the hardest task is working with our colleagues in other NIH institutes to come up with ideas to promote greater community involvement in genetic research. To this end, Dr. Greenberg is chairing a new trans-NIH working group.
As many know, NIGMS does take its commitment to involving communities in research seriously. For example, the NIGMS Pharmacogenetics Research Network established the Populations Advisory Group that was described by Dr. Rochelle Long at a previous Council meeting. Also, NIGMS has a small but growing portfolio of grants that study the ethical, legal, and social issues related to its research interests.
It is still too early to know whether the rest of NIH will buy into the recommendations that emerged from the community consultation. Some of the recommendations are as follows:
There are many reasons that NIH should promote more community involvement:
Dr. John Norvell of the NIGMS Division of Cell Biology and Biophysics reported on the NIGMS Protein Structure Initiative (PSI), which began in 1999 with the goal of developing a national program to support structural genomics. This emerging field features high-throughput structural determination of representative members of most protein families in nature. Taking advantage of genomic sequence data and both computational and experimental technology developments, the PSI will lead to a new public resource of protein structures. This new initiative, which resulted in part from recommendations made at three NIGMS-sponsored workshops, is designed to organize a cooperative, large-scale effort in this emergent field. The initiative is composed of two components. The NIGMS structural genomics request for applications (RFA) announced a support program for research centers, each involving all the experimental and computational tasks of structural genomics. These research centers will test strategies for high-throughput operations and will serve as pilots for large-scale research networks of the future. The Institute funded seven research centers in September 2000, each costing about $4 million annually. The RFA has recently been reannounced for 2001. The NIGMS structural genomics program announcements (PA) are designed to encourage methodology and technology development in this field. This support will be provided through individual research grants, program project grants, and small business innovation research grants. Background information, summaries of the workshops, and the RFA and PAs can be found on the NIGMS Web site at Protein Structure Initiative .
Dr. Norvell also described international aspects of structural genomics. He first summarized industrial efforts in high-throughput crystallography and structural genomics and then listed public programs underway in numerous countries, including the United States, the United Kingdom, France, Germany, Italy, Japan, and Canada. In April 2000, NIGMS and the Wellcome Trust, a U.K.-based medical research charity, cosponsored the first international structural genomics meeting near Cambridge, U.K., to discuss worldwide cooperation. The list of issues discussed by the participants included the goals of the effort; necessary resources and infrastructure; cooperation with industry; and policies on data release and deposition, publication, and intellectual property. A Structural Genomics Informatics Task Force with five subgroups was formed to examine these various issues and to prepare reports. The task force and its subgroups met in November 2000 during the recent international structural genomics conference in Yokohama, Japan. Members from each subgroup discussed the definitions and problems for each of the issues, as well as the different viewpoints of various stakeholders, and possible conclusions. NIGMS is currently organizing a second international meeting on April 4-6, 2001, in nearby Virginia. The Wellcome Trust and RIKEN of Japan are co-sponsoring the meeting. At this meeting, the task force will discuss the subgroups' reports as well as other scientific issues facing this field.
Dr. John Schwab of the NIGMS Division of Pharmacology, Physiology, and Biological Chemistry reported on a proposed initiative at the chemistry/biology interface, "Centers of Excellence in Chemical Methodology and Library Development." This initiative was originally discussed at the September 2000 Council meeting. At that time, Council recommended that the initiative be revised to address Council concerns and discussed once more at the January 2001 meeting.
The proposed initiative would 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 application of synthetic organic chemistry, polymer science, analytical chemistry, and perhaps even engineering disciplines (e.g., for robotically controlled sample delivery). The intent is to support method development through the establishment of collaborative, multi-investigator centers. A key modification to the proposed initiative (from what was proposed in September 2000) is that each center would be required to establish a core facility for library synthesis. The purpose of this core would be to optimize and validate new methodologies for combinatorial chemistry applications and to further validate these methodologies by designing and producing libraries for biological screening. The library synthesis core would provide a focal point for chemistry-biology collaborations. The estimated costs in the first year would be $10 million.
Dr. Schwab noted that much of the discussion at the September 2000 Council meeting concerned whether there was a genuine need for more methods for combinatorial chemistry as well as a rather vague delineation of the roles of chemists and biologists in the proposed centers. He indicated that the latter point has been addressed by the requirement for the library synthesis core, which will provide a point of contact to the biology research community and allow each center's methods development research to focus on chemistry and not biological applications. The need for more and better methods is supported by the fact that few "off-the-shelf" methods have been found to work well for combinatorial chemistry; industry dedicates little time and effort to the development of new methods; and academic chemists have tended not to embrace combinatorial chemistry methods development.
The modified initiative was enthusiastically received and approved.
X. Perspectives on Modeling and Analysis of Complex Biological Systems
Dr. Douglas Lauffenburger gave a presentation on experimental and theoretical approaches to the understanding of complex biological systems. The behavior of biological systems is difficult to predict because they may have a large number of components with multiple interactions and operate over multiple space or time scales. The goal of theoretical analysis and computational modeling of biological systems is to both understand them (reverse engineer) and manipulate them (forward engineer). Dr. Lauffenburger discussed examples of approaches to complex systems, including cancer, metabolism, asthma, inflammation, the EGF receptor, and autocrine loop responses.
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.
A summary of applications reviewed by Council is attached (available from NIGMS).
The meeting adjourned at 12:00 p.m. on Friday, January 25, 2001.
I hereby certify that the foregoing minutes are accurate and complete to my knowledge.
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