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Spring 1990 Report on the President: [Dr. Joshua Lederberg] Judith N. Schwartz
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Recommended Citation Schwartz, Judith N., "Report on the President: [Dr. Joshua Lederberg]" (1990). Rockefeller University Research Profiles. Book 37. http://digitalcommons.rockefeller.edu/research_profiles/37
This Article is brought to you for free and open access by the Campus Publications at Digital Commons @ RU. It has been accepted for inclusion in Rockefeller University Research Profiles by an authorized administrator of Digital Commons @ RU. For more information, please contact [email protected]. THE ROCKEFELLER UNIVERSITY ('Every creative act involves.. .a new innocence ofperception) liberated from the cataract ofaccepted belief» ARTHUR KOESTLER The Sleepwalkers RESEARCH
((There is no end to our searchings... No generous mind stops within itself. Its pursuits are without limit; itsfood is wonder, the chase) PROFILES ambiguity. » MONTAIGNE (1533-1592) SPRING 1990
Report on the President
For more than forty years, Joshua Lederberg has rarely been far from the center of scientific activity and debate. In 1946, at the age of twenty-one, he burst upon the biological world with the announcement that bacteria have a sex life. In 1958, he was awarded a Nobel Prize (at the age of33) for his stud Joshua Lederbe-r;g ies oforganization and recombination ofgenes in bacteria. Possessed of an intellectual appetite that has been described as "omnivorous," and a penchant for questioning the common wisdom, his speculations have propelled him, at various times, into outer space (figuratively speaking), into the "brains" of computers, and into the councils of govern ment and industry. Before his 1978 appointment as president of The Rockefeller University, Lederberg led distinguished genetics departments at the University ofWisconsin and the Stanford University School of Medicine. His pioneering research into the molecular mechanism of genes and their application in recombinant DNA technology today informs virtually every field of biology and promises to revolutionize medical diag nosis and treatment. Page 2
Transmission ofgenetic THE "LONG-SHOT" EXPERIMENT Gene Genies: information between two E. Joshua Lederberg was a pre-medical student at Columbia In addition to a main chromosome, bacteria contain plasmids coli bacteria occurs during a University in 1944 at the time of the first experimental evi small, circular molecules ofdouble-stranded DNA which process known as conjugation. dence that DNA-deoxyribonucleic acid-was the genetic replicate autonomously. Scientists are able to insertforeign Dr. Lederberg discovered this material, at least in bacteria. This work was published by DNA into plasmids, which then multiply and produce cells process in 1946, proving that Oswald Avery, Colin MacLeod, and Maclyn McCarty, scien containinggenetically identical material, or clones. a form ofsexual reproduction tists working at the research hospital of The Rockefeller To introduce a humangene (in this case, the one for insulin) occurs in these asexual Institute for Medical Research (later The Rockefeller into a plasmid, scientists take the plasmid out ofan E. coli microorganisms. In the University). bacterium, break the plasmid open at a specific site by means of micrograph below, two Some years earlier, it had been observed that non-viru a restriction enzyme, and splice in insulin-making human bacteria make cell-to-cell lent strains of pneumonia bacteria became infectious when DNA. The resulting hybrid plasmid can be inserted into contact through the mixed with heat-killed, infectious strains. Painstaking inves another E. coli bacterium, where it replicates together with the formation ofa connecting tigation of this puzzling phenomenon revealed to Avery bacterium, making it capable ofproducing large quantities of bridge. The bacterium acting and his team that the non-infectious bacteria picked up insulin. as a male donor contributes loose threads of DNA that had been released from their Pancreas '"'--" lJ)":;:;- DNA to the bacterium acting once-lethal neighbors, and that the acquired DNA and its E coIl..bacteria. taken from human ..Intestine rI)'- as a female recipient. The power of infectivity were retained in the progeny of the recipient incorporates the new transformed bacteria. ~CJ N",',"'~ genetic information into its A medical degree was then considered the proper route to ",=,,,, own chromosome by the goal of biomedical research, but Lederberg spent most of recombination and passes the his time in the laboratory of geneticist Francis Ryan, where ... E coli chromosome ~ ~ /TTh recombined set on to its the Rockefeller discovery caused a considerable stir. As Plasml~ W~ ~ ~ progeny by replication. Q Strand of DNA from Human DNA cut Lederberg later wrote: "When biologists of that era used human cell Jinto pieces terms like protein, nucleic acid, or nucleoprotein, it can hard Plasmid cut open by by restriction ly be assumed that the words had today's crisp connotations restriction enzyme at a specific site enzyme of defined chemical structure. Sleepwalking, we were all _.1111 •• groping to discover just what was important about the chem .u' Hum~gene ical basis of biological specificity. It was clear to the circle I PlasmidOremoved .. frequented at Columbia that Avery's work was the most from E colt ...... exciting key to that insight." The inspired young medical student deliberated on how to Human "advance these new hints about the chemistry of the gene" Recombinant DNA Insulin gene (hybrid plasmid) 1 and the genetics of bacteria. It had been assumed that bacte I ria always reproduce simply by dividing into two genetically o...Two pieces spliced together identical daughter cells, making comparative analysis impossi ~ Hybrid plasmid C::? C:::» inserted into E coli cell ble. However, since there were other microorganisms known ~ to have a sexual stage, a few microbiologists had pondered the possibility in bacteria. It seemed clear to Lederberg that
Bacteria with hybrid plasmid replicate, creating clones capable of producing insulin Page 3
Lederbe1'lJ Through the Years: "questions about the biological significance of transformation research on sexual behavior. With Ryan's encouragement (I. to. r.) Joshua Lederbe'0 as in bacteria (i.e. Avery's finding) would continue to fester so and Tatum's agreement, Lederberg took what he thought a pre-med student, 1945; at long as bacteria remained inaccessible to conventional genetic would be a short break from his medical studies to go to the University ofWisconsin, analysis for lack ofa sexual stage." Tatum's lab in March 1946 and try what he termed a "long 1958; at Stanford University, Francis Ryan had done postdoctoral research at Stanford shot" experiment. circa 1960; installed as University with George Beadle and Edward Tatum who It succeeded beyond his "wildest expectations." Within a president ofThe Rockefeller would later share a Nobel Prize (awarded the same year as few weeks he had uncovered a system whereby two bacteria University, 1978. Joshua Lederberg's) for their discovery that genes control attach and form a connecting bridge through which one pass chemical reactions through the proteins called enzymes. es a chromosomal strand to the other. The discovery of this Tatum had recently moved his laboratory to Yale, where he mechanism, called conjugation, helped to confirm the exis was developing a mutant strain of a common bacterium, E. tence ofbacterial genes and made bacteria available for genet coli, which Lederberg believed might be a suitable model for ic research. Page 4
eltO- ('&kS:l ; before tWO unstressed syllables (k'so), prefiX'O (before a vowel sometimes reduced to ex-), repr. Gr. lEw, without, in many compounds of modern formation, as PLASMIDS AND RECOMBINANT DNA TECHNOLOGY e"arte'ritiS, ,exo_arte'ritiS (see ARTERITIS), With new discoveries and 'Path., inflammation of the outer coat of an Lederberg never returned to medical school. After earning a artery; exoatrnos'pheric a., occurring or concepts come the need for new Ph.D. with Tatum in 1947 he received an appointment at the working outside the atmosohere; names. Here are some words University of Wisconsin, where for the next dozen years, he coined byloshua Lederber;g, and his colleagues continued to explore the ramifications of both alone and in conjunction bacterial recombinations. with his research colleagues, as Recombinant DNA technology exploits the capacity of they appear in the Oxford bacteria to carry extra rings of genetic material, called plas English Dictionary. mids (a term coined by Dr. Lederberg), outside of their chro mosomes. In gene cloning, a' plasmid is removed from a bacterium, cut open with enzymatic "scissors," and a seg ment of foreign DNA (for example, the gene for human insulin) is spliced into the plasmid ring. The recombinant plasmid is then closed up and returned to the bacterium, which proceeds to churn out daughter cells containing the 01' Plasmlas -.. nOt obsc as VIrUSes S ,- ..... ~ I ne raxo inserted gene. heredita ure careful' .Hnb'.onts, Or nOmIc CJasSln transd . ,-.-I Par071lecZ Or parhologicadescnptions tJasrnagenes shatlol1 The development of recombinant DNA technology t"allSd"c~~tiOlJ (tra:nS'~kf t e variou;:' f~~;;~'ar'b,J' ~~;O+~lb'd ~'4',~i~ runc::~~~ actJon f n-e11Z (U ~n tr let' 0 plasmid- h J5 review h P aSfTlJd in derived from scientists' observations of natural recombinant 1. Th~ t:;t(llS)dtic:,.~:a~l: Irad"::::S:"1;,,) [ad. L. nd~~;~toC;t~rdi~;':d ~~~~~:arya~~;'~:~::t~ tOn of Tll.>\DUC£ ]• n. of -. _SomeWhere b~~nes, With 'he mechanisms in bacteria. Tills involved the crossing over of ra"e.16 lead' e 56 B Ing Or b . . ------.: ween, • rema",,' LOUNr G' nnging l independent genetic combinations through transformation, ApI :t:,ng from {ossoK'" r across _ . ,·I'JQ:l;t"mi one place TOnsdll a ,.· . ff as the Pu :t~d, InhOd ;,~ aIlorhfr 0", a lead' ,.. __ .. hr~ . through conjugation, and most analogously, through trans trQ1tSd . 'Pose .' lerl,! ( g';1 . Q 1816 B 109 oVer'-- 2 T'le/lon, .. andreqUlre., wIJ 30) '9 In}' £"'r"~",, Olffi' .' he . So fOnh I be b' 'eu ofadd. ' duction, a process discovered by Rockefeller Professor SIgnal aCtIon O· 5U ~oined b '''It'o" 10. . r proceSS f a dl/ Professor in the University of Melbourne laboratory of time friend Joshua Lederberg (one of the subjects of her immunologist Sir MacFarlane Burnet. He participated in book and a sometimes collaborator in studies of the history research on antibody production that would earn Burnet a and sociology of science), as a man whose interests are "deep Nobel Prize in 1960, and he witnessed the ascent of Sputnik and diverse enough for several life histories." in the southern skies on October 4, 1957, an event that filled During his Stanford years, from 1959 to 1978, his aca him with both awe and apprehension. On returning to his demic titles included professor and chairman of genetics, pro own laboratory, he read extensively on astronomy and rock fessor of biology, and professor of computer science. His ,. ,-. 'Il- etry and, by December, he had sent off memos to several extracurricular activities, in addition to participation in the ,.;, ;lv'> influential scientists asking their help to avert what he saw as space program, included membership in nine or ten govern . t • a potential "cosmic catastrophe": the contamination of life mental and scientific agencies and commissions, including forms that might be present on other planets by organisms panels of the President's Science Advisory Committee. He J; ; If· \ carried from earth via space flight. served on President John F. Kennedy's Panel on Mental ".. "I was the only biologist at that time who seemed to take Retardation and directed research on the genetics, develop .I' the idea of extraterrestrial exploration seriously," he remarks. ment, and neurobiology of retardation at the Kennedy / "People were saying it would be a hundred years before we Laboratories for Molecular Medicine at Stanford. even got to the moon." Combined with his deep respect for His appointment to Stanford's medical school faculty gave Joshua Lederberg receiving the evolutionary inventiveness, he was probably also the only him the opportunity he had been wanting: to relate genetics Presidential Medal ofHonor biologist who had just steeped himselfin space technology. "I to the wider context ofhuman health and biology, particular from George Bush) 1989. was convinced," he says, "that once the first satellite was up ly neurobiology and mental illness--subjects that had inter the timetable would be very short, and my fear was that the ested him since childhood. As chairman of genetics, he space program would be pushed ahead for military and politi oversaw a large and diverse research group. He also helped cal reasons without regard for the scientific implications." institute a human biology curriculum for undergraduates. Among those to whom he had written and who paid heed His involvement with the space program had introduced to his warnings were Detlev Bronk and Frederick Seitz, offi him to the potential of computers for data analysis and prob cers of the National Academy ofSciences (who, coincidental lem solving, which he wanted to apply to biology. He formed ly, served successively as presidents of The Rockefeller a collaboration with Edward F~igenbaum, chairman of com University, preceding Dr. Lederberg). By February 1958, the puter science at Stanford. With the participation of another Academy'S council had expressed formal concern, and an computer scientist, Professor Bruce Buchanan and, later, Carl international committee was formed to establish guidelines Djerassi, a professor of chemistry, they created DENDRAL, a and plan methods for detecting and protecting life in space. computer program to generate structures of organic Dr. Lederberg served on the Academy's committees on molecules and to explore how molecules exist in nature. It space biology from 1958 to 1977, and on NASA's lunar and became the prototype for all so-called expert systems. They planetary missions boards, involved with the Mariner and followed DENDRAL with a program for experiment design Viking missions, from 1960 to 1977. and data analysis in molecular genetics, and a computerized consultant in infectious diseases. In 1974, with support from THE STANFORD YEARS the National Institutes of Health, they established SUMEX, Sociologist Harriet Zuckerman, author of Scientific Elite) a the Stanford University Medical Experimental Computer, to study of American Nobel Laureates, characterizes her long- provide hardware for research projects allover the country. Page 6 In 1966, deciding that there was a need for increased pub university's thrust in such areas as heart disease, cancer, men lic awareness and understanding of science, he initiated and tal and neurological illness, and infectious diseases, including wrote a weekly column for The Washington Post, in which, diseases ofthe Third World. over a period of six years, he commented on everything from Building new laboratories and renovating old ones, not to manipulating genes to manipulating weather, science ethics, mention trying to resolve the problem of attracting promis science education, the environment, the history of medicine, ing young investigators to a city of astronomical housing and the state ofscience reporting itself. costs, has required a lot of planning, revenue management, and fund-raising. This past fall a new university apartment AS UNIVERSITY PRESIDENT building, Scholars Residence, opened next to the existing The move to New York brought Dr. Lederberg back to the Faculty House. A superb new laboratory building is currently city where he grew up and where his distinctive styl~ of under construction, part of which will house scientists who RESEARCH PROFILES is debate was honed in "quasi-Talmudic argumentation" with share joint appointments on the Rockefeller faculty and as published four times a year by The his rabbi father- His precocity was apparent early-he asked investigators in a unit of the Howard Hughes Medical Rockefeller University. This issue was written by Judith N. Schwartz. questions his teachers couldn't answer. His hunger for science Institute, which was established at the university during Dr. Inquiries should be addressed to was fed in the library. If there were, as he says, no "dark Lederberg's tenure. the University's Public Information Office, 1230 York Avenue, New clouds" in his childhood, he does remember being "very York 10021; or phone (212) 570 lonely" for someone to share his interests, a problem that was THE FUTURE 8967. Photograph: Page 1: Ingbet Grlittner. Micrograph: Page 2: resolved upon his admission to Stuyvesant High School, one Dr. Lederberg received the National Medal of Science, the courtesy of Dr. Joshua Lederberg, of the city's renowned training grounds for budding nation's highest scientific award, this past October- Now, The Rockefeller University. Photographs: Page 3: (I. to r.) Nobelists. Like many of New York's children of immigrant after twelve years, he reaches mandatory retirement age as courtesy of Nature Magazine; parents, his passage to higher education was made on scholar president this coming July 1 and returns to research as a pro courtesy of Dr. Joshua Lederberg, The Rockefeller University; ships, the subway, and the New York Public Library. fessor at the Rockefeller. He plans to continue lab work and courtesy of Stanford University; The venerable New York City institution he returned to the study of theory formation in molecular genetics. He also courtesy of the Rockefeller Archive Cente;. Photograph: Page 5: preside over had undergone some changes since Oswald plans to maintain his participation in public activities, particu courtesy of Dr. Joshua Lederberg, Avery's day. The 1950s and 1960s had brought -physical larly in international arms cpntrol as a member of the NAS The Rockefeller University. Illustration by Dennis Stillwell. expansion to the campus and the establishment of a graduate Committee on International Security and Arms Control. He Design by the Stillwell Group, degree program. His own thinking, however, coincided with is deeply concerned about the threats to humanity from natu NYC. © 1990 The Rockefeller University, Primed in the United what the board of trustees had been deciding: there was a rally emerging viruses. In addition, as co-chairman of the States ofAmerica. need to re-emphasize the university's traditional strengths. Carnegie Corporation's blue-ribbon commission, he will Continuing its long-standing policy to actively support equality Almost all of the new laboratories that have been estab assess and advise the federal and state governments on issues of opportunity for all persons, The lished during Dr. Lederberg's administration concentrate on ofscience and technology. As a voluntary adjunct professor at Rockefeller University forbids discrimination on the basis of race, biomedical investigations and lean heavily on the insights and his alma mater, Columbia University, he will again counsel color, religion, sex, national origin, methods of molecular biology. Their leaders have been undergraduate students on their research interests in the or handicap. The Administration has ali Mfirmative Action Program recruited from across the country and the world, as well as broad fields ofscience in which he has knowledge. to increase the employment of from the university's own ranks. While the Rockefeller retains A busy agenda, he admits, adding that the allure of bench women and members of minority groups in all areas of the its long-standing commitment to basic research in the biolog research is still quite strong. "There are still some elementary ical and physical sciences, the new groups have expanded the but important tasks left undone in bacterial genetics," he says_D