Rockefeller University Digital Commons @ RU Rockefeller University Research Profiles Campus Publications Spring 1990 Report on the President: [Dr. Joshua Lederberg] Judith N. Schwartz Follow this and additional works at: http://digitalcommons.rockefeller.edu/research_profiles Part of the Life Sciences Commons 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 .