Hot Papers

Health As Hot Research Areas Editor's Note: Throughout the year, the newsletter Science Watch, published by the Institute for Scientific Information in Philadelphia, lists the 10 currently most cited research papers in biology and medicine. The lists provide a glimpse of recent trends in basic and applied biomedical science. The following article discussing biology's hot papers (Science Watch, 7[1]:8, 1996), by Jeremy Cherfas, a science writer who works with the Biological Sciences Research Council of the United Kingdom in Swindon, U.K., shows that nonpolyposis colon cancer is still in the spotlight. The accompanying medical research article (Science Watch, 7[1]:5, 1996), by David W. Sharp, deputy editor of Lancet, describes a mental-health survey conducted in the United States (see also Hot Papers, The Scientist, Jan. 8, 1996, page 14). Following are the Science Watch reports, reprinted here with permission of the newsletter and ISI. For more information on the citation databases and papers discussed in the article, contact Christopher King, editor of Science Watch, ISI, 3501 Market St., Philadelphia, Pa. 19104; (800) 523-1850, Ext. 1341. Fax: (215) 387-1266. E-mail: cking@isinet.com. See both Hot papers in biology and medicine. Last June, Science Watch touched on two papers that addressed an entirely new kind of cancer gene (Science Watch, 6[6]:5, June 1995). A group led by Richard Kolodner of the Dana-Farber Cancer Institute in Boston beat Kenneth Kinzler of Johns Hopkins University and his colleagues by just three weeks to hMSH2, the human homolog of mutS, a gene responsible for repairing DNA mismatches in E. coli. Now the two teams have done it again in the same order with yet another gene, but by a slightly narrower margin. Their papers, although falling just below the top 10, are the featured items this time. Two other papers on the top-10 list-Nos. 7 and 9-also cover studies in this area of cancer biology. The Kinzler team came in at No. 11 (N. Papadopoulos et al., "Mutation of a mutL homolog in hereditary colon cancer," Science, 263:1625-9, with 310 total citations through February 1996). Kolodner and colleagues ranked 12th (C.E. Bronner et al., "Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary nonpolyposis colon cancer," Nature, 368:258-61, 1994, with 285 total citations through February 1996). The new gene is called hMLH1, human mutL homolog, and like the mutS homolog, it is closely associated with hereditary nonpolyposis colon cancer (HNPCC). This is one of the most common genetic diseases among humans, affecting as many as one in 200 individuals. Studies of families affected by HNPCC reveal the presence of genetic stutters-areas along the chromosome in which the same pair of nucleotide bases is repeated many different times. Such defects are a sign of defective proofreading enzymes. The homolog mutS codes for just such a protein, but it is not alone: mutH and mutL are members of the same team of proofreaders. Furthermore, hMSH2 is not alone in causing HNPCC; it accounts for only 60 percent of cases. Pausing only to draw breath, the two teams of researchers raced on in search of the other genes involved, but along distinct tracks. Bert Vogelstein at Johns Hopkins calls the mutS-mutL-mutH trio "the mothers of all housekeeping genes," and in common with this exalted position they are highly conserved, evolutionarily, from bacteria to yeast to mice to ourselves. So the obvious answer was to use the sequence of those genes in bacteria to find them in people. This both teams did, but in entirely different ways. Kinzler and Vogelstein availed themselves of Craig Venter's collection of DNA fragments collected at the Institute for Genomic Research (TIGR) in Rockville, Md. (see "Genome Investigator Craig Venter Reflects On Turbulent Past And Future Ambitions," The Scientist, July 24, 1995, page 1). Venter pioneered the sequencing of cDNA copies of messenger RNAs, the logic being that only expressed genes end up as RNA. Therefore these sequences perform a first filter on the genome. TIGR stores hundreds of thousands of sequences in a database, but usually does not know anything about the gene they represent. Kinzler and Vogelstein reasoned that a housekeeping gene as basic as mutL, which is expressed in many different tissue types, had probably already been sequenced. Kinzler called Venter with the mutL sequence. "Within a few minutes of checking they told us that they had three such genes," Kinzler told reporters (R.F. Service, Science, 263:1559-60, 1994). The closest match turned out to be hMLH1, which was quickly cloned, sequenced in full, and localized to chromosome 3 to a marker known to be associated with cases of HNPCC. Kolodner's approach was to contact Michael Liskay at Oregon Health Sciences University in Portland. Liskay had pursued mutL from bacteria to mice, and in a spirit of idle curiosity used the mouse mutL as bait for the human homolog. He found a couple of fragments but no more. Kolodner asked Liskay for the fragments to use as probes for the full gene. Liskay agreed, and within a matter of weeks the team had found the whole human gene, sequenced it, and pinned its location down to the same spot on chromosome 3. The new gene now takes the proportion of HNPCC cases that can be accounted for by known genetic lesions up to 90 percent. Both teams have other candidates in their sights, and Kinzler and Vogelstein's group recently isolated another two human homologs of mutL: hPMS1 and hPMS2. Both are mutated in patients with HNPCC, which, they point out, doubles the number of genes associated with the disease and may help to explain its very high incidence. HOT PAPERS IN BIOLOGY, RANKED BY CITATIONS RECEIVED IN SEPTEMBER AND OCTOBER 1995 RankPaperCitationsSep-Oct'95Totals(Through Feb '96) 1.G. Gyapay et al., "The 1993-94 Généthon human genetic linkage map," Nature Genetics,7:246-339, 1994. 80 581 2.W.S. El-Deiry et al., "WAF1, a potential mediator of p53 tumor suppression," Cell,75:817-25, 1993. 72 752 3.A. Kamb et al., "A cell cycle regulator potentially involved in the genesis of many tumor types," Science, 264:436-40, 1994. 68 586 4.J.W. Harper et al., "The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases," Cell, 75:805-16, 1993. 56 717 5.M. Serrano, G.J. Hannon, D. Beach, "A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4," Nature, 366:704-7, 1993. 51 425 6.D.M. Hockenbery et al., "Bcl-2 functions in an antioxidant pathway to prevent apoptosis," Cell, 75:241-51, 1993. 49 458 7.R. Fishel et al., "The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer," Cell, 75:1027-38, 1993. 45 454 8.T. Nobori et al., "Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers," Nature, 368:753-6, 1994. 45 330 9.F.S. Leach et al., "Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer," Cell, 75:1215-25, 1993. 41 443 10.Y. Miki et al., "A strong candidate for the breast and ovarian cancer susceptibility gene BRCA 1," Science, 266:66-71, 1994. 40 240 Source: ISI's Hot Papers Database In 1978, a United States presidential commission asked for a nationwide survey of mental illness. At the time this was an impossible task. The scale of such a project meant that the necessary interviews would have to be done by staff who were trained but not necessarily psychiatrists, and the tools for such a project were not available. The National Institute of Mental Health soon corrected that defect with an interview schedule tailored to the purpose. The National Comorbidity Study (NCS), the subject of paper No. 2, is the latest product of that development. Comorbidity recognizes that people who are mentally sick may not have depression only or an anxiety disorder in isolation, for example. More than 8,000 respondents took part, and one can well see why the U.S. taxpayer might have been reluctant to shell out for psychiatrists to do all those interviews across 48 states. Importantly, the psychiatric disorders surveyed included substance abuse and dependence, in liquid or solid form. The detailed analysis looks at the findings from many angles, including the geographical, but the simplest way of summarizing is to look at the lifetime prevalence, for both sexes combined. The figures are: 19.3 percent for affective disorders (mainly major depression), 24.9 percent for anxiety disorders, 26.6 percent for substance-use disorders, and 4.2 percent for antisocial personalities and nonaffective psychoses. That sounds like three-quarters of the population of the U.S. Comorbidity brings that alarming figure down to just below half. Future studies aim to elucidate possible explanations for these figures (Hot Papers, The Scientist, Jan. 8, 1996, page 14). The figure for schizophrenia and other nonaffective disorders is only 0.7 percent. The prevalence in the survey was much higher, but the layperson interviews were found to have low validity for these disorders and the figure used in the paper comes from reinterviews by clinicians. Only 40 percent of respondents with a lifetime history of at least one of the psychiatric disorders ever obtained professional help of any sort: Only one in four obtained treatment in the mental health specialty sector, and about one in 12 was treated in substance-abuse facilities. This observation has been made before in research studies, including those that used similar interview methods to the ones in NCS, but NCS is finding a considerably more unmet need for mental health services than its predecessors did. Farther down the list, some familiar topics return to the top 10. Papers No. 3 and 5 examine how resistance to activated protein C may underlie as many as one-fifth of cases of venous thrombosis (Science Watch, 6[9]:6, October 1995). They are joined this time by paper No. 9. The topic of apolipoprotein polymorphism and its link to Alzheimer's disease and other dementias also returns to the list in papers No. 6 and 8, which appeared in the same issue of the Lancet (Science Watch, 6[5]:5, May 1995). Paper No. 10 reports the favorable results of a trial of high-dose tacrine in patients with Alzheimer's. Among those who received higher doses, the investigators noted improvements on performance-based tests, on global evaluations by clinicians and care-givers, and on quality-of-life measures. HOT PAPERS IN MEDICINE, RANKED BY CITATIONS RECEIVED IN SEPTEMBER AND OCTOBER 1995 RankPaperCitationsSep-Oct'95Totals(Through Feb '96) 1.P.W. Serruys et al., "A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease," New England Journal of Medicine, 331:489-95, 1994.23 118 2.R.C. Kessler et al., "Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States," Archives of General Psychiatry, 51:8-19, 1994.22 134 3.P.J. Svensson, B. Dahlbck, "Resistance to activated protein C as a basis for venous thrombosis," New Engl. J. Med., 330:517-22, 1994.21 166 4.E.J. Lewis et al., "The effect of angiotensin-converting enzyme inhibition on diabetic nephropathy," New Engl. J. Med., 329:1456-62,1993.20 206 5.T. Koster et al., "Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden Thrombophilia Study," Lancet, 342(8886-7): 1503-6, 1993. 19 156 6.J. Poirier et al., "Apolipoprotein E polymorphism and Alzheimer's disease," Lancet, 342(8873):697-9, 1993.18 171 7.D.L. Fischman et al., "A randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease," New Engl. J. Med., 331:496-501, 1994.17 100 8.A.M. Saunders et al., "Apolipoprotein E e4 allele distributions in late-onset Alzheimer's disease and in other amyloid-forming diseases," Lancet, 342(8873):710-1, 1993.16 116 9.J.H. Griffin et al., "Anticoagulant protein C pathway defective in majority of thrombophilic patients," Blood, 82:1989-93, 1993.15 119 10.M.J. Knapp et al., "A 30-week randomized controlled trial of high-dose tacrine in patients with Alzheimer's disease," Journal of the American Medical Association, 271:985-91, 1994.14 95 Source: ISI's Hot Papers Database

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