-rrent Cnmments” EUGENE GARFIELD INSTITUTE FOR SCIENT($IC lNFOFiMATION@ 3501 MARKET ST PHILADELPHIA PA 19104 The 1989 in or 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 . 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) , 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 , 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 , 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 . 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 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. 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 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 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. 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. Some re- available today had not yet been fully searchers theorized about gene mutation in developed. the etiology of cancer, as did Joshua Bishop, Varmus, and their colleagues de- Lederberg, now president, The Roeicefeller veloped a DNA probe that identified only University, in a 1946 Science papers In the src gene.T Using molecular hybridiza- 1969 George J. Todaro and Robert J. tion, in which chains of DNA or RNA nu- Huebner, National Cancer Institute, pro- cleic acids attach to specific nucleic acid posed that viral cancer genes are found in counterparts, they found that the src se- normal cells, perhaps acquired through viral quences are found in the normal cells of infection early in evolution. These genes lie chickens and other birds. These results were dormant until they are stimulated by carci- published in the 1976 Nature paper that

127 received credit from the Nobel committee. 1 former colleague of Bishop and Varmus, Since its publication, it has been cited over Ramareddy V. Guntaka, now at the Depart- 435 times and is the third most-cited paper ment of Molecular and Im- published by Bishop and Varmus. munology, University of Missouri, Colum- In later studies the src gene was also found bia. Guntaka served as an assistant research in the normal cells of mammals, including microbiologist in the Bishop-Varmus lab in humans, and in fish.g Subsequent work the 1970s. As he notes in his letter, he had provided further confirmation that the src started the work on the src probe under gene discovered in vertebrates was not a Bishop and Varmus’s direction and, after viral gene after all, but a cellular gene, later obtaining favorable results, turned this task called a proto-oncogene. g Proto-oncogenes over to Sk?helin in order to pursue other were afso found to play an active role in nor- projects. Implying that Stihelin had no more mal cells, producing proteins necessary for claim to the prize than he did himself, cell function. 10 Guntaka supports the decision of the Nobel committee. 1Z The Nobel committee has been inconsis- Controversy tent in the past in apportioning credit where The controversial protest raised by many collaborators were involved. A recent St4helin stems from the key experimental editorial in Nature cited two interesting work done during the mid- 1970s. St6helin cases, one of them concerning Jocelyn Bell, was a visiting scientist on leave from the who was excluded from the 1974 Nobel in CNRS to work in San Francisco with Bishop physics despite her contribution to the dis- at the time the prizewinning work was done. covery of pulsars, an achievement for which He points out that he not only produced the Antony Hewish received Nobel recognition molecular probe corresponding to the src (Hewish shared the 1974 prize with Martin oncogene, but he also performed the exper- Ryle). Conversely, Georges J.F. Kohler was iments showing that these viraf oncogenic a visiting scientist in C&r Milstein’s labo- sequences had a counterpart in normal host ratory at the British Medical Research Cotm- DNA. 1I He claims further that, afthough cil’s Laboratory of in Bishop as well as Varrmrs afways acknowl- Cambridge, UK, when they unraveled edged his crucial contribution in those ex- monoclonafantibody technology. Yet he stilf periments, the eight-page announcement shared the 1984 prize in physiology or med- from the Nobel committee omitted any men- icine with Milstein. is We discussed Kohfer tion of his name and did not include refer- wtd Milstein’s work in an earlier essay. 14 ences to the key papers on which he ap- In .kienfijic Elite, Zuckerman discusses peared as first author. [,7 In his open letter :his question of “distinguishing between to the Nobel committee, St6helin requested Ml-fledged scientific collaboration and su- that the committee “find a way of respect- m-vised research assistance, between re- ing the history of this discovery, which is ~laceable and irreplaceable contributions to in the process of being rewritten as a direct xi-ze-wirmingresearch. “s (p. 56) She men- consequence of their intervention. I ask that .ionsthe controversy surrounding the Nobel they repair a wrong that they have done me ~orthe discovery of , awarded personally and are doing themselves in de- o in 1952. Although a forming what was an objective reafity which :ourt of law had determined two years may no longer be so.”4 xirlier that Waksman’s colfeague Albert In the wake of St6helin’s claims, other re- Jchatz was a full collaborator and was en- searchers offered their own views of the itled to a share in the royalties from the dis- work that led to the prize. One notable ex- :overy, and although the case had been ample was a letter to Nature by another tighfy publicized in the US, the Nobel com-

128 Figure 1: Year-by-year citaticm to the mwt

250

2 200 0 .- Z z

: 150

= z 100

50

0

Year mittee claimed not to have known of one questions that both Bishop and Varmus Schatz’s contributions.s (p. 55-6) are deserving of this coveted prize. Zuckerman aIso discusses the case of Oreste Piccioni, who in 1972 brought suit Further Research on Oncogenes against Owen Chamberlain and Emilio Segrk, winners of the physics prize in 1959. The Nobel committee announcement of Piccioni claimed that the two laureates had the Nobel Prize in medicine or physiology not acknowledged his contribution to their states, “The explosive development of this prizewiming discovery of the antiproton, field of research has led to the identifica- even though they mentioned him in their tion of more than 40 different oncogenes original publication. Piccioni, however, un- which direct different events in the complex like Bell and Schatz, lacked supporters in signal systems that regulate the growth and the scientific community. Although a judg- division of cells. Changes in any one or ment of dismissal was rendered in the suit, more of these oncogenes may lead to can- the case took over two years to settle and cer.”’5 These proto-oncogenes are acti- involved a total of 65 separate legal vated to cause cancer in a variety of ways, actions.3 (p. 56) some of which are still under investigation. Unfortunately, no matter how valid a Proto-oncogenes can be altered by chemicals complaint may be, an overturned decision or radiation to cause cancer. But they can by the Nobel committee would be unprece- also malfunction when a virus infects the cell dented and highly unlikely; nominations, de- and, during its replicating process, picks up liberations, and ultimate Nobel decisions are part of the proto-oncogene and puts it under final and without appeal. 13In any case, no virrd-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-front number. 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 2 249 88-2674 Oncogenes in trausgeoic mice 8 588 87-2657 Molecular oncobiology 3 370 87-2658 Molecular genetics of cancer 3 399 85-2623 Retrovicd oncogenes and cellular proto-cmccigenes 7 6437 82-0102 Retroviral proviral DNA and its role in maSignant transformation 5 94 82-0686 Retroviruaes from mice 35 27 I 81-0105 Expression and integration of retroviral genes 48 481 80-1019 DNA, RNA, and tumor vimses 6 83 79-1084 Reverse trauacription in viruses 16 153 78-0462 Mamrmuy tumor viruses 12 125 78-1474 Avian rumor virus DNA synthesis 4 4g 77-0028 Oncogenic viruses 112 700 77-1428 Mouse mammary tumor viruses 8 87 77-1560 Human tumor vimaes 5 66 7643303 Avian tumor viruses 6 60 76.1171 RNA tumor viruacs 5 61 7543036 Steroid hormone action and RNA 215 I ,917 74-0003 RNA vimaes 490 3,573 734002 Cancer virus 117 844

— fects another cell, it inserts the kidnapped versions of fundamental genetic parts of our proto-oncogene into an abnonmd slot in the normal cell machinery, as summed up by new cell’s DNA, overwhelming normaf celf- Varmus in a 1982 speech: growth regulation. As is noted in a 1982 Nature paper by G.S. Payne, also at UCSF; [Proto-oncogenes] prove not to be shtm- Bishop; and Varmtrs (see Table 1), a retro- bering beasta, silent invaders of the celf’s household, waiting only to be awakened virus can also insert itself within a cellular by the noises of carcinogens. Instead, proto-oncogene domain and can cause the @XO-oneogerres]are true membersof the latter to overproduce its protein product, family, multiple siblings whose lives and causing tumor growth. workaare easentiafto the household’ssur- vival, but who are nonetheless liable to The details of the oncogenic process are beastfybehavior, hypersetivity, and other described by Bishop in a 1983 review arti- psychopathology,fatal ifhtessesand.. kidn- cle in the Annual Review of . apping by outsiders. 16 As is seen in Table 1, this paper is the most- cited work by Bishop, receiving over 1,100 Bishop and Varsma citations in the seven years since it was pub- lished. Figure 1 illustrates the yearly cita- Interestingly enough, both Bishop and tions to this paper as well as to the 1976 Varmus pursued undergraduate degrees in Nature papsr and a third work published by he liberal arts before becoming medical re- Bishop, Varmus, and colleagues in 1978 in searchers. Bishop attended Gettysburg Co]- Cell that describes the function of the pro- ege, Pennsylvania, and then went on to tein product of the src gene. Citations to both %rvard Medicaf School, where he became the Nature and Cell papers peaked in 1980 ~articularly fascinated with molecular biol- and 1981, whife Bishop’s review paper )gy. In what was considered au unusual ar- peaked in terms of citations in 1985 but is rangement at the time, Bishop substituted still highly cited today. Ml-time research for waditionaf course The prizewinning discovery concerning work in his fourth year of medicfl school. oncogenes ultimately did not bring credenee 4fter graduation he worked as an investi- to Todaro and Huebner’s oncogene hypoth- ~ator in virology at the Nationrd Institutes esis but showed that oncogenes are perverted )f Health (NIH). Bishop joined the faculty

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

“84.8130 Cellular transforming germs nand oncoaenasis I J

-%imi-l- “. . . . . Callular oncqerms and ‘ Oncomcnesin M_nlecilar oenetica Fpmto-oncogenes _5human catcinogrmasis ‘Ftransgenic E&w ‘85-0208 41/945 41/533 mice Onr,ogenea and 8r588 ::cer tZ!EE?ltheir mle In “87-7362 57n200 neoplaatic “84-0576 u, transformation Zr223 Chromosomes, 5vt185 human cancer 1-”ormas, and cancer I 7/313 1- 4n43 l--]

at UCSF in 1%8, where he continued study- groups help identify research fronts. Notice ing cancer viruses. that the work of Bishop and Varmus was in- Varmus received a degree in English from cluded in three research fronts from 1977, Amherst College, Massachusetts, and then reflecting the importance of their findings went on to study seventeenth-century liter- the year before. Figure 2 shows a historio- ature at Harvard University, Eventually, he graph of the wimers’ contributions to on- made his way to Columbia University for cogene research between the years 1983 and his medical degree. Following that, he 1988. Each box contains the research-front worked in Ira Pastan’s laboratory at NIH. name with the numbers of core and citing Varmtas joined Bishop at UCSF as a post- papers in the lower right-hand corner. Re- doctoral fellow in 1970, at which time they search fronts included in this historiograph began their prizewiming work. are determined by continuity of the core lit- erature from year to year. If the same core Research-Front Data documents are cited at the requird thresh- olds in two adjacent years, then a “string” Table 2 presents the research fronts in is established. This figure illustrates that which the publications of Bishop and Var- Bishop and Varmus continue to be highly mus occur as core documents. Briefly, a re- cited core authors more than a decade after search front develops when authors cite a their Nobel research. paper to indicate its relevance to their own Currently, Bishop and Varmus are con- research. Paprs that are frequently cited to- tinuing to publish studies of retrovirttses, gether, or co-cited, share common features, src, and oncogene transcriptional behavior such as topics, results, methods, or discus- and transformations. 17 Bishop’s current sions. As a result, the citing authors them- work involves studies of expression and reg- selves categorize papers into subject-related ulation of rrryb and rrryc oncogenes, 1g,1g clusters of research. These co-citation while Varmtrs’s recently published work in-

131 eludes studies of ribosomal frameshifting laureates in chemistry: Sidney AItman, Yale and other prmesses involving the Rous sar- University, New Haven, Connecticut, and coma virus.zo,z 1 , University of Colorado, In forthcoming essays, as is our custom, Boulder, we will examine the prizewinning work by the 1989 Nobel laureates in physics: ***** Norman F. Ramsey, Harvard University; Hans G. Dehmelt, University of Washing- My thanks to C.J. Fiscus, Lisa Ho[land, ton, Seattle; and Wolfgang Paul, Universi- aria’Christopher King for their help in the ty of Bonn, Federal Republic of Germany. preparation of this essay. We will also review the work of the G:XuMI

REFERENCES

1, St6hetirs D, Vrrrmus H E, Bfshop J M & Vugt P K. DNA related to the transforming gene(s) of avian sarcoma 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 .$cierrrisr 3(22): 18; 21, 13 Novemhcr 1989. 3. Znckerrnrm H. .kienf(r$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 of avian sarcoma virus are present in DNA of uninfected vertebrates. Proc. Nat. ,4cad Sci. fJS4 75:4102-6, 1978, 9. Parker R C, Varmus H E & Bishop J M. Cellular homologue (C-WC)of the transforming gene of Rous sarcoma 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 . 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. USA 86:2525-9, 1989. 18. Duwna K M, Martfn G R & Bfahop J M. Contrasting partcms of rrrycand N-myc expression during gastmlation 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 Rous sarcoma 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 conserved residue in the SH-2 domain of pp60v-src restricts transformation in a hostdependent mrmner. J. Virol. 63:338-4g. 1989.

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