Hot Papers

With a new decade as well as a new year upon us, The Scientist conducted a review of the scientific literature of the past 10 years to identify the 1980s' most significant research developments. There are, of course, many ways to pinpoint important events or trends, but in this case the criterion used was the number of citations to scientific papers published since 1980, as recorded in the Science Citation Index (SCI) of the Institute for Scientific Information (ISI) in Philadelphia. Using this methodology, signal transduction, AIDS, and superconductivity emerged as three key research areas of the decade. The accompanying table lists the 10 papers of the 1980s that garnered the greatest number of citations by the end of 1988. (The citation tallies for 1989 were not yet complete at the time of writing.) Excluded were methods papers, which because of their wide applicability tend to be much more frequently quoted than reports and reviews. The first-ranking paper of the top 10 earned more than 3,000 citations since its publication in 1984. The 10th-ranking report, also published in 1984, earned almost 1,500 citations. By contrast, the average paper in the SCI received only about two citations per year in the 1980s. Plainly, these 10 papers represent the citation créme de la créme. They are the citation superstars of the 1980s. Although articles dealing with topics in molecular biology, biochemistry, and immunology dominate the list - which is to be expected, given the relatively greater pop- ulation of publishing scientists working in these realms than in any others - two breakthrough reports on high-temperature superconductivity, both from the second half of the decade, made the list with citations to spare. The name of Yasutomi Nishizuka and that of Michael J. Berridge each appears on two of the 10 most- cited papers of the decade. Nishizuka is chairman of the department of biochemistry at Kobe University School of Medicine, Japan. Berridge is with the Agricultural Research Council Unit of Insect Neurophysiology and Pharmacology at the University of Cambridge, England. Both are pioneers in the field of signal transduction, which deals with the biochemical pathways inside the cell that are activated by extracellular agents, such as hormones and growth factors. Both Nishizuka and Berridge were recently selected, along with Edwin G. Krebs and Alfred G. Gilman, as co-winners of the 1989 Albert Lasker Basic Medical Research Award for their discoveries concerning signal transduction and cell regulation. The year before, the pair were joint recipients of the Gairdner Foundation International Award. And, in 1986, Berridge received the Louis Jeantet Award for Medicine, given annually to an outstanding scientist working in Western Europe. Owing to their outstanding scientific discoveries, their production of highly cited papers, and their history of winning prizes that have often foreshadowed the selections of the Nobel Assembly, the names of Nishizuka and Berridge were included in this newspaper's recently published list of 20 scientists who may one day find themselves among the Nobel immortals (The Scientist, Oct. 2, 1989, page 14). It was Nishizuka who wrote the most-cited paper of the decade - a review article on protein kinase C, an enzyme he discovered in the late 1970s that is activated by diacylglycerol, a so-called second messenger produced in the cell membrane in response to extracellular stimuli. In his 1984 review, Nishizuka described the biochemical activation and properties of protein kinase C, and explained how tumor-promoting phorbol esters, when introduced into the cell membrane, can take the place of diacylglycerol and continually activate protein kinase C, resulting in uncontrolled cell division. By uncovering this mechanism, Nishizuka paved the way for a new, more detailed understanding of cell regulation and carcinogenesis. (Another review by Nishizuka, "The molecular heterogeneity of protein kinase C and its implications for cellular regulation," appeared in Nature [334:661-5, 1988]; with 144 citations to date, for the past nine months it has been one of the hottest papers in biology.) In the path that Nishizuka blazed, thousands of scientists have followed. One of the earliest followers was Monique Castagna of the Institute for Scientific Research on Cancer, a Centre National de la Recherche Scientifique establishment in Villejuif, France. She is the lead author on the fourth most-cited paper of the decade, co-written with Nishizuka. Castagna had been searching for a link between signal transduction and cancer when, at a garden party in Brussels in the summer of 1980, she had the opportunity to hear about protein kinase C from Nishizuka. In a "Citation Classic" commentary, Castagna recalled that "when Nishizuka described to me the properties of [protein kinase C] that had recently been discovered by his group at Kobe University, it struck me that this was the molecule I was looking for." Castagna knew that tumor-promoting phorbol esters had a high-affinity binding site in cell membranes, but the receptor was then unknown. However, "the features of this unknown receptor were predictable and amazingly similar to those Nishizuka was enumerating for protein kinase C." The two agreed to test the hypothesis, and a year later Castagna brought her phorbol ester samples to Nishizuka in Kobe. Together they confirmed that phorbol esters substituted for diacylglycerol "and in doing so mimicked physiological signals" (M. Castagna, Current Contents/Life Sciences, 31:20, 1988). Their 1982 paper received nearly 400 citations in 1988 and nearly 500 citations in each of the previous two years. The other chief contributor to the signal transduction revolution of the 1980s was Michael Berridge. In 1969, Berridge had discovered that calcium, which fuels internal cellular processes, was activated not directly by an extracellular stimulant's interaction with a receptor, but indirectly through the cell membrane by some unknown second messenger. Together with Robin F. Irvine, also of Cambridge, he isolated the agent as a breakdown product of a lipid in the cell membrane: inositol trisphosphate (Ins1,4,5P3). He and Irvine showed that extracellular signals trigger the intracellular release of calcium by means of this second messenger. The discovery was significant because the release of calcium is key to regulated and uncontrolled growth, nerve transmission and muscle contraction, metabolism, and a host of other physiological processes. "Perhaps the most remarkable aspect of the events leading up to the discovery of Ins1,4,5P3 as a second messenger," Berridge recalled in his "Citation Classic" commentary on this paper, "is that they coincided almost exactly with the discovery of the second messenger action of diacylglycerol (DG) by Yasutomi Nishizuka. It soon became apparent to those of us at the center of these new discoveries that this phosphoinositide system was spawning not one but at least two second messengers, which motivated me to write a review to bring together the idea of a bifurcating signaling system. This review was submitted to Nature in March 1983 but was rejected and subsequently found a home here and has been highly cited." (See the fifth-ranking paper in the table.) Rank Paper 1. Y. Nishizuka, "The role of protein kinase3,074 C in cell surface signal transduction and tumour promotion," Nature, 308:693-8, 1984 2. M.J. Berridge, R.F. Irvine, "Inositol tris-2,445 phosphate, a novel second messenger in cellular signal transduction," Nature, 312:315-21, 1984 3. J.G. Bednorz, K.A. Muller, "Possible high2,031 Tc superconductivity in the Ba-La-Cu-O system," Zeitschrift fur Physik B - Condensed Matter, 64:189-93, 1986 4. M. Castagna, Y. Takai, K. Kaibuchi, K. Sano,1,975 U. Kikkawa, Y. Nishizuka, "Direct activation of calcium-activated, phospholipid- dependent protein kinase by tumor-promoting phorbol esters," Journal of Biological Chemistry, 257:7847-51, 1982 5. M.J. Berridge, "Inositol trisphosphate and1,900 diacylglycerol as second messengers," Biochemical Journal, 220:345-60, 1984 6. M.K. Wu, J.R. Ashburn, C.J. Torng, P.H. Hor,1,854 R.L. Meng, L. Gao, Z.J. Huang, Y.Q. Wang, C.W. Chu, "Superconductivity at 93°K in a new mixed phase Y-Ba-Cu-O compound system at ambient pressure," Physical Review Letters, 58:908-10, 1987 7. W.Y. Cheung, "Calmodulin plays a pivotal1,748 role in cellular regulation," Science, 207:19-27, 1980 8. F. Barre-Sinoussi, J.C. Chermann, F. Rey,1,728 M.T. Nugeyre, S. Chamaret, J. Gruest, C. Dauguet, C. Axler-Blin, F. Vezinet-Brun, Rouzioux, W. Rozenbaum, L. Montagnier, "Isolation of a T-lymphotrophic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS)," Science, 220:868-71, 1983 9. R. Breathnach, P. Chambon, "Organization 1,594 and expression of eukaryotic split genes coding for proteins," Annual Review of Biochemistry, 50:349-83, 1981 10. R.C. Gallo, S.Z. Salahuddin, M. Popovic,1,496 G.M. Shearer, M. Kaplan, B.F. Haynes, T.J. Palker, R. Redfield, J. Oleske, B. Safai, G. White, P. Foster, P.D. Markham, "Frequent detection and isolation of cytopathic retro- viruses (HTLV-III) from patients with AIDS and at risk for AIDS," Science, 224:500-3, 1984 Source: ISI's Science Citation Index The editors of Nature told Berridge that the review by Nishizuka (No. 1 in the table), which had already been submitted and accepted, covered some of the same territory he was describing. But "since the review by Nishizuka concentrated on the DG/C-kinase limb of the bifurcating signal pathway," Berridge explained, "I felt I had a strong case for having a platform to provide equal coverage of the Ins1,4,5P3/Ca2+ pathway" (Current Contents/Life Sciences, 31:16, 1988). Nature's editors relented, the paper was accepted, and it went on to be the second most-cited article of the decade, with some 2,445 citations by the end of 1988. Berridge also wrote a 1987 review for the Annual Review of Biochemistry (56:159-93). The paper, entitled "Inositol trisphosphate and diacylglycerol: Two interacting second messengers," has been among the hottest papers of the last two years, having accumulated 591 citations to date. And, in September 1989, Berridge updated his 1984 review with "Inositol phosphates and cell signalling," Nature (341:197-205), which, if past performance is any indicator, is destined for citation stardom. The landmark discoveries of Nishizuka and Berridge ignited an explosion of research that has been one of the most prominent - and one of the most promising - scientific developments of the decade. Two other papers representing the realms of biochemistry and molecular biology are the seventh- and ninth-ranking items in the table. The 1980 review on calmodulin by Wai Yiu Cheung, then of the Department of Biochemistry, St. Jude's Hospital, Memphis, is the oldest paper in the group. Cheung coined the term "calmodulin" in 1978 for the activator protein of phosphodiesterase he discovered that regulates a broad spectrum of Ca2+-dependent processes, as well as Ca2+ itself. In 1983, when the paper was only a few years old but had already received more than 700 citations, the author observed that "my article reviews the salient features of calmodulin: its discovery, its molecular mechanism of action, its central role in cellular functions, criteria for calmodulin-regulated reactions, and some future directions. This wideranging coverage, coming at a time when interest in calmodulin was building rapidly, may be the reason for the paper's frequent citation" (see W.Y. Cheung, Current Contents/Life Sciences, 26:21, 1983). During the years 1981 to 1985, this review received more than 200 citations annually. In the last three years, however, it has attracted only half that many each year. The ninth-ranking paper, with nearly 1,600 citations, is a 1981 review of protein-coding split genes, by Richard Breathnach and Pierre Chambon of the Institute of Biological Chemistry in Strasbourg, France. The authors reviewed the organization and expression of split genes, and the mechanism of RNA splicing involved. Breathnach and Chambon concluded their survey by observing that "some long-standing paradoxes have been resolved at least partially, and there is a feeling that we have grasped the general evolutionary significance of the split gene organization. The case for the fundamental importance of duplication events in evolution has been strengthened, and a remarkable evolutionary plasticity of the eucaryotic genome (apart from the protein-coding sequences) has been discovered. `Dead' genes (pseudogenes) have been found, and their discovery raises the interesting possibility that the origin of at least some of the intergenic DNA could be related to ancient gene duplication events no longer recognizable. Molecular evolutionists are having a field day" (p. 376). This review has shown staying power: Each year between 1985 and 1988 it collected between 250 and 300 citations. It will come as no surprise that research on AIDS appears among the significant scientific developments of the 1980s. Two of the 10 most-cited papers of the decade deal with the AIDS virus, now known as the human immunodeficiency virus, or HIV. The more frequently cited paper of the two is by Luc Montagnier and his team at the Pasteur Institute in Paris. Their May 1983 article, published in Science, suggested that the cause of AIDS might be a new retrovirus that they termed lymphadenopathy associated virus, or LAV. In that same issue of Science, Robert C. Gallo and his group at the National Cancer Institute, Bethesda, Md., also suggested a retroviral origin for AIDS: human T-cell leukemia virus-III, or HTLV-III (R.C. Gallo, et al., Science, 220:962-3, 1983). That paper by Gallo and company, however, is not the group's most cited. Their most-cited article, published the following year and ranking 10th in the table, demonstrated that HTLV-III, isolated from a number of patients with AIDS, represented the AIDS-causing virus. In a recently published, citation-based examination of AIDS research, Henry Small and Edwin Greenlee, both of the department of corporate research at ISI, concluded that "although Montagnier's group appears to have received priority for discovery of the AIDS virus, Gallo's group has received credit for confirming that the virus actually caused AIDS. This is indicated by the number of citations received by Gallo's 1984 paper [No. 10 in the table], which is comparable to the number received by the 1983 Pasteur Institute paper [No. 8 in the table]" (H. Small, E. Greenlee, "A co-citation study of AIDS research," Communication Research, 16:658-9, 1989). If AIDS research dominates the early part of the decade, and signal transduction studies the middle, then superconductivity stands as the most prominent feature in the scientific landscape of the decade's second half. An off-the-books, "little science" project on the part of a pair of IBM scientists in Zurich in 1986 turned into a tidal wave of research in 1987. J. Georg Bednorz and Karl Alex Muller published in September 1986 their discovery of superconductivity in a lanthanum-based compound at 30°K (see No. 3 in the table). A scant 13 months after their report was published, the pair were awarded the Nobel Prize. By early 1987, thousands of researchers worldwide were reaching for mortar and pestle in a frantic search for their own higher-temperature superconducting compounds. One of the most successful efforts, by M.K. Wu, then at the University of Alabama at Huntsville, and C.W. ("Paul") Chu at the University of Houston, and colleagues, was the creation of a yttrium-barium copper oxide compound that exhibited a superconducting transition temperature of 93øK. Their report (No. 6 in the table) became the classic reference for those working with the yttrium or "1-2-3" compounds. In 1988, the Bednorz and Muller report and the paper by Wu, et al., each received about 1,100 citations. Because of their importance, superconductivity, AIDS, and signal transduction studies undoubtedly will continue to be key research topics in the 1990s. But as for what new significant areas will emerge, only time will tell. David Pendlebury is an analyst in the Research Department of the Institute for Scientific Information in Philadelphia and editor of the ISI newsletter Science Watch.

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