The “study” role of past National Institutes of Health study sections

Abstract

The original National Institutes of Health (NIH) study sections had two missions. The review of grant applications was the enduring one that we all recognize. The second original function, less remembered today, was to stand ready to advise the NIH, and in fact the entire community in a given biomedical field, on the current state of that discipline, as well as to opine on what new vistas were arising and to suggest (or occasionally even launch) appropriate courses of action. The present contribution is intended to remind us of this lesser-known original function of NIH study sections. We might ponder whether today's study sections, although more overworked than Sisyphus, should again take up this second function.

INTRODUCTION

On 4–6 June 2012 the American Society for Cell Biology (ASCB) held a strategic retreat, the idea of ASCB President Ron Vale and kindly hosted by the Howard Hughes Medical Institute at their headquarters in Chevy Chase, MD. Although the focus was the state of the field of cell biology, at breaks there were other conversations. At lunch one day, my table got into a discussion about National Institutes of Health (NIH) study sections. It was not the usual one (all gripes, all negative, “everyone serving is guilty of poor judgment” even though “everyone” is us, etc.). Instead, the conversation flowed back to some cases I happened to mention when NIH study sections did more than review grant applications. This sparked some interest, and the discussion continued. One of the people at this lunch table was MBoC Editor David Drubin. He decided that this was a theme worth getting out there; hence this invited contribution, for which I thank him for giving me the opportunity.

THE ORIGIN OF STUDY SECTIONS AND THEIR CHARGE

Most MBoC readers will be surprised to learn that the organization we today call the NIH can be traced back as far as 1879. At first a loosely defined series of federal bodies overseeing medical science and U.S. public health, usually more in terms of policy than funding, these evolved over the next 70 years into a more coherently organized set of intermeshed operating agencies. A comprehensive treatise on the history of NIH peer review by Richard Mandel (Mandel, 1996) vividly recounts that in the post–World War II era the NIH dramatically morphed from an internal policy group into an outward-reaching funding agency, a transformation that was effected primarily by the 1946 creation of the Division of Research Grants within NIH, catalyzed by the visionary Cassius Van Slyke. Notwithstanding the growing intramural research program of NIH itself, the mounting requests for extramural funding at this time required the creation of a defined review system. One of the most evocative points Mandel brings forth is how diligently and passionately NIH officials such as Van Slyke visited universities and medical schools throughout the United States to promote the emerging existence of accessible funds for deployment outside, not just within, the walls of the NIH. We frustrated applicants today can hardly imagine a time when NIH officials went out as “circuit riders” to announce the ready availability of funds, but it really happened.

As these efforts triggered increasing requests, Van Slyke and his team saw the need to reorganize what had been a rather loosely defined review process in the preceding years. Thus 1946 saw the revamping of the peer review system via the creation of the study section program. Table 1 lists the initial NIH study sections. It is interesting to note that these included ones focused on specific and timely public health issues along with others with vast breadth in biology and medicine. The first to meet was the Syphilis Study Section, on 7–8 February 1946 (Figure 1). One of the issues they took up was a discovery strategy as familiar to us today as it was to them, namely a proposal to screen thousands of biological compounds, held by the Office of Scientific Research and Development, as potential drugs for this disease. The chair of this first NIH study section, Joseph Earle Moore, M.D., of Johns Hopkins University and Hospital, had been among the first to study the clinical utility of penicillin in the treatment of syphilis, and so it is an interesting historical note that he nonetheless was so supportive of additional drug searches for this disease.

TABLE 1:

The first NIH study sections.

Antibiotics

Biochemistry and Nutrition

Cardiovascular

Dental

Hematology

Malaria

Pathology

Physiology

Virus and Rickettsial Diseases

Syphilis

Compiled from Mandel (1996).

FIGURE 1:

The NIH Syphilis Study Section—the first study section—photographed at its inaugural meeting in 1946. Reproduced from Mandel (1996).

The creation of these “study” sections envisioned two distinct functions—the peer review of grant applications on one hand and periodic assessments of a given field on the other. In his account of these days when the NIH extramural program was becoming increasingly defined and organized, Mandel put it thus:

Stimulation of research fields proceeded more effectively through the medium of study sections, which emerged in 1948 as a mature function and the vital center of Division activities. Using the National Advisory Health Council as a forum for review and award issues, Director Van Slyke refined the grants administration process, redirected funding toward basic research, and encouraged the study sections to survey research fields and to promote new lines of inquiry. (Mandel, 1996, p. 35)

In this visionary statement resides the doctrine of a dualistic study section function—peer review of applications and self-propelled oversight of their emerging fields. Thus charged, the early study sections aimed for both missions. Let us look at a few cases when this broader “study” role of NIH study sections was in play.

A PRESCIENT TEXTBOOK

In 1958, the NIH Study Section on Biophysics and Biophysical Chemistry did a rather remarkable thing. In addition to dutifully reviewing grant applications at their regular meetings, during the breaks, as well as in correspondence and phone calls between scheduled meetings, the members of this study section decided, without ever being asked, to convene a special meeting. To its credit, the NIH Division of Research Grants supported this idea, both conceptually and financially. The meeting, entitled The Study Program in Biophysical Science, was held in Boulder, Colorado, from 20 July to 16 August 1958—obviously not a standard study section meeting time, but one conducive to a retreat at a pleasant site and in keeping with the notion of “study.” In addition to the study section members, it involved a judicious mix of 120 senior and junior scientists. Afterward, several of the leaders of this monumental meeting decided, in consultation with the study section's members, that many of the talks could form the basis of a textbook. These leaders were John L. Oncley (Harvard Medical School), Francis O. Schmitt (MIT), Robley C. Williams (University of California, Berkeley), Murray D. Rosenberg (Rockefeller Institute), and Richard H. Bolt (MIT). Oncley and Schmitt were the senior statesmen, Williams was midcareer (50 years old at the time), and Rosenberg was a very young colleague of the developmental biologist and study section member Paul Weiss. Bolt was an acoustical engineer at MIT whom the persuasive Schmitt corralled into helping with the book, in part because Bolt was at the time serving a stint at the National Science Foundation (NSF) and was able to garner some support for the project. (Note that the NSF and the NIH collaborated in funding this project.) Over the next year, the book organizers invited, cornered, and coerced a cadre of speakers from the Boulder meeting to each write a chapter. The result was a textbook (Figure 2) that constituted a unique and definitive statement on the states of various subjects within the combined fields of cell physiology, neurobiology, and biophysics (Oncley et al., 1959). In biophysics and its outreaches, touching and indeed informing cell biology in the field's foundational years, nothing like Oncley et al. had ever come forth. As a graduate student in 1963, I encountered this book, with chapters written by luminous stars of cell biology such as the electron microscopists H. Stanley Bennett, Fritiof Sjo˝strand, H. Fernandez-Moran, and Alan Hodge, as well as by the pioneering practitioner of polarized light microscopy Shinya Inoué, the prescient developmental biologist Paul Weiss, and the visionary cytogeneticist Ted Puck. Within 3 years of the book's publication, three of the chapter authors had received a Nobel Prize—Arthur Kornberg in 1959, Melvin Calvin in 1961, and John Kendrew in 1962—and a few years later two others had as well—Halden K. Hartline in 1967 and Bernard Katz in 1970. There is no book on my shelf more worn from very frequent pulling out than this one, and it was all from the “other mission” of this NIH study section.

FIGURE 2:

The extraordinary book organized by John Oncley et al. (1959).

As a footnote, it is to be noted that this same study section was not finished with their work. Later they strongly argued for, and indeed help to implement, the use of molecular models of protein and nucleic acid structures in both classrooms and in research laboratories, as yet another of their prescient view of their “study role.”

HOW TO CLONE A HUMAN

As an “interview” for the NIH Cell Biology Study Section in 1975, I went on a site visit at the University of Texas at Galveston for the review of a program-project grant application by Barbara Bowman and colleagues. She had come up with an ingenious assay of the viscosity of sputum from cystic fibrosis patients—a clinically critical parameter—based on the degree of inhibition of ciliary beating in the gills of oysters. I was fascinated by her insight and the superb quality of her science (her ingenious assay was essentially a kymographic report for the amount of polymerized actin in the sputum). At this site visit I met two future ASCB presidents who were collaborators on her project: T. C. Hsu and Bill Brinkley. Their key roles complemented Dr. Bowman's expertise perfectly—a triple-stranded helix. I can remember this site visit vividly, as if it happened last week. In any case, I apparently passed this trial run and was invited to join the Cell Biology Study Section in the fall of 1975. The chair at the time was the MIT embryologist Paul Gross, who was succeeded a year later by the Stanford biochemist David Korn and then, another year later, by the Purdue developmental biologist L. Dennis Smith.

At one of our meetings in 1977 we had gotten to chatting at dinner about the prospects of cloning a human. This conversation got more and more detailed and continued well after the table had been cleared. We talked about hormonal induction of ovulation, the risk to women so induced (I recall, proudly, that this obvious bioethics issue led our discussion), the low probability of getting an egg altogether, and the low success rate of somatic nuclear transfer as had been done at the time in nonhuman mammals. Other issues, such as a possible inherent incompatibility between a somatic nucleus and an enucleated egg, were also envisioned. Dennis Smith had done his Ph.D. with the amphibian-cloning pioneer Robert Briggs at Indiana University, and other members were experienced in culturing mammalian eggs and embryos, so this discussion was at a very high level. Of course, at this time (spring 1977) we did not know (much) about epigenetic marks on somatic DNA and (nothing) about how telomere length of the chromosomes in the donor nucleus might be a factor. Telomeres were only cytological entities at this time, though the discovery of the telomeric DNA repeat by Liz Blackburn and Joe Gall was just around the corner (only 11 months later).

When we convened the next morning to resume work Dr. Smith stunned us with an incredible announcement. He had just received a phone call from the Director of the NIH, Donald Fredrickson, who had asked him to have the Cell Biology Study Section deliberate on the scientific prospects of cloning a human being! To Fredrickson's amazement, Smith informed him that in fact the entire Cell Biology Study Section had held a lengthy, in-depth discussion of this very issue just the previous evening. After giving Dr. Fredrickson a fairly comprehensive overview of that discussion, he concluded by saying that, as of then, the cloning of a human was entirely possible but technically not very feasible. We later sensed that Dr. Fredrickson's request had arisen due to accounts in the press that such claims had been made, as well as perhaps media attention to a general-audience book on human cloning that had just appeared. In any case, we were not asked to follow up with a written report, and that was the last any of us heard about this inquiry.

THE NIH CENTER FOR SCIENTIFIC RESEARCH: A SECOND “MISSION IMPOSSIBLE”?

This essay was not intended to pile on to the avalanche of criticism of the NIH extramural review process. Nor do I suspect that the second function of NIH study sections I have portrayed here can be reactivated any time soon. I would simply like us all to think about this and gather our thoughts. One specific question is the following: how much of the NIH extramural budget should be in the hands of well-meaning program directors and the grant applications they solicit, followed by arranged ad hoc study sections they empanel? I think this has gotten somewhat out of control, although some of these program director initiatives have certainly been effective. The issue here is one of appropriate balance.

If the original “second function” (namely, “study”) of the NIH study sections were to be reignited somehow, what form would this take? Launching textbooks would not be as opportune as it might have been back in 1959, and the NIH director has many sources of advice beyond the study sections. (I often wondered whether Donald Fredrickson had simultaneously sought the advice of the National Academy of Sciences or the Institute of Medicine on the human cloning issue but I suspect not, as his early Saturday morning phone call suggested that he was in a hurry. I had wanted to ask him about this—we were acquainted, but did not have an opportunity before his untimely death.) Perhaps the first hour of each study section meeting could be devoted to a “state of the field” discussion with any seminal findings transmitted to both the appropriate council and the NIH director. Conversely, perhaps the NIH director could “do a Fredrickson” and envision the study sections as occasional advisory bodies. Realistically however, it might take a sea change in the NIH Director's Office to once again charge study sections to pursue this second mission, as initially envisioned. Perhaps we in the ASCB and the other societies can start the conversation, bearing open minds and examining any pitfalls that might attend the proposition. If a consensus emerges that study sections are a treasure of talent and might be asked to do more than review grant applications, then we would need to find a way to make this happen. But one step at a time.