1993's Top 10 Papers: Superconductor Report Surfaces In Sea Of Genetics

Following a well-established pattern, papers in the field of gene research dominated the list of hottest articles in science for 1993--as determined by citation analysis. It is noteworthy, however, that a physical science report describing a new superconductor placed in a list of the 10 most cited papers published and referred to last year. Rank Paper Citations 1 D.R. Rosen, et al., "Mutations in Cu/Zn 54 superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis," Nature, 362(6415):59-62, 1993. 2 G. Pantaleo, et al., "HIV infection is 53 active and progressive in lymphoid tissue during the clinically latent stage of disease," Nature, 362(6418):355-8, 1993. 3 R.B. Ren, et al., "Identification of a 47 ten-amino acid proline-rich SH3 binding site," Science, 259(5098):1157-61, 1993. 4 J. Embretson, et al., "Massive covert 43 infection of helper T lymphocytes and macrophages by HIV during the incubation period of AIDS," Nature, 362(6418):359-62, 1993. 5 S.N. Putilin, et al., "Superconductivity at 41 94 K in HgBa2CuO4+d," Nature, 362(6417): 226-8, 1993. 6 D. Vetrie, et al., "The gene involved in 40 X-linked agammaglobulinemia is a member of the src family of protein-tyrosine kinases," Nature, 361(6409):226-33, 1993. 7 T. Sollner, et al., "SNAP receptors implicated 39 in vesicle targeting and fusion," Nature, 362(6418):318-24, 1993. 8 C.A. Lange-Carter et. al., "A divergence in 33 the MAP kinase regulatory network defined by MEK kinase and raf," Science, 260(5106):315-9, 1993. 9 A.R. Clarke, et al., "Thymocyte apoptosis 33 induced by p53-dependent and independent pathways," Nature, 362(6423):849-52, 1993. 10 R. Rossaint, et al., "Inhaled nitric oxide 32 for the adult respiratory distress syndrome," New England Journal of Medicine, 328(6): 399-405, 1993. Source: ISI's Hot Papers Database, 1993 Based on data compiled by the Philadelphia-based Institute for Scientific Information (ISI), a listing of the most frequently cited papers covered topics in molecular biology, genetics, and other life science specialties. Life science papers, say ISI analysts, generally tend to gain far more citations, on average, than papers in physics, chemistry, or other fields. This is partially attributable to the comparatively greater number of published papers and researchers in life sciences, as well as the higher average number of articles they cite. As a result, more than half of the "hottest" papers of 1993 related directly or indirectly to molecular genetics, as reported earlier this year in ISI's newsletter Science Watch (G. Taubes, 5[1]:1, January 1994), which used ISI's "Hot Papers" database to come up with its tallies. The newsletter focused on papers describing original research, not review articles. The list that the newsletter published contained 37 papers, each of which had gathered at least 24 citations by the end of the year. Of the 10 most cited papers (see accompanying table), six fall, broadly speaking, into the category of gene research. Three of these articles (Nos. 3, 7, and 8) describe the role of various proteins in the signal-transduction pathway of cells and how this ultimately relates to oncogenesis. Two other papers identify a genetic cause for amyotrophic lateral sclerosis (ALS), commonly known as Lou Gehrig's disease (No. 1), and X-linked agammaglobulinemia (No. 6). Among the top 10, the remaining gene research paper (No. 9) covers the role of the p53 tumor suppressor gene in genetically programmed cell death. The other papers in the top 10 discuss the activity of HIV during the AIDS latency period (Nos. 2 and 4) and adult respiratory distress syndrome (No. 10). Other life science papers in Science Watch's report encompassed such diverse subjects as the identification of carbon monoxide as a putative neural messenger; a genetic linkage analysis in familial breast and ovarian cancer; genetic mapping of human colorectal cancer; and the isolation of a candidate gene for Menkes disease. Also placing quite high in the rankings was a physical science paper describing the discovery and properties of a new mercury-bearing superconductor (No. 5 on the accompanying table). The most frequently cited 1993 paper was an article from the March 4 issue of Nature. The 33 collaborators in this research, working at 13 institutions, report that mutations in copper/zinc-binding superoxide dismutase (SOD1)--an enzyme that normally prevents cellular damage from highly reactive chemicals such as superoxide--are associated with familial ALS. Until now, the cause of ALS--a fatal neurodegenerative disorder of motor nerve cells of the spinal cord, brain stem, and cortex--has been unknown, although about 10 percent of the cases are inherited through a dominant gene on a non-sex chromosome, say ALS researchers. "It's an amazing breakthrough in that this is the first signal that we're getting in terms of what could be causing the disease," says Daniel Rosen, a molecular biologist at the Day Neuromuscular Research Laboratory at Massachusetts General Hospital in Charlestown, and first author on the ALS paper. "We think the value of this research is that it points to a pathophysiological mechanism [for ALS] ... We believe that it is possible that free radical damage could be the cause for the damage" seen in ALS patients, says Rosen. Free radicals--highly reactive atoms or groups of atoms, mostly oxygen--attack cellular constituents such as membrane lipids, proteins, and nucleic acids. This research "represents the first definition of a biochemical defect that can cause this disease" in the more than 120-year history of ALS research, notes Rosen. He explains that the research described in the 1993 Nature paper builds on past work at Massachusetts General, which was directed by Robert Brown, Jr., head of the Day lab. One of the reasons that this paper is so heavily cited might be that researchers are using this information to look into possible therapies and drugs to fight ALS, surmises Rosen. He says that, because of the research in this report, a new avenue of investigation in terms of clinical investigations and therapy has opened up. According to Rosen, this breakthrough comes none too soon for the ALS research community. "There's a great deal of helplessness associated with it [ALS]," he says. "The patient slowly withers away and the physician feels impotent in terms of being able to treat them.... There's a general desire to find some straw that people can grab onto which would provide an answer for this disease," Rosen continues. This discovery may also have implications for solving the mysteries surrounding other neurological conditions, such as Parkinson's disease, says Rosen. "There may be a common mechanism in neurological diseases that involve free radicals," he adds, although no experimental evidence yet exists to link diseases like Parkinson's to free radical scavenging. The second- and fourth-most-cited papers address the recently discovered activity of HIV in the lymph node during the latency period of AIDS. Both studies found that lymphoid organs function as major reservoirs for the virus, even during the asymptomatic phase of AIDS. Because the extent of viral activity in infected people has been underestimated up to now, say AIDS researchers, these papers point to the importance of studying infection early in the course of the disease. The "general picture is that these changes [in how HIV affects cells of the lymph node] not only allow us to understand the viral pathogenesis, but they are allowing us to understand the major progression [of AIDS]," says Giuseppe Pantaleo, a researcher at the National Institutes of Health's National Institute of Allergy and Infectious Diseases in Bethesda, Md., and an author on the second-most- cited paper. Ashley Haase, a microbiologist from the University of Minnesota, Minneapolis, and an author of the fourth-most- cited paper, concludes that "the two big messages [from paper No. 4] are that there is massive covert infection that establishes a reservoir to perpetuate infection" and that there are a "large number of cells that are capable of producing virus at any given time and [are capable of making a] substantial dent in the immune system." Haase explains that a covertly infected cell contains the viral genome, but has no external evidence of infection such as detectable viral proteins or messenger RNA. As far as the immune system is concerned the cell is not infected, but carries the potential to infect, he adds. Both Pantaleo and Haase say that a major implication of these discoveries is that quite early in the course of AIDS much damage to the immune system has already occurred, which has important ramifications for AIDS therapy. "The idea is that you'd want to come in very early in the disease with very effective anti-retrovirus therapies" to limit the size of the reservoir, says Haase. However, he says, finding effective therapies is still a problem and the body could build up a resistance to drugs like AZT if used early on, making the fight against later opportunistic infections more difficult. "I'm actually somewhat optimistic about vaccines," says Haase, explaining that the initial infection might involve relatively small numbers of infected cells so we "might be able to make a huge dent with a vaccine that is only partly efficacious." The third-most-frequently cited paper describes the identification of the SH3 binding domain, a 10-amino-acid long region found on many types of proteins, including kinases, Ras activators, and transcription factors. Ruibao Ren, a postdoctoral fellow in the laboratory of David Baltimore at Rockefeller University, and first author of the paper, explains that "SH3 appears in many important proteins, including many types of oncogenes.... Their binding sites involve other proteins which are mostly all involved in signal transduction," a series of steps whereby information from outside a cell is passed, or transduced, via protein-protein interactions, to the cell nucleus where genes are activated. Because information like this controls basic cellular functions such as growth, immune response, and differentiation, Ren describes the importance of this paper as "real-ly finding the key to how proteins interact ... now people can understand the mechanism of how normal signals are transduced and how, during oncogenesis, normal signals get derailed." Ren attributes the high frequency of citations of this paper to two factors. He explains that because SH3 domains are ubiquitous, the identification of the SH3 domain will guide other researchers in their tests to determine whether the proteins they have isolated contain an SH3 binding domain. In addition, he says that SH3 binding domains will "eventually serve as a target for pharmaceutical treatments to block aberrant pathways," in cancerous cells, for example. Superconductor Surprise An unexpected entry on the top 10 list is the fifth-most- cited paper, a physical science report by a Russian-French team that describes the discovery of a mercury-containing copper oxide superconductor. Massimo Marezio, an author on the paper and a physicist with a dual appointment as director of research at the Laboratoire de Cristallo-graphie in Grenoble, France, and a member of the technical staff at AT&T Bell Laboratories in Murray Hill, N.J., explains the impact of this paper: "At the beginning [the new superconductor] looked like just another compound"; however, "a posteriori, its chemistry looked very interesting because of the specific crystal chemistry of the mercury cations." "Because it is much simpler [than other superconductors], from the structural point of view" he says, we "can study it more easily than more complicated [superconductor] systems, thus providing a simpler model for theorists" who study the properties of superconductors. For now, Marezio describes the potential for practical applications of the superconductor as "promising ... but we are still in the preliminary stages." He attributes the report's high number of citations to the new compound's "physical properties, not its applications." The authors of these highly cited papers all say that they are continuing the lines of research described in the 1993 reports--the Day lab team is conducting genetic analyses to identify other ALS genes; Pantaleo's group is studying infection mechanisms of HIV during the earliest and latest stages of AIDS; Hasse's group is investigating aspects of host immunity; Ren and colleagues are characterizing other SH3-containing proteins; and Marezio and associates are studying pressure effects on the mercury-containing superconductor.

1993's Top 10 Papers: Superconductor Report Surfaces In Sea Of Genetics

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