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The 1989 Nobel Prize in Physiology Or Medicine Is Awarded to J. Michael

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The 1989 Nobel Prize in Physiology Or Medicine Is Awarded to J. Michael -rrent Cnmments” EUGENE GARFIELD INSTITUTE FOR SCIENT($IC lNFOFiMATION@ 3501 MARKET ST PHILADELPHIA PA 19104 The 1989 Nobel Prize in Physiology or Medicine Is Awarded to J. Mkhael Bishop and HaroM E. Varrms for Their Contribution to Cancer Researcls Number 16 Amil 16, 1990 This essay examines the work of J. Michael Bishop and Harold E. Varmus, recipients of the 1989 NotMlPrize in physiologyor medicine for the discovery of the celhdar origin of retroviral oncogenes. The award is entirely consistent with their citation reeords as well as their rankings in ISI” listings of most-cited scientists.The laureates’highlycited papers are examined,as are pertinentresearch fronts. Also discussed is the controversial protest by their former colleague Dominique St4helin. The 1989 Nobel Prize in physiology or Americans have received the majority of medicine was jointly awarded to J. Michael Nobel Prizes in medicine or physiology– Bishop and Harold E. Varrmss, both from of 46 recipients since 1970, 30 have been the University of California, San Francisco US citizens. However, few scientists in the (UCSF), for their revolutionary discovery award’s 88-year history have received a that normal cells contain genes that cart Nobel Prize for research directly related to cause cancer if they are altered. This dis- cancer. Peyton Rous, for example, Rocke- covery was first published in a 1976 land- feller Institute, New York, was awarded the mark article in Nature. 1 prize in 1966 for discovering the first known The choice of Bishop and Varrnus was cancer-causing vims, now known as the hardly a surprise to Nobel forecasters.z In- Rous sarcoma virus. However, as sociolo- deed, these two scientists had already won gist Harriet Zuckerrnan, Columbia Univer- the Lasker Basic Medical Research Award sity, New York, points out in her book Sci- in 1982 and the Gairdner Award in 1984, enfijic Elite, Rous had to wait 55 years for two highly prestigious awards that have fre- this recognitions (p. 47) David Baltimore, quently anticipated the Nobel. then at the Massachusetts Institute of Tech- If citation history is an indicator of Nobel- nology, Cambridge, now president-desig- class research, and it has been in the past, nate, The Rockefeller University, along with these two scientists are surely of that cali- Renato DuRrecco, director, Salk Institute of ber. Both were on our list of the 200 most- Biological Studies, La Jolla, tMfornia, and cited scientists between 1973 and 1984. Howard Ternin, McArdle Laboratory of Bishop’s work has been cited over 10,000 Cancer Research, University of Wisconsin, times, making him the 24th most-cited sci- Madison, shared the 1975 prize for their entist in the ISI” database for 1973-1984; studies of tumor virus replication. Varmus is ranked 55th, with over 8,700 ci- While the significance of the research rec- tations.z Table 1 lists 29 papers published ognized by the Nobel committee is unques- by Varmus and Bishop, either individ- tioned, the decision to limit recognition to ually or together, that have been cited over Bishop and Varrnus has been protested by 150 times. one of their former coauthors-Dominique 125 J, Michael Bishop Harold E. Varrrw Table 1: Harold E. Varnms’s and J. Michael Bkhop’s works cited over 15s3times. Dam are taken from the SCP, 1945-1988. A= number of citations. B= bibliographic data. A B 1,125 Bishop J M. Cellular oncogenes and retroviruses. Artnu. Ret,. Biochem, 52:301-54, 1983. 449 Levinson A D, Qrpermatm H, Levkrtow L, Varnma H E & 5~hop J M. Evidence that the transforming gene of avian asrcrrrns virus encodes a protein frinase associated with a phoaphoprotcin. Cell 15:561-72, 1978, 435 St4hefin D, Varrrrus H E, Bfakop J M & Vogt P K. DNA related to the transforming gene(s) of avian aarcorna viruses is present in normal avian DNA. Nature 2fK: 170-3, 1976. 427 Varnms H E. The molecular genetics of cellular oncogenes. ,4rmu. Rev. Gerret. 18:553-612, 1984. 421 Biahnp J M. Viral oncogenes. Cell 42:23-38, 1985, 390 Bishop J M. The molecular genetics of cancer. Science 235:305-11, 1987, 368 Varrrms H E. For-m and function of retrovind proviruses, Science 216:812-20, 1982. 328 Bffhop J M. Retrovimses. Armu. Rev. Biorhem. 47;35-88, 197g. 321 Shank P R, Hughes S H, Kung H F, Majors J E, Quiitrell N, Guntrdrn R V, Bishop J M & Varmua H E. Mappingunintegratedaviansarcomavirus DNA: temini of linearDNA bear 3tXl nucleotides present once or twice in two species of circufar DNA. Cell 15:1383-95, 1978. 293 Payne G S, Bishop J M & Varmrrs H E. Multiple arrangements of viral DNA and an activated host oncogene in bumaf Iymphorrms. Nature 295:20S-14, 1982. 266 Hsrgkas S H, Shmsk P R, Sfxctor D H, Kung H F, Bishop J M, Varmus H E, Vngt P K & Breitrrrmt M L. Proviruses of avirm sarcoms virus are terrnimdly redundant, co-extensive with unintegrated finear DNA and imegratcd at tmmy sites, Cell 15:1397-410, 1978. 263 Oppermmm H, LArrson A D, Varrmra H E, Levfntow L & Bishop J M. Uninfected vertebrate ceffs contain a protein that is closely related to the product of the avian xsrcoms virus transforming gene (src). Proc. Nat. Ad. Sri. USA 76:1804-8, 1979. 227 Bishop J M. Enemies withirr the genesis of retrovinrs oncogenes. Cell 23:5-6, 1981, 219 Payne G S, Courtrreidge S A, Crittenderr L B, Fadiy A M, BLshop J M & Varrmrs H E. Analysis of avisn Ieukosis virus DNA and RNA in burssl tumors: viral gene expression is not required for maintenance of the tumor ststc. Cell 23:31 i -22, i981. 216 Vmmms H E, Vogt P K & Bfahop J M. integration of deoxyribonucleic acid specitic for Rous sarcoma virus after infection of permissive and nonpermissive hosts. Prac. Ntrr. Acad. Sci. USA 703Ct67-7i, 1973. 215 St4hdfn D, Gurrtaka R V, Varmrrs H E & B~hop J M. Purification of DNA complementary to nucleotide sequences required for neoplastic transformation of fibroblasts by avirm sarcoma viruses. J. Mol. Biol, 101:349-65, 1976. 126 208 Taylor J M, Dnay A, Karl Y W, Varnms H E, LieInjo L E, Grmearm J & Tadd D. Genetic lesion in homozygous alpha thrdasaaeroia (hydrops fetrdis). Nature 251:392-3, 1974. 206 ~kh w J, Luciw P A, (%dnmrt H M, Vamms H E & Bishop J M. Molecular cloning and characterization of avisrr sarcama virus circular DNA molcculcz. J. k’iroL 36: SO-61, 1980. 199 Weiss S R, Varrtma H E & Bfshop J M. The size srrd gerwtic composition of virus-specific RNAs in the cytoplasm of cells praducing avian sarcoma-leukosis viruses, Cell 12:983-92, 1977, 194 Ringold G M, Ysmamoto K R, Tomkins G M, Bishop J M & Varmus H E. Oexmrretbasone- mediated induction of mouse mammary tummvirusRNA:a systemfor studyingglucocorticoid action.Ce[l6:299-305,1975. 190 Ringold G M, Yamamoto K R, Bkhop J M & VarmrLSH E. Glucocorticoid-stimulated accumulation of mouse mammary rumor virus RNA: increased rate of synthesis of viral RNA. Proc. Nat. Acad. Sci. USA 74:2879-83, 1977. 176 Varmus H E, QuiMreU N & Ortia S. Retroviruses as mutagens: insertion arrd excision of a nontrsnsforming provirus at?cr expression of a resident trsmforming provims. Cc// 25:23-36, 1981 173 Dah[berg J E, Sawyer R C, Taylor J M, Faras A J, Levtnann W E, Gcdm$trI H M & Bkhop J M. Transcription of DNA aarcomn virus. 1. Identification of a spccitic 4S RNA which serves as primer. J. Virol. 13:1126-33, 1974. 173 Varmrrs H E, Qrrfntiell N, Medeiros E, Bkhop J M, Nowirrstd R C & Sarkar W H. Transcriptionof maws mammarytumor virus genes in tissues from hi8h and low tumor incidence mouse strains. J. Mol. Biol, 79:663-79, 1973. 171 Ringold G, Lasfargues E Y, B~hop J M & Varmrrs H E. Production of mouzc mammary tumor virus by cultured cells in the absence and presence of hormones: assay by molecular hybridization. Virology 65:135-47, 1975. 170 Spector D H, Varrmrs H E & Bishop J M. Nuckrtide sequences related to the transforming gene of avian sarcoma virus are present in DNA of uninfected vertebrates. Proc. Nat. Acad. Sci. USA 75:4102-6, 1978. 161 Bishop J M, Levinaon W E, QuintrelI N, Suftivmt D, Fanabier L & Jackson J. The low molecular weight RNAs of Rous sarcoma virus. 1, The 4S RNA. Virofogy 42:182-95, 1970. 160 Kmr Y W, Dwzy A M, Varmus H E, Taylor J M, Holland J P, Lie-InJo L E, Gamaan J & Tadd D. Deletion of alpha-globin genes in haemoglobin-H disease demonstrates multiple alpha- globk structural Iuci. Nature 255:255-6, 1975. 157 Biaftop J M. Fmrctions arrd origins of retroviral transfonrring genes. (Weiss R, Teich N, Var’mus H & Coffin 1. wk.) RNAtumor-viruses.Cold SPrinR Harbor;NY: Cold.%in~ HarborLabIJratorY, 1982. p. 999-1108. St6helin of France. St6helin is now direc- nogenic factors, such as chemicals or radia- tor of research, NationaJ Scientific Research tion, at which time they convert cells to Center (CNRS), Pasteur Institute, Line, cancerous growth.6 France. In an open letter to the Nobel com- To explore this hypothesis, Bishop and mittee, he claimed that his crucial contribu- Varmus in the mid- 1970s decided to inves- tions to the discoveries were ignored.q The tigate whether the cancer-causing gene of the controversy is discussed in more detail later. Rous sarcoma virus, called src, could be found in the DNA of normal cells. Finding Oncogene Hypothesis one gene out of the thousands found in the Since the Rous sarcoma virus was first genome of vertebrates was a formidable task discovered in 1910, scientists have been that no one had managed to accomplish, struggling to find the exact connection be- given that the gene manipulation tools tween tumor viruses and cancer.
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