Changing Scientific Times Drive NIGMS Research Agenda

SIDEBAR: High Risk, High Payoff From the early days of research in molecular biology--the discovery of restriction enzymes, which paved the way for recombinant technology, for example--to pharmacologist Alfred G. Gilman's 1994 Nobel Prize-winning investigations of G proteins, scientists funded by the National Institute of General Medical Sciences (NIGMS) have been advancing the life sciences. In fact, more than half of the National Institutes of Health-supported Nobel Prize winners have received grants from NIGMS. Today the institute--which supports extramural investigators almost exclusively--funds basic research in such areas as cell biology, genetics, and biochemistry aimed at finding out how systems work, usually before the implications for specific diseases are known. Last October, NIGMS reorganized its administrative structure with the purpose, according to an institute statement, of becoming more efficient in its support of basic biomedical research and training and to reflect the increasingly interdisciplinary nature of science. Specifically, four program branches--cellular and molecular basis of disease; genetics; biophysics and physiological sciences; and pharmacology and biorelated chemistry--have been reorganized into three divisions: cell biology and biophysics; genetics and developmental biology; and pharmacology, physiology, and biological chemistry. Two other NIGMS programs have also become divisions: minority opportunities in research and extramural activities. Cost-cutting measures, as part of the Clinton administration's efforts to decrease the federal work force--particularly middle management--was a secondary, but not a deciding, factor shaping the reorganization, institute officials maintain. They point out that no one at the institute has lost his or her job as a result of the restructuring; however, they say, NIGMS is meeting its goal of reducing employee numbers by not filling some open positions. HIGH RISK, HIGH PAYOFF In a Nov. 7, 1994, letter, Marvin Cassman, acting director of the National Institute of General Medical Sciences (NIGMS), informed NIGMS grantees that the institute is "making special efforts" to fund applications that contain risky or unorthodox ideas or methods. Specifically, these would be applications that contain ideas that challenge current dogma; include experimental approaches that have inherent or unavoidable elements of risk; propose experimental models that are not fully developed or whose utility is not adequately shown; and/or are lacking data to establish the feasibility of the proposed ideas. "A lot of people in the field don't seem to know that about a year ago the institute and our council recommended that we take 5 percent of our competing research dollars and set it aside to support 'risky' research," Cassman says. These types of grants are typically funded for two years for a total of $120,000 in direct costs. "These are applications that would have gone through the normal peer-review process, not a separate [call for proposals]," and would likely have been denied, he explains. "These would be applications where the [study section] said: 'This is really a terrific proposal. It has exciting possibilities. But the preliminary experiments aren't done yet. But we're not sure that it's going to work. But the investigator hasn't had much experience in this area.' "It's all of these 'buts' that are so damaging in peer review. We're looking for applications where the reviewers themselves said: 'If it works, it's potentially very important.' And it's those [proposals] that we're taking a flyer on." "We're trying to subtly influence [grant applicants'] behavior," maintains W. Sue Shafer, associate director for extramural activities. "We want scientists in the field to be a little less conservative and put some of their riskier ideas that they feel would really have a high payoff into their applications. We're not asking for any special treatment in the review process, although DRG [NIH's Division of Research Grants] is encouraging reviewers to note--regardless of how they are scoring the applications--where they think there is something that is risky but if it panned out would be very important." Judith Greenberg, director of the genetics and developmental biology division, adds: "In my own view, investigators are so conditioned by the system that they need to submit a safe application. Even though they have novel ideas, they often keep them to themselves." In the long run, however, for the progress of science, these applications need to be funded, she asserts: "You never know what's going to turn up [in conducting science]. It could be a bomb, but on the other hand, the payoff could be enormous. If it turns out to be correct it could really result in a whole paradigm shift." Greenberg maintains that NIGMS is actively driving to change at least part of its funding strategy because "although scientific research is in the midst of an era of tight budgets, [researchers] still need to push science." --K.Y.K. "Part of the immediate incentive was the requirement to streamline as with all other parts of the federal government," explains Marvin Cassman, acting director of NIGMS. "You just can't ignore that. In addition, the [old] programs have been in place for a long time, 10 years for some and 20 for others." He says that "it was time to reconsider how we grouped our research portfolio" to reflect the way science has grown and the different directions in which it has developed. He adds that Ruth Kirschstein, NIGMS director from 1974 to 1993 and currently deputy director of NIH, was instrumental in focusing the institute's research and training programs. W. Sue Shafer, associate director for extramural activities, says that some NIGMS-funded scientists were concerned that certain areas of science would no longer "have a home at NIGMS." But because the institute solicited broadly for comment from its scientific constituents during the review phase of the reorganization proposal, she maintains, groups such as professional societies that were especially concerned did have input into the restructuring, thereby dissipating their apprehension. John Perkins, president of the Rockville, Md.-based American Society for Pharmacology and Experimental Therapeutics (ASPET), concurs with Shafer's assessment, noting that ASPET officials were involved in an external review of the reorganization and pronouncing ASPET "comfortable" with the scheme. "We're still funding the same constellation of projects. What we hope is that the new organization will stimulate new interactions and perhaps new connections between areas of research that we support," stresses Cassman. One area that is new is an initiative to fund projects that contain risky or unorthodox ideas and methods (see accompanying story). James Cassatt, division director of cell biology and biophysics, says this division "brings together the cellular aspects of biomedicine--how the cell is organized and how things happen within the cell--with those programs where people are trying to explain these same things but in molecular terms." He adds that the division's programs also dovetail with initiatives that look at "the detailed three-dimensional structures of many of the molecules that are involved" in cellular processes. Among many "exciting" areas of research in the division, Cassatt cites projects elucidating the three-dimensional structure of such mo-lecular motors as the muscle protein actin; studying the proteins embedded in cellular membranes; and determining the structure of various G proteins and nucleic acid-binding proteins. In biophysics, Cassatt remarks, "we're supporting a lot in the area of protein folding. If you're working for a biotech company and you make a protein, you have to make sure it folds properly. "Recently it's been discovered that there are helper molecules called chaperonins that help in the folding process. Ultimately what one would like to do is to look at an [amino acid] sequence and deduce from that sequence the structure of the folded protein. Nature, of course, does this very well and the information is there, we just don't know how to interpret it completely." Judith Greenberg, director of the genetics and developmental biology division, comments that "one of the extremely hot areas" of research in her division has focused on cell-cycle regulation. Scientists in this field, she explains, study what causes cells to divide, what stops cells from dividing, and how cells proceed through the process of replicating DNA to undergoing mitosis. "In the last several years, cell-cycle regulation has really been taking off in a big way," she elaborates. "There have been a lot of discoveries in what appear to be disparate areas of research that have all been coming together and causing just an explosion of information. A lot of this feeds into cancer research, also." She mentions that the study of cell-cycle regulation is also important to determining what genes regulate very early development in embryos. "It will have an impact, I think, on understanding birth defects," Greenberg predicts. Another "explosive" research topic, she reports, is "the whole area of homologous recombination, better known these days as gene targeting." This basically entails coming up with a way of substituting one gene for a very similar one in a cell, which is useful in creating transgenic mice, among other applications. "A big breakthrough a number of years ago was the ability to get a specific piece of DNA into the right location on a chromosome. These cells are put back into a mouse, so you can create a mouse that is lacking a specific gene or one that has a gene that's in some way been modified from the norm." She says two NIGMS grantees originated some of those gene-targeting technologies, which eventually led to the development of the mouse model for cystic fibrosis. "Another area that we have just been moving into is transcriptional regulation--what turns a gene on and makes it active," adds Greenberg. "This [field of study] has now moved beyond what I would consider genetics into structural biology. What's happening is that scientists refine certain protein-DNA interactions, such as transcription factors, in the genetics program. This work then moves over into the realm of structural biology as people start to look at [molecules involved in transcription] with X-ray crystallography and NMR [nuclear magnetic resonance imaging]." Michael Rogers, acting director of the newly formed pharmacology, physiology, and biological chemistry division, says that research in his section covers a number of areas, including molecular pharmacology; the molecular basis of the action of anesthetics; and understanding the pathogenesis of septic shock and the molecular basis of wound healing in burn victims. Specifically, he notes that biochemistry-related projects that fall under the aegis of this new division "look at basic problems of how proteins are handled in the body--how they actually carry out their catalytic function." This division also has a large program in synthetic chemistry, which is primarily directed towards drug synthesis, namely learning how to produce drugs that come in only one chemical configuration. "You can have drugs that are the same [substance], but exist in different configurations [isomers], sort of like your two hands, which are the same, but they don't fit on top of each other," Rogers explains. "Working out ways to prepare just one molecule is very important right now to the drug industry." Rogers likens this scientific conundrum to finding the right molecular key to fight diseases: "Sometimes those drugs--the right-handed key vs. the left-handed key--might have very different effects on the body. But most chemical reactions will produce both the right-handed and the left-handed forms, and most drugs on the market today are an equal mix of both forms. Sometimes one of those is the active drug and sometimes the one that's inactive may be involved in some of the [drug's] side effects. So there's been a push to develop new medicines that only have one of the isomers," so as to minimize the harmful side effects. For more information on NIGMS programs, contact W. Sue Shafer, associate director for extramural activities, National Institute for General Medical Sciences/National Institutes of Health, 45 Center Dr., MSC 6200, Natcher Building, Room 2AN-32C, Bethesda, Md. 20892-6200; (301) 594-4499. Fax: (301) 480-1852. E-mail: wst@cu.nih.gov.

Changing Scientific Times Drive NIGMS Research Agenda

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