Advisory Council Minutes, May 18-19, 2000

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, May 18, 2000, 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 May 18 from 11:05 a.m. to 5:00 p.m. and was followed by the closed session for consideration of grant applications.

Members Present:

John N. Abelson, Ph.D.
Jay C. Dunlap, Ph.D.
Lila M. Gierasch, Ph.D.
Wayne A. Hendrickson, Ph.D.
Angeline A. Lazarus, M.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:

Slayton A. Evans, Jr., Ph.D.
Daniel J. Kevles, Ph.D.
Neil S. Mandel, Ph.D.

Special Consultants Present:

Carlos J. Bustamante, Ph.D.
Department of Molecular and Cell Biology
University of California, Berkeley
Berkeley, CA

Robert D. Goldman, Ph.D.
Department of Cell and Molecular Biology
Northwestern University Medical School
Chicago, IL

Barbara J. Meyer, Ph.D.
Department of Cell and Molecular Biology
University of California, Berkeley
Berkeley, CA

Christian Raetz, Ph.D.
Department of Biochemistry
Duke University Medical Center
Durham, NC

Daniel Romo, Ph.D.
Associate Professor
Department of Chemistry
Texas A&M University
College of Science
College Station, TX

Debra A. Schwinn, M.D.
Department of Anesthesiology
Duke University Medical Center
Durham, NC

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:

Ms. Luciana Lopez, FDC Reports
Ms. Pamela Moore, Capitol Publications
Dr. Georgia Persinos, Washington Insight
Mr. Brad Smith, American Chemical Society

Federal Employees Present:

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).


I. Call to Order and Opening Remarks

Dr. Cassman called the meeting to order and introduced and welcomed the guests and the six ad hoc members: Dr. Carlos Bustamante, professor, Department of Molecular and Cell Biology, University of California, Berkeley; Dr. Robert Goldman, professor, Department of Cell and Molecular Biology, Northwestern University Medical School; Dr. Barbara Meyer, professor, Department of Molecular and Cell Biology, University of California, Berkeley; Dr. Christian Raetz, professor, Department of Biochemistry, Duke University Medical Center; Dr. Daniel Romo, associate professor, Department of Chemistry, Texas A&M University; and Dr. Debra Schwinn, professor, Department of Anesthesiology, Duke University Medical Center.

Carol Tippery, a grants management officer in the NIGMS Division of Extramural Activities, has left the Institute to take a position in the Office of the Director, NIH.

Dr. Irene Glowinski, a scientific review administrator in the NIGMS Office of Scientific Review has left the Institute to take a position at the National Institute of Allergy and Infectious Diseases.

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

  • Dr. Isiah Warner has been named the recipient of the Eastern Analytical Symposium Award for Outstanding Achievements in the Fields of Analytical Chemistry.
  • Dr. Richard Weinshilboum received the 2000 Henry W. Elliot Award for distinguished service from the American Society for Clinical Pharmacology and Therapeutics.
  • Dr. Barbara Meyer, an ad hoc member, was recently appointed to the National Academy of Sciences.

Jennifer Doudna, an NIGMS grantee, has received the National Science Foundation's Alan T. Waterman Award to young researchers. She is the 25th recipient and the third woman to receive this award.

II. Consideration of Minutes

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:

September 13-14, 2000
January 25-26, 2001
May 17-18, 2001
September 13-14, 2001
January 24-25, 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.

IV. Report From the Director, NIGMS: Status of Appropriations and Other Matters

Dr. Cassman briefly commented on the progress of the FY 2001 budget. He noted that the Senate Appropriations Committee had agreed to an increase of 14.8 percent, $200 million, for NIGMS. Although the House Appropriations Subcommittee deliberations were somewhat more complicated, they had also expressed an intention to provide a similar increase. Dr. Cassman indicated that this was a very good beginning to the budget process, although there is still a long way to go.

Dr. Cassman then summarized recent activities in structural genomics. He reminded Council that the applications for pilot projects in this area would be considered at the September Council meeting. Structural genomics has been getting increasing attention worldwide. There was a meeting on April 4-6, 2000, in the United Kingdom that gathered many of the investigators interested in this area. It was co-sponsored by NIGMS and the Wellcome Trust, with an attendance of about 50. The discussion generated a consensus document that defined the intent of the international structural genomics effort and described a set of questions in areas such as informatics, data release, and intellectual property. Task forces will be assembled to report at the next international meeting to be held April 4-6, 2001, at the Airlie Center in Virginia. Dr. Cassman also mentioned another international meeting on structural genomics, sponsored by the Organization for Economic Cooperation and Development, to be held in Florence, Italy, in June 2000. He stated that he and several other NIGMS staff had been invited to attend.

Finally, Dr. Cassman concluded by reminding Council of two meetings that the Institute would be sponsoring: "Metals in Medicine: Targets, Diagnostics, and Therapeutics," June 28-29, 2000, and "Community Involvement for the Responsible Collection and Use of Samples for Genetic Research," September 25-26, 2000.

V. Pharmacogenetics Steering Committee

Dr. Rochelle Long of the NIGMS Division of Pharmacology, Physiology, and Biological Chemistry described the Pharmacogenetics Research Network and Knowledge Base awards. The awards began on April 1, 2000 (for more information, see the news release on the NIGMS Web site at, and the first meeting of the steering committee took place on May 15-16, 2000. The steering committee established four subcommittees to develop policies for the network, including a human subjects subcommittee, an intellectual property and technology subcommittee, a communications subcommittee, and a knowledge base subcommittee. The network members agreed to work together to develop and support the PharmGKB, a repository for pharmacogenetics information designed to serve as a resource for all investigators and as a foundation for future hypothesis-driven research. Dr. Richard Weinshilboum commented that this is an example of a paradigm-shift taking place in the way that research is conducted and the way results are shared among the scientific community. It was noted that there are significant intellectual property issues, as well as ethical and social issues, being addressed by the network as this new paradigm is being established. Council members commented that this is an excellent chance to interface with the pharmaceutical industry to learn of mutually complementary opportunities to move the field of pharmacogenetics forward. This is a trans-NIH initiative with participation from NIGMS, the National Heart, Lung, and Blood Institute, the National Cancer Institute, the National Human Genome Research Institute, the National Library of Medicine, and the National Institute of Environmental Health Sciences.

VI. Supplements for Funding Microarrays

Dr. Laurie Tompkins of the NIGMS Division of Genetics and Developmental Biology requested concept clearance for an administrative supplement program for microarray resources. The purpose of the supplement program is to enable principal investigators (PIs) who will not be submitting competing renewals in the near future to obtain resources for DNA microarray analysis that is directly related to the aims of the parent grant. The supplement program will be a one-time solicitation with a single receipt date, tentatively set for October 1, 2000. NIGMS-funded PIs will be able to request up to $50,000 for equipment, supplies, and part-time personnel (e.g., statistical consultants); requests that are solely for personnel will not be considered. Supplement requests will be reviewed by NIGMS staff, with consultation from appropriate outside reviewers, if necessary. NIGMS intends to commit up to $5 million to the microarray supplement program in FY 2001; the Institute anticipates funding 60 to 70 supplement requests. Based on the experiences of other NIH institutes that have offered supplements for microarray analysis, NIGMS expects to receive more requests for supplements than it is able to fund.

In response to questions from Council, Dr. Tompkins agreed that $50,000 is not sufficient to pay for all of the equipment that a PI would need to do microarray analysis. Although other institutes at NIH have funded centers for microarray analysis, NIGMS has decided not to fund centers, since unsolicited supplement requests from NIGMS-funded PIs are typically for one piece of equipment or for a set of microarray chips. This implies that the PIs already have access to some or all of the equipment that they need. Dr. Tompkins also noted that groups of NIGMS-funded PIs can apply for supplements to purchase equipment that they will share, and that institutional cost sharing will be encouraged. In response to other Council questions, Dr. Tompkins told Council that a PI whose only NIGMS support was a training grant would not be eligible for a supplement, and that administrative supplement requests that are recommended for funding would not have to be approved by Council.

At the end of the presentation and discussion, Council members expressed support for the administrative supplement program.

VII. High-Risk/High-Payoff Grants

Dr. James Anderson of the NIGMS Division of Genetics and Developmental Biology summarized a report distributed to the Council members outlining the findings of a staff committee that reviewed the high-risk/high-payoff program. The review, which was stipulated by Council at the time the program was authorized in September 1996, focused on outcomes as defined by the overall objective of promoting exploration of novel ideas. To date, 337 applications have been received, with an overall success rate of 26 percent. The program appears to have stabilized at approximately 20 applications per Council round, with an expected continuing expenditure of $3.4 million per year. Staff who administer these awards were polled on their views on how the proposals were reviewed, the adherence of the proposals to program objectives of risk and impact, and the specific accomplishments of the research to date. Although the program is still quite new, with most of the awards made thus far still in their 2-year term, there was majority agreement that the program is fulfilling expectations. Some specific accomplishments were singled out as of particular high impact. Council agreed with the recommendation that the program be continued. Some concerns that surfaced in the staff evaluations, particularly emphasizing the high-risk/high-impact criteria to applicants and reviewers, will be addressed in the reannouncement of the program.

VIII. Bridges Update

Dr. Irene Eckstrand of the NIGMS Division of Minority Opportunities in Research summarized the mission of the Bridges to the Future Program. The Bridges to the Future Program is to make available to the biomedical science research enterprise and to the nation the intellectual talents of an increasing number of underrepresented minority group members. It does so by facilitating the transition of students from associate to baccalaureate degree-granting institutions and from master's to doctoral degree-granting institutions. The program promotes effective inter-institutional partnerships that lead to improvement in the quality and quantity of underrepresented minority students being trained as the next generation of scientists.

Jointly funded by the Office of Research on Minority Health and NIGMS since 1993, the Bridges Program has grown from 30 to nearly 90 programs, involving 378 institutions. One of the key features of the Bridges Program is its online database, E-STAR, which enables staff to track Bridges students through their educational and career paths. It is also an excellent tool for program evaluation and planning. E-STAR data show that:

  • After 5 years, 70 percent of all baccalaureate Bridges students have transferred to a 4-year institution (nationally, 26 percent of all community college students transfer to a 4-year program);
  • Of the baccalaureate Bridges students who transfer, 45 percent complete the 4-year degree;
  • After 5 years, 57 percent of doctoral Bridges students have transferred to a Ph.D. program;
  • Of these students, about 60 percent have obtained or are still seeking an advanced degree.

In September 1999, NIGMS convened a working group to create a program-planning document, which describes the following goals for the Bridges Program:

  • Increase the number of underrepresented minority biomedical scientists.
  • Improve the ability of educational institutions to train and graduate underrepresented minority students in the biomedical sciences.
  • Develop partnerships that support and facilitate underrepresented minority student transfers at key points in the educational pipeline.

Specific objectives and measures of success are included in a report titled "Planning and Priorities of the Bridges to the Future Program," which is available on the NIGMS Web site at: The report ends with a vision of the future for the Bridges Program.

The Bridges to the Future Program is one piece of a larger mosaic of programs at NIH that are designed to increase the number of underrepresented minority scientists engaged in research and to improve the health of minority communities. The Bridges to the Future Program is becoming increasingly important in addressing the problem of under-representation of minorities in the sciences. The success of the program depends on its ability to set ambitious but reasonable goals and to measure its progress toward achieving these goals. Ultimately, the program will succeed when, as a result of its interventions, students who would have received terminal predoctoral degrees see new opportunities for careers as scientists, and their ambitions are supported by the highest possible quality of education and training.

IX. MARC Predoctoral Fellowship Program Report

Dr. Hinda Zlotnik of the NIGMS Division of Minority Opportunities in Research reported on the Minority Access to Research Careers (MARC) Predoctoral Fellowship Program. Since its initiation in 1981, the major aim of the MARC Predoctoral Fellowship Program has been to identify and support the doctoral preparation of former MARC undergraduate trainees who wish to pursue careers in biomedical and behavioral research. To assess the extent to which the program has been achieving its goals, the NIGMS Office of Program Analysis and Evaluation compiled and analyzed available information on 129 fellows who received MARC predoctoral support between the years of 1981 and 1993. A broad set of indicators were examined to assess the fellows' accomplishments in the following areas: (1) educational attainment, including the time elapsed from the receipt of the baccalaureate degree to completion of the Ph.D.; (2) postdoctoral training support from NIH and other sources; (3) research-related employment; (4) application for, and award of, NIH research grants; (5) research support from non-NIH sources; and (6) research productivity as defined by publications in peer-reviewed journals. Overall, the results of this study showed a favorable achievement pattern for former MARC predoctoral fellows that is consistent over three cohorts. Further, the data obtained parallels the results in previous evaluations of National Research Service Award trainees and fellows. Even though these results should not be generalized because of the small sample size, they do suggest that the potential for individuals supported by MARC predoctoral fellowships for pursuing active careers in research is very good. This report is available on the NIGMS Web site at

X. Report From the Acting Director, NIH

Dr. Cassman welcomed Dr. Ruth Kirschstein, acting director of NIH, to the Council meeting. Dr. Kirschstein explained that she has been visiting with all of the institutes' advisory councils in order to share her views on a number of developments and issues of importance to NIH. She began by describing the gratifying reception the institutes had received at both the House and Senate Appropriations Subcommittee hearings for the FY 2001 budget. She reported that the hearings in the House had focused on NIH building a strong, detailed explanation of the research made possible by the past years' sizable budget increases. In addition, Congressman Jesse Jackson, Jr., made a point of challenging the institutes to better address the health disparities present in the country and to more aggressively prepare underrepresented minorities to engage in biomedical research. Subsequent to the hearings, discussions Dr. Kirschstein has had with members of the Black and Hispanic caucuses have echoed Rep. Jackson's concerns.(Dr. Kirschstein noted that she was pleased that Dr. Anthony Fauci would be briefing Council on NIH's plans to address health disparities.) Dr. Kirschstein said that the Senate hearing had focused on a number of issues, including stem cell research, fetal tissue research, and the relationships between the private sector and the Human Genome Project. Dr. Kirschstein said that she was encouraged by the early actions by both the House and Senate subcommittees regarding the FY 2001 appropriation levels, which indicate a continuing commitment to annual increases of 15 percent. She expressed the view that action on the FY 2001 appropriation might come very late, perhaps even after October 1.

Dr. Kirschstein then explained that she and others at NIH are devoting a great deal of time to addressing several concerns regarding the proper conduct of research. Foremost among these is how NIH might better ensure that clinical research, including gene therapy research, is conducted according to the highest ethical standards, and that NIH is exercising proper oversight of the clinical research it supports. She said that reports of overworked institutional review boards, insufficient attention to conflict of interest issues on the part of investigators and institutions, and confusion in the community over the roles of the Food and Drug Administration (FDA) and NIH in overseeing clinical research demand NIH attention so that the public's trust in the research enterprise and NIH stewardship of research are not compromised. One area of research that is presently undergoing careful review is stem cell research. NIH received over 50,000 comments on the draft stem cell guidelines that were published in February. She reported that NIH is considering all of the comments in preparation for publishing final draft guidelines sometime this summer. One aspect of these guidelines will be that NIH will have an oversight function for stem cell research. NIH must very carefully draft its stem cell guidelines given the diversity of views in Congress and among the public about conducting stem cell research. Another concern that Congress and NIH are addressing is how to care for animals used in research. As one example of this, she pointed to congressional hearings on establishing sanctuaries for chimpanzees used in research.

Finally, she explained that NIH is implementing a "just-in-time" approach to institutional review board (IRB) review of research involving human subjects. This is being done to lessen the review workloads of IRBs, which heretofore have had to review all protocols being submitted as part of NIH grant applications. Under the new procedure, the IRBs would examine only those 20 to 30 percent of clinical research applications that are being seriously considered for funding following peer review. It is hoped that this will allow for more in-depth review. She also explained that NIH will "put more teeth" into monitoring Phase 1 and Phase 2 clinical trials, and that it will require that clinical investigators take rigorous training in the bioethics of doing clinical research.

In response to questions from Council, Dr. Kirschstein reviewed some of the lessons learned from the October 1999 death of a patient in a gene therapy clinical trial. Council members shared the opinion that gene therapy trials should not be stopped and that much clinical research involves risk. All who spoke agreed, however, that the community of clinical researchers needs to more rigorously inform patients of risks, more assiduously follow protocols, and more strictly adhere to established procedures for reporting adverse events. Furthermore, Dr. Kirschstein noted that both those conducting clinical trials and NIH need to better educate the public about clinical research. She cited as an example of success in this regard the large study termed the "Women's Health Initiative," in which participating investigators speak with potential subjects 3 to 5 times prior to seeking informed consent to enroll in the study.

In response to a question about NIH's efforts to address the issue of protecting private genetic information being gathered during NIH-sponsored research, Dr. Kirschstein explained that Congress is moving slowly toward action on legislation to address this concern. She mentioned that about 30 states have laws to protect the confidentiality of genetic information. Furthermore, the Department of Health and Human Services (DHHS) will soon issue privacy regulations that take some steps in the direction that many would like to see DHHS and NIH move.

Finally, in response to another question, Dr. Kirschstein spoke about the need to clarify under what circumstances NIH-supported clinical researchers must seek FDA approval for their clinical trials. She acknowledged that the recent trend toward industrial sponsorship of these trials has led to confusion in the grantee community over the roles of the FDA and NIH.

XI. Health Disparities

Addressing health disparities is an important priority for NIH institutes individually and for NIH as a whole. Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, briefed Council members on the status of NIH's most recent efforts to address ethnic and racial health disparities.

In 1998, the President of the United States announced a new initiative with the goal of eliminating, by the year 2010, disparities in the health status of racial and ethnic minority groups, and gave the Department of Health and Human Services primary responsibility for the initiative. Dr. Fauci and Dr. Yvonne Maddox, acting deputy director of NIH, chair the NIH committee that is formulating NIH's strategic planning in response to this initiative. Drs. Fauci and Maddox have been talking about the strategic plan to the institutes and centers' advisory councils to highlight the plan's overall importance to NIH, the DHHS, and the White House. In addition, they wish to ensure that institutes and centers have the opportunity to include in their 5-year budgetary planning processes the health disparities initiatives outlined in the plan. Initiatives outlined in the plan are projected for initial funding in FY 2002.

Dr. Fauci indicated that the "NIH Strategic Plan to Reduce and Ultimately Eliminate Health Disparities" addresses the six focus areas that were identified by the White House--infant mortality, cancer screening and management, cardiovascular disease, diabetes, HIV and AIDS, and immunizations. In preparation for developing an NIH strategic plan, NIH institutes and centers prepared drafts of their plans, submitted them for public comment, and on April 3, forwarded the resulting drafts to the committee chaired by Drs. Fauci and Maddox. The committee, which is composed of institute and center directors, plans to integrate and consolidate the individual institutes' plans into an overall NIH plan that is greater than its individual parts. The committee plans to forward a draft of the overall NIH strategic plan to the acting director, NIH, by May 26. Dr. John Ruffin, head of the NIH Office of Research on Minority Health, is coordinating the entire process.

Dr. Fauci concluded his presentation by providing examples of health disparities and current NIH efforts to address them, and by emphasizing the importance of consulting minority communities in the development of the strategic plan and in setting priorities for the proposed initiatives. NIGMS' plan for reducing health disparities is available on the NIGMS Website at

XII. American Indian Research Training Needs

Dr. Clifton Poodry, director of the NIGMS Division of Minority Opportunities in Research, described a meeting held on August 23-24, 1999, sponsored jointly by NIGMS and the Indian Health Service (IHS) titled "American Indian Research Training Needs." The purpose of the meeting was to learn what the needs and/or concerns of American Indians are with regard to biomedical research training and the barriers to increasing their professional engagement in biomedical research. NIH and IHS observers heard from the American Indian community their views on how to build trust and engage and train American Indians as biomedical researchers. The first part of the meeting consisted of brief presentations and discussions of concerns and barriers and activities that have been successful in developing the skills of American Indian students. It became clear that the gap in trust and credibility that separates American Indian communities from the NIH-funded research community is still a major concern for the communities. The background discussions were followed by sessions in breakout groups that led to recommendations for NIH and IHS. A report with recommendations was delivered in early April 2000. The desired outcome of the meeting was an enhancement of existing mechanisms or the development of more effective research and research-training programs based on American Indian leadership and advice.

XIII. NIGMS/IHS Collaboration

Leo Nolan, senior policy analyst and assistant to the director of the Indian Health Service, presented the background and a description of the proposed new initiative to promote, help develop, and support Native American Research Centers for Health (NARCH). Mr. Nolan described the history and primary responsibility of the Indian Health Service. He presented a number of sobering statistics revealing the widening disparities in health of American Indian and Alaska Natives relative to the population as a whole and called for research into causes and potential remedies. He explained that IHS supports a very small amount of research and evaluation that is conducted by tribes or tribal organizations, but that funding for research, about $600,000, must be taken from funds that provide direct healthcare services. Thus, within the IHS responsibility for delivering healthcare services, there is little flexibility to support research or research training. Mr. Nolan stated that the responsibility for healthcare of American Indians and Alaska Natives lies not just with IHS but with all of DHHS.

The proposed centers will be partnerships between Native American tribes (American Indian or Alaska Native tribes or tribal-based organizations such as the Area and National Indian Health Boards) and research-intensive organizations. The NARCH Program will offer opportunities to develop the biomedical and behavioral research capabilities of the Native American faculty and students at each center through support of faculty-initiated, scientifically meritorious research projects, including pilot research projects, and through projects designed to increase the numbers, and to improve the research skills, of Native American students. The hallmark of the initiative is that the applicants will be Indian Tribes or tribal organizations that may legally receive funds from the Indian Health Service, so the tribes will be managing partners and will be able to weigh in on the kind of research that is needed and permitted in their communities. NIGMS will provide the initial funding for the program; IHS will manage it. Review will be conducted by the Center for Scientific Review, and the NAGMS Council will provide the second level of review.

XIV. MARC Post Baccalaureate Apprentice Scientist Award

Dr. Adolphus Toliver of the NIGMS Division of Minority Opportunities in Research reported on the MARC Post Baccalaureate Apprentice Scientist Award (PASA). In the NIH Revitalization act of 1993, NIH was encouraged to increase the number of underrepresented minorities participating in biomedical and behavioral research. In response to the act, the MARC Branch is proposing the establishment of a new institutional program, the Post Baccalaureate Apprentice Scientist Award, to encourage underrepresented minority students who hold a recent baccalaureate degree in the biomedically relevant sciences to pursue a research doctorate. This program will target those talented and promising minority baccalaureate graduates who, for a variety of reasons, have decided to postpone application to graduate school. The purpose of the proposed program is to maintain the interest of the post-baccalaureate participants in scientific research and to promote an interest in research dealing with health disparities. It is anticipated that this program will result in strengthening the research skills and competitiveness of PASA participants necessary for their successfully pursuing and eventually completing graduate school leading to the Ph.D., M.D.-Ph.D. or other combined professional degree-Ph.D. An expectation is that participation in this program could also facilitate the development of a cohort who could become the scientists that address the health problems that disproportionately affect minorities and the medically underserved. Applications for this program would be accepted from domestic private and public universities and research institutions or centers with graduate programs that offer a solid research environment as evidenced by a high level of faculty involvement in biomedical and/or behavioral research.

XV. Single Molecule Workshop Summary

Dr. Carlos Bustamante of the University of California, Berkeley, reported on an April 17-18, 2000, NIGMS-sponsored workshop titled "Single Molecule Detection and Manipulation," in which he served as co-chair. The purpose of the workshop was to explore the progress and potential for targeted research in single molecule studies. There were 19 invited speakers and over 120 attendees at the workshop. In addition to making presentations on their most recent work, the speakers were asked to discuss how to further develop the technologies to facilitate progress in this field.

Dr. Bustamante began his presentation by pointing out that there is currently a need for new techniques in high-resolution structural studies. NMR and X-ray crystallography are powerful methods that have been used extensively over the past decade to study high-resolution structures of many diverse biological molecules, but these methods give only a static view or an ensemble average of dynamic processes. Over the last 10 years, there have been a number of significant technical developments that enable high-resolution studies to be carried out using alternative methods. These developments include the control of space through piezo-electric positioners, improvements in the dynamic range of CCDs and avalanche photodiodes, and improved micromechanical actuators. These technical advances have provided the basis for progress to be made in several methods that are used to study single molecules. These include biomechanical studies using optical tweezers, imaging and manipulation of single molecules with atomic force microscopy (AFM), and single molecule fluorescence microscopy.

Dr. Bustamante presented examples of biological systems that are currently being studied using single molecule methods. These were: (1) distance measurements, conformational dynamics, and time trajectories in protein and RNA folding; (2) dynamic heterogeneity and mechanisms of enzyme catalysis; (3) mechanisms of mechano-chemical processes as they occur in transcription, replication, translation, and the movement of myosin and kinesin; and (4) the molecular mechanisms of conduction and gating in ion channels. These examples highlighted the major advantages of single molecule techniques--measurements that can be made on individual molecules rather than on the "ensemble" average, and that the dynamic behavior of individual molecules can be followed as it occurs in real time in vivo.

For single molecule research to be fully realized there are several technical challenges that need to be met. One of the most immediate challenges will be improvements in the photophysical properties of fluorophores to create probes with higher quantum yields, high extinction, reduced photobleaching and photoisomerization, and small singlet-to-triplet cross-sections to reduce blinking. In addition, improved chemistry will be required to develop more versatile methods of inserting site-specific labels in target molecules to create molecular handles to manipulate, track, and immobilize samples. Improved instruments are also needed to optimize high-resolution measurements in the 1 to 100 nanometer range while allowing molecules to move freely. Specific technical challenges in instrumentation include: (1) high-temporal resolution AFMs with smaller cantilevers; (2) fast-exchange microchambers with computer-controlled flow to allow mixing in the 0.01 msec range; (3) improved optical traps with higher force and spatial resolution; (4) high spatial control magnetic manipulators; and (5) time-resolved/time-gated CCDs for faster and more sensitive detection of single molecules. The ultimate challenges in single molecule methods are to achieve observation and mechanical manipulation of processes and individual components inside the cell in real time using ultra high-resolution optical microscopes.

Dr. Bustamante summarized the recommendations that resulted from the workshop by stating that the needs of single molecule research could be addressed through a program announcement with the following components:

  • Promote study of the dynamic behavior of single molecules and their stochastic behavior and compare these studies to corresponding studies of ensemble behavior.
  • Promote collaborations between biophysicists and chemists to generate chemical labels with improved photophysics and better methods to insert them into macromolecules at specific locations (better handles).
  • Promote instrumentation that is tailored in each laboratory for specific applications. Its development has to be recognized as a legitimate research activity.
  • Promote development of new, more powerful instrumentation for in vivo and in vitro work.
  • Promote commercialization of single molecule technology and instrumentation to improve access to a broader range of researchers.
  • Promote collaboration with computational scientists.

XVI. Report on the Biomedical Information Science Initiative at NIH

Dr. Cassman reported on the development of an NIH-wide Biomedical Information Science and Technology Initiative (BISTI). This initiative is in response to a study prepared in 1999 by a working group headed by Dr. Larry Smarr, director of the National Center for Supercomputing Applications at the University of Illinois and Dr. David Botstein, professor and chair of the Department of Genetics at Stanford University.

There were five recommendations in this report. An internal NIH committee, co-chaired by Dr. Richard Klausner, director of the National Cancer Institute, Dr. Francis Collins, director of the National Human Genome Research Institute (NHGRI), and Dr. Marvin Cassman, was convened to discuss the NIH response. The first, and arguably most important, recommendation was to establish between five and 20 programs of excellence in biomedical computing. It was felt that in many cases the research community was not prepared to organize effectively to generate such centers, and consequently, it was recommended that an NIH-wide initiative be generated to stimulate the submission of planning grants for these centers. However, this does not preclude individual institutes and centers at NIH from issuing their own proposals for centers at any appropriate time. NHGRI has released such an announcement targeted largely to the application of computational approaches to analysis of genomic data.

Another initiative soon to be released by NIH is targeted to individual investigators and will provide phased innovation awards, which combine the opportunity to move rather quickly from speculative small-scale proposals too much larger programs without the necessity of extensive resubmission and review. The proposals will combine a preliminary assessment phase with a more extensive description of what will be carried out if the preliminary analysis is successful. Both of these will be reviewed simultaneously. Benchmarks will be established, and if these are reached, an administrative review will be sufficient to move to the larger-scale funding.

Finally, another recommendation of the BISTI panel was to focus funding on Information Storage, Curation, Analysis, and Retrieval (ISCAR). This is and has been an area of great interest for NIGMS. The Institute will be considering approaches for dealing with this over the next year.

NIH programs in the areas of bioengineering, bioinformatics, and computational biology will be coordinated by a central organization in the Office of the Director, NIH.


XVII. Procedure for Conduct of Meeting

Dr. Cassman brought to the attention of Council members the procedures for the conduct of the meeting. Council members were reminded that all of the review materials furnished are privileged information. Although most conflicts of interest involving institutional affiliation already had been identified, members were asked to absent themselves during discussion of any application in which there was a personal conflict that was not readily apparent.

XVIII. Review of Applications

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


The meeting adjourned at 12:00 p.m. on Friday, May 19, 2000.


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

Marvin Cassman, Ph.D.
National Advisory General
Medical Sciences Council