EUGENE GARFIELDIN ST ItUTE FoR SCIENTIFIC IN FOe M.4T10N@3501 MARKET ST PHILADELPHIA PA 19104

A Tribute to Cold Spring HarborLaboratory 011 Its IO(MI Biih(ky:

Jan A. Witkowski Reviews Its HisEory andthe Highest Impact Sympsia Publications

Number 28 July 9, 1990

In March of this year, i%e Scienrist@pre-sented a survey of small, independent re-search institutions in the US. 1Twenty suchinstitutions were ranked by the citation im-pact of their papers published between 1973and 1987. Although the Salk Institute forBiological Studies and the Scripps Clinic andResearch Foundation, both of San Diego,California, received the most citations (over124,000 each), the institution that topped thelist by citation impact was the Cold SpringHarbor Laborato~, New York. As DavidPendlebury observed, papers published fromCold Spring Harbor had a citation impactmore than five times greater than the averagefor the entire Science Citation Indexm data-base. Furthermore, the impact factor for thislab was nearly twice that of the average forthe 20 institutions listed. I (The entire listappears in Table 1.)

The following guest essay, however, doesnot really concern Cold Spring Harbor’scurrent preeminence in life-sciences re-search, but rather its dk.tinguished past—specifically, the yearly symposia in experi-mental biology that have taken place therefor more than a half-century: Jan A.Witkowski, director of the laboratory’s Ban-bury Center, discusses the 51 most-cited ar-ticles in the Cold Spn”ng Harbor Symposiaon Quantitative Biology. His account in-cludes a brief history of the laboratory itself,from its beginnings as a summer school atthe end of the last century to its currentrenown. The evolution of the symposia isako described, tlom the fust meeting in1933, with 16 scientists in attendance, towhat Witkowski calls the” frenetic, action-packed meetings that we know today.”

A mtive of Birmingham, UK, Witkowskireceived a BS degree in zoology from the

University of Southampton in 1968 and aPhD in biochemistry from the University ofLondon in 1972. Between 1972 and 1982he was a research fellow at the Institute ofChild Health, London, and at the MayoClinic, Rochester, Mimesota. From 1982to 1986, he was a lecturer in the Departmentof Pediatrics, Royal Postgraduate MedicalSchool, University of London. He thenserved as director, Kleberg DNA DiagnosticLaboratory, and assistant professor, Institutefor Molecular Genetics, at Baylor Collegeof Medicine, Houston, Texas.

Witkowski came to Cold Spring Harborin 1987. As director of the Banbury Center,he determines topics for conferences at thecenter, arranges meetings for congressionalstaff and science journalists, and assists withthe publication of meetings. His own majorresearch interest is in human genetics, butWitkowski notes that he has a long-standinginterest in the history of science—especiallytopics relating to the development of ex-perimental biology in this century. He hasalso published papers discussing significantstudies in biochemistry, embryology, tissueculture, and molecular biology.2

The papers discussed in this study span40 years of research, from 1940 to 1982.Although there is a predominance of papersfrom the 1960s-the period Witkowski re-fers to as’ ‘the fist golden age of moleculargenetics’ ‘—dtisstudy demonstrates the con-sistency with which the symposia have pro-duced highly cited works over the years. AsWitkowski notes, this year marks ColdSpring Harbor’s 100th birthday, and as thesymposia continue to address the latesttopics in biological research, this output ofimportant and influential work is certain tocontinue.

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.. ........ ... ..

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)

Name

1. Cold Spring Harbnr L&ratory, Cold Spring Harbnr, NY2 Salk Institute for Biological Studies, San Diego, CA3. Fred Hutchinson Csncer Research Center, Seattle, WA4. Whitehead Jnstitufe for Biomedical Research, Csmbridge, MA5. Roche Institute of Molemdar Biology, Nuttey, NJ6. Carnegie Institution of Washington, Baftimore, MD, snd

Wsahington, DC7. Trudeau Institute, Sarsna.c Lake, NY8. Scripps Ctinic and Research Foundation, La JoOa, CA*

9. Wisrar Institute, Philadelphia, PA10. New York Blnod Center, New York, NY11. La Jolts Csncer Research Foundation, La Jolla, CA12. Joslin Diabetes Center, Boston, MA13. American HeaJth Foundation, New York, NY14. Jackson Laboratory, Bar Harhnr, ME15. Worcester Foundation for Experimental Biology, Shrewsbury, MA16. Public HeafUr Research Institute of the City of New York, NY17. Forsyth Dental Center, Ekuston, MA18. Palo Alto Medical Foundation Research Institute, Pako Alto, CA19, Boston Biomed]czd Research Institute. Boston. MA20. Center for Bleed Research, Boston, MA

*Scripps is no longer an AIRf member.

Source: Mm’s ScienceIndicators fde, 1973-1987.

Although the laboratory’s research flour-ished under earlier directors, notablyMilislav Demerec and John Cairns, it is thepresent director who has played the majorrole in the growth of the laboratory’s in-fluence. He is, of course, Nobel laureateJames D. Watson, who has been director atCold Spring Harbor since 1%8. Previously,in a broad discussion of Citation Ce’assicsW,I’ve noted that perhaps the most influentialpaper of the century-Watson and FrancisH.C. Crick’s 1953 publication on thedouble-helix structure of DNAq—has beencited “only” about 1,000 times. ‘f Thisseemed to me to indicate an upper limit oncitations that one could expect for such awork. It is also understandable that neitherWatson nor Crick would provide us with acommentary on this paper. You might saythat with the publication of Watson’s Z7teDouble ffeh.d and Crick’s recent autobi-ography, WhatMad Pursuit, 6 they have

Papers

8392,8341,756

2081,7311,695

2884,9721,586

734405304820

9941,347

796

617

539

6%

180

Citations

49,217124,94259,800

6,62453,45051,8%

8,358124,32338,75817.6208,9156,437

17,12719,87226,80715,7691I ,2709,808

12,0753,088

Citation

58.744.134.131.830.930.6

29.025.024.424.022.021.220.920.019.919.818.318.217.317.2

already provided the ultimate commentaries.Although I am hopeful that other authors

listed in the Bibliography that follows theessay will have contributed commentarieson their papers by the time we go to press,the main reason for their absence is ourfailure to invite them until now. Severrd ofthem have written commentaries on paperspublished in other journals. Success in ob-taining commentaries depends upon the righttiming-it is preferable to invite authors towrite Citation Classic commentaries beforethey receive the Nobel Prize or other majorrecognition, lest they be too preoccupiedwith other pressing obligations.

*****

My thanks to Christopher King and Erici%urschweli for their help in the prepara-

tion of this essay,

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 19903 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 !O 1982.7. Awther IW Cimlion Classics:

tie Watson-Crickdouble klix bas its rum. E.wavsof m infonnaion scientist: rhosr.witine and ocher essavxPbitadelphrw1S1press, 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.

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The 51 Most-Cited Articles in theCold SpriDg Harbor Symposia on Quantitative

Jan A. WitkowskiThe Banbury Center

Cold Spring Harbor LaboratoryCold Spring Harbor, NY 11724

Biology

The Cold Spring Harbor Symposia onQuantitative Biology are a venerable andvenerated part of experimental biology.Established in 1933, the symposia have sincethat time charted progress in research in awide range of sui&cm, subjects chosen fortheir excitement, me need for dispassionateand critical review, and above all by thebelief that they were rhe subjects that wouldcontinue to define the leading edge of re-search in biology. However, as John Cairns,director of Cold Spring Harbor Laboratoryfrom 1963 to 1968, has written on the sym-posia: “any catalog of the virtues of thevarious Symposia, even if perfectly doneand in the liveliest style, would miss thewhole point of the exercise. These meetingshave meant much more to many people thancould possibly be guessed at from lookingat the contents of the books . . . . When welook at the published volumes... we arelooking at the history of a scientific era. ” 1(p. 3) So before discussing the citationrecord of the symposia, some historicalbackground is needed to appreciate the na-ture of the symposia and why they have con-tinued with ever-increasing success for57 years.

Quantitative Biobgy

The period at the begiming of the twen-tieth century was marked by the increasingemployment of experimentation and quan-titative methods in the biological sciences.This was most evident in the increasingnumbers of physicochernicrd studies of liv-ing organisms, and the work of JacquesLoeb, The Rockefeller Institute for MedicalResearch, New York, exemplified thismechanistic, physiochemical analysis ap-

preach.z As Loeb wrote with WinthropJ. V. Osterhout, Harvard University, Cam-bridge, Massachusetts, and Thomas HuntMorgan, Columbia University, New York,in the editors’ announcement to the seriesMonographs on Experimental Biology,“Biology, which not long ago was purelydescriptive and speculative, has begun toadopt the methods of the exact sciences,recogui2ing that for permanent progress notonly experiments are required but quan-titative experiments.”3 Indeed, Loeb wentso far as to define “scientific biology” asthe attempt to reduce Iife phenomena ‘‘com-pletely to physiochemical terms.’ ‘dFoUowing the work of the physical chemists,a colloidal theory of living matter becamevery popular and experiments were per-formed to determine the effects of changesin the physical environment on organisms.Typical of these studies were investigationsof osmosis and diffusion of molecules acrossmembranes, the colloidal properties of pro-teins such as gelatin and albumin, and theeffects of ions on developing embryos andof X rays on cells.

The Biological Laboratory and theStation for Experimental Evolution atCold Spring Harbor

In the late nineteenth century, the NapksZoological Station, Italy, founded in 1872,was the mecca for experimental biology.~$Such luminaries as British biologist ThomasH. Huxley; Louis Agassiz, Harvard Univer-sity; Charles M. Child, University ofChicago, Illinois; Edmund B. Wilson, Co-lumbia University; and Morgan all visitedthere to carry out research on the marineorganisms abundant in the bay. Morgan was

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so impressed by the Naples Station that hebecame a prime mover in promoting theMarine Biological Station at Woods Hole,Massachusetts, (1888) as the Americanequivalent. T (However, not everyonesubscribes to the view that the station hadsuch an impact on the development of USbiology. g) Later, when Morgan went to theCalifornia Institute of Technology (Caltech),Pasadena, he established the institute’smarine station at Corona del Mar, California,in 1936.

In 1890 the Brooklyn Institute of Arts andScience, New York, created the BiologicalLaboratory at the southwest corner of ColdSpring Harbor, an inlet on the north shoreof Long Island, New York.g The BiologicalLaboratory began by teaching courses inzoology, botany, comparative anatomy, andnature study to biology teachers and studentsthrough the summer months. In 1898Charles B. Davenport was appointed direc-tor of the Biological Laboratory. Davenporthad been professor of evolutionary biologyat Harvard University, and he is remem-bered especially for his interest in eugenicsand for establishing the Eugenics Record Of-fice. 10 In 1904 he applied to the CarnegieInstitution of Washington, DC, for supportof a program to carry out research ongenetics. The Carnegie Institution estab-lished the Station for Experimental EvohI-tion on the same site as the Biological Lab-oratory, and Davenport became director ofboth, The history of these institutions iscomplex and the two were not formallyamalgamated until 1962 when they becameCold Spring Harbor Laboratory.

Thus began a long and distinguished re-search program at Cold Spring Harbor.George H. Shun began work on comgenetics at the station in 1905. He producedpure lines of com by self-pollination overseveral seasons and found that when thesepure lines were crossed, the hybrid progenywere healthy and produced more cornstrains. This was the first demonstration ofhybrid vigor.

The laboratory’s long association withcancer research began in 1916 whenClarence C. Little demonstrated that mouse

Jan A. Witkowski

strains varied in their susceptibility totransplanted tumors, work continued byE, Carleton MacDowell. (Little went on tofound the Jackson Laboratory at Bar Har-bor, Maine.) Both Alfred D. Hershey andBarbara McClintock carried out their re-search at the station. Hershey is best knownfor the famous “Waring blender” experi-ment that helped demonstrate that DNA isthe molecule of heredity, II and McClintockfor her cytogenetic studies and the discoveryof movable genes in maize. 1z They wereawarded the Nobel Prize in physiology ormedicine in 1969 and 1983, respectively.

The Symposia on Quantitative Biology

While the Station for Expirnental Evolu-tion at Cold Spring Harbor flourished, theBiological Laboratory fared less well, re-maining a summer camp for teaching. Itunderwent a rejuvenation in 1924 when itwas taken over by a group of scientists andlocal citizens who formed the Long IslandBiological Association (LIBA). In that sameyear, Davenport’s son-in-law, ReginaldHarris, bec~e director. He began buildinga research program with the support ofLIBA and instituted year-round research.

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The vogue was still for physiochemicalstudies in biology, and Harris’s determina-tion to make the laboratory a center formodem biological research was evident inhis appointment of Hugo Fricke, formerdirector of biophysics at the ClevelandClinic Foundation, Ohio, as the laboratory’sfirst full-time investigator. Within a fewyears of Harris’s appointment as director,there were research programs in biophysics,endocrinology, and pharmacology.

Harris realized that the laboratory’s aimscould be promoted, and the general courseof research advanced, by holding specialmeetings at Cold Spring Harbor. As notedin the 1934 annual report,

Now it happens in modem biologicalresearch that the problem of a givenbiologist, or group of biologists, may havemuch more in commonwith that of a givenchemist or physicist, or a small group ofeither, than with that of a second groupof biologists.,.. Yet the meetings of thevarious Ieamed societies in this countrystill fail to take this into account..,. Theprimary motive of the conference-symposia is to consider a given biologicrdproblem from its chemical, physical andmathematicrd, as well as from its biolog-ical aspects. 13

In 1933 Harris organized the first of theCold Spring Harbor Symposia on Quantita-tive Biology on “Surface Phenomena. ”These early meetings were not the frenetic,action-packed meetings that we know today.Instead a small group of 16 scientists stayedfor one month at the laboratory, and31 par-ticipants came periodically to present papersand to participate in symposia. The meetingswere recognized immediately as being aunique contribution to science. The Rocke-feller Foundation provided $5,000 towardsthe cost of the second symposium and con-tinued to make an annual grant for thefollowing 12 years.

Despite having to edit a vast amount ofdiscussion, of which 30,000 words werepublished, Harris managed to brirsg the bookout in the same year as the meeting. Pttblica-tion of the first volume of the Cold SpringHarbor Symposia on Quantitative Biology(CSHSQB) series was also remarkable forthe establishment of the format of the pa-

pers. They were, and have continucxi to be,a very successlid hybrid of’ research paperand review article. Authors are given an op-portunity to set their experirnerttrd results ina wider context, and the importance of pa-pers in the CSHSQB series is undoubtedlydue to this. Harris died in 1936 at the ageof 35, supposedly of exhaustion from theburden of bringing out the CSHSQB volumewithin six months of the meeting. Cairnsremarked that, when he read of Harris’s ex-perience, “I resolved never to get the bookout before the New Year, and I notice thatJim Watson [the current director] takes evengreater precautions in this regard!”)(p. 5-6) Harris was succeeded in 1936 byEric Ponder, a biophysicist, who continuedto hold meetings on physiochemical aspectsof biology, including such topics as “Pro-tein Chemistry” (1938), “Biological Oxida-tions” (1939), and “Permeability and theNature of Cell Membranes” (1940).

Molecular Biology and Genetics

In 1941 there was an abrupt shift in sym-posium topics when Demerec became direc-tor of the Carnegie Institution’s Departmentof Genetics (as the Station for Experimen-tal Evolution was now called) and theBiological Laboratory. Demerec had cometo the Carnegie Institution of Washington atCold Spring Harbor in 1923 and becamedirector in 1941. He was originally aDrosophila geneticist, but his interestschanged to bacterial and phage genetics. Itwas during Demerec’s tenure as director thatthe laboratory established its reputation asone of the world’s centers for research onbacterial and phage genetics. SalvadorLuria, at that time a research assistant at theCollege of Physicians and Surgwns of Co-lumbia University, and Max Delbriick, thenat Vanderbilt University, Nashville, Ten-nessee, worked together at the laboratory forthe first time in the summer of 1941, andDelbriick began teaching the legendaryphage course in 1945. (The two men sharedthe 1969 Nobel Prize in physiology ormedicine with Hershey. ) James D. Watson

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Table 1: Citation-frequency distribution for tbe 705articles published in the COU Spring Har60r Symposiuon Quantimive Biology with 50 or more citatims,1945-1988 SCP

Citation Number of Items Percent ofLevel at Level Total Items

1,0rn3 2 0.39CSI-999 1 0,18W899 o 0.0700-799 1 0.16(X-699 2 0.35(X-599 2 0.34(X)-499 7 1.03cn3-399 10 1.42W299 36 5.1lot-199 180 25.5

50-99 464 65.8

came as a student to Cold Spring HarborLaboratory in 1948.

The first of Demerec’s symposia was alandmark meeting on “Genes and Chromo-somes: Structure and Organization” and thefirst of the post-World War II meetings wason “Heredity and Variation in Microorgan-isms. ” These symposia were signposts forresearch in genetics through the decadesspanning the 1950s and 1960s. This was agolden age of molecular genetics, and thelist of participants in the symposia of thatperiod is a roll call of those who establishedmolecular genetics. This is reflected in thecitation anrdysis discussed below. At thesame time that bacterial and phage geneticswere the dominating themes, the symposiahave covered a remarkable variety of topics.These have included “The MammalianFetus” (1954), “Biological Clocks” (1960),“The Synapse” (1975), and “Evolution ofCatalytic Function” (1987),

The nature of the symposia changed withDemerec. The average number of partici-pants at the first eight meetings had been 56.The same figure for the first eight ofDemerec’s meetings was 160, with 305 atthe 1951 symposium on “Genes and Muta-tions. ” Demerec also instituted one of thehallmarks of the CSHSQB, the collection ofphotographs of participants appearing ineach volume. These began in 1949, andDemerec took many of the early photo-graphs himself. The early pictures showsmall groups of scientists conversing, and

the earnest faces of Hermann J. Muller, In-diana University, Bb-xnington; Leo Szilard,University of Chicago; Jacques Monod,Pasteur Institute, Paris, France; and otherslook out at us. The scenes reflect an unhur-ried style of meeting that has now disap-peared, but the organization of the week-long meeting, with the afternoons free anda picnic on the lawn of the director’s house,still contrives to provide opportunities forquiet conversations.

The Impact of the CSHS@l

Publication of the CSHSQB began in1933, but we begin our analysis in 1945,currently the earliest date in the ScienceCitation hdex~ (XT@), and end with 1988.Table 1 gives the citation frequency distribu-tion for the ’705articles with 50 or more cita-tions published in that period, in absolutenumbers and as a percentage of the totalpapers in the CSHSQB. These figures makean interesting comparison with those for theentire SC] file. Otdy 1.53 percent of papersin the SCYare cited 50 times or more, com-pared with about 20 percent for those pub-lished in the CSHSQB volumes. For the51most-cited papers published in the CSHSQB,the citations range from 218 to 1,495. Themean and median values are 389 and 299,respectively. These figures are much higherthan for research journals and comparablewith those for review journals. This refleetsthe hybrid nature of the symposia papers,that they give the authors an opportunity todevelop their case as well as present data,

One estimate of the importance of scien-tific papers is their SC{ impact factor. For1988, this figure is the number of 1988 cita-tions to a paper published in the period1986-1987. The impact factor for the paperspublished in a journal is obtained by averag-ing the number of citations for all papers inthe journal, and this figure for CSHSQBpapers k 2.25. This compares with thefigure of 1.49 for all publications in the SCliatabase, and the CSHSQB ranks 418th outof the 4,232 journals that were used to~alculate this impact factor.

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Table 2: Chronologieaf etlstribrrtion of publicationdates for tfre51 most+ited srticles from the Cdd SpringHarbor Symposia on Qm’tat@e Biology, 1945-1988scI@

Pubficatiorr Number ofYear Papers

1940-1944 11945 -t949 21950-1954 31955-1959 31960-1964 151%5-1969 91970- I974 101975-1979 7198(&19S4 1

An indication of how well articles pub-lished in the CSHSQB “age” is given by the1988 six-year impact factor. This is theaverage number of 1983-1988 citations to1983 articles, and for the CSHSQB thefigure is 43.12. This is far higher than theestimated figure of less than eight for theentire SCI ffle and suggests that those paperspublished in the 1983 CSHSQB have con-tinued to be cited for longer than mostpapers. This reflects the data of Table 1 thatshow that CSHSQB papers are cited muchmore frequently than other papers in the SCIfile.

The cited half-life of a journal is themedian age of the journal’s articles that werecited in a particular year. For the entire 1988SC1 data ffle, the cited half-life for a journalwas 5.9. The value for the CSHSQB was 7.2for the same period, again showing that thearticles retain their value for longer.

Overall Citation Reeord

The chronological dkribution of publica-tion dates for the 51 most-cited articles isshown in Table 2. The oldest paper is thatby Merkel H. Jacobs, University of Penn-sylvania School of Medicine, Philadelphia,published in the 1940 volume and deals withcell permeability to ions, a classical subjectin biophysics. The most recent paper waspublished by Werner W. Franke, GermanCancer Research Center, Heidelberg,Federal Republic of Germany (FRG), andcolleagues in 1982.

It is striking that 47 percent of the 51most-cited papers were published in the1960s. As this period might be regarded asthe first golden age of molecular genetics,and given the Laboratory’s historically im-portant role in this area, it is not surprisingto fmd that symposia papers from this periodare among the most highly cited; 4 of thetop 5, and 12 of the top 20 papers appearin volumes published between 1960 and1969. The 1963 symposium on “Synthesisand Structure of Macromolecules” accountsfor 4 of these top 20 papers. However, itis something of an oversimplification toassume that highly cited papers come justfrom symposia on molecular genetics. Imentioned that symposia topics were chosenfor their timeliness and importance, and notnecessarily because of their relevance toresearch going on at the laboratory. For ex-ample, symposia topics other than moleculargenetics include subjects as diverse as ‘‘Bio-logical Clocks” (1960), “Antibodies”(1967), “The Mechanism of Muscle Con-traction” (1972), and “The Synapse”(1975). All these gave rise to highly citedpapers. Furthermore, when these figures arebroken down by year, it is remarkable tofmd that 18 of the 20 symposia held between1960 and 1979 have at least one highly citedpaper. It is testimony to the laboratory direc-tors’ knowledge of what is going on in theworld of biology that they have picked win-ners so consistently.

The recent decline in cited papers is morelikely to reflect the short time that haselapsed for citations to accumulate ratherthan any frdl in the value of symposia con-tributions. A glance at the titles of the sym-posia held through the 1980s shows thatthere is every reason to believe that they willcontinue to generate highly cited papers.

The Five Most-Cited Papers

Of the five most-cited papers in theCSHSQB volumes, four come from the1960s and represent the two major tieIds ofresearch in molecular biology in that period.Three papers are examples of classicalmolecular genetic analysis in the prere-

259

combhnt DNA era, analysis that was char-acterized by the elegant exploitation ofbacterial and viraf genetic behavior. Theother paper is an example from the field ofstructural molecular biology. The fiRtr papercomes from the late 1970s and shows howrapidly molecular genetics moved from in-direct inferences based on genetic analysisto direct anrdysis of nucleotide sequences.

Sutchye

The most highly cited paper in theCSHSQB comes from the 1979 symposiumon “DNA: Replication and Recombina-tion. ” It is a technical tour de force—thedetermination by Greg Sutcliffe, HarvardUniversity, of the entire 4,362 base pair se-quence of the cloning plasmid pBR322. Theplasmid had been developed by FranciscoBolivar and colleagues in Herbert W.Boyer’s laboratory at the University of Cali-fornia, San Francisco, and rapidly becameone of the most widely used vectors. 14,15

The continuing citation of Sutcliffe’s paperreflects the fact that pBR322 is the basis formany modem vectors and his work remainsthe primary reference for its sequence.Sutcliffe was working in Walter Gilbert’slaboratory at Harvard Medical School,Boston, Massachusetts, and used the DNAsequencing method devised by Allan M.Maxam and Gilbert. lb Sutcliffe’s commentson the project make interesting reading inrelation to the current efforts to map and se-quence the larger genomes of Escherichiacoli, Caenortuzbditis elegans, and humans.He found that “chemical problems wereminor compared with the clerical problemsof handling the data. ‘‘1TThe sequence datawere read on three separate occasions andthe finaf printed sequence checked exten-sively against the master handwritten copyby “many people. “ 17 Nowadays, hand-written notes have been replaced by com-puter hard discs, and sequencing films areread using digitizer tablets. Sutcliffe took 13months to sequence 4,362 base pairs ofpBR322. Automated sequencing machinesare now capable of generating 12,000 basepairs of sequence per day, but handling andanalyzing this amount of data are becoming

increasingly serious problems for large-scalesequencing and mapping.

Jacob and Monod

The symposium in 1%1 was on ‘‘CellularRegulatory Mechanisms” and the paperFran~ois Jacob and Jacques Monod, PasteurInstitute, presented is the fifth most cited(643 citations) in the CSHSQB. In it theyreviewed the data on the regulation ofprotein synthesis in bacteria and discussedmRNA and operators and the operon as theunit of coordinated gene expression. Itmakes a striking contrast with the paper ofSutcliffe. Jacob and Monod’s anafysis of theelements controlling gene expression in-volved elegant reasoning based on geneticexperimental evidence. In contrast, Sut-cliffe’s discussion of the origin of replica-tion, the structures of the arnpr and tetf, andprotein coding regions of pBR322 is basedon knowledge of the exact structure (nu-cleotide sequence) of the DNA. This paperby Jacob and Monod would probably havehad a much higher citation rate but for thepublication of their great review “Geneticregulatory mechanisms in the synthesis ofproteins” in the Journal of Molecular Bi-ology] 8 just one week before the sym-posium, However, they were able to incor-porate into the CSHSQB paper a discussionof McClintock’s work that had been omit-ted from the Journal of Molecular Biologypaper. Another highly cited symposiumpaper, on “The structure of DNA” by Wat-son and Francis H.C. Crick, was also“scooped” by publication elsewhere. 19This talk by Watson at the 1953 symposiumon “Viruses” was the first presentation ofthe double helix at a public meeting. It isranked 16th amortg the CSHSQB papers.

Jacob and Colleagues

Ten years after Watson’s presentation, thesymposium was on “Synthesis and Struc-ture of Macromolecules, ” and Jacob, nowin collaboration with Sydney Brenner, Me&cal Research Council Laboratory of Molec-ular Biology, Cambridge, UK, and FranqmisCuzin, Pasteur Institute, presented what is

260

the second most-cited CSHSQB paper with1,216 citations. They reviewed the experi-mental work on DNA replication in bacteriaand presented a detailed discussion of the‘‘replicon” model that Jacob and Bremerhad outlined in a brief publication inChptes Renaks Hebahadaires &s Wncesde 1‘Acaa%de des Sciences.zo They defineda replicon as a genetic element capable ofreplication and gave episomes and bacterialchromosomes as examples. The replicon isformally similar to the operon and hasremained a useful concept. Jacob et al.discussed how the concept might relateDNA replication in eukaryotes. The nameis also used to describe the many individualregions of replicated DNA in the chromo-somes of higher eukaryotes.

Epstein and Co[[eagues

The third most-cited paper at 929 citationsalso comes from the 1%3 symposium on the“Synthesis and Structure of Macromole-cules” and shows how genetic and structuralstudies were begiming to come together inan analysis of the assembly of the complexT4 bacteriophage. The great advances inmolecular genetics in the 1950s and 1960sdepended on the choice of organism and theavailability of mutants that could be selectedfor and mapped. Ideally the phenotypes ofthe mutants should reveal something of thefunction of the genes involved. This paperby R.H, Epstein and his colleagues, Univer-sity of Geneva, Switzerland, listed the 47genes of phage T4 for which temperaturesensitive (ts) and amber (am) mutations wereavailable and described their phenotypes.Thirty-seven of these were associated withthe assembly of the virus particles, affect-ing, for example, the tails of the phage. Anotable featrm of the analysis is the re-alization that genes affecting particular func-tions were grouped together and that the se-quential expression of these genes contrib-uted to the orderly assembly of the virusparticles. (The origin of the strange name“amber” for these mutations is an interest-ing footnote in the history of molecularbiology and deserves to be better known.Robert S. Edgar, University of California,

Table 3: Tfre numberof authors per paper for the51most-cited articles from the CW Spring HarborSymposia on Qrumritarive Biology, 1945-1988 SC1@.

Number of NumberAuthors of

per Paper Papers

10 19 18 27 35 24 23 42 131 23

Santa Cr-uz, recounts that Epstein and C .M.Steinberg, then at Cakech, had promisedHarris Bernstein, then at Yale University,New Haven, Connecticut, that the mutants,if any were found, would be named after hismother. They were found and “amber” isthe English equivalent of “Bernstein.’ ’21)

Caspar and Klug

“Structural” molecular biology led to thediscovery of the DNA double helix and con-tinued to flourish in the following years,even as it seemed that the “informational”approach was in the limelight. Indeed it isoflen forgotten that in 1956 the Crick andWatson team made a second major contribu-tion to molecular biology with their discus-sion of the structures of small or simpleviruses.zz The paper by D.L.D. Caspar andAaron Klug, Harvard Medical School, fromthe 1%2 symposium on “Basic M~hrmismsin Animal Virus Biology, ” is a iucid anddefinitive review of their elegant studies onthe structure and assembly of simple helicalviruses like tobacco mosaic virus and smallregular viruses like turnip mosaic virus andadenovirus. Caspar and Klug’s icosaheciralmodel for the latter group of viruses hadbeen inspired by the designs of BuckminsterFuller and a photograph of the geodesicdome illustrated the article. The paper ranksfourth on the list with 765 citatiotts.

Authors

There are 135 authors of these51 papers.As shown in Table 3, one paper has 10

261

Table 4: Nobel Iaureat= listed as authors of the 51most-cited articles from the Cold Spn’ng HarborSymposia on Quanf~kuive Bio(ogy, 1945-1988 SCI@,showing the field and year of their awards.

Nobelist Prize Year

Baltimore, David Medicine 1975Crick, Francis H.C. Medicine 1962Gilbert, Waker Chemistry 1980Jacob. Fran$ois Medicine 1%5Klug, Aaron Chemistry 1982McClintwk, Earbara Medicine 1983Mmmd, Jacques Medicine 1965Perurz, Max F. Chemistry 1962Watson, James D. Medicine 1962

authors (Epstein er al. ) followed by Frankeet al. with 9 authors and the papers by F.L.Graham, University of Leiden, The Nether-lands, et al. and Wolfram Zillig, MaxPlanck Institute for Biochemistry, Munich,FRG, et al. with 8 authors, Nevertheless,71 percent of the papers have one or twoauthors, giving an average of 2.6 authorsper paper compared with the value of 5.1authors per paper for the 101 most-cited life-sciences papers in 1987 .2s This may reflectthe fact that CSHSQB articles resemblereview articles and so have small numbersof authors or may indicate the style of anera when research was performed by smallgroups. The most frequently occurringauthor is Jacob, who appears four times,appropriately coauthoring two of thosepapers with Monod. The remaining threeauthors who appear twice are David Balti-more, Massachusetts Institute of Technol-ogy, Cambridge; D. S. Hogness, StanfordUniversity School of Medicine, California;and McClintock.

Nobel Laureates

In his 1934 annual report, Harris pointedout that one of the participants in the 1934symposium had received the Nobel Prize forchemistry. Rather disingenuously prefacinghis remarks with “While we do not wish tostress the fact unduly, ” Harris suggestedthat this could be taken as an indication ofthe quality of the meetings. 13This has con-tinued to be a feature of the symposia and

over 70 Nobel iaureates have attended the54 meetings held since 1933. Given thisattendance record and that Nobel laureatesconsistently publish classic papers as judgedby their citation record, it is hardly surpris-ing that Nobel laureates should featurestrongly in the most-cited papers from theCSHSQB (Table 4). There are nine Nobellaureates listed as authors on 12 of the top51 papers.

However, this emphasis on Nobel laure-ates tends to overshadow the remarkablequality of all the scientists who attend thesymposia and the quality of the science theypresent. The contents pages of any volumelist the names of those who created molec-ular biology, one of the triumphs of twen-tieth-century science, and each new volumeshows those who continue to advance thatwork.

Table 5: tkwgraphic areas represented by the institu-tional affitions given by auttmrs in k Bibliography.listed in descending order by the number of papersproduced (column A). B =number of papers co-authored with researchers affdiated with institutionsin otier countries. C = national Iccations of institutionsIisted by coauthors.

LocationofHltutions AB c

us

New YorkCaliforniaMassachusettsNew JerseyOregonWisconsinColoradoComecticutMarylandMinnesotaPemsylvaniaTennessee

UK

FranceFRG

JapanSwitzerlandAustriaBelgium

DenmarkThe Netherlands

35 5

11763221111I1

84

6131

212211

Belgium, Japan,The Netherlands,Switzerland, UK

Denmark, France,us

UKAustria,

SwitzerlandusAustria, USFRG, SwitzerlandThe Netherlands,

usUKBelgium. US

262

Geographical Distribution of Authors andInstitutions

These papers came from 49 unique institu-tions in 10 countries and the majority ofpapers have US authors (35). (See Table 5.)Remarkably, however, a US institute doesnot head the list of institutions with the mostnumber of papers. Instead, the Pasteur In-stitute leads, reflecting its position as oneof the great centers for molecular biologyand genetics throughout the period coveredby this analysis. There are five papers fromthe Pasteur, authored by J.-P. Changeux,Y. Hirota, Jacob, Cuzin, and Monod. Thereare five institutions each with three appear-ances in this list: Caltech; Cold Spring Har-bor Laboratory; Medical Research Council;Princeton University, New Jersey; and TheRockefeller Institute.

Conclusion

The CSHSQ3 continues to thrive asreflected in the titles of the individual

volumes, “Organization of tbe Cytoplasm, ”“Molecular Neurobiology, ” “MolecularBiology of Homo sapiens’ ‘—the broadsweep of these topics reflects the corttldenceof the organizers and participants that mo-lecular biology is the key to a deep under-standing of the nature of living organisms.Harris left a legacy that has stimulated thegenerations of molecular biologists that havecome each year to talk, argue, and gossipat the symposium. He is quoted in the in-troduction to the first volume as saying thatthe meetings, like the laboratory itself,“should be centers of growth and dissemina-tion of new methods and iaeas inbiology.’ ’24 The citation record of thevolumes shows that Harris’s aspirationshave been well served by the directors whofollowed him. As the laboratory enters itssecond century with the 1990 symposium on“The Brain, ” there is every reason tobelieve that the CSHSQB will continue tooccupy a special place in experimentalbiology.

. Im1s1

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

A

345

376505

218382

246

518492

765

218

929

261

246

256

414

361

232

229

324

266

Bib~apbic Data

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”rrgHarborSynrp. 33:289-305, 1%8.

Ames B N & Harttnan P E. The histidine operon. Cofd Spring Harbor Syrrrp. 28:349-56, 1%3.As&off J. Exogenous and endogenous cmnpnrrents in circmian rhythms. Cold Spring Harbor

SymP. 25:11-28, 1960.88-1306Baftimore D. Tumor viruxes: 1974. Cold Spring Harbor Symp. 39:1187-200, 1975.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.

Bhrmentbaf A B, Kriegateirr H J & Hngnma D S. The units of DNA replication in Drosophilamelanogmter chromosomes. Cofd Spring Harbor Syrnp. 38 :20S-23, 1973.

Cairna J. The cbromoamnc of E.rcherichia coli. Cofd Spring Jfarfrar Symp. 28:43-6, 1%3.Cantor H & Boyae E A. Reguhrtinn of celfufar and humoral immune respnnses by T-cell

subclasses. Cofd Spring Harbor Syrnp. 41:23-32, 1977.●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)CJmrrgeux J-P. Allosteric interactions on biosynthetic L-threonine demnirrase from E. o/i K12,

Cold Spring Harbor Syrryr. 28:497-504, 1%3,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 conditionallethal mutants of bacteriophage T4D. Cofd Spring Harbor Symp. 28:375-94, 1963,

Fhsnegarr D J, Rubfn G M, Yormg M W & Hogrress D S. Repeated gene famifies in DrosopJrihnterhnogaster. Cofd Spn”ng Harbor Syrrrp. 42:1053-63, 1977.

Franke W W, Scbndd E, ScJriUer D L, Winter S, Jaraach E D, Moll R, Drink H, JacksonB 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, 1982.88-0288Frankfin R M & BoJtJmore D. Patterns of macromolecular synthesis in normal and virus-infected

msrmnaliarr cefls. Cofd Spring Harbor Syrnp 27:175-98, 1%2.Gilbert W & Dressier D. DNA replication: the roJJing circle medel. Cofd Spring Harbor Syrnp.

33:473-84, 1%8.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 ofhuman adennviruses and simian virus 40, Cofd Spring Harbar Syrnp, 39:637-50, 1975.

Halberg F. Tempnral coordination of physiologic function, Crrfd Spring Harbor Symp.25:289-310, 19&3.

Haaefgrove J C. X-ray evidence for a confirmational change in the actin-containing ftients ofvertebmte striated muscle. Cold Spring Harbor Syrnp. 37:341-52, 1973.

Hirota Y, Ryter A & Jacob F. Thermoaensitive mutants of E, ccdi afkted in the prwesaes ofDNA synthesis and cefbdar division. Cold Spring Harbor Syrrrp. 33;677-93, 1968.

Hnnd L, Gray W R, %rrders B G & fJreyer W J. Light chain evolution, CM Spring HarborSyrrrp. 32:13346, 1%7.

264

A

254

427

355

1,216

643

233

418

283

614498

345299

251

332

223

308

237

236

479

278

236274

249

230

251

410

237

1,495

393

282

270

Bibfiugraptdc Data

Hotcbio J. The biology of choriomeningitis infection: virrrs-induced immune disease. Co&fSpringHarbor Symp. 27:479-99, 1%2,

Hutchinams G E. Peculation studies: animal ecology and demography. Concluding remarks. ColdSpring Harbor Syrnp. 22:415-27, 1957.

Huxley H E. Stmctumf changes in the actin- and myosin-containing fdarnents during contraction.Cofd Spring Harbor Symp, 37:361-76, 1973,

Jacob F, Warmer S & CuziOF. On the regulationof DNAreplication in bacteria. Cofd SpringHarbor $mrp. 28:32948, 1%3.

Jacob F & Monnd J. On tfre regulation of gene activity. Cofd Spring Harbor Syrnp. 26:193-211,1961.

Jacobs M H. Some aspects of cell permeability to weak electrolytes. Cofd Spring Harbor Syntp.8:30-9, 1940,

Jones R T. Stmctursf studies of arninnethylated hemoglobins by automatic pcptidechromatography. Co./d Spring Harbor Syrrrp. 29297 -30g, 1964,

Katea J. Transcriptionof the vaccinia virus genome and the recurrence of polyriboadenylic acidsequences in messenger RNA, Cold Spring Harbor Symp. 35:743-52, 1970.

Mngaaardk B. Catabnlite repression. Cofd Spring Harbor Synrp. 26:249-56, 1961.MXXintockB. chromosome organization and genie expression. Cold Spring Harbor Synrp.

16:13-47, 1951.88-5265McCffotock B. Controlling elements and the gene. Cofd Spring Harbar Symp. 21:197-216, 1956.Mfc3saelL$L. The nature of the interaction of nucleic acids and nuclei with basic dyestuffs. Cofd

Spring Harbor Synrp. 12:13142, 1947.Mitdiaoo N A. Antigen recognition respmrsible for the induction in vitro of the secondary

response. Cold Spring Harbar Syrrrp. 32:431-9, 1967.Monnd J & Jacnb F. Generaf conclusions: tcleonomic medrardsms in cellular metabolism,

growth, and differentiation. Cafd Spring Harbar Synrp. 26:389-401, 1%1.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.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.Otsukrr M & KmMrf S. Substance P and excitatory transmitter of primary senanry neurons, Crxlf

Spring Harbor Syrrrp. 40135-43, 1976,Perutx M F & TenEyck L F. Stereochemistry of cooperative effects in hemoglobin. Cofd Spring

Harbor Symp. 36:295-310, 1972.Pfttendrigh C S. Circadian rhythms and the circadian organization of living systems. Co&f Spring

Harbor Syrrrp. 25:159-84, 1960.88-1306PollfaterA W & Ria H. Nucleoproteirr determination in cytological preparations. Cofd 5@ng

Harbar Synrp, 12:147-57, 1947.Rrmxcff W L. X-ray induced mutations in mice. Cofd Spring Harbor Syrrrp. 16:327-36, 1951.Safaer W. Globin MRNA sequences: analysis of base pairing and evolutionary implications. Cofd

Spring Harbor Syrnp. 42:985-1002, 1978.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.Sbeldrlek P & Bertbelot N. Inverted repetitions in the chromosome of herpes simplex vims. Cofd

Spring Harbar Symp. 39:667-78, 1975.Smith G P. Unequal crossover and the evolution of multigene families. Cold Spring Harbor

Syrnp.3tl:507-t3, 1973.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.Srreoka N & Qufrm W G. Membrane attachment of the chrornuamne reification origin in Bacillus

subtilis, Cofd Spting Harbor Symp. 33x595-705, 1%8.Suteffffe J G. Complete nucktide sequence of the Escherichia coli plasmid PBR322. Cofd Spring

Harbor Syrrrp. 43:77-90, 1979.Watxon J D & Crfck F H C. The structure of DNA, Cofd Spring Harbor Synrp. lg:123-3i,

1953.Witfdn E M. Time, temperature, and protein synthesis: a study of ultraviolet-induced muttmon in

bactecia, Cofd Spring Harbor Symp. 21:123-40, 1956.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 thetranscription process. Co.ki Spring Hrrrbar Synrp. 35:47-5g, 1970.

265