-rrent Cnmments”EUGENE GARFIELD

INSTITUTE FOR SCIENT($IC lNFOFiMATION@3501 MARKET ST PHILADELPHIA PA 19104

The 1989 Nobel Prize in Physiology orMedicine Is Awarded to J. Mkhael

Bishop and HaroM E. Varrms for TheirContribution to Cancer Researcls

Number 16 Amil 16, 1990

This essay examines the work of J. Michael Bishop and Harold E. Varmus, recipients of the 1989NotMlPrize in physiology or 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” listingsof most-cited scientists.The laureates’highlycited papers are examined,as are pertinentresearchfronts. Also discussed is the controversial protest by their former colleague Dominique St4helin.

The 1989 Nobel Prize in physiology ormedicine was jointly awarded to J. MichaelBishop and Harold E. Varrmss, both fromthe University of California, San Francisco(UCSF), for their revolutionary discoverythat normal cells contain genes that cartcause cancer if they are altered. This dis-covery was first published in a 1976 land-mark article in Nature. 1

The choice of Bishop and Varrnus washardly a surprise to Nobel forecasters.z In-deed, these two scientists had already wonthe Lasker Basic Medical Research Awardin 1982 and the Gairdner Award in 1984,two highly prestigious awards that have fre-quently anticipated the Nobel.

If citation history is an indicator of Nobel-class research, and it has been in the past,these two scientists are surely of that cali-ber. Both were on our list of the 200 most-cited scientists between 1973 and 1984.Bishop’s work has been cited over 10,000times, making him the 24th most-cited sci-entist in the ISI” database for 1973-1984;Varmus is ranked 55th, with over 8,700 ci-tations.z Table 1 lists 29 papers publishedby Varmus and Bishop, either individ-ually or together, that have been cited over150 times.

Americans have received the majority ofNobel Prizes in medicine or physiology–of 46 recipients since 1970, 30 have beenUS citizens. However, few scientists in theaward’s 88-year history have received aNobel Prize for research directly related tocancer. Peyton Rous, for example, Rocke-feller Institute, New York, was awarded theprize in 1966 for discovering the first knowncancer-causing vims, now known as theRous sarcoma virus. However, as sociolo-gist Harriet Zuckerrnan, Columbia Univer-sity, New York, points out in her book Sci-enfijic Elite, Rous had to wait 55 years forthis recognitions (p. 47) David Baltimore,then at the Massachusetts Institute of Tech-nology, Cambridge, now president-desig-nate, The Rockefeller University, along withRenato DuRrecco, director, Salk Institute ofBiological Studies, La Jolla, tMfornia, andHoward Ternin, McArdle Laboratory ofCancer Research, University of Wisconsin,Madison, shared the 1975 prize for theirstudies of tumor virus replication.

While the significance of the research rec-ognized by the Nobel committee is unques-tioned, the decision to limit recognition toBishop and Varrnus has been protested byone 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 theSCP, 1945-1988. A= number of citations. B= bibliographic data.

A

1,125449

435

427421390368328321

293

266

263

227219

216

215

B

Bishop J M. Cellular oncogenes and retroviruses. Artnu. Ret,. Biochem, 52:301-54, 1983.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 aphoaphoprotcin. Cell 15:561-72, 1978,

St4hefin D, Varrrrus H E, Bfakop J M & Vogt P K. DNA related to the transforming gene(s) ofavian aarcorna viruses is present in normal avian DNA. Nature 2fK: 170-3, 1976.

Varnms H E. The molecular genetics of cellular oncogenes. ,4rmu. Rev. Gerret. 18:553-612, 1984.Biahnp J M. Viral oncogenes. Cell 42:23-38, 1985,Bishop J M. The molecular genetics of cancer. Science 235:305-11, 1987,Varrrms H E. For-m and function of retrovind proviruses, Science 216:812-20, 1982.Bffhop J M. Retrovimses. Armu. Rev. Biorhem. 47;35-88, 197g.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 3tXlnucleotides present once or twice in two species of circufar DNA. Cell 15:1383-95, 1978.

Payne G S, Bishop J M & Varmrrs H E. Multiple arrangements of viral DNA and an activatedhost oncogene in bumaf Iymphorrms. Nature 295:20S-14, 1982.

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 withunintegrated finear DNA and imegratcd at tmmy sites, Cell 15:1397-410, 1978.

Oppermmm H, LArrson A D, Varrmra H E, Levfntow L & Bishop J M. Uninfected vertebrateceffs contain a protein that is closely related to the product of the avian xsrcoms virus transforminggene (src). Proc. Nat. Ad. Sri. USA 76:1804-8, 1979.

Bishop J M. Enemies withirr the genesis of retrovinrs oncogenes. Cell 23:5-6, 1981,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 notrequired for maintenance of the tumor ststc. Cell 23:31 i -22, i981.

Vmmms H E, Vogt P K & Bfahop J M. integration of deoxyribonucleic acid specitic for Roussarcoma virus after infection of permissive and nonpermissive hosts. Prac. Ntrr. Acad. Sci. USA703Ct67-7i, 1973.

St4hdfn D, Gurrtaka R V, Varmrrs H E & B~hop J M. Purification of DNA complementary tonucleotide sequences required for neoplastic transformation of fibroblasts by avirm sarcoma viruses.J. Mol. Biol, 101:349-65, 1976.

126

208

206

199

194

190

176

173

173

171

170

161

160

157

Taylor J M, Dnay A, Karl Y W, Varnms H E, LieInjo L E, Grmearm J & Tadd D. Geneticlesion in homozygous alpha thrdasaaeroia (hydrops fetrdis). Nature 251:392-3, 1974.

~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.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,Ringold G M, Ysmamoto K R, Tomkins G M, Bishop J M & Varmus H E. Oexmrretbasone-

mediated induction of mouse mammary tummvirusRNA:a systemfor studyingglucocorticoidaction. Ce[l6:299-305,1975.

Ringold G M, Yamamoto K R, Bkhop J M & VarmrLSH E. Glucocorticoid-stimulatedaccumulation of mouse mammary rumor virus RNA: increased rate of synthesis of viral RNA.Proc. Nat. Acad. Sci. USA 74:2879-83, 1977.

Varmus H E, QuiMreU N & Ortia S. Retroviruses as mutagens: insertion arrd excision of anontrsnsforming provirus at?cr expression of a resident trsmforming provims. Cc// 25:23-36, 1981

Dah[berg J E, Sawyer R C, Taylor J M, Faras A J, Levtnann W E, Gcdm$trI H M & BkhopJ M. Transcription of DNA aarcomn virus. 1. Identification of a spccitic 4S RNA which serves asprimer. J. Virol. 13:1126-33, 1974.

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 incidencemouse strains. J. Mol. Biol, 79:663-79, 1973.

Ringold G, Lasfargues E Y, B~hop J M & Varmrrs H E. Production of mouzc mammary tumorvirus by cultured cells in the absence and presence of hormones: assay by molecular hybridization.Virology 65:135-47, 1975.

Spector D H, Varrmrs H E & Bishop J M. Nuckrtide sequences related to the transforming geneof avian sarcoma virus are present in DNA of uninfected vertebrates. Proc. Nat. Acad. Sci. USA75:4102-6, 1978.

Bishop J M, Levinaon W E, QuintrelI N, Suftivmt D, Fanabier L & Jackson J. The lowmolecular weight RNAs of Rous sarcoma virus. 1, The 4S RNA. Virofogy 42:182-95, 1970.

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.

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-tor of research, NationaJ Scientific ResearchCenter (CNRS), Pasteur Institute, Line,France. In an open letter to the Nobel com-mittee, he claimed that his crucial contribu-tions to the discoveries were ignored.q Thecontroversy is discussed in more detail later.

Oncogene Hypothesis

Since the Rous sarcoma virus was firstdiscovered in 1910, scientists have beenstruggling to find the exact connection be-tween tumor viruses and cancer. Some re-searchers theorized about gene mutation inthe etiology of cancer, as did JoshuaLederberg, now president, The RoeicefellerUniversity, in a 1946 Science papers In1969 George J. Todaro and Robert J.Huebner, National Cancer Institute, pro-posed that viral cancer genes are found innormal cells, perhaps acquired through viralinfection early in evolution. These genes liedormant until they are stimulated by carci-

nogenic factors, such as chemicals or radia-tion, at which time they convert cells tocancerous growth.6

To explore this hypothesis, Bishop andVarmus in the mid- 1970s decided to inves-tigate whether the cancer-causing gene of theRous sarcoma virus, called src, could befound in the DNA of normal cells. Findingone gene out of the thousands found in thegenome of vertebrates was a formidable taskthat no one had managed to accomplish,given that the gene manipulation toolsavailable today had not yet been fullydeveloped.

Bishop, Varmus, and their colleagues de-veloped a DNA probe that identified onlythe src gene.T Using molecular hybridiza-tion, in which chains of DNA or RNA nu-cleic acids attach to specific nucleic acidcounterparts, they found that the src se-quences are found in the normal cells ofchickens and other birds. These results werepublished in the 1976 Nature paper that

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received credit from the Nobel committee. 1Since its publication, it has been cited over435 times and is the third most-cited paperpublished by Bishop and Varmus.

In later studies the src gene was also foundin the normal cells of mammals, includinghumans, and in fish.g Subsequent workprovided further confirmation that the srcgene discovered in vertebrates was not aviral gene after all, but a cellular gene, latercalled a proto-oncogene. g Proto-oncogeneswere afso found to play an active role in nor-mal cells, producing proteins necessary forcell function. 10

Controversy

The controversial protest raised bySt4helin stems from the key experimentalwork done during the mid- 1970s. St6helinwas a visiting scientist on leave from theCNRS to work in San Francisco with Bishopat the time the prizewinning work was done.He points out that he not only produced themolecular probe corresponding to the srconcogene, but he also performed the exper-iments showing that these viraf oncogenicsequences had a counterpart in normal hostDNA. 1I He claims further that, afthoughBishop as well as Varrmrs afways acknowl-edged his crucial contribution in those ex-periments, the eight-page announcementfrom the Nobel committee omitted any men-tion of his name and did not include refer-ences to the key papers on which he ap-peared as first author. [,7 In his open letterto the Nobel committee, St6helin requestedthat the committee “find a way of respect-ing the history of this discovery, which isin the process of being rewritten as a directconsequence of their intervention. I ask thatthey repair a wrong that they have done mepersonally and are doing themselves in de-forming what was an objective reafity whichmay no longer be so.”4

In the wake of St6helin’s claims, other re-searchers offered their own views of thework that led to the prize. One notable ex-ample was a letter to Nature by another

former colleague of Bishop and Varmus,Ramareddy V. Guntaka, now at the Depart-ment of Molecular Microbiology and Im-munology, University of Missouri, Colum-bia. Guntaka served as an assistant researchmicrobiologist in the Bishop-Varmus lab inthe 1970s. As he notes in his letter, he hadstarted the work on the src probe underBishop and Varmus’s direction and, afterobtaining favorable results, turned this taskover to Sk?helin in order to pursue otherprojects. Implying that Stihelin had no moreclaim to the prize than he did himself,Guntaka supports the decision of the Nobelcommittee. 1Z

The Nobel committee has been inconsis-tent in the past in apportioning credit wheremany collaborators were involved. A recenteditorial in Nature cited two interestingcases, one of them concerning Jocelyn Bell,who was excluded from the 1974 Nobel inphysics despite her contribution to the dis-covery of pulsars, an achievement for whichAntony Hewish received Nobel recognition(Hewish shared the 1974 prize with MartinRyle). Conversely, Georges J.F. Kohler wasa visiting scientist in C&r Milstein’s labo-ratory at the British Medical Research Cotm-cil’s Laboratory of Molecular Biology inCambridge, UK, when they unraveledmonoclonafantibody technology. Yet he stilfshared the 1984 prize in physiology or med-icine with Milstein. is We discussed Kohferwtd Milstein’s work in an earlier essay. 14

In .kienfijic Elite, Zuckerman discusses

:his question of “distinguishing betweenMl-fledged scientific collaboration and su-m-vised research assistance, between re-~laceable and irreplaceable contributions toxi-ze-wirmingresearch. “s (p. 56) She men-.ions the controversy surrounding the Nobel~orthe discovery of streptomycin, awardedo Selman Waksman in 1952. Although a:ourt of law had determined two yearsxirlier that Waksman’s colfeague AlbertJchatz was a full collaborator and was en-itled to a share in the royalties from the dis-:overy, and although the case had beentighfy publicized in the US, the Nobel com-

128

Figure 1: Year-by-year citaticm to the mwt<ited works by J.M. MsJIop and H.E. Vanmu. White bsr=%%dinD et al., Nature 260:170-3, 1976. GreY bar= L.evinson A D ef af., Cell 15:561-72. 1978. Blackbar=BishopJ M, Annu. Rev. Biochem. 52:301-54,-1983

300

250

2 2000.-

Z

z

: 150

=

z 100

50

0

mittee claimed not to have known ofSchatz’s contributions.s (p. 55-6)

Zuckerman aIso discusses the case ofOreste Piccioni, who in 1972 brought suitagainst Owen Chamberlain and EmilioSegrk, winners of the physics prize in 1959.Piccioni claimed that the two laureates hadnot acknowledged his contribution to theirprizewiming discovery of the antiproton,even though they mentioned him in theiroriginal publication. Piccioni, however, un-like Bell and Schatz, lacked supporters inthe scientific community. Although a judg-ment of dismissal was rendered in the suit,the case took over two years to settle andinvolved a total of 65 separate legalactions.3 (p. 56)

Unfortunately, no matter how valid acomplaint may be, an overturned decisionby the Nobel committee would be unprece-dented and highly unlikely; nominations, de-liberations, and ultimate Nobel decisions arefinal and without appeal. 13In any case, no

Year

one questions that both Bishop and Varmusare deserving of this coveted prize.

Further Research on Oncogenes

The Nobel committee announcement ofthe Nobel Prize in medicine or physiologystates, “The explosive development of thisfield of research has led to the identifica-tion of more than 40 different oncogeneswhich direct different events in the complexsignal systems that regulate the growth anddivision of cells. Changes in any one ormore of these oncogenes may lead to can-cer.”’5 These proto-oncogenes are acti-vated to cause cancer in a variety of ways,some of which are still under investigation.Proto-oncogenes can be altered by chemicalsor radiation to cause cancer. But they canalso malfunction when a virus infects the celland, during its replicating process, picks uppart of the proto-oncogene and puts it undervirrd-activated control. When the virus in-

129

Table 2: ISI” res.arcft fronts in wfdefs J.M, Biafsop and/or H.E. Vmmm.s are core mitbors. A = research-frontnumber. B = research-front name. C = number of core papers, D =number of citing papers.

A B c D

88-2673 Oncogene expression and mouse —ary rumor vims 2 24988-2674 Oncogenes in trausgeoic mice 8 58887-2657 Molecular oncobiology 3 37087-2658 Molecular genetics of cancer 3 39985-2623 Retrovicd oncogenes and cellular proto-cmccigenes 7 643782-0102 Retroviral proviral DNA and its role in maSignant transformation 5 9482-0686 Retroviruaes from mice 35 27 I81-010580-101979-108478-046278-147477-002877-142877-1560764330376.1171754303674-0003734002

Expression and integration of retroviral genesDNA, RNA, and tumor vimsesReverse trauacription in virusesMamrmuy tumor virusesAvian rumor virus DNA synthesisOncogenic virusesMouse mammary tumor virusesHuman tumor vimaesAvian tumor virusesRNA tumor viruacsSteroid hormone action and RNARNA vimaesCancer virus

48 481

fects another cell, it inserts the kidnappedproto-oncogene into an abnonmd slot in thenew cell’s DNA, overwhelming normaf celf-growth regulation. As is noted in a 1982

Nature paper by G.S. Payne, also at UCSF;Bishop; and Varmtrs (see Table 1), a retro-virus can also insert itself within a cellular

proto-oncogene domain and can cause thelatter to overproduce its protein product,causing tumor growth.

The details of the oncogenic process aredescribed by Bishop in a 1983 review arti-cle in the Annual Review of Biochemistry.As is seen in Table 1, this paper is the most-cited work by Bishop, receiving over 1,100citations in the seven years since it was pub-lished. Figure 1 illustrates the yearly cita-tions to this paper as well as to the 1976Nature papsr and a third work published byBishop, Varmus, and colleagues in 1978 inCell that describes the function of the pro-tein product of the src gene. Citations to boththe Nature and Cell papers peaked in 1980and 1981, whife Bishop’s review paperpeaked in terms of citations in 1985 but isstill highly cited today.

The prizewinning discovery concerningoncogenes ultimately did not bring credeneeto Todaro and Huebner’s oncogene hypoth-esis but showed that oncogenes are perverted

6 8316 15312 1254 4g

112 7008 875 666 605 61

215 I ,917490 3,573117 844

—

versions of fundamental genetic parts of ournormal cell machinery, as summed up byVarmus in a 1982 speech:

[Proto-oncogenes] prove not to be shtm-bering beasta, silent invaders of the celf’shousehold, waiting only to be awakenedby the noises of carcinogens. Instead,@XO-oneogerres]are true members of thefamily, multiple siblings whose lives andworkaare easentiafto the household’ssur-vival, but who are nonetheless liable tobeastfybehavior, hypersetivity, and otherpsychopathology,fatal ifhtessesand.. kidn-apping by outsiders. 16

Bishop and Varsma

Interestingly enough, both Bishop andVarmus pursued undergraduate degrees inhe liberal arts before becoming medical re-searchers. Bishop attended Gettysburg Co]-ege, Pennsylvania, and then went on to%rvard Medicaf School, where he became~articularly fascinated with molecular biol-)gy. In what was considered au unusual ar-rangement at the time, Bishop substitutedMl-time research for waditionaf coursework in his fourth year of medicfl school.4fter graduation he worked as an investi-~ator in virology at the Nationrd Institutes)f Health (NIH). Bishop joined the faculty

130

Figure 2: Hiioriograph of research fronts, 19S3-19S8, on oncogene research. Numbers of core/citing papersare indicated at the bottom of each box. Asterisks (*) irrd]cate research fronts in which J M. Bkhop and/or H. E.Varmus are core or citing authors.

n

“84.8130Cellulartransforming germsand oncoaenasis

E&wM_nlecilar oenetica-%imi-l“. . . . .-

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F _5 ‘FCallular oncqerms and ‘ Oncomcnes inpmto-oncogenes human catcinogrmasis transgenic

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41/945 41/533 mice8r588

their mle In “87-7362neoplaatictransformation

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at UCSF in 1%8, where he continued study-ing cancer viruses.

Varmus received a degree in English fromAmherst College, Massachusetts, and thenwent on to study seventeenth-century liter-ature at Harvard University, Eventually, hemade his way to Columbia University forhis medical degree. Following that, heworked in Ira Pastan’s laboratory at NIH.Varmtas joined Bishop at UCSF as a post-doctoral fellow in 1970, at which time theybegan their prizewiming work.

Research-Front Data

Table 2 presents the research fronts inwhich the publications of Bishop and Var-mus occur as core documents. Briefly, a re-search front develops when authors cite apaper to indicate its relevance to their ownresearch. Paprs that are frequently cited to-gether, or co-cited, share common features,such as topics, results, methods, or discus-sions. As a result, the citing authors them-selves categorize papers into subject-relatedclusters of research. These co-citation

groups help identify research fronts. Noticethat the work of Bishop and Varmus was in-cluded in three research fronts from 1977,reflecting the importance of their findingsthe year before. Figure 2 shows a historio-graph of the wimers’ contributions to on-cogene research between the years 1983 and1988. Each box contains the research-frontname with the numbers of core and citingpapers in the lower right-hand corner. Re-search fronts included in this historiographare determined by continuity of the core lit-erature from year to year. If the same coredocuments are cited at the requird thresh-olds in two adjacent years, then a “string”is established. This figure illustrates thatBishop and Varmus continue to be highlycited core authors more than a decade aftertheir Nobel research.

Currently, Bishop and Varmus are con-tinuing to publish studies of retrovirttses,src, and oncogene transcriptional behaviorand transformations. 17 Bishop’s currentwork involves studies of expression and reg-ulation of rrryb and rrryc oncogenes, 1g,1gwhile Varmtrs’s recently published work in-

131

eludes studies of ribosomal frameshiftingand other prmesses involving the Rous sar-coma virus.zo,z 1

In forthcoming essays, as is our custom,we will examine the prizewinning work bythe 1989 Nobel laureates in physics:Norman F. Ramsey, Harvard University;Hans G. Dehmelt, University of Washing-ton, Seattle; and Wolfgang Paul, Universi-ty of Bonn, Federal Republic of Germany.We will also review the work of the

laureates in chemistry: Sidney AItman, YaleUniversity, New Haven, Connecticut, andThomas Cech, University of Colorado,Boulder,

*****

My thanks to C.J. Fiscus, Lisa Ho[land,aria’Christopher King for their help in thepreparation of this essay.

G:XuMI

REFERENCES

1, St6hetirs D, Vrrrmus H E, Bfshop J M & Vugt P K. DNA related to the transforming gene(s) of aviansarcoma viruses is present in normal aviarr DNA. Namre 260:170-3, 1976.

2, PenrUebury D. The new Nobelists:a lnok ar their citation histories. 7?re .$cierrrisr3(22): 18; 21, 13 Novemhcr 1989.

3. Znckerrnrm H. .kienf(r$c dire. New York: Free Press, 1977.335 p.4. Stdhefirr D. An open letter to the Nobel Cnrmnittce of Physiology/Medicine. 10 November 1989.5, Lerferberg J. A nutritional concept of cancer, Science 104:428, 1946,6. Tndarn G J & Huebner R J. The viral mrcogene hypntbesis: new evidence. Pmt. Nat. Acad. .$ci. (/S,4

69:1009-15, 1972.7. Sti$heffn D, Grmtaka R V, Vm-rrms H E & BKhop J M. purification of DNA complementarytn

nucleoridc aquences rqrircd for neoplastic tmnsformation of fibroblasta by avimr sarcoma viruses.J. Mol. Biol. 101 :349(55, 1976,

8 Spector D H, Varrmrs H E & Bfahop J M. Nuclcotide sequences related to the transforming gene ofavian sarcoma virus are present in DNA of uninfected vertebrates. Proc. Nat. ,4cad Sci. fJS475:4102-6, 1978,

9. Parker R C, Varmus H E & Bishop J M. Cellular homologue (C-WC)of the transforming gene of Roussarcoma virus: ianlation, mapping, and transcriptional amifysis of c-src and flanking regions,Pmt. Nat. Acrrd. Sci. USA 78:5842-6, 1981.

10. B~fIop J M. Cellular oncogenes and retroviruses. Armrr. Rev, JJiockm. 52:301-54, 1983,11. St4helbr D. Personal comrrnmicatinn. 22 February 1990.12. Gmrtaka R V. Letter to editor. (Antecedents of a NoM Prize.) Natrrre 343(6256):302,

25 January 1990.13. Conduct unbecoming. Nurrrre 342:328, 1989.14. GarfSeM E. The 1984 Nobel Prize in medicine is awarded to Niels K. Jemc, C&ar MiJstein, and

Gemrges J .F. Kohfer for their contributions to immunology. Essays of an information scierrfisf:ghostwriting and other essays. Philadelphia: 1S1 Press, 1986. Vol. 8. p. 416-31.

15. Karolfrtaa Irratitute. Nobel Assembly. Press release. 9 Gctober 1989.8 p.16. Varrmsa H E. Convocation tafk presented in bmror of the f-asker Award, 9 September 1982.

San Fmnciaeo, CA. 9 p.17. Brnwn P O, Bowerrnan B, Varmua H E & Bishop J M. Retroviral integration: structure of the initial

covafent product and its precursor, and a role fnr the viral fN protein. Proc, Nar. Acud. .%i. USA86:2525-9, 1989.

18. Duwna K M, Martfn G R & Bfahop J M. Contrasting partcms of rrrycand N-myc expression duringgastmlation nf the mouse embryo. Gene. Develop. 3:860-9, 1989.

19. Shtfvebrmer E & BishopJ M. The PVTgenefrequentlyamplifieswithmycin tumorceUs.Mol. CeU.Bio/. 9:1148-54,1989.

20. JrscfraT, MwfbarsiH D, MrsairmF R & VarsrmaH E. Signafsfor rihoammdframeshiftingin the Roussarcoma vims GAG-POL region. Cell 55:447-58, 198g.

21. Verdermne M F, Kapfmr J M & Varmoa H E. A mutation in v-src that removes a single conservedresidue in the SH-2 domain of pp60v-src restricts transformation in a hostdependent mrmner.J. Virol. 63:338-4g. 1989.

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