They Wand 0SS tk Slmsldera of Giants: Sol S@egelman, a Piomer in l$lokcular Biology

Number 21 May 23,1983

Science in our century has been Indeed, it is upon his widely acclaimed marked by tremendous upheavals in un- discoveries that much of the framework derstanding, brought about by momen- of the discipline now rests. Sol was still tous discoveries and extraordinary pe~ deeply involved in a number of projects ple. One such upheaval has occurred in when, tragically, he died following a biology. It began in the 1930s, when a brief illness on January 21, 1983.2 This new field, , was born essay is dedicated to his memory, and to of the synthesis of five distinct disci- the surviving members of his family: hw plines: physical chemistry, crystallogra- wife, Helen; his daughter, Marjorie; and phy, , microbiology, and bio- hk sons, Willard and George. chemistry.1 I deeply regret that Sol did not have Molecular biologists try to explain the opportunity to read this long biological phenomena at the molecular overdue discussion of his work. I had level. By the mid-twentieth century, planned to do this as part of our series of they had settled several problems that essays on various awards in science—in plagued previous generations of biolo- particular, the Feltnnelfi prize, men- gists. For instance, proteins and nucleic tioned later. Sol was one of the true acids had been known since the nine- giants of modem science. So it is with a teenth century to be very large mole- mixed sense of pain and gratitude that I cules, each consisting of long chains of use thk opportunity to pay tribute to a subunits—amino acids in the case of man whose genius was unique. protein, punnes and pynmidines in the Sol was born on December 14, 1914, case of nucleic acid. But it remained for in City to Max and Eva (Kra- molecular biologists to discover the long mer) Spiegelman. Even as a child, he ex- sought after sequence in which these hibited a deep interest in biology.s But subunits occurred. During the 1930s, when he began his undergraduate career however, answers to fundamental ques- at the CoUege of the City of New York in tions involving the structure of DNA, 1933, he found his biology courses so and the processes by which it regulates disappointing that he majored in mathe- cell metabolism, still lay in the future. 1 matics and physics instead. However, he It was during this turbulent, revolu- read biology on hk own. And in 1936 tionary time that my friend Sol Spiegel- and 1937, he interrupted his schooling to man completed his undergraduate train- work as a researcher in the Richard Mor- ing and entered the field of molecular ton Koster Research Laboratory, Crown biology. He would become one of the Heights Hospital, Brooklyn, New York. major figures in the then infant science. There he completed his first research pa-

164 zymes is under direct genetic control,~ Spiegelman felt that knowledge of how the genes themselves are controlled was vital to an understanding of malfunc- tioning enzymes. He began his investiga- tions in the mid- 1940s. The work occu- pied him for a full decade. But in the end, he and his colleagues were able to show clearly that enzymes could be al- tered without necessarily involving an accompanying mutation in the genes controlling them. Spiegelman suggested that changes or abnormalities in en- zymes occurred when critical fractions of genes were inappropriately activated or deactivated—a phenomenon known familiarly today as switching a gene on or off. Sol Spiegelman The implications for cancer research were enormous. During most of the per-an analysis of the mutation of a 1940s, the wild multiplication of some bactenum,q written under the supervi- cells at the expense of others that is so sion of the lab’s dwector, A. Shapiro. He characteristic of cancer had been as- returned to City College in 1938 to finish cribed to genetic mutation. Spiegel- hk undergraduate career, and graduated man’s results, however, made it possible with a bachelor of science degree in to test the idea that the genes of a can- 1939. cerous celf might be intact, but that the Spiegelman went on to begin graduate control mechanism had gone berserk. work in cellular physiology at Columbia And Spiegelman’s suggestion that copies University in 1940. After two years of the information encoded within DNA there, he continued his postgraduate are transmitted into the cefl’s cytoplasm studies from 1942 through 1944 at Wash- for protein synthesisb.T had great signifk ington University, St. Louis, Mksouri. cance for future research into messenger During this time, he also lectured in RNA. physics and in applied mathematics. He During 1945 and 1946, Spiegelman received hm PhD from Washington served as an instructor in bacteriology at University in ceflular physiology and Washington University School of Medi- mathematics in 1944. cine. He was then promoted to assistant In his early investigations, Spiegelman professor of bacteriology, a post he held wanted to describe how cells form their for more than two years, until 1948. He enzymes, and what factors determine became so widely known and admired the types of enzymes a celf has. Enzymes for the elegance of hk experiments that are proteins that stimulate, direct, and the American Cancer Society offered to regulate the complex chemicaf reactions set him up in his own research program underlying the life processes of an or- with an annual budget of S25,000-a ganism. It was suspected that abnormal- sum greater than the budget of the entire ities in certain enzymes involved in the biology department.3 Spiegelman ac- regulation of tissue building played a cepted the offer. In 1948 he left St. role in the development of cancer. Since Louis, taking the grant with him, and it was known that the synthesis of en- went to work with ‘tie US Public Health

165 Service at the , for an enzyme that would duplicate, or Minneapolis. When the money ran out a replicate, the viral RNA directly. year later, he left Minneapolis for the In 1963, Spiegefman and several col- University of Illiiois, Urbana. There he leagues found the enzyme they were was named professor of microbiology, looking for: one capable of specifically and there he would remain for the next recognizing viral RNA among all the 20 years. other bacterial RNA within a cell. 12 It By the mid- 19S0s, a few years after his was the first of the nucleic acid polymer- arrival at Illkois, Spiegelman began the ases—enzymes aiding in the formation work that eventually led to the discovery of nucleic acid-discovered to possess for which he is best known, While study- such a quality, which was later named ing the synthesis of nucleic acids, he and template spectilcity. IS Spiegelxnan’s an- an associate, Benjamin D. HaLl, found it nouncement of the discovery at a Cold necessary to pair a strand of viral DNA Spring Harbor symposium in New York with a strand of matching viral RNA, B was greeted with skepticism. 14 But This was possibly the most important within two years he demonstrated, technique in molecular biology, then or together with I. Haruna, that an enzyme now—RNAIDNA hybridization. The coded for by still another virus, known new technique led Spiegehnan and hk as phage Q~, was also template specif- colleagues directly to the discovery that ic. 13The enzyme proved relatively easy only one strand of DNAs double helii to isolate and purify. Within the year, transmits the genetic information to the Spiegelman was using Q~s RNA repli- celf’s protein-making machmery. g cating enzyme-or RNA replicase-to In 1961, Spiegehnan turned his atten- manufacture RNA in test tubes. 15 tion to those viruses which contain RNA The “artificial” RNA proved as viable rather than DNA. The central biological and infectious as its “natural” counter- dogma of the time held that the direction part. Spiegehnan used it to observe Dar- of transmission of genetic information winiin selection at the relatively simple was always from DNA to RNA. Thus, it molecular level, a stage removed from was relatively easy to understand how a the complexities of evolution at the DNA virus used a bacterium to repro- cellular level. lb,17 His experiments duce itself: it simply injected the cell culminated in 1966 with the discovery of with its own DNA, which interposed be- a type of RNA that was a fraction of the tween the cell’s DNA and the cellular original Q? phage—a “little” Qfl. l~m It RNA. However, in the case of viruses could do little more than grab the ap- contatilng RNA rather than DNA, the propriate rep ficase enzyme and copy it- problem was to describe how an RNA self. Presumably, this extremely liiited virus completes its life cycle in a celf capacity for simple replication is alf that dominated by DNA. Spiegefman seemed primeval nucleic acid molecules were to confirm the view of RNA as subor- able to achieve. Why, then, had they dinate to DNA when he failed to find ever evolved beyond that capacity, to evidence that viral RNA could somehow the point where they were capable of usurp a bacterium’s genetic machinery directing the synthesis and functioning to produce copies of itself that were of something as complicated as a cell? made of DNA, rather than RNA. 10How- Spiegehnan’s work made possible some ever, as we shall see, just such a reverse hypotheses and further work concerning tmnscription of RNA to DNA would be the environmental pressures that had dwcovered nine years later. 11 In the forced primordial nucleic acids to meantime, Spiegehnan began to search become increasingly complex in order to

166 survive. Cells were evolved by nucleic breast cancers of 60 percent of Amer- acids in an attempt to create a safe, con- ican women with family hktories of trolled environment for reification. breast cancer.= Moore and Spiegehnan Without the pressure to create such an collaborated to show that the virus con- environment, ceflular evolution would tained the reverse transcription en- have been a totally umecessary com- zyme.~ Spiegehnan then derived DNA plication. Spiegehnan’s work in this area copies from the mouse tumor RNA. He is being continued today by his col- reasoned that if human breast cancer did leagues at Columbia. involve a virus, the RNA of that virus In 1969, Spiegehnan left Illinois to might be similar in structure to that of return to his native city of New York to the mouse tumor virus. Thus, the human become dwector of Columbia’s Institute RNA would be attracted to the DNA de- of Cancer Research and professor of rived from the mouse tumor RNA. The human genetics and development in the experiment worked. The viral DNA university’s College of Physicians & neatly hybridized with the RNA of a high Surgeons. By the early months of 1970, proportion of the cancerous human tis- Spiegehnan’s new lab was functioning sue he tested.z7 Moreover, the associ- smoothly. But in May, at the 10th Inter- ation was tumor-specific, meaning that national Cancer Congress in Houston, the viral DNA failed to hybridize with Texas, Howard Temin announced his the human RNA from any other type of discovery of an enzyme withii RNA vi- human tumor. Experiments using ruses that was capable of reverse tran- various types of human cancers contin- scription, or manufacturing DNA from ued to occupy him until his death. In- RNA.11 It was just the sort of enzyme deed, a method of detecting cancer by Spiegehnan himself had looked for years assaying plasma samples for the pres- earlier, but had not found. Spiegelrnan ence of viral-related proteins, invented immediately set his team to work putting by Spiegelrnan, was recently granted a Temin’s results to use. They soon US patent.~ demonstrated that a number of other Spiegelruan’s achievements have been RNA viruses also carried the reverse en- recognized with a long list of honors and zyme, and that the DNA produced awards. In 1974, for instance, he re- within the infected cell by the enzyme ceived the prestigious Albert Lasker was a COpy Of the viral RNA.ZM5 The Basic Me&cal Research Award for his viral DNA then invaded the bact erium’s 1965 synthesis, in collaboration with nucleus. Most importantly, however, Haruna, of the infectious viral phage Spiegehnan and his colleagues devel- Q~s RNA.15 In 1981, he was awarded oped a “simultaneous detection test,”zs the Antonio Feltrinelli International with which they could identify the Prize in Biology for his contributions presence of RNA, reverse transcriptase, over the previous 45 years to molecular or DNA in tumor tissue, The technique biology, bacterial and molecular genet- made it possible for the first time to ex- ics, and experimental biology. The Fel- amine cancerous human tissue for evi- trinelli prize is administered by the dence of viraf agents. [talian National Academy of Sciences The groundwork was laid for Spiegel- for the Fekrinefli Foundation, and in- man’s next series of experiments: the at- cludes a cash award of 100 million lire, tempt to prove a link between human ~pproximately $83,000.~ And in addk cancer and viruses. An epidemiological tion to holding ten honorary doctorates, survey by Dan Moore and colleagues Spiegehuan was a member of the Ameri- had found particles identical to a mouse can Society of Biological Chemists, the mammary tumor virus in the milk and American Society for Microbiology, the

167 Genetics Society of America, the Na- selected as a Citation Classic for Current tional Academy of Sciences (NAS), and Con tents” (CtP’ ) in 1977.~ Another several foreign societies, to name just a paper by Spiegelrnan and colleagues% is few of his affiliations. featured as a Citation Classic in this The importance and relevance of week’s CC/Life Sciences. Spiegehnan’s work is reflected in many It would have been fun to ask Sol to of ISP’s citation studies. For example, rank each of his papers and to comment in our recent study of the 1,000 most- on those he considered the most impor- cited authors publishing between 1965 tant. Putting numbers on his varied ac- and 1978,~ he appeared as the thirtieth complishments may even trivialize most-cited author. Our earlier study of them, if not seen in the proper context. the top 300 scientists cited between 1961 But it is always of interest to the public to and 1976 revealed that Spiegehnan learn how creative people view their ranked first among microbiologists and own accomplishments. virologists.sl When we publish the 1955- I first met Spiegehnan when he be- 1964 Science Citation Index” (.KW ), came a member of the advisory commit- we will have more data on the crucial tee of the Genetics Citation Index (GCl) 19S0S.s2 But even now one can estimate project. Together with L.L. Cavalli- that there were probably over 15,000 Sforza, Joshua Lederberg, Gordon citations to the more than 35(3papers he Allen, George Lefevre, Joseph MeK~ck, published during his career. The 25 most and Victor McKusick, we worked out cited of his papers are presented in Table the design for GCZ. In the years that fol- 1. Among them is an article published in lowed, I met Sol occasionally and was al- Nature, “Characterization of the prod- ways impressed by his willingness and ucts of RNA-directed DNA polymerases patience to explain to me, in terms a lay- in oncogenic RNA viruses. “z1 It ap- person could understand, the progress peared on LSI’Slist of the 301970 papers of the research in which he was currently most cited from 1970 to 1973.33 And his involved. I last saw him on the occasion paper, “Electrophoretic separation of of the NAS award ceremonies where we viral nucleic acids on polyacrylamide congratulated Victor McKusick on re- gels, “34produced in 1967 at the Intern- ceiving the NAS Award for ExceUence ational Laboratory of Genetics and in Scientflc Reviewing.@ We had Biophysics in Naples, Italy, appeared in agreed that I would come visit his lab to our 1977 study of highly cited articles demonstrate and talk about our new mi- from Italian journals and laboratories.ss crocomputer system for managing re- Spiegehnan was perhaps best known prints.41rqz for the technique of RNA/DNA hybrid- But scientists pay a price for having so ization. The method of cajoling DNA to many talented friends. Often, we know seek out and pair with RNA was original- them best through their writings. But ly developed in 1961 in collaboration because we are aU so caught up with our with HalL8 The paper reporting the orig- own day-to-day concerns, we may miss inal technique has been explicitly cited much along the way. Then we grow about 300 times. But in 1965, the tech- older, and good friends die unexpected- nique was improved upon by Spiegel- ly. You remember their sparkling eyes man and David Gillespie, then a gradu- and their enthusiasm for new projects. ate student at the University of Illinois. And you regret the lost opportunity to The paper reporting the improved tech- get to know them better. niqu~ was quoted over 1,700 times by Throughout his career, Sol always the end of 1982. One of the most-cited wanted to do something “useful. ” He articles of the 1960s,37 it was already tried to work on problems whose sohJ-

168 Tab!e 1: The 25 most-cited articles by Sol Spiegelman. Total Cftatkms 1%1-1982 Bfblfegra@fc Data

1,718 Gfllespfe D & Spfegefmaa S. A quantitative assay for DNA-RNA hybridswith DNA immobtid on a membrane. J. Mol. Biol. 12:829-42, 1%5. 751 BfshepD H L, Claybrook J R & Spiegafman S. Electrophoretic separation of viral nucleic acids on polyacrylsmide gels. J. Mol. Biol. 26:37>87, 1%7. 4’75 Rftnsm F M & Spfagehoaa S. LcwAization of DNA complementary to ribosomal RNA in the nucleolus organizer region of Drosophila mefanogaster. Prwc. Nat. Acad. Sri. US 53;737-45, 1%5. 312 Spfegelmaa S, Bnrny A, Das M R, Keydar J, Scbfona 1, Trwnicek M & Wabmn K. Characterization of the products of RNA-directed DNA polymerasea in oncogenic RNA ViN*S. Natura 227:5f&7, 1970. 305 Kacfmr D L, Watsen K F, Brmry A & Spfagefrrmn S. Purification of the DNA polymerase of avian myeloblastosia virus. Biochim. Biophys. Acts 246:365-83, 1971. 290 Hall B D & Spfegefmaa S. Sequence complementarily of T2-DNA and ‘f%pecific RNA. Proc. Nat. A cad. Sci. US 47:137-46, 1%1. 268 Hayasld M & Spfegebrum S. The selective synthesis of informmtionaf RNA in . Proc. Nat. Acad. Sci. US 47:1564-S0, 1%1. 263 Nomura M, Haff B D ~ Spfegehnrm S. Characterization of RNA synthesized in l?scherikhia coli sfter bacteriophage T2 infection. 1 .Mof, Biof. 2:M6-26, 1960. 225 Hartma 1 & Spfegehmm S. Specific template requirements of RNA replicates. Proc. Nat, A cad. Sci, US 54:579-8’7, 1%5, 217 Scfdom I & Spfegefman S. Simultaneous detection of reverse transcrip- and high molecular weight RNA unique to oncogenic RNA viru$ea. Science 174:S40-3, 1971. 204 Kaclrm D L. Spfegefman S, Bank A, Teds M, Metsfom S, Dow L & Markc PA. in vitro synthesis of DNA components of human genes for globlris. Nature New Biol. 235:167-9, 1972. 252 Spfegelmaa S, Buray A, Dar M R, Keydar 1, Seldom 1, Traded M & Wataon K. Synthetic DNA-RNA hybrids and RNA-RNA duplexes as templates for the polymerases of tbe cmcogerric RNA viruses, Nature 228:4X+2, 1970. 192 Rftuaaa F M, Atwond K C & Spfcgelmtm S. A rnolecufsr explanation of the bobbed mutants of Drosophila as partial deficiencies of “ribosomal” DNA. Genetics 54:819-34, 1966. 184 Goodman N C & Spfegafnma S. Dwtiuguishing reverse tranacriptase of an RNA tumor virus from other known DNA polymerases. Prwc. Nat. A cad. Sci. US 6S:2203-6, 1971. 181 Hsydd M, Hayrrahf M N & Spfagefman S. Restriction of in vivo genetic transcription to one of the complementary strands of DNA. Pmt. Nat. Acad. Sci, US 50:664-72, 1963. 170 Yaakofaky S A & Spfegdnraa S. The idmrt~lcation of the riboaomal RNA ciatron by sequence complementmity, IL Saturation of and competitive interaction at the RNA cistron. Proc. Not. A cad. Sci, US 4S: 146&72, 1%2. 169 Baxt W, Hebfmaaa R & Spfcgefman S. Human leukaernic cefls contain reverse transcriptase associated with a high molecular weight virus-related RNA. Nature New Biol. 240:72-5, 1972. 161 Ysakofsky S A & Spfegelmmr S. D~tinct cistrons for the two ribosomal RNA components. Proc, Nat, Acad, Sci. US 49538-44, 1963. 159 Harrma I, Nom K, Ohteh Y & Spfegelrnaa S. An RNA “repficssc” induced by and selective for a viral RNA: isolation and properties. Proc. Nat. A cad. Sci. US 50:905-1!, 1%3. 158 Scbfom J, Spfagdman S & Moore D. RNA-dependent DNA pnlymerase activity in vinrs- Iiie particles isolated from human mifk. Naturs 231:97-103, 1971. 158 Yankofaky S A & Spfcgefman S. The identification of the ribosomal RNA cistmn by sequence complementarily, I. Specflcity of complex formation. Proc. Nat. Acad. Sci. US 48:1069-78, 1%2. 140 Rftusm F M, Atwood K C, Lfarfaley D L & Spfegelmaa S. On the chromcrsomal distribution of DNA complementary to ribosnmal and soluble RNA. Nat. Cancer Inst. Monogr. 23:449-72, 1966. 139 Axel R, Scfdom I & Spfcgefmarr S. Presence in human breast cuncer of RNA homologous to mouse mammary tumour virus RNA. Nature 235:32-6, 1972. 135 Spfegelrrran S, Burny A, Das M R, Keydar J, Scfdom I, Travnfcek M & Watson K. DNA-directed DNA polymeruse activity in oncogenic RNA viruses. Nature 227: 102!+31, 1970. 130 Gfacomord D & Spfegehrrmr S. Origin and biologic individuality of the genetic dictionary. Science 138: 132S-31, 1%2.

169 tions would explain big chunks of a field, tion. I can think of no better tribute to rather than just a particular phenome- Sol himself than his own poem: non. He didn’t want to waste his time searching for explanations that would not be worth his efforts once he had Tim Gentle Glmtts them in hand.b3 Although his first alle- giance was to basic research, he de- There are the gentle giants plored the lag time between the obtain- Who walk softly through our lives. ing of results and their application. “The No shrill demand for early recognition days of the gentleman scientist are Commands our attentive admiration. over,” he once remarked. “We’re pro- fessionals, we’re paid well, our activities No blidkg glare of brilliance are costly, and we’re going to have to Announces their presence among us. listen to the people paying the bills.”~ They are the quietly courageous ones His work stands as a monument to hk Who plant for future generations. determination to live up to this philoso- They are the creators and searchers phy. A poem he wrote in tribute to a fel- Who teach and celebrate the truth. low cancer researcher Anna Gold- feder4s is as applicable to Sol as it was to ***** her. He said that her life that sang My thanks to Stephen A. Bonaduce praises to the wonder of our universe, and Tern”Freedman for their help in the and added honor to the human condi- preparation of thi~ essay. ,,,m,~,

REFERENCES

1. larfsrm H F. The eighth day of creation. New York: Simon and Schuster, 1979. 6S6 p. 2. Webster B. Dr. Sol Spiegelman, microb~ologist at Columbia and geneticist, dies. NY Times 22 January 19S3, p. 16. 3. Moritz C, ed. Current biogmphy yearbook. 1980. New York: Wifson, 19S0. p. 372-5, 4. Sfurpfro A, S@e@rmn S & Kester H. A rspid methnd for the study of genetics in large populations, J. Genet. 34:237-45, 1937, s. Portngsf F H & Cohen I S. A century of DNA. Cambridge, MA: MIT Press, 1977, 3S4 p, 6. Spke@mam S & Kamen MD. Genes and nucleoproteicrs in the synthesis of enzymes, Science 104:581-4, 1946. 7, Spfegehtmn S. Carcinogenesis and the mechanism of gene action. Cancer Res. 7:42-3, 1947. 8. Haf! B D & S@cgdmari S. Sequence complementarily of T2-DNA and T2-specK1c RNA. Pmt. Nat. A cad. Sci. US 47:137-46, 1%1. 9. Hayasfd M, Hayashi M N & Spfegelmmr S. Restriction of in vivo genetic transcription to one ot the complementary stmnds of DNA. Prec. Nat. A cad. Sci. US 50:66472, 1963. 10. Doi R H & Spfegdman S. Homology test between the nucleic acid of an RNA virus and the DNA in the host ceff. Science 13& 1270-2, 1%2. 11. Tesafsr H M & Mfzmtanf S. RNA-dependent DNA polymerase in ririons of Rous sarcoma virus. Nature 226:1211-3, 1970. 12. Harmm 1, Nom K, Ohtafm Y & Spfegehrmn S. An RNA “replicase” induced by and selective for a tin] RNA: isolation and properties. Proc, Nat. A cad. Sci, US 50:905-11, 1963. 13. Harnna 1 & Spfegefmtrm S. Specific template requirements of RNA replicates. Proc, Nat. Acad, Sri. US 54:579-87, 1%5. 14. S@r@rrrari S & Hmyashf M. The present status of the tmrrsfer of genetic information and its control. Cold Spring Harbor Symp. 28:161-81, 1963. 15. Harrma I & !$pfegefman S. Autocatslytic synthesis of a viral RNA in vitro, Science 150:884-6, 1%5, ]6. Spiegdr?mn S. The development and use of an extraceffular RNA replicating system. Harvey ,!,ect. 64:1-67, 196S. 17, Levfsofrn R & Spk@rmn S. Further extmceffular Darwinian experiments with replicating RNA molecules: diverse variants isolsted under dtiferent selective conditions. Proc, Nat. A cad, Sri. US63:S05-11, 1%9. 18, W D R, Bkrhop D H L & Sph=gelmsn S. The mechanism and direction of RNA synthesis templated by free minus strands of a ‘little” variant of Q/?-RNA. Proc. Nat. Acad. Sci. US 60:713-20, 196S.

170 19. Levisofm R & Spfegafman S. The cloning of a aeff-replicating RNA molecule. Proc. Nat. Acad, Sci. US 6WW5-72, 1968. 20. B&hop D H L, MfUs D R & Spfegehrran S. The sequence at the 5’ terminus of a self-replicating variant of viral Qfl ribunucleic acid. Biochemi$rry- USA 7:3744-53, 1968. 21, Spfegcdrnrm S, Brmry A, Das M R, Keydar J, Scfdom J, Tmvmfcek M & Watson K. Characterization of the prnducts of RNA-dwected DNA polymeraaes in oncogenic RNA fises. Nature 227:563-7, 1970. 22, ------Synthetic DNA-RNA hybrids and RNA-RNA duplexes as templates for the polymerases of the orrcogenic RNA ti=S. Nature 228:439-2, 1970. 23. SdcJora J, Spfagefmrm S & Moore D. RNA-dependent DNA polymerase activity in virus-lie particles isobrted from human mifk. Natur-s 231 :97-1(X3, 1971. 24. Goodman N C & SpfegefrrmmS. Distin@shing reverse trarrscriptase of an RNA tumor virus from other known DNA polymers.ws. Proc, Nat. A cad, Sci, US 68:2’203-6, 1971. 25. Schfom J & Spfegefman S. Simultaneous detection of reverse transcriptsse and high molecufar weight RNA unique to oncogenic RNA viruses. Science 174:S@3, 1971. 26. Moore D H, Cbamey 1, Krmnarrky B, Laafargrma E Y, Sarkar N H, Brennarr M J, Burrows J H, Sfrmt S M, Paymaster J C & Vafdya A B. Search for a human breast crmcer virus. Natura 229:611-5, 1971. 27. Axel R, ScJdom J & SpfegeJrmm S, Presence in human bresst csncer of RNA homologous to mouse msmmary tumour virus RNA. Nature 235:32-6, 1972. 28. Splegefmam S. Afe(hod~or detecting cancer. US patent 4,379,839.12 April 1983. 29. Guffeld E. The awards of science: beyond the Nobel prize. Part 1. Tbe determinants of prestige. Currenf Contents (4):5-14, 24 January 1983. X3. ------The 1,cHX3contemporary scientists most-cited 1%5-1978. Part 1. The bsaic fist and introduction. Current Content~ (41):5-14, 12 October 1981. 31. ------The 300must-cited authors, 1%1-1976, including c~authors at last, 1, How the names were selected. Esmy$ of an information scienti.rt, PfrUadelphis: 1S1 Press, 1980. Vol. 3. p. 538-50. (Reprinted from: Currmrf Coriterrt.r (28):5-1 7, 10 July 1978.) 32. ------The 195>1964 Science Citation Index cumulation-a major new bibfiograpfdc tnnl for historians of science and aU others who need precise information retriewd for the age of space and molecufar biology. Currcrrt Contents (5):5-8, 31 January 1983. 33. ------The 1970papersmostfrequentlycited from [email protected] an irrforrmrtion tcientist. PhUadelpfda: 1S1 Pres.$, 1977. Vol. 1. p, 519-22. (Reprinted from: Current Contents (51):5-8, 19 December 1973.) 34. Bfshop D H L, CJaybrook J R & Spfegefman S. Electrophoretic separation of viral nucleic acids on pnlyac+rnide gels. J. Mol. Biol. 26:373-87, 1%7. 35. Guffefd E. Highly cited articles. 24. Articles from ItaUan journrds and from Itafian faborstories. Jhays of an information mienti$t. Philadelphia: 1S1 Press, 19&3. Vol. 3. p. 34-41. (Reprinted from: Current Conferrt.r(6):5-12,7 February 1977.) 36. Gfffeapfe D & Spfegefmrm S. A quantitative asssy for DNA-RNA hybrids with DNA irnmofrifkd on a membrsne. J. Mol. Biol. 12:829-42, 1%5. 37. GarffeJd E. Most-cited srticles of the 1960s. 2. Biochemistry and molecufar biology. hays of an information scientht. Philadelphia: 1S1 Press, 1981. Vol. 4. p. 254-63. (Reprinted from: Current Content$ (35):5-14, 27 August 1979.) 38. Gffkpfa D. Citation Cfasdc. Commentary on J. Mol. Biol. 12:829-42, 1%5. Current Conkmta (11):14, 14 March 1977. 39. Kac&u D L, Watson K F, Jkrrny A & Spfegefmam S. Purification of the DNA polymeraee of avian myeloblaatoais virus. Biochim. Biophys. Actu 246:365-83, 1971. 40. Guffeld E. The 1982 NAS fourth J.M. Luck Award for Excellence in Scientific Retiewing goes to Victor McKusick for hia mapping of the literature in human genetics. Currerrl Contents (18):5-9, 3 May 1982. 41, ------Introducing Sci-Mate—a menu-driven microcomputer software package for onfine and offline information retrieval. Psrt 1. The Sci-Mate Personal Oata Manager. Current Contents (12):5-12, 21 March 1983. 42. ------Introducing Sci-Mate-a menu-driven microcomputer software psckage for onfine snd offline irrforrnation retrievaf. Psrt 2. The Sci-Mate Universal Online Searcher. Current Contents (14):5-15, 4 April 1983. 43. Atwood KC. Telephone communication. 15 March 1983. 44. Chedd G. Spiegefman’s descent from the ivory tower. New Sci, 54:373-6, 1972. 45. Spfegefrnen S. A tribute to Ama Goldfeder. Ann. NY A cad. Sci. 397:ix-xii, 1982.

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