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A Tribute to Joshua Lederberg: Highlights I of a Remarkable Sdentific Career Number 38 Se~tember 17, I!J91

Last July, Joshua Lederberg reached the cesses of scientific progress;6 and scientific mandatory retirement age as president of biography and discovery. 7 The material The Rwkefeller University, New York, and reprinted in this essay outlines his key ef- returned to fitll-time research as a professor. forts in , , and exo- To commemorate his 12-year tenure as the , all of which are terms he coined. institution’s chief executive, the Spring 1990 Now that he has more time to devote to issue of The Research research, Professor Lederberg plans to con- Projiles was dedicated to him. 1 After read- centrate on genetic expression and mutation. ing this special tribute issue, I felt it suc- He explains: ceeded rather well in summarizing the many major milestones in Josh’s extraordinarily The particular problem that I’m begin- diverse and productive scientific career, and ning to focus on... is the intercomection decided to reprint it here. of what happens to DNA to control its ex- pression and Useawessibility of DNA for It was surprising to realize that a com- mutatiomd or evolutional change. That parable tribute had not previously appeared interconnection has &en very hugely in Currenf Contents@ (C@), since Josh neglected, and since I have a predilection was an early and active supporter of ISI@. for working on unpopular subjects, I My ftrst contact with Josh came in 1958 when thought that’s almost enough reason to I received his letter asking what became of pursue it.g my idea for a citation index for science.’2 In fact, it was Josh’s suggestion that I apply In addition, he plans to explore further how for a grant from the National Institutes of to bring expert systems into molecular Health that eventually led to the Genetics biology: Cilti”on Me-x experiments This in tltm led to the first Science Citation Index@ (SCP ) covering the literature of 1%1. Over the I have in mind trying to look a little years, we have continued to benefit from more closely at the conceptual structure Josh’s advice, encouragement, and wisdom of . The belief smxtures as a member of 1S1’s Board of Directors as of biology are more subtle than, say, well as the advisory board of the WI. He . It is much more complex than also serves as an editorial advisor to 7he how you put a collection of atoms with corusczdng links togelher. I call these doc Scientist@. trineathe’’haff-truths wetiveaddieby, ” In recent years, several CC essays have We have to live by them because you dealt with various aspects of Josh’s work. can’t be questioning every one of your The topics have included basic research in assumptions d the time. However, every genetic t-ezombination,d.s for which he won once in a while you’ve got to invert that the in 1958; the factors and pro- to stay alive, and you must reexamine your

346 premises, In the computer lingo that is I discussed in some detail in a previous CC called ‘‘truth maintenance. ” This is as essay on . i 1 In a future much philosophy of science as it is com- essay, we’ll review the subsequent impact puter application, and it’s roughly the do- it had on science, business, and society. main I’d like to dabble in,8

The last time Josh “dabbled” in this do- main with Ed Feigenbaum, Bruce Buchanan, and other colleagues at Stanford ***** University, California, was created-~e first practical demonstration of a worfcing expert computer system .9,to DENDRAL was a chemistry exprt system, My thanks to Al Welljams-Doroffor his designed to automatically identi& molecular help in the preparation of this essay. structures of organic comAwuncis. It was Iwo[s1

REFERENCES

1. Schwartz j R. Repofi on tire President. (Whole issue. ) 7he Rockefeller University Research Projiles Spring 1990.6 p. 2. Garfield E. Citation indexes for science. Science 122:108-11, 1955. (Reprinted in: Garfield E. fka.vs of an irsfortndori scienris~. Philadelphia: 1S1Press, 1984. Vol. 6. p. 468-71 .:) 3. Siser I H & UafieM E. “TheGenetics Citation Index experiment. Proceedings of /he Amen’can Docunsemarion hsszitute, 26th Annaal Meeting. Chicago, IL: American Doeumentatw, institute, 1963. p. 63-4. 4. Gafileki E. The impact of basic research in genetic recombination—a personal account by Joshua Leaerberg. Parts 1 & 2.. Current Conrenrs (24):3-17, 13 June 1988; (25):3-14, 20 June 1988. 5. -=------Postmature scientific discovery and the sexuat recombination of –the shared fx?rspectives of a scientist and a sociologist. Currenf Con/enrs (3):3-10, 16 January 1989. 6, --...... =-. Joshua Lederkrg on the nature of scientific progress. Current Contents (48):3- 12, 27 November 1989, 7. -----=------Scientific biograpby—contemporary reflections on The e.rciremenr and fascination of science, Currenr Conrenfs (5):3- 11, 29 January 1990. 8. The once and future professor. (Interview) 77se Rockefeller University News and Notes 21(5): 1-2, May-June 1990. 9. Lederberg J & Feigsmlwsm E A. Mechanization of inductive inference in organic chemistry, (Kleinmcmtz B, d.) Formal representation of human judgment. New York: Wiley, 1968, p. 187-218. 10. Lindsay R K, Buchanan B G, Feigtmhstn E A & Lederberg J. Applications of artificial intelligence for chemical inference: the DENDRAL project. New York: McGraw-Hill, 1980.256 p. 11. Garfield E. Artificial intelligence: using computers to think about thinking. Parts 1 & 2. Essays of an information scientisf. Philadelphia: 1S1Press, 1984. Vol. 6. p. 404-12; 430-42.

347 <‘Every creative act involves... a new innocence of perception, liberated from the cataract of accepted belief.” Arthur Koestler ‘flse Sleepwalkers

-‘There is no end to our search ings... No generous mind stops within itselfi Its pursuits are wirhout limit; its food is wonder, the chase, ambiguity. ” Morttaigne (1533-1592) Report on the Fresident

For more than forty years, Joshua Lederberg has rarely been far from the center of scientific ac- tivity and debate. In 1946, at the age of twenty- one, he burst ups the biological world with the announcement that bacteria have a sex life. In 1958, he was awarded a Nobel Prize (at the age of 33) for h]s studies of organization and recombi- nation of genes in bacteria. Possessed of an intellectual appetite that has been described as “omnivorous,” and a penchant for questioning the common wisdom, his specula- tions have propelled him, at various times, into outer space (figuratively speaking), into the “brains” of computers, and into the councils 01 government and industry. fJefore his 1978 ap@srtment as president of The Rwkefefler University, Lederberg led distinguisfwd genetics depamnents at the University of Wisconsin and the School of Medicine. His pioneering research into the molecular mech- anism of genes and their application in recombi- nant DNA technology today informs virtuafly every field of biology and promises to revolu- Joshua .!.zderbere tionize medicaf diagnosis and treatment. A medical degree was then considered the Tw “LONG.SHOT” EXPERIMENT proper route to the goaf of biomedkxd research, but J..ederberg spent rrmst of his time in the labora- Joshua Lederbcrg was a pre-medicaf srodent at tory of geneticist Francis Ryan, where the Rocke- in 1944 at the time of the feller discovery caused a considerable stir. As first experimental evidence that DNA—deoxyri- Lederberg later wrote: “When biologists of that bcmucleic acid—was the genetic material, at least era used terms like protein, nucleic acid, or m bacteria. This work was published by Oswafd nucleoprotein, it can hardly be assumed that the Avery, Colin MacLeod, and Maclyn McCarty, words had today’s crisp connotations of defined scientists working at the research hospital of The chemicaf structure. SIeepwafking, we were all Rockefeller Institute for Medical Research (later groping to discover just what was important about The Rockefeller University). the chemicrd basis of biological specificity. It was Some years earlier, it had bat observed that clear to the circle 1 frequented at Columbia that non-virulent mains of poeuenonia bacteria became Avery’s work was the most exciting key to that irrfeztious when mixed with heat-killed, infectious insight. ” strains. Painstaking investigation of this puzzfing The inspired young medicaf student deliberated phenomenon reveafed to Avery and MS team that on how to “advance these new hints abut the the rr+m-irrfcrtiousbacteria picked up lcmse threads chemistry of the gene” and the genetics of bac- of DNA that had been released from their once- teria. It had been assumed that bacteria always Iethaf neighbors, and that the acquired DNA and reproduce simply by dividing into two genetically its ~wer of infectivity were retained in the identical daughter cells, making comparative progeny of the transformed bacteria. analysis impossible. However, since there were

Rcprmkd w!th pemuss,on from The Rmkefeller Um vcrwry Research Profiles Sprms 1990 6 p

348 other microorganisms known to have a sexual Transmission of genetic information between stage, a few microtiloiogists had pondered the IWOE. coli bacteria occurs during a process possibility in bacteria, It seemed ciear to Leder- known as conjugation. Dr. Lederberg discovered berg that “questions a-bout the biologicsd signifi- this process in 1946, proving that a form of cance of martsformation in bacteria (i.e. Avery’s sexuol reproduction occurs in these asexual tinding) wordd cmttisrm to fester so long as m“croorganisrns. In the nricrogmph below, two bacteria remained inaccessible to conventional bacteria make ceil-to-cell contact through the formation of a connecting bridge. lhe bacte- genetic analysis for back of a sexual stage.’” rium acting as a male donor contributes DNA Francis Ryan had done postdoctoral research to the bacterium acting as a female recipient. at Stanford University with George Beadfe and 7he recipient incorporates the new genetic in- Edward Tattmr who woukt later share a Nobel formation into its own by recomb- Prize (awarded the same year as Joshua Leder- ination and posses the recombined set on to berg’s) for the!r discovery that genes control its progeny by repiicah”on. chemical reactions through the proteins called enzymes. ‘Morn had re.a.t[y moved his labora- ...... =:. tory to Yale, where he was developing a mutant .:2: ;:;,..,.,...... :::. strain of a common imxemtm, E. cofi, which .. .“ “.+},,,.,.:.:,,:,,;:.’ ;2 ,:’ ..,,.,,,,;:.:.:..,.’ # Lederberg believed might be a suitable model for *Y>. .,., ..... research on sexuai behawor. $Vidr Ryan’s encour- ,..,,.. ..; agement and Tatum’s agreement, Lederberg tcmk ..... ‘..,.:R...,...... what he thought would be a short break from his ..... ,:,: ....::...... medicrd studies to go to Tatum’s lab in March ,;!:....$..’::..,...,,..“:: 1946 and try what he termed a “long-shot” ‘f14.::;’.....’,....” experiment. It succeeded beyond his’ ‘wildest expectations. ” Wlttin a few weeks he had uncovered a system whereby two bacteria attach and form a connect- involved the crossing over of independent genetic ing bridge through which one passes a chro- combinations through transformation, through mosornrd atmrrd to the other. The discovery of this conjugation, and most analogously, through mechanism, called conjugation, helped to confirm transduction, a process discovered by Rockefeller the existence of bacterial genes and made bacteria Professor Norton Zhtder while he was a graduate available for genetic research. student in Dr. Lederberg’s Wisconsin laboratory. Like odrer organisms, bacteria are subject to PLASMIDS AND RECOMBINANT infection by viruses. The viruses that attack DNA TECHNOLOGY bacteria are called bacteriophages, or phages for short. What Dr. Zhtder learned was that bacte- Lederberg never returned to medicat school. A& riophages cart pick up genes from one bacterium earning a Ph.D. with Tatum in 1947 he received and move them to another. “It was an exciting an appointment at the University of Wisconsin, time, ” Dr. Lderberg says. “We were explor- where for the next dozen years, he and his col- ing a completely new territory that we only dimfy leagues continued to explore the ramifications of tmderatood. We weren’t looking for traosduetion– bacterial recombination. we bumped into it. We weren’t looking for plas- Recombinant DNA technology exploits the mids-we bumped into them. Every dme we tnsned capacity of bacteria to carry extra rings of genetic around we found something unexpected. ” material, called phwrrrids (a term coinext by Dr. Lederberg), outside of their . PLANET PROBES [n gene , a plasrrdd is removed from a bacterium, cut open with enzymatic “scissors,” Other kinds of excitement were to come when and a segment of foreign DNA (for example, the Dr. I.&ferberg spent a few months in Austrafia gene for human inatdin) is spliced into the pfasmid as a Ftdbright Visiting Professor in the Univer- ring. The recombinant is then closed up sity of Melbourne laboratory of immunologist Sir and returned to the bacterium, which prmxeds to MacFarlane Bumet. He participated in research chum out daughter cells corttahritrg the inserted on antibody production that would earn Ihmret gene. a Nobel Prize in 1960, and he witnessed the ascent The development of recombinant DNA tech- of Sputnik in the southern skies on October 4, nology derived from scientists’ observations of 1957, an event that filled him with both awe and natural recombinant mechanisms in bacteria, This apprehension, On mtuming to his own laboratory,

349 Ixderberg ‘llrough the Years: (L to r.) Joshua f.ederberg as a pre-rraed studen~, 1945; at the University of Wisconsin, 1958; ins~alled as president of The Rockefeller University, 1978. he read extensively on astronomy and rocketry THE STANFORD YEARS and, by December, he had sent off memos to several influential scientists asking their help to %eiologist Harriet Zuckermasr, author of Scien- avert what he saw as a potential “cosmic catas- tific Hire, a study of Ameriean Nobel f_aureates, trophe”: the contamination of life forms that characterizes her long-time friend Joshua Leder- might be present on other planets by organisms berg (one of the subjects of her book and a carried from earth via space flight. sometimes collaborator in studies of the history “1 was the only biologist at thst time who seemed and sociology of science), as a man whose in- to take the idea of extraterrestrial exploration terests are “deep and diverse enough for several seriously, ” he remarks. “People were saying it life histories. ” would be a hundred years before we even got to During his Stanford y.%us, from 1959 to 1978, the moon. ” Combined with his deep respect for his academic titles included professor and chair- evolutionary inventiveness, he was probably also man of genetics, professor of biology, and pro- the onfy biologist who had just steeped himself fessor of computer science. His extracurricular in space technology. ‘‘1was convinced, ” be says, activities, in addition to participation in the space “that once the first satellite was up the timetable program, included membership in nine or ten would be very short, and my fear was that the govemrnerrtal and scientific agemies and commis- space program woufd b pushed ahead for military sions, ineludittg panels of the President’s Science and political reasons without regard for the sci- Advisory Committee.. He served on President entific implications. ” John F. Kennedy’s Panel on Mental Retardation Among those to whom he had written and who and directed research on the genetics, develop- paid hca4 to his warnings were Detfev Brmrk and ment, and neurobiology of retardation at the , officers of the Natiorrrd Academy Kemedy Laboratories for Molecular Medicine at of Sciences (who, coincidentally, served suc- Stanford. cessively as presidents of ‘llre Rockefeller Urriver- His appointment to Stanford’s medical school sity, preceding Dr. Lederberg). By Febmroy faculty gave him the opportunity he had been 1958, the Academy’s emmeil had expressed wanting: to relate genetics to the wider context formal emtcem, and an intemrdionrd mmsmittee of human health and biology, particularly neuro- was formed to establish guidelines and plan biology and mental ilhess-subjects that had in- methods for detecting and protecting fife in space. terested him since childhood. As chairman of Dr. Lederberg served on the Academy’s com- genetics, he oversaw a large and diverse research mittees on space biology from 1958 to 1977, and group. He also helped institute a human biology on NASA’s lunar and planetary missions boards, curriculum for undergraduates, involved with the Mariner and Viking missions, His involvement with the space program had horn 1960 to 1977. introduced him to the potentiaJ of computers for

350 With new discoveries and concepts come the need for new names. Here are some words coined by Joshua Lvierberg, lwtii ulone and in conjunction with his research colleagues, as they ap- pear in the Oxford English Dictionary.

data anafysis and problem solving, which he support from the Nationaf Institutes of Health, wanted to apply to biology. He formed a col- they established SUMEX, the Stanford Univer- laboration with , chairman sity Medical Experimental Computer, to provide of computer science at Stanford. With the par- hardware for research projects afl over the ticipation of another computer sciemist, Professor country. Bruce Buchanan and, later, Carl Djersasi, a pro- In 1966, deciding that there was a nrxxf for in- fessor of chemistry, they created DENDRAL, a creased public awareness and understanding of computer program to generate structures of science, he initiated and wrote a wcx?ldy column organic molecules and to explore how molecules for l?re Washington Post, in which, over a period exist in nature. It became the prototype for afl so- of six years, he commented on everything from called expert systems. Thev followed DENDRAL manipulating genes to manipulating weather, with a program for expet&ent design and data science ethics, science education, the environ- analysis in molecular genetics, and a computerked ment, the history of md]cine, and the state of consultant in infectious diseases. In 1974, with science reporting itself.

351 AS UNIVERSITY PRESIDENT

The move to New York brought Dr. Lederberg back to the city where he grew up and where his distinctive style of debate was honed in “quasi- Talmudic argumentation” widr his rabbi father. His precocity was apparent early-be asked ques- tions his teachers couldn’t answer. His hunger for science was fed in the library. If there were, as he says, no “dark clouds” in his childhood, he does remember being “very lonely” for someone to share his interests, a problem that was resolved upon his admission to , one of the city’s renowned training grounds for Joshua Lederberg receiving the Presidernial budding Nobdists, Like many of New York’s Me&d of Honor @om George Bush, 1989. children of immigrant parents, his passage to higher education was made on scholarships, the THE FUITJRE subway, and the New York Public Library, The venerable institution he Dr. Lederberg received the National Medal of returned to preside over had undergone some Science, the nation’s highest scientific award, this changes since Oswrdd Avery’s day. The 1950s past October. Now, after twelve years, he reaches and 1960s had brought physical expansion to tie mandatory retirement age as president this com- campus and the establishment of a graduate degree ing July 1 and returns to research as a professor program. His own thinking, however, coincided at the Rockefeller. He plans to continue lab work with what the board of trustees had been deciding: and the study of theory formation in molecular there was a need tore-emphasize the university’s genetics. He also plans to maintain his participa- traditional strengths, tion in public activities, particularly in intema- Almost all of the new laboratories that have fiotd SITIIScorttrd as a member of the NAS Com- been established during Dr. Lederberg’s adntin- mittm on International Security and Arms Con- istration cxmcermate on biomedical investigations trol. He is deeply concerned about fhe threats to and lean heavily on the insights and methods of humanity from naturally emerging viruses. In molecular biology. Their leaders have been addition, 55 cm-chairman of the Carnegie Corpora- recruited from across the country and the world, tion’s blue-ribbon commission, he will assess and as well as from the university’s own ranks, while advise the federal as-d state governments on issues the Rockefeller retains its long-standing comtttit- of science and technology. As a voluntary adjunct ment to basic research in the biological and professor at his alma mater, Columbia Univer- physical sciences, the new groups have expanded sity, he will again cowl undergraduate students the university’s thrust in such areas as heart on their research interests in the bread fields of disease, cancer, mental and neurological illness, science in which he has knowledge. and infectious diseases, including diseases of the A busy agenda, he admits, arkiing that the allure Third World, of bench research is still quite strong. “There are Building new laboratories and renovating old still some elementary but important tasks leh ones, not to mention frying to resolve the problem undone in bacterial genetics, ” he says. of attracting premising young investigators to a city of astronomical housing costs, has required a lot of planning, revenue management, and fund- tESEARCH PROFJLES 1Spubhshed four times a year by The lockefelker Univermy. Tfus issue vm.s vmrren by Judd N raising. This past falf a new university aparfment khwm-m fquiria shrmkf be a&ressd 10 IJICUniwmry’s Pubfic building, Scholam Residence, opened next to the nforrnation Office, 1230 YorkAvenue, ?@) York 113D21: or existing Faculty House. A superb new laboratory IhOrle(2t2) 570-S%7 PfIoIosr?.ph:Past 7: l@xx Griimer rficrograph: Page S: courtesy of Or Josfws Iakxberg, ‘& building is currently under construction, part of bxkefettex Umvemity phorogmphs: PSge 9: (1. to r.) murtesjj which will house scientists who share joint ap- ,f NmMc W&z&; murresy of Dr. Jostm Led.?rkerg, The pointments on the Rockefeller faculty and as in- bxkefetter University; murtcsy of & Rocke!d!er Archwe btcr PMograpfu Page 1I: murravy of Or. Joshua Ledat?erg, vestigators in a unit of the Howard Hughes IIC Rockefetter Univmiiy. JUumarion by Oem”is Stifkdl. De Medical Institute, which was established at the i= by ~ S~Wdl GWP, NYC. @ IWO ?lrc Rockefetfer Um- university during Dr. Lederberg’s tenure. ersiry, Printed in tic Unmd Srates of America

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