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BACKGROUND. The Medicinal Chemistry (MCHA) Study Section is a peer review group of the Division of Research Grants (DRG) of the National Institutes of Health (NIH). The mandate of MCHA is to evaluate applications for grants-in-aid in the general area of medicinal chemistry. In 1978, its portfolio of applications was quite broad and touched upon organic synthesis, medicinal chemistry, bioorganic chemistry and natural product isolation. The workload at that time was 120-130 R01 (Investigator initiated) and R23 (New Investigator Research Award) applications per review cycle (three cycles per year). This demanding review responsibility required the help of various ad hoc panels (specifically set up for a single session) to aid the MCHA Study Section.
This workload continued until around 1980, when a reorganization occurred and the Bioorganic and Natural Products Chemistry (BNP) Study Section was chartered. The BNP panel assumed the responsibility for review of biosynthesis, natural product isolation, enzyme inhibitors, nucleoside/nucleotide chemistry and peptide chemistry. The MCHA Study Section focused on organic synthesis and general medicinal chemistry. The anticipated and observed result was a lowering of the number of applications coming to the MCHA review group to around 70-per cycle. However, since 1988 to the present, the MCHA workload has experienced a steady, dramatic decline. In FY 1994, for example, approximately 50 applications per cycle were submitted. This trend prompted the MCHA Study Section to sponsor a workshop at the Doubletree Hotel in Rockville, MD on June 6, 1995, to explore possible reasons for this decline, and to determine the status of Organic Chemistry and related areas that impact on it.
CHARGE TO THE WORKSHOP PANEL. The workshop panel sought to answer the following questions:
The workshop consisted of a round table discussion with 13 academic and industrial leaders of the organic and bioorganic chemistry communities, including past and present members of the MCHA and BNP Study Sections. The group was supplemented with junior members of the academic community to provide insight into the difficulties of establishing programs and serve as resources to the new developing areas of organic chemistry. A representative of the Chemistry Division of the National Science Foundation (NSF) was included since the NSF is the second largest funding agency for organic chemistry research. The panel members were chosen for their interest in and concern for their fields of endeavor and the NIH peer review process.
The panel composition was as follows:
Moderator: Dr. William R. Roush, Indiana University
Dr. Paul A. Anderson, Dupont/Merck Company
Dr. Peter A. Beak, University of Illinois, Urbana
Dr. Erick M. Carreira, California Institute of Technology
Dr. Charles P. Casey, University of Wisconsin, Madison
Dr. David A. Evans, Harvard University
Dr. M. Reza Ghadiri, Scripps Research Institute
Dr. Eric N. Jacobsen, Harvard University
Dr. Larry E. Overman, University of California, Irvine
Dr. Matthew S. Platz, Ohio State University
Dr. George M. Rubottom, National Science Foundation
Dr. W. Clark Still, Columbia University
Dr. D. Amy Trainor, Zeneca Pharmaceuticals
Dr. Barry M. Trost, Stanford University
THE STATUS OF ORGANIC SYNTHESIS. The morning session began with discussion of whether organic synthesis is a mature art. The response was a resounding NO! It was noted that the word art is somewhat pejorative and suggests, incorrectly, that organic synthesis is not a science. Organic synthesis is an enabling science that is necessary for solving problems in many other fields. The problems change with time, especially in the pharmaceutical industry as pricing pressures, for example, place new demands on the need for highly efficient, cost-effective ways of synthesizing products.
Part of the problem is that the community has overly dramatized its successes and not publicized its difficulties. It is still challenging to make a few milligrams of new classes of molecules and difficult to make even a few grams of a complex substance of well-studied classes of molecules. Despite its dramatic successes, organic synthesis remains quite empirical and heavily based on trial and error. There is much room for improvement in the predictability of reactions. One cannot synthesize everything that is desired and those syntheses that can be accomplished are very time consuming. The need for new, more powerful methods is clear. The field is rapidly developing and more exciting now than at any time in the past. Some important future goals might be (1) control of the biological and physical properties of a material as well as its structure. Molecular recognition studies depend heavily on the ability to design and synthesis new types of molecules. Medicinal chemistry requires the ability to design a drug as well as to synthesize. Use of organic synthesis for the preparation of materials as in the synthesis of nanotubes and other nanoscale assemblies is a promising area. (2) Development of more reliable methods and procedures to increase reaction predictability are needed. Most synthetic methods are still not as general as desired and may fail in key steps in the syntheses of complex molecules. (3) Improved understanding of reaction mechanisms in a wide variety of areas are needed and will inevitably lead to improved synthetic methods useful for medicinal chemistry. (4) New reactions and modified procedures are needed that can be safely and economically be used on a large scale. Some of the powerful new methods developed during the past twenty years use toxic or expensive reagents or require low temperature or other reaction conditions that are not applicable to large scale work. (5) Improvement in synthetic efficiency is still needed since syntheses of complex molecules are still often too long to be practical. The development of new catalysts are needed to carry out transformations efficiently and although much has been accomplished in the area of catalytic asymmetric transformations in the past decade, there is still much room for development in this essential field. (6) Environmental concerns require continued refinement and development of synthetic reagents and reaction conditions to minimize waste disposal problems. (7) Preparation of biologically functional and bioengineering materials should benefit significantly from new developments in organic synthesis. (8) Combinatorial methods are being widely embraced by the pharmaceutical industry as a new method of rapidly preparing molecules for screening molecules as drug candidates. The full utilization of this promising procedure will require further investigation and refinement of solid phase techniques for organic synthesis, and the development of analytical techniques for monitoring solid phase reactions, determining the structures of the products and evaluating the biological properties of the target compounds produced.
WHERE ARE THE APPLICATIONS GOING ? The discussion centered on why the number of applications to MCHA had dropped to such a low level. There are many possible contributing factors: (1) Chemistry faculty may respond to "hard times" e.g. low funding levels very differently than medical school faculty, who submit the majority of NIH applications. Chemistry faculty salaries are paid by universities from "hard money" so that chemists respond to the low percentile score needed for funding by dropping out of the grant system and concentrating on their teaching duties. Medical school faculty salaries are paid from grants so that these faculty must respond to decreasing funding levels by submitting more applications. This fact may contribute to declining applications from chemists while application pressure to NIH as a whole is increasing. (2) As a result of the recent trend to very lucrative start up packages for new chemistry faculty members, assistant professors may not submit their first application until their third year. (3) The decrease in applications may correlate with departmental hiring trends. There is a tendency to seek out multi-disciplinary scientists who would be expected to submit multi-disciplinary proposals. As a more basic science Study Section, MCHA may not receive many of these applications. There appears to be a perception in the chemistry community that applications to NIH need to be interdisciplinary in nature. The workshop panel stressed that this was not necessary, a basic health science focus is perfectly acceptable. (4) In lieu of submission of applications as Principal Investigators, many chemists have taken a support role in multi-disciplinary programs or participate in program project grants as a means to generate funding for themselves. This of course leads to a lowering of the number of applications reviewed by MCHA.
There is concern that many chemists do not have a good sense of the funding climate at NIH. The statistics show that for the new investigator community, the success rate is better than average at the NIH. In general, the NIH is treating chemistry relatively well.
During the workshop it became clear that many chemists do not understand the NIH use of percentiles in funding decisions. The percentile rank of an MCHA application, for example, is the relative position or rank of the priority score of that application (along a 100 percentile band) among the applications reviewed by the MCHA Study Section in three consecutive meetings. For example, a percentile rank of 25.0 in MCHA means that 25 percent of the applications reviewed by MCHA received equal or better scores. The formula for calculating percentiles is P=100(k-1/2)/N where P is the percentile rank, k is the numerical rank and N is the total number of applications in the three meeting base (the current round plus the two previous rounds).
This method of evaluation has an important implication. Since the NIH primarily uses percentiles rather than raw scores in its funding decisions, the greater the number of applications that are reviewed by a given study section, the greater the number of applications that will fall at lower, fundable percentile values. This means that the organic chemistry community cannot retreat from application submission in bad times. More chemistry applications will most likely generate more chemistry funding.
There is also the perception that the Study Section has favored areas of science and that the probability of an enthusiastic review is low outside those areas. It is not clear how this perception arose, but it needs to be emphasized that the MCHA Study Section has always responded positively to good science, irrespective of area.
POSSIBLE ACTIONS. The workshop ended with a discussion of ways to increase the number of applications submitted to the MCHA Study Section. It was agreed that the study section needed to be more constructive and encouraging in their reviews to new investigators. Insensitive and inflammatory comments serve no useful purpose and discourage resubmission. Young investigators should know that preliminary results are essential. Without them, a program is not usually viewed with high enthusiasm. It is also important that they learn about the NIH peer review process early in their career. They should certainly apply for grant support before the end of their third year. The workshop panel felt strongly that the NIH should encourage new investigators by providing a set-aside amount of funding for the R-29 program. This community represents the pipeline of new researchers in science and should be given all the incentives that are possible.
The scope of the science reviewed by the MCHA Study Section should be broadened. The general feeling was that the Study Section should review applications that involve organic synthesis, medicinal chemistry, some bioorganic chemistry, physical organic chemistry, host-guest chemistry, solid phase synthesis, physical chemistry and molecular modeling of small molecules, and even some analytical methods development.
Reorganization of the Initial Review Group (IRG) to which the MCHA Study Section belongs, to achieve a better workload balance might be a desirable and reasonable approach.
SUMMARY. To the applicant pool, the advice is to continue to submit applications. Application pressure will undoubtedly result in more funding for chemistry. To the Study Section, the recommendation is to be more constructive and sensitive in review of applicant programs. To the NIH, the suggestions are to broaden the guidelines of the MCHA Study Section, perhaps by reorganization within the IRG or other overloaded Study Sections and to consider the provision of set-aside funds for the R-29 program. Organic chemistry is a basic and vital science and its continued and strong support through NIH extramural funding is in the best interests of the biomedical community and the Public Health Service.
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