A SCIENTIFIC DIRECTOR'S VIEWS 

by Allen M. Spiegel, Scientific Director, NIDDK

NIDDK's strong support of chemistry is the legacy of Bernhard Witkop and other key chemists from a previous generation, including John Daly and Kenner Rice (present lab chiefs) and their academic "progeny," including Don Jerina, Phil Skolnick, and Ken Jacobson. Notwithstanding the complaints that chemists are making now, this tradition of support continues. In addition to having two major chemistry labs (Daly's and Rice's) with substantial space, positions, and budgets, there is a service facility (Lab of Analytic Chemistry) with three staff scientists and expensive mass spectrometry and nuclear magnetic resonance imaging equipment devoted to the analysis of compounds made by our chemists as well as by those of other institutes, such as NCI. NIDDK Director Phil Gorden has only half-jokingly referred to NIDDK's intramural research program as "the Intramural Research Program of NIGMS," reflecting our strength in many of the basic sciences traditionally supported extramurally by that institute. NIDDK's intramural research program obviously supports "mission-oriented" research in diabetes and digestive and kidney diseases, but it also heavily supports fundamental research in areas such as structural biology (both X-ray crystallography and NMR spectroscopy) and molecular biology. In this context, NIDDK's support of chemistry research is not an anomaly. It is in keeping with our general commitment to outstanding basic science.

The key question is, Why should NIH's successful and well-supported chemists evince such low spirits now? I suspect that this stems from a feeling of being eclipsed by other, newer research approaches. Until the late '70s and early '80s, much of what now goes on at NIH and other biomedical research facilities (recombinant DNA, transgenic and knockout mice, novel cell-imaging techniques) didn't exist. It isn't difficult to imagine that chemists feel as if their time has passed when they see such powerful new approaches dominating the biomedical research scene.

I believe that what chemistry at NIH needs now is a sustained commitment to excellence in which we continue to recognize and support truly important chemistry research where it already exists and recruit its practitioners where needed. Stuart Schreiber at Harvard and Roger Tsien at the University of California at San Diego (UCSD) exemplify the types of chemists the intramural program would be more than happy to have working here. Rather than lament the eclipse of traditional chemistry by molecular and cell biology, these scientists have aggressively embraced new disciplines - not by abandoning synthetic chemistry but by combining the old and the new in creative, synergistic ways. Even if we lack the resources to attract established scientists such as Schreiber and Tsien, we may well be able to replace departing chemists with outstanding junior recruits.

Allen Spiegel

There is no doubt that medicinal chemistry research still has a major role to play in biomedical research; despite the rise of biotechnology, most drugs that are useful for treating human disease still come from classic screening and/or synthesis programs. There is also little doubt that organic chemistry research has a major role to play in biomedical research. The recent development of combinatorial chemistry techniques is but one example. An important question here, however, is where such research is best and most appropriately done? Most medicinal chemistry has traditionally been done by drug companies that have the infrastructure to support all relevant aspects of the process.

For medicinal chemistry to be pursued successfully at NIH, it must be connected in some meaningful way to pharmacology and other biologic disciplines that can take a collection of molecules and determine where and how they act. Rice's program on opioids and other neuroactive drugs exemplifies how this can be done well. Compounds he has synthesized have been key in defining novel opiate receptor subtypes and have been used in PET scanning. The crucial point is that he always interacted with collaborators to study relevant biologic aspects. Jacobson's is another example of a successful program in which synthetic organic chemistry has been joined with molecular biology. His compounds were critical for labeling and purifying adenosine receptors. But synthetic organic chemistry cannot stand alone; in my view, it must be done in a biologic context. Daly embodies the effective joining of chemistry and pharmacology in a single individual and program. He has been able to identify novel and unique natural products and define both their structure and pharmacology. Many of these compounds have become important tools used by biochemists, physiologists, and pharmacologists. NIDDK will continue to support chemistry as long as it is outstanding and has the potential to have an impact on biomedical research.

I make no apologies with respect to our insistence - and the insistence of our board of scientific counselors (BSC) - that chemical work should have biological relevance, because we all interpret biologic relevance in the broadest sense. The work of Ad Bax, one of NIDDK's most outstanding "chemists," is not "biologic" in any strict sense - he works on fundamental aspects of NMR (see box). However, his work provides the basis for using NMR to solve the 3-D structure of biologically relevant macromolecules. As scientific director of NIDDK, I am delighted to support this type of fundamental research because it is absolutely outstanding and creative. We can readily see its biologic relevance.

Complaints about the evaluation of chemistry and the use of ad hoc counselors by the BSC are hardly unique to chemistry. NIDDK has a large and diverse intramural program. Even with a distinguished and broad BSC it is not possible for its members to represent every discipline and subdiscipline of those being evaluated. In part to meet that concern, NIDDK implemented an additional approach to the BSC review about a year and a half ago. We now obtain letters from scientists outside NIH evaluating everyone being reviewed (not just the people being promoted) before the BSC visit. These letters are obtained from individuals in the same discipline as those being reviewed. The BSC reads them after they have reviewed the written material and heard the labs' presentations, and the letters are subsequently incorporated in the BSC's written reports. Although not perfect, this approach helps ensure that there is input from individuals working in the same area as those being reviewed.

In response to reports from the BSC, I have closed branches and downsized labs, but the cuts have not fallen disproportionately on chemistry and have included areas such as cell biology and endocrinology. Harold Varmus and Michael Gottesman can't tout the rigor of intramural review to our external advisors and other oversight groups if the scientific directors do nothing in response to poor reviews. Inevitably, members of labs being "squeezed" will complain, but this cannot be viewed as an assault on chemistry as a discipline. As for the complaint that the programs of retiring chemists are not being continued, NIH has no entitlements or mandates that any specific scientific programs must continue in perpetuity, including when a principal investigator departs.

In this era of no-growth budgets, such hard-nosed scrutiny and reassessment of research priorities has become a fact of life in order to make room for new, cutting-edge science. I see important growth areas for NIDDK in revitalizing our clinical research effort. Toward this end, we have recruited a new liver disease section chief and are currently recruiting a thyroid investigator for our NIDDK-NICHD endocrine training program; bolstering the areas of transgenic and knockout mice, and continuing vigorous support of structural biology through tenure-track recruitments made in solid-state NMR and X-ray crystallography.