CHEMISTRY AND BIOLOGY,
FINDING THE EQUILIBRIUM AT NIH

by Celia Hooper and Rebecca Kolberg

Maybe it's just part of the age-old scramble for scientific resources and respect. Maybe it's much ado about nothing. But then again, maybe it's a Kuhnian paradigm shift in which NIH scientists are increasingly turning to molecular biology, rather than pure organic chemistry, as the favored source of new raw materials, molecules, and ideas for their biomedical research.

Amy Hauck Newman

Whatever is going on, one thing is certain: it's not easy being an organic or medicinal chemist at NIH these days. Some senior chemists report being squeezed out of lab space or finding themselves afraid to ask for funds to buy essential equipment. Younger chemists are fighting to convince their molecular biology colleagues - as well as tenure-review committees - that they are much more than simple craftspeople. And newly minted Ph.D.s in organic and medicinal chemistry are finding a dearth of postdoc slots in intramural labs.

On the basis of such concerns, the American Chemical Society (ACS) has repeatedly called on NIH over the past two years to strengthen organic and medicinal chemistry in the intramural program. In a 1995 letter to NIH, ACS President Ronald Breslow said he had looked into the situation of health-related organic chemistry in the intramural program "... and have been assured by some chemists at NIH that the situation is as bad as I had feared."

In the same vein, a former ACS president, Ned Heindel, wrote to NIH in late 1994 to warn about the "weakening" of NIH's biological and medicinally related chemistry programs and to inform him that "the attractiveness of postdoctoral work at NIH for chemists has diminished."

Both Breslow and Heindel acknowledge that NIH has a proud tradition of organic and medicinal chemistry, represented by Bernhard Witkop, William Clark, Claude Hudson, and Lyndon Small, among others. However, they express concern that when luminaries such as these retire, they and many of their programs have not been replaced. To continue the intramural chemistry tradition, Breslow, a professor of chemistry at Columbia University in New York, is advocating that NIH recruit an organic or medicinal chemist of "international stature."

To get a bearing on whether NIH - especially its chemists - see the same problems and support the same solutions as the leaders of their professional society, The NIH Catalyst asked our readers and a variety of intramural chemists - from those just placed on the tenure track to long-time lab chiefs - for their opinions on the state of chemistry today, including the role for chemists in today's biomedical research environment and how they think NIH has treated the chemistry profession. In this issue, we present a sampling of the responses we received along with articles featuring insights from the chief of one of the largest chemistry labs at NIH, John Daly; one of the most-cited scientists in chemistry literature, Ad Bax; and a distinguished biologist and scientific administrator at the center of the storm, NIDDK Scientific Director Allen Spiegel.

WHAT THE CHEMISTS SAY

Louis Cohen, NIDDK: "As a science, chemistry can never die. It is the practice of chemistry that is dying, but only because the NIH administration and directors of the individual institutes have chosen to kill it. This choice is terribly misguided and short-sighted. The currently popular arts - molecular biology, genetic manipulation, immunology, virology - are all built on the basis of chemistry and will sooner or later hit a stone wall without the input and collaboration of chemistry and chemists."

Ronald Breslow

Victor Marquez, NCI: "It is obvious that many of our friends in biology ignore the fact that everything in their biology is happening through chemistry. Chemistry is still regarded as a subservient science at NIH."

Thomas Spande, NIDDK: "The current research climate is not particularly supportive of chemistry, either medicinal or organic, as evidenced by these personal observations: three major natural products programs in NHLBI, NCI in Frederick, and NIDDK have been severely cut back; the long tradition of a biweekly seminar for organic chemists [has] died ... there just were not enough participants; the Building 8 chemical stockroom is now the only one on the Bethesda campus (there were three previously); chemists have to periodically fend off proposals by the NIH library to discontinue even key chemical reference works, such as Beilstein; and chemically oriented NIH labs are lucky to find even one chemist (if so, usually an ad hoc addition) on panels of outside scientific counselors.

Jane Sayer, NIDDK: "In general, facilities and support services are designed to meet the needs of biological scientists rather than chemists. For example, subscriptions to several major chemical journals and reference works are being discontinued by the NIH Library. ... In the design of our [Bldg. 8] hood system, no provision was made for conditioning or dehumidifying the incoming air, with the result that handling moisture-sensitive materials in these hoods presents a considerable challenge. ...The Building 8 chemical stockroom, the only such facility on campus, is in need of inventory and extensive reorganization."

Henry Fales, NHLBI: "While chemists themselves are accepted as useful, perhaps even necessary, professionals, chemistry is not recognized as a valid activity in its own right. There is indeed no encouragement to create or study molecules for the light they may shed on physical or chemical, as opposed to biological, processes."

Kenneth Kirk, NIDDK: "Chemistry is treated with respect and appreciation by most senior, practicing scientists, particularly those who have worked with chemists. However, administrators and policy makers sometimes give the impression that they think of chemists as slightly misguided scientists who don't quite understand what biomedical research is about."

Mark Sassaman, CC: "Sadly, the field of chemistry is a neglected discipline in the intramural program. The tremendous achievements at the interface of chemistry and biology are now to be found at institutions such as Scripps Research Institute (La Jolla, Calif.), which have reorganized their research programs to utilize the science and art of chemistry as the central focus in multidisciplinary surroundings. The consequence of such reorganization has led to an immense body of work, including the synthesis of taxol and other chemotherapeutic agents, the discovery of sleep-producing lipids in the brain, asymmetric syntheses of complex carbohydrates, self-assembling molecular cages, and the discovery of 'new' chemistry."  

Medicinal Chemistry Award One sign that all is not doom and gloom in NIH's chemistry community is the recent awarding of one of chemistry's most prestigious honors to an NIH chemist, Kenner Rice of NIDDK. Rice received the 1996 American Chemical Society Division of Medicinal Chemistry Award in June for his research on neurotransmitters in the central nervous system, with an emphasis on drugs of abuse. Currently chief of NIDDK's Laboratory of Medicinal Chemistry, Rice earned his Ph.D. at Georgia Institute of Technology in Atlanta and came to NIH in 1972 after stints at Walter Reed Army Institute of Research in Washington, D.C., and Ciba-Geigy Corp. in Summit, N.J. A process that Rice developed, called the "Rice process," is the only practical method for the large-scale production of medical opiates by total synthesis. In addition to giving the United States independence from foreign sources of opiates for use in medicine and research, Rice's work has furnished medicinal chemists with valuable new research tools and the potential for developing new nonnarcotic drugs.

Paul Torrence, NIDDK: "There is little doubt that NIH and its hierarchy possess a diminished appreciation of chemistry - the central science. For instance, biomedical researchers have quickly forgotten the years of esoteric and mostly unheralded nucleic acid chemistry that now makes it possible for anyone who can read and count to use a DNA synthesizer.... Organic and medicinal chemistry are viewed as handmaidens or apothecaries to the medical sciences."

Kenneth Jacobson, NIDDK: "Researchers in industry know well that synthetic chemistry has not been superseded by molecular biology. There is an impression by some at NIH that the Human Genome Project and gene therapy will solve most medical problems in the future. As more protein targets are identified for therapeutic intervention, we will need small molecules to interact with these proteins. Structural biology is a major focus at NIH, but using this knowledge for therapeutic goals can generally benefit from a chemical synthetic approach."

Paul Kovac, NIDDK: "No matter whether some like it or not, everything around us is chemistry, including us, functioning or malfunctioning. Understanding any chemical phenomenon better can potentially help us understand complex phenomena in the life sciences. Therefore, any attempt to cut support of chemistry at NIH would be, putting it mildly, short-sighted."

On Changes Over the Past Decade

Spande: "Years ago, I collaborated in the probing of the binding site of one of Michael Potter's myeloma antibodies by synthesizing a heavy-atom-containing phosphorylcholine ester. This collaboration involved X-ray crystallographers, an M.D. (Potter), and biochemists, and it led us to one of the first visualizations of an antibody combining site by X-ray crystallography. I don't see this sort of collaboration occurring so readily now. I am uncertain of the reason, but it may have to do with the diminished visibility, due to declining numbers, of the chemical community at NIH. A lot of researchers may simply be unaware of our existence. Our numbers may be dropping below the threshold necessary to make waves or wield much clout."

Fales: "It seems unlikely that the contributions of the chemical community at NIH were better appreciated in the past, but due to easier sources of money and labor, we were better tolerated."

Kovac: "NIDDK's Laboratory of Chemistry was the oldest, one of the most successful, and, arguably, one of the most widely known and respected parts of NIH. That almost legendary institution no longer exists today as a structural unit."

Kirk: "I feel fortunate that I am not a young chemist at NIH because present-day postdocs in chemistry have virtually no opportunity to consider NIH as a career, no matter [how great] their talent. And I have very impressive postdocs."

Amy Hauck Newman, NIDA: "I have recently received over 50 applications for a postdoctoral position in my laboratory. Many of these applicants are coming from top-of-the-line laboratories and expect to have the opportunity to do cutting-edge research in medicinal chemistry. If chemistry is relegated to being a service and there isn't funding to conduct high-quality research, these young scientists will not be attracted to NIH."

Victor Marquez and Maqbool Siddiqui

On Criteria for Judging Chemists' Work

Marquez: "The impact that structural chemists have had in recent years on solving complex biological structures is beginning to be appreciated more fully. Sometimes, however, these people are not identified as chemists, but simply as X-ray crystallographers or NMR spectroscopists. The impact of synthetic organic chemistry is much less. If the molecular targets are too complex, the work is considered to be an esoteric exercise. If the molecules are simpler, after a few publications, the chemistry is gradually forgotten."

Jacobson: "It is rare that medicinal chemistry is accepted in the big-name journals; thus, this should be less of a criterion for judging chemists' merit. Biological relevance of the chemical work is essential at NIH."

James Silverton, NHLBI: "Science and Nature are very interesting journals, but do chemists and other physical scientists publish much there today? For myself, publications in the preeminent chemical journal, the Journal of the American Chemical Society, represent my highest achievements."

A Senior Chemist's Perspective by John Daly, Ph.D., NIDDK I came to NIH in 1958 as a postdoctoral chemist with Bernhard Witkop of NIAMD's Laboratory of Chemistry after receiving my Ph.D. in natural products chemistry at Stanford University in Palo Alto, Calif. Thirty-eight years later, I find myself chief of NIDDK's Laboratory of Bioorganic Chemistry, which, with nearly 50 scientists, is one of the largest - if not the largest - chemistry labs in the intramural program. John Daly One could write a book on how important chemistry is to all other research conducted at NIH, including the currently emphasized molecular biology research aimed at gene therapy. Our discipline has designed and synthesized or isolated and elucidated structures of virtually all drugs used to treat human disease. Despite this overwhelming evidence of the value of chemical research in achieving biomedical goals, NIH today is suffering from an acute lack of appreciation for chemistry, a serious diminution of resources for chemistry, and a disturbing decline in the morale of its chemists. In this era of fiscal restraint, NIH chemists often do not compete well for resources with the very costly field of molecular biology. At one time, my fellow chemists and I believed that our science was appreciated and fairly judged by the Board of Scientific Counselors, who used to have one chemist member rather than the current token, ad hoc chemist. Now, the counselors' reports usually state that our chemistry is good, but so what? If the biological aspects are not being pursued with brilliant success either by biologically oriented staff within the group or by strong collaborations outside the group, the program is judged a failure. If chemistry is a dying art at NIH, it is not dying because of the lack of excellent chemistry, but because of lack of money, positions, space, adequate review processes, and opportunities for collaboration. Another difficulty facing chemists at NIH is the new two-pronged career path, which relatively early on classifies a promising postdoc as an independent "tenure-track scientist" or a more collaborative "staff scientist." During postdoc training, chemists develop insights into how chemical approaches can be applied to achieve biomedical objectives, for example, in pharmacology, drug design, and molecular biology. It is often easy to recognize an outstanding practitioner of the "art" of chemistry, but in most cases, only years will tell whether he or she will develop the all-important interface with biologically relevant programs. The tenure-track system does not serve chemistry well because most senior chemists at NIH have inadequate numbers of postdocs to pursue their own goals and hence are loathe to bring on a promising young chemist and provide him or her with two postdocs and complete independence for six years. If I were to do that, I would have no postdocs to pursue my own projects. Unfortunately, chemistry now appears to be considered a science that NIH should, at best, keep at token levels. Consequently, the mindset of many intramural chemists has markedly changed for the worse over the years. Many biological scientists now seem to think that any chemistry needed at NIH could merely be contracted out. Somehow, strong, true collaborative links between biologists and chemists are now relatively rare at NIH, and chemists are often treated like "service providers." The development of such collaborations receives no apparent encouragement from the NIH leadership. I feel that NIH should increase or at least maintain support for chemistry, even if the good basic research does not have an obvious biomedical impact. No one can truly predict the direction and impact of basic research in chemistry - or in any other scientific discipline. At NIH, if there is not immediate biomedical gratification, chemistry receives poor marks. Many other NIDDK chemists and I perceive, perhaps incorrectly, that the treatment of chemistry in our institute is designed to encourage us to leave, as well as to keep us from bringing on any young chemists to replace us. In fact, I have been told that my program will be abolished when I retire. I see in this decision a bittersweet recognition of my personal importance, and simultaneously, a failure to recognize the importance of natural products research to our institute and of chemistry to biomedical research as a whole. The programs of several other senior chemists also seem destined to be abolished when they retire. If no steps are taken to change the attitude toward chemistry at NIH, I fear that at some point, there will be no one left to continue NIH's once-proud tradition of chemistry.

Kirk: "One concrete step [toward improving the morale of NIH chemists] would be to allow us to be evaluated by a Board of Scientific Counselors that understands chemistry. This review committee is gaining increasing power over the fate of intramural researchers. It is discouraging - even frightening - to have one's research program evaluated and future career influenced by a panel of scientists who have such a bias toward their own approach to biomedical research - and who don't seem to understand either the problems or the promises of chemistry."

C.P.J. Glaudemans, NIDDK: "Over the years, the [boards of scientific] counselors have been given power in lieu of their counseling role. I do not believe that the scientific directors hide behind the counselors to execute their own agenda. I do believe that the counselors can force the hand of the scientific directors by their own agenda. This is an executive tragedy and negates the responsibility of the scientific director, as well as the laboratory and section chiefs. ...We should abolish the practice of counselors altogether, or at least go back to the role of counselors as counselors, as in the past."

Fales: "My biological colleagues have always exhibited the deepest interest in my techniques and in my general welfare at NIH. Sure, they probably do regard me as a "craftsman." Why wouldn't they? I perform a valuable task in helping with a crucial part of their experiments, but the emphasis usually is on part. They also understand vaguely that I must have some other 'chemical' project that is my main interest. They would be universally shocked if I suggested that this was elucidating the pathway of oncogene regulation or something similar. On the other hand, in the board of scientific counselors' review, this is precisely the sort of activity in which I am expected to be engaged."

On the Solutions

Torrence: "The very last thing NIH needs ... is a knight in shining armor of great repute brought in from the outside with his or her research clique. This would be a coup de grace to morale among those present at NIH... . Instead, resources could be allotted to the chemistry effort as a whole across campus. An outside individual could then be recruited as a 'chemistry chair' to further develop and implement a vision of chemistry in a biomedical environment, not for his or her personal aggrandizement but to establish a first-class department. ... This chair would report directly to the NIH director and be able to bring new investigators on board to suit his or her vision. With much good fortune, such an individual could help restore chemistry to its critical role in biomedical research at NIH."

Sayer: "Two measures that should be considered to support and revitalize chemistry at the NIH are 1) to change the way review groups are selected and organized, and 2) recruit one or two outstanding chemists who already have established programs and strong international reputations, either to set up new laboratories here or to take over the leadership of existing ones when laboratory chiefs retire."

Spande: "Acquiring some illustrious chemist from the outside would only make matters worse. ... It would be better, I think, to increase the number of chemists at NIH and add to the support staff. NIH does have a nucleus of outstanding chemists; what is needed is a pool of younger chemists to provide the next generation of leaders. NIH might also create a permanent lecture series ... inviting experts to present new techniques or topics of general interest to chemists. This would benefit not only NIH chemists, but the entire local chemical community."

Jacobson: "The synthesis of new molecules of biological interest could contribute to many projects ongoing at NIH. This does not mean starting programs devising new synthetic methods, i.e. 'chemistry for its own sake,' but rather using synthesis as a means of solving medical problems. If NIH is to recruit a well-known chemist, it should be someone who already works at the interface of chemistry and biology."

Sassaman: "The NIH infrastructure needs to be amended to take advantage of such an important resource. Ideally, this would include establishing a chemistry colloquium to allow for discussions, seminars, and collaborations within and across disciplines; expanding the chemical community; and encouraging research in chemistry, where goals are not narrowly defined by the mission of a particular institute, but by a broader sense of biomedical exploration."

Newman: "The lines of communication between chemists and scientists in other fields seem to have diminished to a point that the importance of our science to overall research at NIH has been forgotten. In many ways, the responsibility of enlightening our colleagues to the synergistic potential that we could provide by putting our heads together, is ours. With support (both in resources and morale), this responsibility would be more readily assumed."

Torrence: "Chemists are a disempowered minority that will continue to diminish in stature at NIH unless it finds a united, political voice. ... Simply put, in the present situation of multiple chemical fiefdoms, it is impossible to defend turf."

Cohen: "Unfortunately, too much damage has already been done, and repair may be extremely difficult and time-consuming. NIH has lost its international reputation as a Mecca for bioorganic-medicinal chemists because the word is out that these areas of research are receiving minimal support and recognition."

Ad Bax NIH's Most-Cited Chemist Ad Bax, Chief of the Section on Biophysical NMR Spectroscopy, Laboratory of Chemical Physics, NIDDK, was listed as the most-cited chemist in the world by the Institute for Scientific Information in 1993 based on the average citation rate of his papers in the 1980s. He discussed his impressions of chemists and chemistry with The NIH Catalyst. Q: Do you see yourself as a chemist? Bax: I don't have a degree in chemistry - I'm a physicist by training - but the kind of work we do now is more related to chemistry and biochemistry. Q: How did you get into chemistry? Bax: I worked for my Ph.D. degree on the development of magnetic resonance techniques that are applied in chemistry. This required a little bit more physics than most normal chemistry-type experiments. A physics background is quite common among NMR spectroscopists. The postdocs in my lab have either a physics or chemistry background. Q: What do you consider your most significant achievement? Bax: We've been able to develop a number of techniques in magnetic resonance that have become very useful to a lot of my colleagues for solving important problems. So, it's not one particular single achievement, it's a number of contributions that people are using widely now. Q: How do you think the science of chemistry is regarded at NIH compared with other biomedical institutions? Bax: I think there's a lot of respect for chemists, but then there's also possibly a feeling, particularly in the medical community, that a lot of the important questions are in areas such as molecular biology, structural biology, and cellular biology. As an institution, NIH seems to be quite supportive of chemists, as far as I've been able to tell. Q: The American Chemical Society has called upon NIH leadership to recruit one or more chemists of international stature to replace the ones who've left recently. Bax: I sympathize both with the ACS and the NIH leadership who would have problems, possibly, in making the commitments of space needed to hire a big name chemist, because it would be at the expense of something else. Q: Chemistry papers generally don't get published in Cell, Nature, and Science. Do you think this handicaps tenure at NIH for chemists? Bax: Possibly, if they were exclusively evaluated by people working in biology or medicine, because those are considered the top journals in those fields. In my experience, the tenure committees have been diversified enough that there always were people who could put it in perspective and evaluate the quality of science that is not always related to the journal in which it has been published. I can't speak for all of NIH, but I don't think that tenure decisions have adversely affected the quality of chemistry here. Q: It seems as though chemistry journals don't get the same citation rates as the molecular biology journals. Bax: That's true; they're typically lower. It's another order of magnitude lower in mathematics. It doesn't mean that the mathematical sciences are of a lower scientific level. One cannot directly equate the number of citations with the importance or quality of scientific work that people conduct. Q: How have you evolved as a chemist? Bax: Maybe I've evolved into a chemist! I've evolved from working in small molecules to working on nucleic acids and proteins, and developing methods for studying them. NIH was a natural environment for me to start doing this, primarily stimulated by my colleagues. I've been extremely lucky that I was at NIH at the right time to apply the newest methodology to proteins, and that there were sufficient funds available for this type of expensive work. In academia it would have been very difficult for me to do this at the same kind of speed, because there's this enormous timelag while one applies for funds. At the time, the field was developing very rapidly, so this allowed us to stay ahead of the pack. Q: Do you have any concrete suggestions for improving the status of chemistry and chemists here at NIH? Bax: It is critical for NIH to keep a sharp eye on where in chemistry significant advances are anticipated and to take advantage of its ability to rapidly build up in such an area.

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