National Institutes Of Health Study Sections Research Articles

A short history of the initial application of anti-5-BrdU to the detection and measurement of S phase.

Because this article is a bit of history rather than ascientific paper, we will depart from the formality of ajournalarticle.Thisarticlehastwopurposes.Thefirstistogive credit to two deceased individuals, Albert Castro,M.D., and Howard Gratzner, Ph.D. (1). Castro was the keyperson who was able to produce a polyclonal antibodythat was specific for bromodeoxyuridine (BrdU). For 10years, Gratzner took the lead in converting an idea into afunctional assay that affected DNA analysis and led to thedevelopment of many other assays with similar method-ologies. The second is to inform young scientists that (a)inventions or creations have utility in fields other than thepurpose for which they were created; (b) it is possible todo useful work in an institution that certainly would nothave been classified as one of the best; and (c) the pres-ence of talented people who are willing to collaborate isinvaluable.Scientifically, Gratzner is best known for the develop-ment of the first monoclonal antibody (mAb) to BrdU andiododeoxyuridine. This work was the culmination of pre-vious efforts with Robert Leif to develop polyclonal anti-bodies, which detected BrdU with variable specificity.Collaborations with scientists at the Lawrence LivermoreLaboratory encouraged the development of a widely usedflow cytometric test for the simultaneous measurementsof DNA and BrdU. The use of mAbs to halogenated pyri-midines was a significant scientific advance and currentlyis an integral tool for the analysis by flow and digitalmicroscopy of the cell cycle.On a personal level, Gratzner’s enthusiasm for scienceand his intelligence, curiosity, loyal interactions with fel-low collaborators, and friendship are sorely missed by allwhoknewhim.Hewasgenuinelyawarmandnicepersonwho was liked by almost everyone with whom he came incontact (1).Castro was a jovial man who interacted well with hiscollaborators. He was generous and very knowledgeable.He ran an immunodiagnostics laboratory at the universi-ties of Oregon and Miami and was an expert in the pro-duction of antibodies in animals. His warm smile, gener-ous giving of his knowledge, common sense, enthusiasmfor scientific research, and ability to get the job done wereessential to this project.Because this is a story of events that happened approx-imately 30 years ago and the existing records are limited,the accuracy of this article is limited by our memory andthose of our colleagues who have kindly helped with thisproject. Of course, this is our version of the events.Cell division and DNA replication are fundamental tobiology and specifically to the biology of cancer. Thisarticledescribeshowasimpleprocedureforthedetectionand quantitation of DNA synthesis was developed. Theprecise determination of when S phase occurs in the cellcycle is of use to maximize the selective killing of tumorcells with cycle-specific chemotherapeutic drugs. Ofgreater significance, studies of the control of the cellcycle, including its detour into apoptosis, can provideextremely useful insights into the creation of new thera-peutic regimens.The original process to detect S-phase cells included theuse of tritiated thymidine with autoradiography to mea-sure the labeling index (percentage of S-phase cells)and/or the fraction of labeled mitotic cells. Before and atthe infancy of flow cytometry, it was believed that thequantitative DNA analysis of normal and neoplastic cellsmight provide an objective marker for the diagnosis ofneoplasia. These measurements were performed with amicroscope on Feulgen-stained cells. In a normal popula-tion, it was established that there were two predominantpeaks in the DNA distribution, with a ratio of 1:2 in DNAcontent, and that cells that were synthesizing DNA (Sphase) were scattered in between, with a relative DNAcontent between 1 and 2. The detection of tritiated thy-

NIH Study-Section Scoring

The proposed changes for the U.S. National Institutes of Health (NIH) Center for Scientific Review (B. M. Alberts et al. , Policy Forum, Science's Compass, 30 July, p. [666][1]) do not address a critical factor in NIH study-section scoring procedures—a built-in bias against new and unfamiliar ideas. The way scores are allocated is that two primary readers and two secondary readers get to set the score level at the beginning of a discussion of a given proposal. So for proposals on topics and strategies that are unfamiliar to the majority of the study section, members have a hard time countering the biases of “acknowledged experts” on the panel. This means that basically one or two section members can control an entire subfield. A case in point is the study of biomolecular conformation changes using small-angle x-ray scattering. This field matured in the 1950s through the work of Glatter and Kratky in Europe, but it is now undergoing fundamental improvements because of the availability of synchrotron radiation x-ray beams and new algorithmic developments for interpreting the data. However, relatively few studies of biomolecular conformations using this approach have been funded by NIH. The effects of this practice may be seen by comparing the activity in this field in different geographical regions. The number of relevant publications worldwide in 1997 through mid-1999 (from the Science Citations Index) is around 170, of which 94 are from Europe, 35 from Japan, 8 from Russia, and 33 from the United States. Part of the explanation for the much greater output in Europe is the expert training handed down from the early days of the field. However, the relatively weak level of development of this field in the United States may also be attributed in part to the blocking of research proposals to NIH to exploit modern versions of this technology. One way to help alleviate this kind of bias would be to solicit outside mail reviews from a broad spectrum of reviewers (as practiced by the National Science Foundation). This could also help NIH overcome some of its problems in reviewer recruitment, because using mail reviews in conjunction with a modified system of study sections would spread the reviewing burden more widely. [1]: /lookup/doi/10.1126/science.285.5428.666

Urology Peer Review at the National Institutes of Health

Purpose Urology is a field with many subspecialties and, as a consequence, urological research grant applications are distributed to a variety of different study sections at the National Institutes of Health (NIH). It has long been the conviction of urological investigators that urological grant funding suffers as a result of this distribution. We investigated the composition of these study sections to identify the prevalence of urological expertise (or lack thereof). The review challenges the concept that urological research grant applications are being subjected to adequate peer review. Materials and Methods Aided by personnel from the National Institute for Diabetes, and Digestive and Kidney Diseases, and the National Cancer Institute, 22 study sections to which urological grants are distributed were identified. A 3 to 5-year retrospective MEDLINE analysis of all the scientific publications of each study section member was done. Urological experts were identified by the criterion of having more than 1 urological publication published per year or a proportional equivalent. An equivalent analysis was performed for the study sections reviewing cardiology grants to serve as a comparison. Results Data analysis revealed that only 12 of 351 study section members reviewing urological grants are urological experts (3.4 percent). Only 3.1 percent of the collective published productivity of these members is in the broadly defined field of urological investigation. Omitting the published productivity of these 12 experts, less than 1 percent of the published works of the remaining 339 members reflects interest or expertise in urological investigations. Of the 22 study sections only 8 have urological expertise represented in their membership. Except for 1 study section, representation of urological experts was usually limited to 1 individual reflecting a 5.9 to 11.1 percent minority in these study sections. Conclusions The lack of urological expertise represented on the NIH study sections reviewing basic and clinical urological research grant applications has far reaching ramifications. Consequently, grant applications on genitourinary diseases that commonly afflict a preponderance of Americans are inadequately reviewed at the NIH. Only through the provision of appropriate peer reviewers will this problem be solved.