sign in sign up
<<
Home , Milislav Demerec, Walter Gilbert

EUGENE GARFIELD IN ST ItUTE FoR SCIENTIFIC IN FOe M.4T10N@ 3501 MARKET ST PHILADELPHIA PA 19104 A Tribute to Cold Spring Harbor Laboratory 011 Its IO(MI Biih(ky: Jan A. Witkowski Reviews Its HisEory and the Highest Impact Sympsia Publications

Number 28 July 9, 1990 In March of this year, i%e Scienrist@pre- University of Southampton in 1968 and a sented a survey of small, independent re- PhD in from the University of search institutions in the US. 1Twenty such London in 1972. Between 1972 and 1982 institutions were ranked by the citation im- he was a research fellow at the Institute of pact of their papers published between 1973 Child Health, London, and at the Mayo and 1987. Although the Salk Institute for Clinic, Rochester, Mimesota. From 1982 Biological Studies and the Scripps Clinic and to 1986, he was a lecturer in the Department Research Foundation, both of San Diego, of Pediatrics, Royal Postgraduate Medical California, received the most citations (over School, University of London. He then 124,000 each), the institution that topped the served as director, Kleberg DNA Diagnostic list by citation impact was the Cold Spring Laboratory, and assistant professor, Institute Harbor Laborato~, New York. As David for Molecular , at Baylor College Pendlebury observed, papers published from of Medicine, Houston, Texas. Cold Spring Harbor had a citation impact Witkowski came to Cold Spring Harbor more than five times greater than the average in 1987. As director of the Banbury Center, for the entire Science Citation Indexm data- he determines topics for conferences at the base. Furthermore, the impact factor for this center, arranges meetings for congressional lab was nearly twice that of the average for staff and science journalists, and assists with the 20 institutions listed. I (The entire list the publication of meetings. His own major appears in Table 1.) research interest is in human genetics, but The following guest essay, however, does Witkowski notes that he has a long-standing not really concern Cold Spring Harbor’s interest in the history of science—especially current preeminence in life-sciences re- topics relating to the development of ex- search, but rather its dk.tinguished past— perimental in this century. He has specifically, the yearly symposia in experi- also published papers discussing significant mental biology that have taken place there studies in biochemistry, embryology, tissue for more than a half-century: Jan A. culture, and .2 Witkowski, director of the laboratory’s Ban- The papers discussed in this study span bury Center, discusses the 51 most-cited ar- 40 years of research, from 1940 to 1982. ticles in the Cold Spn”ng Harbor Symposia Although there is a predominance of papers on Quantitative Biology. His account in- from the 1960s-the period Witkowski re- cludes a brief history of the laboratory itself, fers to as’ ‘the fist golden age of molecular from its beginnings as a summer school at genetics’ ‘—dtisstudy demonstrates the con- the end of the last century to its current sistency with which the symposia have pro- renown. The evolution of the symposia is duced highly cited works over the years. As ako described, tlom the fust meeting in Witkowski notes, this year marks Cold 1933, with 16 scientists in attendance, to Spring Harbor’s 100th birthday, and as the what Witkowski calls the” frenetic, action- symposia continue to address the latest packed meetings that we know today.” topics in biological research, this output of A mtive of Birmingham, UK, Witkowski important and influential work is certain to received a BS degree in zoology from the continue.

253 ......

Table 1: The too 20 I&h immwt Asanciation of lndeuendent Research Institutes (A13Ul members (among those &at pub~shed-more than lCO papers, 1673-1987) Citation Name Papers Citations 1. Cold Spring Harbnr L&ratory, Cold Spring Harbnr, NY 839 49,217 58.7 2 Salk Institute for Biological Studies, San Diego, CA 2,834 124,942 44.1 3. Fred Hutchinson Csncer Research Center, Seattle, WA 1,756 59,800 34.1 4. Whitehead Jnstitufe for Biomedical Research, Csmbridge, MA 208 6,624 31.8 5. Roche Institute of Molemdar Biology, Nuttey, NJ 1,731 53,450 30.9 6. Carnegie Institution of Washington, Baftimore, MD, snd 1,695 51,8% 30.6 Wsahington, DC 7. Trudeau Institute, Sarsna.c Lake, NY 288 8,358 29.0 8. Scripps Ctinic and Research Foundation, La JoOa, CA* 4,972 124,323 25.0 9. Wisrar Institute, Philadelphia, PA 1,586 38,758 24.4 10. New York Blnod Center, New York, NY 734 17.620 24.0 11. La Jolts Csncer Research Foundation, La Jolla, CA 405 8,915 22.0 12. Joslin Diabetes Center, , MA 304 6,437 21.2 13. American HeaJth Foundation, New York, NY 820 17,127 20.9 14. Jackson Laboratory, Bar Harhnr, ME 994 19,872 20.0 15. Worcester Foundation for Experimental Biology, Shrewsbury, MA 1,347 26,807 19.9 16. Public HeafUr Research Institute of the City of New York, NY 796 15,769 19.8 17. Forsyth Dental Center, Ekuston, MA 617 1I,270 18.3 18. Palo Alto Medical Foundation Research Institute, Pako Alto, CA 539 9,808 18.2 19, Boston Biomed]czd Research Institute. Boston. MA 6% 12,075 17.3 20. Center for Bleed Research, Boston, MA 180 3,088 17.2 *Scripps is no longer an AIRf member. Source: Mm’s ScienceIndicators fde, 1973-1987. Although the laboratory’s research flour- already provided the ultimate commentaries. ished under earlier directors, notably Although I am hopeful that other authors Milislav Demerec and John Cairns, it is the listed in the Bibliography that follows the present director who has played the major essay will have contributed commentaries role in the growth of the laboratory’s in- on their papers by the time we go to press, fluence. He is, of course, Nobel laureate the main reason for their absence is our James D. Watson, who has been director at failure to invite them until now. Severrd of Cold Spring Harbor since 1%8. Previously, them have written commentaries on papers in a broad discussion of Citation Ce’assicsW, published in other journals. Success in ob- I’ve noted that perhaps the most influential taining commentaries depends upon the right paper of the century-Watson and Francis timing-it is preferable to invite authors to H.C. Crick’s 1953 publication on the write Citation Classic commentaries before double-helix structure of DNAq—has been they receive the or other major cited “only” about 1,000 times. ‘f This recognition, lest they be too preoccupied seemed to me to indicate an upper limit on with other pressing obligations. citations that one could expect for such a ***** work. It is also understandable that neither Watson nor Crick would provide us with a commentary on this paper. You might say My thanks to Christopher King and Eric that with the publication of Watson’s Z7te i%urschweli for their help in the prepara- Double ffeh.d and Crick’s recent autobi- tion of this essay, ography, WhatMad Pursuit, 6 they have

RmERaNct?s

1. Pemtfebrrry D. Cold Spring Harbor tops among ind~dent labs. 7SICScmntut 4(6):20, 19 March 1990. 2. WltkowakdJ A. Personal communication. 10 May 1990 3 Wataon J D & Crkk F H C. MoiecuIaImucture of nucle~cacids: a structure for deoxwibose nudtic acid Na-mre171:737-8, 1953. 4 Garfisld E. The arricles most cited in tk SCI from 1%1 !O1982.7. Awther IW Cimlion Classics: tie Watson-Crickdouble klix bas its rum. E.wavsof m infonnaion scientist: rhosr.witine and ocheressavx Pbitadelphrw1S1press, 19S6 Vol 8. p (87-%; - 5 Watson J D. J’fIedouble h.lu. New York: Norron. 1980.298 p. 6. Crick F H C. J+’?wmad pursuit. New York Basic, 1988. 182 p.

254 The 51 Most-Cited Articles in the Cold SpriDg Harbor Symposia on Quantitative Biology

Jan A. Witkowski The Banbury Center Cold Spring Harbor Laboratory Cold Spring Harbor, NY 11724

The Cold Spring Harbor Symposia on preach.z As Loeb wrote with Winthrop Quantitative Biology are a venerable and J. V. Osterhout, , Cam- venerated part of experimental biology. bridge, , and Thomas Hunt Established in 1933, the symposia have since Morgan, , New York, that time charted progress in research in a in the editors’ announcement to the series wide range of sui&cm, subjects chosen for Monographs on Experimental Biology, their excitement, me need for dispassionate “Biology, which not long ago was purely and critical review, and above all by the descriptive and speculative, has begun to belief that they were rhe subjects that would adopt the methods of the exact sciences, continue to define the leading edge of re- recogui2ing that for permanent progress not search in biology. However, as John Cairns, only experiments are required but quan- director of Cold Spring Harbor Laboratory titative experiments.”3 Indeed, Loeb went from 1963 to 1968, has written on the sym- so far as to define “scientific biology” as posia: “any catalog of the virtues of the the attempt to reduce Iife phenomena ‘‘com- various Symposia, even if perfectly done pletely to physiochemical terms.’ ‘d and in the liveliest style, would miss the FoUowing the work of the physical , whole point of the exercise. These meetings a colloidal theory of living matter became have meant much more to many people than very popular and experiments were per- could possibly be guessed at from looking formed to determine the effects of changes at the contents of the books . . .. When we in the physical environment on organisms. look at the published volumes... we are Typical of these studies were investigations looking at the history of a scientific era. ” 1 of osmosis and diffusion of molecules across (p. 3) So before discussing the citation membranes, the colloidal properties of pro- record of the symposia, some historical teins such as gelatin and albumin, and the background is needed to appreciate the na- effects of ions on developing embryos and ture of the symposia and why they have con- of X rays on cells. tinued with ever-increasing success for 57 years. The Biological Laboratory and the Station for Experimental Evolution at Quantitative Biobgy Cold Spring Harbor

The period at the begiming of the twen- In the late nineteenth century, the Napks tieth century was marked by the increasing Zoological Station, Italy, founded in 1872, employment of experimentation and quan- was the mecca for experimental biology.~$ titative methods in the biological sciences. Such luminaries as British biologist Thomas This was most evident in the increasing H. Huxley; Louis Agassiz, Harvard Univer- numbers of physicochernicrd studies of liv- sity; Charles M. Child, University of ing organisms, and the work of Jacques Chicago, Illinois; Edmund B. Wilson, Co- Loeb, The Rockefeller Institute for Medical lumbia University; and Morgan all visited Research, New York, exemplified this there to carry out research on the marine mechanistic, physiochemical analysis ap- organisms abundant in the bay. Morgan was

255 so impressed by the Naples Station that he became a prime mover in promoting the Marine Biological Station at Woods Hole, Massachusetts, (1888) as the American equivalent. T (However, not everyone subscribes to the view that the station had such an impact on the development of US biology. g) Later, when Morgan went to the California Institute of Technology (Caltech), Pasadena, he established the institute’s marine station at Corona del Mar, California, in 1936. In 1890 the Brooklyn Institute of Arts and Science, New York, created the Biological Laboratory at the southwest corner of Cold Spring Harbor, an inlet on the north shore of Long Island, New York.g The Biological Laboratory began by teaching courses in zoology, botany, comparative anatomy, and study to biology teachers and students through the summer months. In 1898 Jan A. Witkowski Charles B. Davenport was appointed direc- tor of the Biological Laboratory. Davenport strains varied in their susceptibility to had been professor of evolutionary biology transplanted tumors, work continued by at Harvard University, and he is remem- E, Carleton MacDowell. (Little went on to bered especially for his interest in eugenics found the Jackson Laboratory at Bar Har- and for establishing the Eugenics Record Of- bor, Maine.) Both Alfred D. Hershey and fice. 10In 1904 he applied to the Carnegie Barbara McClintock carried out their re- Institution of Washington, DC, for support search at the station. Hershey is best known of a program to carry out research on for the famous “Waring blender” experi- genetics. The Carnegie Institution estab- ment that helped demonstrate that DNA is lished the Station for Experimental EvohI- the molecule of heredity, II and McClintock tion on the same site as the Biological Lab- for her cytogenetic studies and the discovery oratory, and Davenport became director of of movable genes in . 1z They were both, The history of these institutions is awarded the Nobel Prize in physiology or complex and the two were not formally medicine in 1969 and 1983, respectively. amalgamated until 1962 when they became Cold Spring Harbor Laboratory. The Symposia on Quantitative Biology Thus began a long and distinguished re- search program at Cold Spring Harbor. While the Station for Expirnental Evolu- George H. Shun began work on com tion at Cold Spring Harbor flourished, the genetics at the station in 1905. He produced Biological Laboratory fared less well, re- pure lines of com by self-pollination over maining a summer camp for teaching. It several seasons and found that when these underwent a rejuvenation in 1924 when it pure lines were crossed, the hybrid progeny was taken over by a group of scientists and were healthy and produced more corn local citizens who formed the Long Island strains. This was the first demonstration of Biological Association (LIBA). In that same hybrid vigor. year, Davenport’s son-in-law, Reginald The laboratory’s long association with Harris, bec~e director. He began building cancer research began in 1916 when a research program with the support of Clarence C. Little demonstrated that mouse LIBA and instituted year-round research.

256 The vogue was still for physiochemical pers. They were, and have continucxi to be, studies in biology, and Harris’s determina- a very successlid hybrid of’research paper tion to make the laboratory a center for and review article. Authors are given an op- modem biological research was evident in portunity to set their experirnerttrd results in his appointment of Hugo Fricke, former a wider context, and the importance of pa- director of biophysics at the Cleveland pers in the CSHSQB series is undoubtedly Clinic Foundation, Ohio, as the laboratory’s due to this. Harris died in 1936 at the age first full-time investigator. Within a few of 35, supposedly of exhaustion from the years of Harris’s appointment as director, burden of bringing out the CSHSQB volume there were research programs in biophysics, within six months of the meeting. Cairns endocrinology, and pharmacology. remarked that, when he read of Harris’s ex- Harris realized that the laboratory’s aims perience, “I resolved never to get the book could be promoted, and the general course out before the New Year, and I notice that of research advanced, by holding special Jim Watson [the current director] takes even meetings at Cold Spring Harbor. As noted greater precautions in this regard!”) in the 1934 annual report, (p. 5-6) Harris was succeeded in 1936 by Now it happens in modem biological Eric Ponder, a biophysicist, who continued research that the problem of a given to hold meetings on physiochemical aspects biologist, or groupof biologists,may have of biology, including such topics as “Pro- much more in commonwith thatof a given tein ” (1938), “Biological Oxida- or physicist, or a small group of either, than with that of a second group tions” (1939), and “Permeability and the of biologists.,.. Yet the meetings of the Nature of Cell Membranes” (1940). various Ieamed societies in this country still fail to take this into account..,. The primary motive of the conference- symposia is to consider a given biologicrd Molecular Biology and Genetics problem from its chemical, physical and mathematicrd, as well as from its biolog- In 1941 there was an abrupt shift in sym- ical aspects. 13 posium topics when Demerec became direc- In 1933 Harris organized the first of the tor of the Carnegie Institution’s Department Cold Spring Harbor Symposia on Quantita- of Genetics (as the Station for Experimen- tive Biology on “Surface Phenomena. ” tal Evolution was now called) and the These early meetings were not the frenetic, Biological Laboratory. Demerec had come action-packed meetings that we know today. to the Carnegie Institution of Washington at Instead a small group of 16 scientists stayed Cold Spring Harbor in 1923 and became for one month at the laboratory, and31 par- director in 1941. He was originally a ticipants came periodically to present papers Drosophila geneticist, but his interests and to participate in symposia. The meetings changed to bacterial and phage genetics. It were recognized immediately as being a was during Demerec’s tenure as director that unique contribution to science. The Rocke- the laboratory established its reputation as feller Foundation provided $5,000 towards one of the world’s centers for research on the cost of the second symposium and con- bacterial and phage genetics. Salvador tinued to make an annual grant for the Luria, at that time a research assistant at the following 12 years. College of Physicians and Surgwns of Co- Despite having to edit a vast amount of lumbia University, and Max Delbriick, then discussion, of which 30,000 words were at Vanderbilt University, Nashville, Ten- published, Harris managed to brirsg the book nessee, worked together at the laboratory for out in the same year as the meeting. Pttblica- the first time in the summer of 1941, and tion of the first volume of the Cold Spring Delbriick began teaching the legendary Harbor Symposia on Quantitative Biology phage course in 1945. (The two men shared (CSHSQB) series was also remarkable for the 1969 Nobel Prize in physiology or the establishment of the format of the pa- medicine with Hershey. ) James D. Watson

257 Table 1: Citation-frequency distribution for tbe 705 the earnest faces of Hermann J. Muller, In- articles published in the COU Spring Har60r Symposiu diana University, Bb-xnington; Leo Szilard, on Quantimive Biology with 50 or more citatims, 1945-1988 SCP University of Chicago; Jacques Monod, Pasteur Institute, Paris, ; and others Citation Number of Items Percent of look out at us. The scenes reflect an unhur- Level at Level Total Items ried style of meeting that has now disap- 1,0rn3 2 0.3 peared, but the organization of the week- 9CSI-999 1 0,1 long meeting, with the afternoons free and 8W899 o 0.0 a picnic on the lawn of the director’s house, 700-799 1 0.1 6(X-699 2 0.3 still contrives to provide opportunities for 5(X-599 2 0.3 quiet conversations. 4(X)-499 7 1.0 3cn3-399 10 1.4 2W299 36 5.1 lot-199 180 25.5 50-99 464 65.8 The Impact of the CSHS@l

Publication of the CSHSQB began in came as a student to Cold Spring Harbor 1933, but we begin our analysis in 1945, Laboratory in 1948. currently the earliest date in the Science The first of Demerec’s symposia was a Citation hdex~ (XT@), and end with 1988. landmark meeting on “Genes and Chromo- Table 1 gives the citation frequency distribu- somes: Structure and Organization” and the tion for the ’705articles with 50 or more cita- first of the post-World War II meetings was tions published in that period, in absolute on “Heredity and Variation in Microorgan- numbers and as a percentage of the total isms. ” These symposia were signposts for papers in the CSHSQB. These figures make research in genetics through the decades an interesting comparison with those for the spanning the 1950s and 1960s. This was a entire SC] file. Otdy 1.53 percent of papers golden age of molecular genetics, and the in the SCYare cited 50 times or more, com- list of participants in the symposia of that pared with about 20 percent for those pub- period is a roll call of those who established lished in the CSHSQB volumes. For the51 molecular genetics. This is reflected in the most-cited papers published in the CSHSQB, citation anrdysis discussed below. At the the citations range from 218 to 1,495. The same time that bacterial and phage genetics mean and median values are 389 and 299, were the dominating themes, the symposia respectively. These figures are much higher have covered a remarkable variety of topics. than for research journals and comparable These have included “The Mammalian with those for review journals. This refleets Fetus” (1954), “Biological Clocks” (1960), the hybrid nature of the symposia papers, “The Synapse” (1975), and “Evolution of that they give the authors an opportunity to Catalytic Function” (1987), develop their case as well as present data, The nature of the symposia changed with One estimate of the importance of scien- Demerec. The average number of partici- tific papers is their SC{ impact factor. For pants at the first eight meetings had been 56. 1988, this figure is the number of 1988 cita- The same figure for the first eight of tions to a paper published in the period Demerec’s meetings was 160, with 305 at 1986-1987. The impact factor for the papers the 1951 symposium on “Genes and Muta- published in a journal is obtained by averag- tions. ” Demerec also instituted one of the ing the number of citations for all papers in hallmarks of the CSHSQB, the collection of the journal, and this figure for CSHSQB photographs of participants appearing in papers k 2.25. This compares with the each volume. These began in 1949, and figure of 1.49 for all publications in the SCl Demerec took many of the early photo- iatabase, and the CSHSQB ranks 418th out graphs himself. The early pictures show of the 4,232 journals that were used to small groups of scientists conversing, and ~alculate this impact factor.

258 Table 2: Chronologieaf etlstribrrtion of publication It is striking that 47 percent of the 51 dates for tfre51 most+ited srticles from the Cdd Spring most-cited papers were published in the Harbor Symposia on Qm’tat@e Biology, 1945-1988 scI@ 1960s. As this period might be regarded as the first golden age of molecular genetics, Pubficatiorr Number of and given the Laboratory’s historically im- Year Papers portant role in this area, it is not surprising 1940-1944 1 to fmd that symposia papers from this period 1945 -t949 2 are among the most highly cited; 4 of the 1950-1954 3 top 5, and 12 of the top 20 papers appear 1955-1959 3 1960-1964 15 in volumes published between 1960 and 1%5-1969 9 1969. The 1963 symposium on “Synthesis 1970- I974 10 and Structure of Macromolecules” accounts 1975-1979 7 198(&19S4 1 for 4 of these top 20 papers. However, it is something of an oversimplification to assume that highly cited papers come just An indication of how well articles pub- from symposia on molecular genetics. I lished in the CSHSQB “age” is given by the mentioned that symposia topics were chosen 1988 six-year impact factor. This is the for their timeliness and importance, and not average number of 1983-1988 citations to necessarily because of their relevance to 1983 articles, and for the CSHSQB the research going on at the laboratory. For ex- figure is 43.12. This is far higher than the ample, symposia topics other than molecular estimated figure of less than eight for the genetics include subjects as diverse as ‘‘Bio- entire SCI ffle and suggests that those papers logical Clocks” (1960), “Antibodies” published in the 1983 CSHSQB have con- (1967), “The Mechanism of Muscle Con- tinued to be cited for longer than most traction” (1972), and “The Synapse” papers. This reflects the data of Table 1 that (1975). All these gave rise to highly cited show that CSHSQB papers are cited much papers. Furthermore, when these figures are more frequently than other papers in the SCI broken down by year, it is remarkable to file. fmd that 18 of the 20 symposia held between The cited half-life of a journal is the 1960 and 1979 have at least one highly cited median age of the journal’s articles that were paper. It is testimony to the laboratory direc- cited in a particular year. For the entire 1988 tors’ knowledge of what is going on in the SC1 data ffle, the cited half-life for a journal world of biology that they have picked win- was 5.9. The value for the CSHSQB was 7.2 ners so consistently. for the same period, again showing that the The recent decline in cited papers is more articles retain their value for longer. likely to reflect the short time that has elapsed for citations to accumulate rather than any frdl in the value of symposia con- Overall Citation Reeord tributions. A glance at the titles of the sym- posia held through the 1980s shows that The chronological dkribution of publica- there is every reason to believe that they will tion dates for the 51 most-cited articles is continue to generate highly cited papers. shown in Table 2. The oldest paper is that by Merkel H. Jacobs, University of Penn- sylvania School of Medicine, Philadelphia, The Five Most-Cited Papers published in the 1940 volume and deals with cell permeability to ions, a classical subject Of the five most-cited papers in the in biophysics. The most recent paper was CSHSQB volumes, four come from the published by Werner W. Franke, German 1960s and represent the two major tieIds of Cancer Research Center, Heidelberg, research in molecular biology in that period. Federal Republic of Germany (FRG), and Three papers are examples of classical colleagues in 1982. molecular genetic analysis in the prere-

259 combhnt DNA era, analysis that was char- increasingly serious problems for large-scale acterized by the elegant exploitation of sequencing and mapping. bacterial and viraf genetic behavior. The other paper is an example from the field of Jacob and Monod structural molecular biology. The fiRtr paper comes from the late 1970s and shows how The symposium in 1%1 was on ‘‘Cellular rapidly molecular genetics moved from in- Regulatory Mechanisms” and the paper direct inferences based on genetic analysis Fran~ois Jacob and Jacques Monod, Pasteur to direct anrdysis of sequences. Institute, presented is the fifth most cited (643 citations) in the CSHSQB. In it they Sutchye reviewed the data on the regulation of protein synthesis in and discussed The most highly cited paper in the mRNA and operators and the operon as the CSHSQB comes from the 1979 symposium unit of coordinated gene expression. It on “DNA: Replication and Recombina- makes a striking contrast with the paper of tion. ” It is a technical tour de force—the Sutcliffe. Jacob and Monod’s anafysis of the determination by Greg Sutcliffe, Harvard elements controlling gene expression in- University, of the entire 4,362 base pair se- volved elegant reasoning based on genetic quence of the cloning plasmid pBR322. The experimental evidence. In contrast, Sut- plasmid had been developed by Francisco cliffe’s discussion of the origin of replica- Bolivar and colleagues in Herbert W. tion, the structures of the arnpr and tetf, and Boyer’s laboratory at the University of Cali- protein coding regions of pBR322 is based fornia, San Francisco, and rapidly became on knowledge of the exact structure (nu- one of the most widely used vectors. 14,15 cleotide sequence) of the DNA. This paper The continuing citation of Sutcliffe’s paper by Jacob and Monod would probably have reflects the fact that pBR322 is the basis for had a much higher citation rate but for the many modem vectors and his work remains publication of their great review “Genetic the primary reference for its sequence. regulatory mechanisms in the synthesis of Sutcliffe was working in Walter Gilbert’s proteins” in the Journal of Molecular Bi- laboratory at Harvard Medical School, ology] 8 just one week before the sym- Boston, Massachusetts, and used the DNA posium, However, they were able to incor- sequencing method devised by Allan M. porate into the CSHSQB paper a discussion Maxam and Gilbert. lb Sutcliffe’s comments of McClintock’s work that had been omit- on the project make interesting reading in ted from the Journal of Molecular Biology relation to the current efforts to map and se- paper. Another highly cited symposium quence the larger genomes of Escherichia paper, on “The structure of DNA” by Wat- coli, Caenortuzbditis elegans, and humans. son and Francis H.C. Crick, was also He found that “chemical problems were “scooped” by publication elsewhere. 19 minor compared with the clerical problems This talk by Watson at the 1953 symposium of handling the data. ‘‘1TThe sequence data on “Viruses” was the first presentation of were read on three separate occasions and the double helix at a public meeting. It is the finaf printed sequence checked exten- ranked 16th amortg the CSHSQB papers. sively against the master handwritten copy by “many people. “ 17 Nowadays, hand- Jacob and Colleagues written notes have been replaced by com- puter hard discs, and sequencing films are Ten years after Watson’s presentation, the read using digitizer tablets. Sutcliffe took 13 symposium was on “Synthesis and Struc- months to sequence 4,362 base pairs of ture of Macromolecules, ” and Jacob, now pBR322. Automated sequencing machines in collaboration with Sydney Brenner, Me& are now capable of generating 12,000 base cal Research Council Laboratory of Molec- pairs of sequence per day, but handling and ular Biology, Cambridge, UK, and Franqmis analyzing this amount of data are becoming Cuzin, Pasteur Institute, presented what is

260 the second most-cited CSHSQB paper with Table 3: Tfre numberof authors per paper for the51 1,216 citations. They reviewed the experi- most-cited articles from the CW Spring Harbor Symposia on Qrumritarive Biology, 1945-1988 SC1@. mental work on DNA replication in bacteria and presented a detailed discussion of the Number of Number ‘‘replicon” model that Jacob and Bremer Authors of had outlined in a brief publication in per Paper Papers Chptes Renaks Hebahadaires &s Wnces 10 1 de 1‘Acaa%de des Sciences.zo They defined 9 1 a replicon as a genetic element capable of 8 2 7 3 replication and gave episomes and bacterial 5 2 chromosomes as examples. The replicon is 4 2 formally similar to the operon and has 3 4 2 13 remained a useful concept. Jacob et al. 1 23 discussed how the concept might relate DNA replication in eukaryotes. The name Santa Cr-uz, recounts that Epstein and C .M. is also used to describe the many individual Steinberg, then at Cakech, had promised regions of replicated DNA in the chromo- Harris Bernstein, then at Yale University, somes of higher eukaryotes. New Haven, Connecticut, that the mutants, if any were found, would be named after his Epstein and Co[[eagues mother. They were found and “amber” is the English equivalent of “Bernstein.’ ’21) The third most-cited paper at 929 citations also comes from the 1%3 symposium on the Caspar and Klug “Synthesis and Structure of Macromole- cules” and shows how genetic and structural “Structural” molecular biology led to the studies were begiming to come together in discovery of the DNA double helix and con- an analysis of the assembly of the complex tinued to flourish in the following years, T4 . The great advances in even as it seemed that the “informational” molecular genetics in the 1950s and 1960s approach was in the limelight. Indeed it is depended on the choice of organism and the oflen forgotten that in 1956 the Crick and availability of mutants that could be selected Watson team made a second major contribu- for and mapped. Ideally the phenotypes of tion to molecular biology with their discus- the mutants should reveal something of the sion of the structures of small or simple function of the genes involved. This paper viruses.zz The paper by D.L.D. Caspar and by R.H, Epstein and his colleagues, Univer- , Harvard Medical School, from sity of Geneva, Switzerland, listed the 47 the 1%2 symposium on “Basic M~hrmisms genes of phage T4 for which temperature in Animal Virus Biology, ” is a iucid and sensitive (ts) and amber (am) mutations were definitive review of their elegant studies on available and described their phenotypes. the structure and assembly of simple helical Thirty-seven of these were associated with viruses like tobacco mosaic virus and small the assembly of the virus particles, affect- regular viruses like turnip mosaic virus and ing, for example, the tails of the phage. A adenovirus. Caspar and Klug’s icosaheciral notable featrm of the analysis is the re- model for the latter group of viruses had alization that genes affecting particular func- been inspired by the designs of Buckminster tions were grouped together and that the se- Fuller and a photograph of the geodesic quential expression of these genes contrib- dome illustrated the article. The paper ranks uted to the orderly assembly of the virus fourth on the list with 765 citatiotts. particles. (The origin of the strange name “amber” for these mutations is an interest- Authors ing footnote in the history of molecular biology and deserves to be better known. There are 135 authors of these51 papers. Robert S. Edgar, University of California, As shown in Table 3, one paper has 10

261 Table 4: Nobel Iaureat= listed as authors of the 51 over 70 Nobel iaureates have attended the most-cited articles from the Cold Spn’ng Harbor Symposia on Quanf~kuive Bio(ogy, 1945-1988 SCI@, 54 meetings held since 1933. Given this showing the field and year of their awards. attendance record and that Nobel laureates Nobelist Prize Year consistently publish classic papers as judged by their citation record, it is hardly surpris- Baltimore, David Medicine 1975 ing that Nobel laureates should feature Crick, Francis H.C. Medicine 1962 Gilbert, Waker Chemistry 1980 strongly in the most-cited papers from the Jacob. Fran$ois Medicine 1%5 CSHSQB (Table 4). There are nine Nobel Klug, Aaron Chemistry 1982 laureates listed as authors on 12 of the top McClintwk, Earbara Medicine 1983 Mmmd, Jacques Medicine 1965 51 papers. Perurz, Max F. Chemistry 1962 However, this emphasis on Nobel laure- Watson, James D. Medicine 1962 ates tends to overshadow the remarkable quality of all the scientists who attend the symposia and the quality of the science they authors (Epstein er al. ) followed by Franke present. The contents pages of any volume et al. with 9 authors and the papers by F.L. list the names of those who created molec- Graham, University of Leiden, The Nether- ular biology, one of the triumphs of twen- lands, et al. and Wolfram Zillig, Max tieth-century science, and each new volume Planck Institute for Biochemistry, Munich, shows those who continue to advance that FRG, et al. with 8 authors, Nevertheless, work. 71 percent of the papers have one or two authors, giving an average of 2.6 authors per paper compared with the value of 5.1 Table 5: tkwgraphic areas represented by the institu- tional affitions given by auttmrs in k Bibliography. authors per paper for the 101 most-cited life- listed in descending order by the number of papers sciences papers in 1987.2s This may reflect produced (column A). B =number of papers co- the fact that CSHSQB articles resemble authored with researchers affdiated with institutions in otier countries. C = national Iccations of institutions review articles and so have small numbers Iisted by coauthors. of authors or may indicate the style of an

era when research was performed by small Locationof groups. The most frequently occurring Hltutions AB c author is Jacob, who appears four times, us 35 5 Belgium, Japan, appropriately coauthoring two of those The Netherlands, papers with Monod. The remaining three Switzerland, UK authors who appear twice are David Balti- New York 11 California 7 more, Massachusetts Institute of Technol- Massachusetts 6 ogy, Cambridge; D. S. Hogness, Stanford New Jersey 3 University School of Medicine, California; Oregon 2 Wisconsin and McClintock. 2 Colorado 1 Comecticut 1 Maryland 1 Nobel Laureates Minnesota 1 Pemsylvania I Tennessee 1 In his 1934 annual report, Harris pointed UK 84 Denmark, France, us out that one of the participants in the 1934 France 61 UK symposium had received the Nobel Prize for FRG 31 Austria, chemistry. Rather disingenuously prefacing Switzerland Japan 21 us his remarks with “While we do not wish to Switzerland 22 Austria, US stress the fact unduly, ” Harris suggested Austria 11 FRG, Switzerland that this could be taken as an indication of Belgium The Netherlands, us the quality of the meetings. 13This has con- Denmark UK tinued to be a feature of the symposia and The Netherlands Belgium. US

262 Geographical Distribution of Authors and volumes, “Organization of tbe Cytoplasm, ” Institutions “Molecular Neurobiology, ” “Molecular Biology of Homo sapiens’ ‘—the broad These papers came from 49 unique institu- sweep of these topics reflects the corttldence tions in 10 countries and the majority of of the organizers and participants that mo- papers have US authors (35). (See Table 5.) lecular biology is the key to a deep under- Remarkably, however, a US institute does standing of the nature of living organisms. not head the list of institutions with the most Harris left a legacy that has stimulated the number of papers. Instead, the Pasteur In- generations of molecular biologists that have stitute leads, reflecting its position as one come each year to talk, argue, and gossip of the great centers for molecular biology at the symposium. He is quoted in the in- and genetics throughout the period covered troduction to the first volume as saying that by this analysis. There are five papers from the meetings, like the laboratory itself, the Pasteur, authored by J.-P. Changeux, “should be centers of growth and dissemina- Y. Hirota, Jacob, Cuzin, and Monod. There tion of new methods and iaeas in are five institutions each with three appear- biology.’ ’24 The citation record of the ances in this list: Caltech; Cold Spring Har- volumes shows that Harris’s aspirations bor Laboratory; Medical Research Council; have been well served by the directors who Princeton University, New Jersey; and The followed him. As the laboratory enters its Rockefeller Institute. second century with the 1990 symposium on “The Brain, ” there is every reason to Conclusion believe that the CSHSQB will continue to The CSHSQ3 continues to thrive as occupy a special place in experimental reflected in the titles of the individual biology. . Im1s1

REFERENCES

1. Cairns .1. Behind those duskv red books. Oliver and Lorraine Grace Auditorium dedication ceremony, hn; f, 1986. Cold Spri;g Harbor, NY: Cold Spring Harbor Laboratory, 1986.6 p. (Brcehure. ) 2. Pardy P J. Controlling life: Jacques heb and the engineering ideal in biology. New York: Oxford University Press, 1987.252 p. 3. Lab J, Morgrm T H & Oatertmrrt W J V, eds. Editors’ announcement. (MOrgan T H) “fie phy~icaf basis of heredity. Philadelphia Lippincott, 1919. p. 5. 4. Loeb J. 71rerrrecharriwic conception of life. (Fleming D, cd.) Cambridge, MA: HarvardUnivershy Press, 1964.p. 6. 5. Whitman C O. The advantages of study at the Naples Znnlogicrd Station, Science 2:93-7, 1883. 6. AfIen G E. L@ science in rhe twentieth century. New York: Wiley, 1975.258 p. 7. -.-.. -.. — . lhorrras Hunt Morgan: the man and his science. Princetnn, NJ: PrincetonUniversityPress, 1978.447P. s. BensonK R. The NaplesSeazione Zoologica and its impact on the emergence of American nrarine biology. J, Hist. Bici. 21:331-41, 1988. 9. Mickfrra D, Zehl S, Sehechter D & Skag& E. i’hr’jrst hundred years Cold Spring Harbnr, NY: Cold Spring Harbnr Laboratory, 1988.35 p. 10. Kevles D. In the name Of eugenics. New York: Krropf, 1985.426 p. 11. Hershey A D & Chaw M. Independent fimctions of viral protein and in growth of bacteriophage. J. Gen. Physiol. 36:39-56, 1952. 12. McCtirrtnck B. Chromosome organization and genie expression. Cold Spring HarborSymp. 16:13-47, 1951. 13. Long Island WIoh@eal AaaaeiatIon. Annual reporr of the Biobgicuf .hboratory Cold spI’Ihg Harbnr, NY: Imng Island Biological Association, 1934. p. 17. 14. Bnlivar F, Rodrigm R L, Greene P J, Betfach M C, Heyn=ker H L ~yer H W, CM J H & Fatkow S. Construction and characterization of new cloning vehicles. 2. A multi-purpose cloning system. Gene 2:95-113, 1977. 15. Bo4ivar F. Plasmid PBR322: the multipurpnac cloning vector. Focus 10614, 1988. 16. Maxara A M & Gflberf W. A new mettrnd in sequencing DNA. Proc, Nat. Acad. Sci. USA 74:560-4, 1977.

263 17. Sutcfiffe J G. Complete nucleoride sequence of the E.rcJren”cJriaccrfi plasmid pBR322, Cofrf Spn”rrg Harbor Syrnp. 43:77-90, 1978. 18. Jamb F & Morrorf J. Genetic regulatory mecharrisms in the synthesis of proteins. J. Mrrl. Bio/. 3:318-56, 1961. 19. Watsnn J D & Crick F H C. Molecular structure of nucleic acids: a structure for deoxyribose nucleic acid. Nature 171:737-8, 1953. 20. Jacnb F & Bremser S. G&r&ique physiologique—sur la regulation de la syntlkse du DNA chez les bact&ies: l’hypntthe du riplicon (Genetic physiology-on the regulation of the synthesis of DNA with bacteria: hypothesis of the replicon). C. R. Hebd. S&mces Acad. SCI”.256:298-3(X), 1%3. 21. Edgar R S. Conditional Ietbafs. (Cairns J, Stent G S & Watson J D, eds.) Phrege and the origim of nrdecrdur biology. Cold Spring Harbor, NY: Cold Spring Harbnr Laboratory, 1966, p. 166-70. 22. Crick F H C & Watson J D. The structure of smafl vimaes. Nature 177:473-5, 1956. 23. Dixon B. Celf sigrrafing, the immune respmrse, the genetic basis of cancer, arrd the efforrs to pinpnint the genes for AMreimer’s disease, cystic fibrosis, and manic-depressive illness are highlighted in 1987 life-sciences research. Current Contents (17):4-18, 23 Aprif 1990. 24. fntmduction. Cold Spring Harbor Syrrrp 1:v, 1933.

Bibfiipby: The 51 moat-cited articles from the CoLi Spring Harbor Symposia on Quantitative Biology baaed on the 1945-1988 SCP, listed in alphabetic order by first author, Numbers foJfowirrg the bibliographic entry indicate the 1988 SCf/SSCF research fronts for which these are core papers. An asterisk (*) indicates tfrat the paper was the subject of a Citation ClaSSIC@commentary, The issue, year, and edition of the commentary follow the bibliographic reference. A =number of 1945-1988 citations.

A Bib~apbic Data

345 Afberta B M, Amudio F J, Jenkins M, Grrtmann E D & Ferris F L. Studies with DNA- celluloae chromatography. J. DNA-binding proteins from Eschen”cfria co[i. Cold Spn”rrgHarbor Synrp. 33:289-305, 1%8. 376 Ames B N & Harttnan P E. The histidine operon. Cofd Spring Harbor Syrrrp. 28:349-56, 1%3. 505 As&off J. Exogenous and endogenous cmnpnrrents in circmian rhythms. Cold Spring Harbor SymP. 25:11-28, 1960.88-1306 218 Baftimore D. Tumor viruxes: 1974. Cold Spring Harbor Symp. 39:1187-200, 1975. 382 BIatti S P, Ingle.s C J, Lindeff T J, Morris P W, Weaver R F, Weinberg F & Rutter W J. Stmcture and regulatory pro~fiies of eucaryotic RNA pcdymerase. Cofd Spring Harbor Symp. 35:649-57, 1970. 246 Bhrmentbaf A B, Kriegateirr H J & Hngnma D S. The units of DNA replication in Drosophila melanogmter chromosomes. Cofd Spring Harbor Syrnp. 38 :20S-23, 1973. 518 Cairna J. The cbromoamnc of E.rcherichia coli. Cofd Spring Jfarfrar Symp. 28:43-6, 1%3. 492 Cantor H & Boyae E A. Reguhrtinn of celfufar and humoral immune respnnses by T-cell subclasses. Cofd Spring Harbor Syrnp. 41:23-32, 1977. 765 ●Caapar D L D & Kfug A. PhysicaJ principles in the construction of regular viruses. Co&f Spring Harbor S,yrrrp.27:1-24, 1%2. (41841LS) 218 CJmrrgeux J-P. Allosteric interactions on biosynthetic L-threonine demnirrase from E. o/i K12, Cold Spring Harbor Syrryr. 28:497-504, 1%3, 929 Epstein R H, BofJe A, Steinberg C M, Keffenberger E, Bay de la Tour E, Chevaffey R, Edgar R S, SWSmrm M, Derrbardt G H & Lielarssis A. Physiological studies of conditional lethal mutants of bacteriophage T4D. Cofd Spring Harbor Symp. 28:375-94, 1963, 261 Fhsnegarr D J, Rubfn G M, Yormg M W & Hogrress D S. Repeated gene famifies in DrosopJrih nterhnogaster. Cofd Spn”ng Harbor Syrrrp. 42:1053-63, 1977. 246 Franke W W, Scbndd E, ScJriUer D L, Winter S, Jaraach E D, Moll R, Drink H, Jackson B W & Iffmenaee K. Differentiation-related patterns of expression of proreins of intermediate-size ftiament.s in tissues and cultured ceUs. Cold Spring Harbor Syrnp. 46:431-53, 1982.88-0288 256 Frankfin R M & BoJtJmore D. Patterns of macromolecular synthesis in normal and virus-infected msrmnaliarr cefls. Cofd Spring Harbor Syrnp 27:175-98, 1%2. 414 Gilbert W & Dressier D. DNA replication: the roJJing circle medel. Cofd Spring Harbor Syrnp. 33:473-84, 1%8. 361 Gruham F L, Abmfrarns P J, Mssfder C, Heijneker H L, Warnaar S O, de Vrfes F A J, FJera W & van der Eb A J. Studies on in vitro transformation by DNA and DNA fragments of human adennviruses and simian virus 40, Cofd Spring Harbar Syrnp, 39:637-50, 1975. 232 Halberg F. Tempnral coordination of physiologic function, Crrfd Spring Harbor Symp. 25:289-310, 19&3. 229 Haaefgrove J C. X-ray evidence for a confirmational change in the actin-containing ftients of vertebmte striated muscle. Cold Spring Harbor Syrnp. 37:341-52, 1973. 324 Hirota Y, Ryter A & Jacob F. Thermoaensitive mutants of E, ccdi afkted in the prwesaes of DNA synthesis and cefbdar division. Cold Spring Harbor Syrrrp. 33;677-93, 1968. 266 Hnnd L, Gray W R, %rrders B G & fJreyer W J. Light chain evolution, CM Spring Harbor Syrrrp. 32:13346, 1%7.

264 A Bibfiugraptdc Data

254 Hotcbio J. The biology of choriomeningitis infection: virrrs-induced immune disease. Co&fSpring Harbor Symp. 27:479-99, 1%2, 427 Hutchinams G E. Peculation studies: animal ecology and demography. Concluding remarks. Cold Spring Harbor Syrnp. 22:415-27, 1957. 355 Huxley H E. Stmctumf changes in the actin- and myosin-containing fdarnents during contraction. Cofd Spring Harbor Symp, 37:361-76, 1973, 1,216 Jacob F, Warmer S & CuziOF. On the regulationof DNAreplication in bacteria. Cofd Spring Harbor $mrp. 28:32948, 1%3. 643 Jacob F & Monnd J. On tfre regulation of gene activity. Cofd Spring Harbor Syrnp. 26:193-211, 1961. 233 Jacobs M H. Some aspects of cell permeability to weak electrolytes. Cofd Spring Harbor Syntp. 8:30-9, 1940, 418 Jones R T. Stmctursf studies of arninnethylated hemoglobins by automatic pcptide chromatography. Co./d Spring Harbor Syrrrp. 29297 -30g, 1964, 283 Katea J. Transcriptionof the vaccinia virus genome and the recurrence of polyriboadenylic acid sequences in messenger RNA, Cold Spring Harbor Symp. 35:743-52, 1970. 614 Mngaaardk B. Catabnlite repression. Cofd Spring Harbor Synrp. 26:249-56, 1961. 498 MXXintockB. chromosome organization and genie expression. Cold Spring Harbor Synrp. 16:13-47, 1951.88-5265 345 McCffotock B. Controlling elements and the gene. Cofd Spring Harbar Symp. 21:197-216, 1956. 299 Mfc3saelL$L. The nature of the interaction of nucleic acids and nuclei with basic dyestuffs. Cofd Spring Harbor Synrp. 12:13142, 1947. 251 Mitdiaoo N A. Antigen recognition respmrsible for the induction in vitro of the secondary response. Cold Spring Harbar Syrrrp. 32:431-9, 1967. 332 Monnd J & Jacnb F. Generaf conclusions: tcleonomic medrardsms in cellular metabolism, growth, and differentiation. Cafd Spring Harbar Synrp. 26:389-401, 1%1. 223 Nomura M, Micuabicna S, Oaaki M, Traub P & Lowry C V. Structure and fiumtion of ribmomes and their molecular compmrenta. Cofd Spring Harbar Symp. 34:49-61, 1%9. 308 Okamkl R, Okazaki T, Sakabe K, Su@rroto K, Kufmmm R, Sugfno A & Iwatsuki N. fn vivo rnechardsm of DNA chain ,~owtfr. Cofd Spring Harbar Syrryr. 33:129-43, 1968. 237 Otsukrr M & KmMrf S. Substance P and excitatory transmitter of primary senanry neurons, Crxlf Spring Harbor Syrrrp. 40135-43, 1976, 236 Perutx M F & TenEyck L F. Stereochemistry of cooperative effects in hemoglobin. Cofd Spring Harbor Symp. 36:295-310, 1972. 479 Pfttendrigh C S. Circadian rhythms and the circadian organization of living systems. Co&f Spring Harbor Syrrrp. 25:159-84, 1960.88-1306 278 PollfaterA W & Ria H. Nucleoproteirr determination in cytological preparations. Cofd 5@ng Harbar Synrp, 12:147-57, 1947. 236 Rrmxcff W L. X-ray induced mutations in mice. Cofd Spring Harbor Syrrrp. 16:327-36, 1951. 274 Safaer W. Globin MRNA sequences: analysis of base pairing and evolutionary implications. Cofd Spring Harbor Syrnp. 42:985-1002, 1978. 249 Sharp PA, Galffrrrore P H & Flfrrt S J. Mapping of adenovirus 2 RNA aequencca in Iyticalfy infected mdfs and transformed ceff lines. Cold Spring Harbor Syrnp. 39:457-74, 1975. 230 Sbeldrlek P & Bertbelot N. Inverted repetitions in the chromosome of herpes simplex vims. Cofd Spring Harbar Symp. 39:667-78, 1975. 251 Smith G P. Unequal crossover and the evolution of multigene families. Cold Spring Harbor Syrnp.3tl:507-t3, 1973. 410 Strekiiger G, Okada Y, Emrich J, Newton J, Tsngita A, T-i E & InouYe ~. Frames’~ mutations and the genetic cede. Cofd Spring Harbor Syrrrp. 31:77-84, 1966. 237 Srreoka N & Qufrm W G. Membrane attachment of the chrornuamne reification origin in Bacillus subtilis, Cofd Spting Harbor Symp. 33x595-705, 1%8. 1,495 Suteffffe J G. Complete nucktide sequence of the plasmid PBR322. Cofd Spring Harbor Syrrrp. 43:77-90, 1979. 393 Watxon J D & Crfck F H C. The structure of DNA, Cofd Spring Harbor Synrp. lg:123-3i, 1953. 282 Witfdn E M. Time, temperature, and protein synthesis: a study of ultraviolet-induced muttmon in bactecia, Cofd Spring Harbor Symp. 21:123-40, 1956. 270 Zilfig W, ZecbelK, Rnbtmsny D, Sc!mcfrner M, Setbf V S, Prdm P, Hell A & Seifert W. On the rule of different subunits of DNAdeparderrt RNA polymeraae frnm .?. coli in the transcription process. Co.ki Spring Hrrrbar Synrp. 35:47-5g, 1970.

265