I I 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 transduction, plasmids, and exo- To commemorate his 12-year tenure as the biology, 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 Rockefeller University 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 molecular biology. 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 chemistry. 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 Nobel Prize 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 artificial intelligence. 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, DENDRAL 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 bacteria–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 Stanford University 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- Columbia University 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.