Advisory Council Minutes, January 27-28, 2000

The National Advisory General Medical Sciences (NAGMS) Council was convened in closed session for its one-hundred and thirteenth meeting at 8:30 a.m. on Thursday, January 27, 2000, in Conference Rooms E1/E?2, 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 27 from 11:05 a.m. to 4:30 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.
Daniel J. Kevles, Ph.D.
Leslie A. Leinwand, Ph.D.
Neil S. Mandel, Ph.D.
Eva J. Neer, M.D.
D. Amy Trainor, Ph.D.
Isiah M. Warner, Ph.D.
Richard M. Weinshilboum, M.D.

Members Absent:

Slayton A. Evans, Jr., Ph.D.
Angeline A. Lazarus, M.D.
Robert S. Pozos, Ph.D.

Special Consultants Present:

Urs A. Meyer, Ph.D.
Department of Pharmacology/Neurobiology
Biozentrium of the University of Basel
Basel, Switzerland

Jasper D. Rine, Ph.D.
Department of Molecular and Cellular Biology
University of California, Berkeley
Berkeley, CA

Ronald G. Tompkins, M.D.
Department of Surgical Service
Massachusetts General Hospital
Boston, MA

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. George Eyambe, University of Texas-Pan American
Dr. Edet Isuk, Morgan State University
Dr. T.S. Kochhar, Kentucky State University
Ms. Luciana Lopez, FDC Reports
Ms. Pamela Moore, Capitol Publications
Dr. Emmanuel Osagie, Southern University and A&M College
Dr. Georgia Persinos, Washington Insight
Mr. Brad Smith, American Chemical Society

Federal Employees Present:

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 four new members of Council: Dr. John Abelson, professor, Department of Biology, California Institute of Technology; Dr. Jay Dunlap, chair, Department of Genetics, Dartmouth Medical School; Dr. D. Amy Trainor, global product director, CNS (central nervous system), AstraZeneca Pharmaceuticals; and Dr. Richard M. Weinshilboum, professor, Departments of Pharmacology and Medicine, Mayo Medical School. Dr. Cassman also introduced the guests and three ad hoc members: Dr. Urs Meyer, professor, Department of Pharmacology, University of Basel, Switzerland; Dr. Jasper Rine, professor, Department of Molecular and Cellular Biology, University of California, Berkeley; and Dr. Ronald Tompkins, professor, Department of Surgical Service, Harvard Medical School, and chief, Trauma and Burn Services, Massachusetts General Hospital.

Several new NIGMS staff members were introduced: Esther Brooks, the Council and administrative assistant in the Office of the Director; Drs. Richard Anderson and Anthony Carter, program directors in the Division of Genetics and Developmental Biology; Dr. Laura Moen, a scientific review administrator in the Office of Scientific Review; Tina Fleming and Robin Warren, grants assistants in the Grants and Operations Unit; Christine Nesline, a program assistant in the Division of Pharmacology, Physiology, and Biological Chemistry; and Judit Camacho, a program analyst in the Division of Minority Opportunities in Research.

Dr. Bruce Wetzel, a scientific review administrator in the NIGMS Office of Scientific Review, retired in December 1999.

Dr. Cassman then mentioned awards NIGMS Council members, staff, and grantees recently received. Among the Council members:

  • Former Council member Dr. David Clayton was elected vice president for science development at the Howard Hughes Medical Institute. The appointment was effective January 1.
  • Dr. Jay Dunlap was recently named chair of Dartmouth Medical School's new Department of Genetics.
  • Dr. Slayton Evans was named the recipient of the American Chemical Society Award for Encouraging Disadvantaged Students into Careers in the Chemical Sciences, sponsored by The Camille and Henry Dreyfus Foundation, Inc.
  • Dr. Lila Gierasch will present a Distinguished Faculty Lecture at the University of Massachusetts on February 23, and she will receive a Chancellor's Medal following the lecture. The Chancellor's Medal is the highest honor bestowed on individuals for exemplary and extraordinary service to the university.
  • Dr. Daniel Kevles was awarded in November the History of Science Society's 1999 Watson Davis and Helen Miles Davis Prize for his book The Baltimore Case: A Trial of Politics, Science, and Character. The prize is awarded annually to the author of a book that promotes public understanding of the history of science.
  • Dr. Isiah Warner was honored by the American Association for the Advancement of Science with its Lifetime Mentor Award. The award, which will be presented in February, recognizes the mentoring activities Dr. Warner has been involved in since he began teaching chemistry in 1978. It is presented annually to recognize an individual who for 10 or more years has mentored and guided significant numbers of students from underrepresented groups to the completion of doctoral studies or who has impacted the climate of a department, college, or institution to significantly increase the diversity of students pursuing and completing doctoral studies.

Among NIGMS staff:

  • Dr. Judith Greenberg, director of the Division of Genetics and Developmental Biology, and Dr. W. Sue Shafer, who served as deputy director and director of the Division of Extramural Activities until her retirement in October 1999, were among the 12 NIH employees who received 1999 Presidential Rank Awards.
  • Dr. Anthony Rene, associate director for referral and liaison, was honored by Harvard University's Biomedical Science Careers Program for outstanding mentoring. He was recognized for making significant contributions toward assisting students in pursuing careers in biomedical and behavioral research.
Among NIGMS grantees:
  • Dr. Günter Blobel, a long-time NIH grantee, received the 1999 Nobel Prize in physiology or medicine. His prize-winning work on protein signaling in the cell was supported by NIGMS and the National Cancer Institute. Between 1971 and 1989, he received more than $4.5 million in NIH research grant support, primarily from NIGMS. Dr. Blobel is the John D. Rockefeller, Jr. Professor in the Laboratory of Cell Biology at The Rockefeller University.
  • NIGMS grantee Dr. Roderick MacKinnon, a professor in the Laboratory of Molecular Neurobiology and Biophysics at The Rockefeller University, was a recipient of the 1999 Albert Lasker Award for Basic Medical Research. He and two other recipients were recognized for their pioneering research on the functional and structural architecture of ion channel proteins. Dr. MacKinnon's research focuses on the elucidation of the structure and function of potassium channels.

II. Consideration of Minutes

The minutes of the September 23-24, 1999 meeting were approved as submitted.

III. Future Meeting Dates

The following dates for future Council meetings were confirmed:

May 18-19, 2000 — Thursday-Friday

September 14-15, 2000 — Thursday-Friday

January 25-26, 2001 — Thursday-Friday

May 17-18, 2001 — Thursday-Friday

September 13-14, 2001 — Thursday-Friday

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 began with a discussion of the budget for FY 2001. He noted that the increase was 12.5 percent, or about $150 million, over FY 2000, resulting in a final budget that was a bit over $1.35 billion. This included NIGMS' share of the NIH-wide 0.38 percent reduction, which totaled $7.3 million. Approximately $88 million of NIGMS' $150 million increase was charged to the noncompeting line of the budget, which reflects the increased numbers and sizes of new awards made over the 2 years. An additional $11 million was used to provide a stipend increase and to provide family medical insurance to trainees, as well as to provide some institutional support on training grants. The Minority Opportunities in Research programs were given a $20 million increase, and $30 million was allotted to centers, reflecting new initiatives in structural genomics and "glue grants" for integrative and collaborative approaches to research. Given this distribution of resources, the Institute still expects to have a success rate for competing grants in the low-to-mid 30 percent range. However, in order to maintain this success rate, awards will have to be reduced below the recommended levels. Because the Institute provided in FY 1999 a 17 percent increase in the sizes of competing awards, Dr. Cassman stated that such an increase was not sustainable for FY 2000. The increase in average costs for the Institute this year will be 3 percent, resulting in a 20 percent increase over 2 years. Since the requested costs, particularly for new (Type 1) grants, are escalating at a rate far higher than 20 percent over 2 years, reductions will be necessary. A number of Council members suggested that the recent increases might be due to the institution of modular grants; however, they felt it was too early to tell. In response to a question from Council, Dr. Cassman said that the requirement to postpone some funding until the last day of the fiscal year will cause some inconvenience for the Institute, but he said it should not have any impact on the extramural scientific community. Dr. Cassman then added that the Administration had announced, prior to the official budget release, that the FY 2001 NIH budget would reflect a 5.6 percent increase.

Next, Dr. Cassman informed Council members of some developments in programs initiated in FY 2000. First he reported on the status of the "glue grants" initiative. Ten Phase 1 applications were received for the collaborative research grants, or "glue grants." The Phase 1 proposals were for planning grants that would permit the awardees to develop and apply for an award that could total up to $5 million per year for 5 years. Of the ten applications received, three awards were made. The three groups are: an alliance for cell signaling; a study of protein-carbohydrate interactions and cell communications; and a study of inflammation and the host response to injury. The reviews will be conducted in early spring, and awards will be made later this fiscal year. The deadline for Phase 1 applications is the end of June. A reannouncement of the program is planned.

The second initiative mentioned was structural genomics. This initiative is an effort to arrive at a complete representation of protein structures. Applications have been requested for pilot programs to develop high-throughput procedures for identifying and generating protein structures. Fifteen letters of intent were received, and the applications will be reviewed this summer. This initiative is part of an international effort that will begin with a meeting at the Sanger Centre in Cambridge, England, to discuss policy issues regarding data release, intellectual property rights, etc. It is linked to the collaborative effort with the National Cancer Institute to develop a sector at the Advanced Photon Source at Argonne National Laboratory. Synchrotron access will be required for the programs involved in the structural genomics effort, and time will also be made available to NIGMS and NIH grantees and other investigators who are determining macromolecular structures.

Dr. Cassman then concluded by mentioning that the high-risk, high-impact program would be discussed at the May Council meeting. He expressed concern that the applications received were not meeting the goals of the program, and he asked Council members to relay to him any questions that they had about the program. There were concerns expressed by Council members that the program had not been sufficiently understood by the scientific community, and that its review process needed to be improved. During the Council-initiated discussion, some other possible approaches to the high-risk, high-impact approaches were also presented.

Dr. Cassman finally asked for comments on the new procedures that had been implemented to expedite Council review. Council then discussed how the process could be improved. In general, most Council members felt the procedure worked, but they said they thought that paper was still valuable at several points in the review process.

V. Council Operating Procedures

The Council approved the guidelines and operating procedures (available from NIGMS).

VI. Current Perspectives on Pharmacogenetics and Pharmacogenomics

Dr. Urs Meyer of the University of Basel gave a presentation to Council titled "Current Perspectives on Pharmacogenetics and Pharmacogenomics." He explained the principles behind the science of understanding how some drugs work better in some patients than in others, and why some drugs can be highly toxic to certain patients. The key questions in the presentation addressed the basis of why patients differ in their reactions to medications. What are the causes of this variation? Can an individual's response be predicted? Can drug therapy be improved? There are now over 100 drug-metabolizing enzymes identified, expressed mainly in the liver. Common polymorphisms in the cytochrome P450 system and the conjugating enzymes were reviewed, and potential polymorphisms in the drug receptors and other targets were also discussed. Dr. Meyer said that the therapeutic benefits of genotyping and phenotyping have not yet been realized, but he said there is a great potential for cost-effectiveness of pharmacogenetic tests in minimizing and avoiding adverse drug reactions and in predicting therapeutic responders. Genetics, combined with the extent of diversity in the Human Genome Project, interface with the pharmacogenetics initiatives. Of the 3 billion base pairs that are different, which are functionally significant? The objectives of the proposals received in response to the pharmacogenetics request for applications ( RFA GM-99-004, Pharmacogenetic Research Network and Database) are to identify genetically controlled variations in drug responses, to study their molecular mechanisms, to evaluate their clinical significance, and to develop methods by which individuals at risk can be recognized.

VII. Development of Policies Related to Graduate Students and Postdoctorates Supported by NIH Research Grants

Dr. Walter Schaffer of the NIH Office of the Director, Office of Extramural Programs, presented ideas and proposals that have surfaced from extensive discussions in an NIH staff committee. This committee analyzed several recent national reports on graduate and postdoctoral training and focused on specific questions about the length and quality of the training experiences, as well as their salaries and benefits. The committee also focused on the magnitude of NIH's influence over training in the biomedical sciences. The committee concluded that in the past, NIH has not always been clear about the nature of the positions it supports on research grants. Students and postdoctorates supported as research assistants have been relegated to positions that, according to Federal policies, were exclusively employment. This confusion about employment may have resulted in longer-than-necessary periods of training and a blurring of the legitimate distinction between income levels for employees compared to individuals in training. Although most universities properly make such distinctions and provide appropriate training experiences, the committee felt it was time for Federal policies to recognize that both graduate and postdoctoral research assistants are not simply employees, but that they are also receiving research training. Accordingly, the committee proposed that NIH acknowledge the dual role of students and postdoctorates and adjust its policies accordingly. For example, there should be some limits on the total duration of NIH training support derived from a combination of NRSA (National Research Service Award) and research assistantships. Students should not be assigned to specific research grants during their first 1-2 years of graduate school. Finally, postdoctoral students beyond this period of training (5 years was suggested) who are to be retained as staff on specific research projects should be supported in non-training positions with appropriate incomes and benefits. If implemented, the committee proposed that these provisions would be stated as NIH preferences rather than rigid guidelines, in recognition of the fact that there is considerable variability in the individual training experiences of students and postdoctorates. Finally, the committee suggested that NIH begin to collect identifying information on graduate and postdoctoral research assistants at the time of appointment. This information would permit NIH to evaluate the quality of those experiences and to learn for the first time exactly how many students and postdoctorates were being supported. During the submission of a simple electronic appointment form, principal investigators would be reminded that the acquisition of skills and knowledge is an important part of the student's or postdoctorate's experience as a research assistant.

The Council discussed several aspects of this issue, including the appropriate length of postdoctoral training, the need for institutions to develop appropriate postdoctoral programs and policies, the impact of immigration on scientific employment, Ph.D. production levels, the length and nature of dual degree programs, and the appropriate balance of graduate students supported by training grants and research grants. It was pointed out that the National Academy of Sciences (NAS) report on national needs for biomedical and behavioral scientists will be published soon. Dr. Cassman said he would schedule another Council discussion on this issue, probably after the NAS report is published.

VIII. Training Grant Minority Recruitment

Dr. Janna Wehrle of the NIGMS Division of Cell Biology and Biophysics reported on NIGMS' implementation of the requirement for minority recruitment on training grants.

Because NIGMS is responsible for a large fraction of the research training supported by NIH, its procedures for implementing the obligation for NRSA (T32) training grants to actively recruit, enroll, and graduate students and fellows from racial and ethnic groups underrepresented in the biomedical sciences have attracted the interest of other NIH institutes. Approximately 300 minority students are currently supported by NIGMS training grants, along with approximately 35 graduate students supported by the MARC (Minority Access to Research Careers) Program, 85 supported by NIGMS-funded individual minority fellowships, and 70 supported by minority supplements to NIMGS research grants.

Training grant peer-review panels designate recruitment progresses and plans as "Acceptable" or "Unacceptable," according to NIH policy, but NIGMS encourages them to be more specific in their summary statement narrative. Following review by Council, all minority recruitment programs are reviewed by a standing staff Committee on Minority Recruitment (CMR). By reviewing and comparing all of the programs over a long period of time, the CMR provides perspective and institutional memory to evaluation of minority recruitment efforts. Its goal is to promote continuing improvement in the minority recruitment programs of NIGMS training grants.

As mandated by the National Advisory General Medical Sciences Council, the CMR uses a wider range of descriptors for applications considered "Acceptable" ("Commendable," "Satisfactory," or "Marginal,") as well as the rating "Unacceptable." It may occasionally recommend an "Acceptable/Unacceptable" rating different from that of the peer-review panel. The committee provides specific feedback to training principal investigators regarding problems. NIGMS stresses that recruitment activities must succeed or be changed, not just be carried out without evaluation. The information NIGMS gathers on minority recruitment plans is used to identify, publicize, and promote successful strategies.

To ensure that training programs take serious action in response to peer review and CMR review of recruitment plans, NIGMS may award an extra training position to a program with extremely successful recruiting activities. On the other hand, when serious problems have been identified, (for example, if a program has been designated "Marginal" in two consecutive review cycles or when an award has been made following revision of an originally "Unacceptable" plan) the Institute makes the last 2 years of an award contingent upon demonstrated progress in this area. Grants issued with such conditions have already shown tangible improvement in minority recruiting, with one receiving a "Commendable" rating at its last competitive review. A larger number of programs that received conditional awards will to reach their evaluation marks later this year. By next year, NIGMS should be able to fully assess the impact of this approach.

It is difficult, based on application material and site visits, to accurately assess the number of minority students trained as a result of NIGMS institutional training grants. Five years ago, most applications reported around 8 percent underrepresented minority students. This is consistent with the value of 8-9 percent obtained by John Norvell of the NIGMS Office of the Director and Milton Hernandez of the National Institute of Allergy and Infectious Diseases, Division of Extramural Activities, in their evaluation of actual training appointment forms from 1994-1995. More recent competing applications typically report 10-11 percent minority students, or 300-325 individuals. These numbers, if confirmed by the upcoming re-evaluation of appointment form data, indicate some small but steady progress in increasing the number of underrepresented minority scientists trained by NIGMS.

IX. Demonstration of the NIH Commons

For the purposes of exchanging research grants administration information with extramural grantees, NIH is in the process of developing and deploying an Internet-based information handling and storage system called the "NIH ERA Commons." Dr. George Stone, Chief of the Commons, Extramural Inventions and Technology Resources Branch of the Office for Policy and Extramural Research Administration, presented the details of this initiative, including the status of its deployment.

The NIH Electronic Research Administration (ERA) Commons is a virtual meeting place where NIH extramural grantee organizations, grantees, and the public can receive and transmit information about the administration of biomedical and behavioral research. The NIH Commons production platform has been deployed since July 1998, and now it serves the NIH extramural community with free information dissemination through unrestricted portions of the Commons system, as well as a means for exchange of confidential information to authenticated users through restricted portions of the system. Perhaps the most heavily used unrestricted interface is CRISP this provides any member of the public the ability to query the NIH database of current and historical awards, which includes abstracts and awardee details.

Access to restricted sites requires registration by each grantee organization, followed by establishment of accounts by individual scientists and/or administrators at registered institutions. Once accounts are created, authenticated users can access several subsystems that will provide support of the following grants administration business processes.

  • Streamlined Non-competing Award Process (SNAP)--A secure interactive Web interface for submission of scientific and administrative information necessary for continuation of a multi-year grant award.
  • Grant Application/Award Status (STATUS)--A secure Web interface by which grantees and grantee organization administrative officials may obtain information about pending grant applications and awards from their institutions.
  • ERA Accounts Administration (Admin)--An account administration facility that permits the addition, deletion, and modification of user accounts and the viewing and updating of professional and institutional profiles.
  • Trainee Activities System (X-Train)--A secure interactive Web interface for grants administration officials to record and obtain information about their trainees.
  • Competitive Application Receipt (CGAP)--A secure means by which information contained within the HHS form 398 can be submitted to NIH as a stream of information directly from the grantee organization's database into the ERA Commons database. This portion of the Commons system is still in an earlier pilot phase. Few grantee organizations are yet ready to provide this complex set of information in electronic "datastream" format.

Currently, the Commons is being deployed as an extended pilot, with 125 grantee organizations being given access to the restricted sites. From these institutions, approximately 3,000 authenticated users are now logging onto the Commons to conduct the various ERA activities described above. Particular emphasis is being placed on receipt of SNAP applications (Type 5 progress reports for R01 grants). SNAP applications are now being received through the ERA Commons from 15 of the 125 pilot institutions for processing by NIH awarding institutes.

By summer 2000, it is anticipated that an excess of 150 organizations will be active on the ERA Commons, with particular emphasis on expanded receipt of electronic SNAPs. Dr. Stone also spoke of efforts underway to finish development of Commons software to support complex noncompeting awards (e.g, Program Project and Center Grants), as well as the development of a NIH Commons version of the fellowship application. The deployment of these two subsystems will not take place until near the end of FY 2000.

X. High-Resolution Structure Supplements

Dr. Catherine Lewis of the NIGMS Division of Cell Biology and Biophysics reported on supplements for the determination of high-resolution structures that were first announced in May 1997. The purpose of the supplements was to provide funds to enable researchers with existing NIGMS research grants to complete high-resolution structures quickly, without writing a new grant or waiting for the outcome of the review process. The supplements were to be awarded to investigators working on biological projects without structure determination as the primary focus. In many cases, samples suitable for high-resolution structures are obtained, and in collaboration with a structural biologist, sufficient preliminary data are attained to justify the funding of a new project aimed at structure determination. The rationale for the supplements was that high-resolution structures can often be completed quickly, once diffraction quality crystals or resolvable 2-D NMR spectra are available. In these instances, a limited award for 1 year can provide enough support to finish the project without the need to launch a separate research grant for the same purpose.

Following the initial announcement of the program, there were over 80 inquiries from investigators interested in applying for funds. Only one-fifth of these investigators were encouraged to apply because the others were from investigators seeking funds to purchase equipment, to produce samples or grow crystals, or to carry out experiments in mass spectrometry or calorimetry. Since May 1997, a total of 63 applications have been received; of (62 percent) of these have been funded. Of these, 22 and 17 have been for projects using X-ray or NMR methods, respectively. The distribution of funding across the scientific divisions is 16 awards in the Division of Cell Biology and Biophysics, 13 in the Division of Genetics and Developmental Biology, and 10 in the Division of Pharmacology, Physiology, and Biological Chemistry. The total cost of the program has been $2,465,405 ($452,173 in FY 1997; $1,005,615 in FY 1998; and $1,007405 in FY 1999).

One measure that can be used to assess the success of the program is publication of the structures that were supported. Of the 39 awards that have been made, 13 structures have been published and another six are close to publication, resulting in a success rate of 49 percent. It is clear that it is still too early to assess progress on awards made in FY 1999; thus, the overall progress and publication rate is likely to be even higher once these projects are completed. Based on the FY 1997 and FY 1998 data alone, 17 of the 23 awards, or 74 percent, are published or close to publication.

XI. Evolution of Infectious Diseases

Dr. Irene Eckstrand of the NIGMS Division of Genetics and Developmental Biology summarized the results of the NIGMS and National Institute of Allergy and Infectious Diseases (NIAID) initiative on "Evolution of Infectious Diseases" (RFA 99-005). Eighty-seven applications were received in response to the RFA, and they were reviewed by study section in July 1999 and by the NAGMS Council in September 1999. NIGMS paid 13 applications, and NIAID funded four more--a success rate of 20 percent. This is a conservative payline and consistent with NIGMS' desire to fund the best applications. The funded applications cover a wide range of science, from highly theoretical mathematical modeling to clinical studies. All involve collaboration between evolutionary/population biology and sciences related to infectious diseases. The overarching goal is to develop a predictive theories of evolution.


XII. 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.

XIII. Review of Applications

A summary of applications reviewed by Council is available from Pam Haney, 301-594-2172.


The meeting adjourned at 12:00 p.m. on Friday, January 28, 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