Rockefeller University -- Research Profiles Spring 1990 on Professor Joshua Lederberg on occasion of his looming retirement as President (June 1990). REPORT ON THE PRESIDENT In 1946, at the age of twenty-one, Joshua Lederberg "burst upon the biological world" (to quote James Watson of double-helix fame) with the announcement that bacteria have a sex life. In 1958 he was awarded a Nobel Prize for his studies of the organization and recombination of genes in bacteria. For more than forty years, he has rarely been far from the center of scientific activity and debate. Before his 1978 appointment as president of The Rockefeller University, Dr. Lederberg led distinguished genetics departments at the University of Wisconsin and the Stanford University School of Medicine. The science he helped to pioneer, through its discoveries about the molecular mechanisms of genes and its applications in recombinant DNA technology, today informs virtually every field of biology and promises to revolutionize medical diagnosis and treatment. 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 government and industry. Whether presiding at a research colloquium, conferring on biological arms control, or advancing his personal agenda for science in the twenty-first century, Joshua Lederberg, at sixty-four, continues to challenge his intellectual resources and assumptions, and everyone else's. THE "LONG-SHOT" EXPERIMENT Dr. Lederberg approaches science with what he calls an evolutionary perspective; biology viewed, in his words, as "evolutionary drama." In that drama, microorganisms have enjoyed a long and spectacularly successful run. "When you think of microbes inhabiting every conceivable niche on the surface of the plant," he says, "the astonishment of how similar they are to us, and yet how different, you can't help but think about biology on a very fundamental, evolutionary level." Biologists have been able to take advantage of the comparatively simple biology of microorganisms, and extrapolate from microbial studies to considerations of higher organisms, because of the evolutionary conservation of biochemical processes--the fact that all of the basic building blocks of life are found in fundamentally similar chemical structures among all forms of life. The quintessential similarity between microbes and man is encapsulated in nucleic acids, the chemical substance of the genes that direct the cellular activities in all living things. The first experimental evidence that DNA--deoxyribonucleic acid--was the genetic material, at least in bacteria, was contained in a 1944 report by Oswald Avery, Colin MacLeod, and Maclyn McCarty, scientists working at the research hospital of The Rockefeller Institute for Medical Research (later The Rockefeller University). Some years earlier, it had been observed that non-virulent strains of pneumonia bacteria became infectious when mixed with heat-killed, infectious strains. Painstaking investigation of this puzzling phenomenon revealed to Avery and his team that the non-infectious bacteria picked up loose threads of DNA that had been released from their once-lethal neighbors, and that the acquired DNA and its power of infectivity were retained in the progeny of the transformed bacteria. Avery's cautiously couched but clearly implied conclusion--that DNA equaled genes--was not universally accepted. For one thing, many biologists of the day doubted that bacteria contained genes comparable to those in other organisms. For another, DNA seemed too simple a molecule to be performing the virtuoso tasks of orchestrating the biochemistry of cells and the transfer of heredity. In the chromosomal mix of proteins and nucleic acids, proteins, far more complex molecules, were the favored genetic candidates. Joshua Lederberg was a premedical student at Columbia College when Avery's paper first appeared. A medical degree was then considered the proper route to his goal of biomedical research, but he spent most of his time in the laboratory of geneticist Francis Ryan, where Avery's discovery caused a considerable stir. As Lederberg later wrote: "When biologists of that era used terms like protein, nucleic acid, or nucleoprotein, it can hardly be assumed that the words had today's crisp connotations of defined chemical structure. Sleepwalking, we were all groping to discover just what was important about the chemical basis of biological specificity. It was clear to the circle I frequented at Columbia that Avery's work was the most exciting key to that insight." It inspired in the young medical student some ideas of his own about how to "advance these new hints about the chemistry of the gene" and the genetics of bacteria. When organisms reproduce sexually, the genetic contributions of the parents are distributed in different recombinations in their offspring. Because genes could not be seen, the proof of their existence lay in the distribution of inherited traits that could be traced through successive generations. What genes do primarily is order cells to make proteins. Geneticists depend upon experiments in which normal organisms are mated with mutants, organisms with defective or abnormal genes. By comparing the offspring of these matings it becomes possible for scientists to get some insights into what genes are coding for what proteins by seeing what proteins and processes are affected when genes are aberrant. Bacteria normally, and it was assumed always, reproduce simply by dividing into two genetically identical daughter cells, making comparative analysis impossible. Other microorganisms, like algae and yeasts, were known to have a sexual stage, but scarcely any bacteriologists had pondered the possibility in bacteria. To Lederberg it seemed clear that "questions about the biological significance of transformation in bacteria (i.e. Avery's finding) would continue to fester so long as bacteria remained inaccessible to conventional genetic analysis for lack of a sexual stage." Francis Ryan had done postdoctoral research at Stanford University with George Beadle and Edward Tatum, who would later share a Nobel Prize (awarded the same year as Joshua Lederberg's) for their discovery that genes control chemical reactions through the proteins called enzymes. In 1945 Tatum moved his laboratory to Yale, where he was developing a mutant strain of a common bacterium, E. coli, which Lederberg believed might be a suitable model for a search for sexual behavior. With Ryan's encouragement and Tatum's agreement, he took what he thought would be a short break from his medical studies to go to Tatum's lab and try his "long-shot" experiment. Starting in April 1946, it succeeded beyond his "wildest expectations". Within a few weeks he had uncovered a system whereby two bacteria attach and form a connecting bridge through whch one passes a chromosomal strand to the other. The discovery of this mechanism, called conjugation, which helped to confirm the existence of bacterial genes and make bacteria available for genetic research, might easily not have happened, or not then. Tatum's mutant strain was called K-12. "Only later did we learn that K-12 was a remarkable lucky choice," Dr. Lederberg wrote. "Only one in twenty randomly chosen strains would have given positive results in experiments designed according to our protocols." He never returned to medical school. After earning a Ph.D. with Tatum, he accepted an appointment at the University of Wisconsin, where for the next dozen years he and his colleagues continued to explore the ramifications of bacterial recombinations. PLASMIDS AND PLANET PROBES Recombinant DNA technology exploits the capacity of bacteria to carry extra rings of genetic material, called plasmids, outside of their chromosomes. In gene cloning, a plasmid is removed from a bacterium and cut open with enzymatic "scissors" and a segment 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 inserted gene. (The term plasmid was coined by Dr. Lederberg to account for phenomena like virus-mediated transduction). The modern development of recombinant DNA technology derived from scientists' observations of natural recombinant mechanisms in bacteria: transformation, conjugation, and transduction. Like other organisms, bacteria are subject to infection by viruses. The viruses that attack bacteria are called bacteriophages, or phages for short. In transduction, phages can pick up genes from one bacterium and move them to another. Norton Zinder is now a Rockefeller Professor. His role in the discovery of transduction, while he was a graduate student in Dr. Lederberg's Wisconsin laboratory, was recounted in a previous profile, dated winter 1987-88. A virus is a small package of nucleic acids wrapped in a coating of protein. It can survive only by invading a cell and intruding its genetic message (to make more viruses) into the cell's DNA. The eventual outcome is the destruction of the cell. But not always. There is a phenomenon called lysogeny in which a phage enters a bacterium and remains dormant for a time. When it finally breaks out to invade another cell it carries with it some DNA from the first bacterium. The lysogenic phage in E. coli K-12, called "lambda" remains a much used tool in genetic engineering. "It was an exciting time," Dr. Lederberg says. "We were exploring a completely new territory that we only dimly understood. We weren't looking for transduction, we bumped into it. We weren't looking for plasmids or lysogenicity, we bumped into them. Every time we turned around we found something unexpected." Other kinds of excitement were to come when Dr. Lederberg spent a few months in Australia as a Fulbright Visiting Professor in the University of Melbourne laboratory of immunologist McFarlane Burnet. He participated in research on antibody production (that helped earn Burnet a Nobel Prize in 1960,) and he witnessed the ascent of Sputnik in the southern skies on October 4, 1957, an event that filled him with both awe and apprehension. On returning to his own laboratory, he read extensively in astronomy and rocketry, and by December he had sent off memos to several influential scientists asking their help to avert what he saw as a potential "cosmic catastrophe"--the contamination of life forms that might be present on other planets by organisms carried from earth via space flight. "I was the only biologist at that time who seemed to take the idea of extraterrestrial exploration seriously," he remarks. "People were saying it would be a hundred years before we even got to the moon." Combined with his a priori respect for evolutionary inventiveness, he was probably also the only biologist who had just steeped himself in space technology. "I was convinced," he says, "that once the first satellite was up the timetable would be very short, and my fear was that the space program would be pushed ahead for military and political reasons without regard for the scientific implications." Among those to whom he had written and who paid heed to his warnings were Detlev Bronk and Frederick Seitz, officers of the National Academy of Sciences (who, coincidentally, served successively as presidents of The Rockefeller University preceding Dr. Lederberg). By February 1958, the Academy's council had expressed formal concern and an international committee was formed to establish guidelines and plan methods for detecting and protecting life in space. Dr. Lederberg served on the Academy's committees on space biology from 1958 to 1977, and on NASA's lunar and planetary missions boards, involved with the Mariner and Viking missions, from 1960 to 1977. Although our forays in space have not so far yielded evidence of other planetary biota, Dr. Lederberg believes it is shortsighted to "foreclose the possibility." Pointing out that Mars, for example, has only been partially investigated, he says, "many large-scale topographic features seem to signify ancient oceans and rivers," which may contain fossils of a "more hospitable" epoch in Martian history. THE STANFORD YEARS Sociologist Harriet Zuckerman, author of Scientific Elite , a study of American Nobel Laureates, characterizes Joshua Lederberg, one of the subjects of her book, a sometime collaborator in studies of the history and sociology of science and a longtime friend, as a man whose interests are "deep and diverse enough for several life histories." During his Stanford years, from 1959 to 1978, his academic titles included professor and chairman of genetics, professor of biology, and professor of computer science. His extracurricular activities, in addition to participation in the space program, included membership in nine or ten governmental and scientific agencies and commissions, including panels of the President's Science Advisory Committee. In 1966, deciding that there needed to be better public awareness and understanding of science, he initiated and wrote a weekly column for the Washington Post , in which, over a period of six years, he commented on everything from manipulating genes to manipulating weather, science ethics, science education, the environment, the history of medicine, and, not surprisingly, the state of science reporting. His appointment to Stanford's medical school faculty gave him the opportunity he had been wanting to relate genetics to the wider context of human health and biology, particularly neurobiology and mental illness, subjects that had interested him since childhood. He served on President John F. Kennedy's Panel on Mental Retardation, and directed the Kennedy Laboratories for Molecular Medicine, at Stanford, in research on the genetics, development, and neurobiology of retardation. For undergraduates at Stanford he instituted a well-received Human Biology Program. As chairman of genetics, he oversaw a large and diverse research group. Laurie Eckhardt, now a member of the biology faculty at Columbia University was a graduate student in the department in the late 1970s. She vividly recalls Dr. Lederberg's ability to convey "a very wide view of what genetics could do." His involvement with the space program introduced him to the potential of computers for data analysis and problem solving, which he wanted to apply to biology. He formed a collaboration with Edward Feigenbaum, chairman of computer science at Stanford. With the participation of another computer scientist, Professor Bruce Buchanan and, later, Carl Djerassi, a professor of chemistry, they created DENDRAL, a computer program to generate structures of organic molecules and to explore how molecules exist in nature. It became the prototype for all so-called expert systems. DENDRAL became a prototype for programs for experiment design and data analysis in molecular genetics, and a computerized consultant in infectius diseases. In 1974, with support from the National Institutes of Health, they established SUMEX, the Stanford University Medical Experimental Computer, to provide time shared computer access for research projects all over the country. Another, and not the least of his achievements, whilst at Stanford, Dr. Lederberg met and wooed a research fellow in pediatrics, Dr. Marguerite Stein Kirsch. She is now a psychiatrist on the medical staff of Memorial Sloan-Kettering Cancer Center. Their family comprises his stepson, David Kirsch who graduated from Harvard College magna cum laude in 1988, and a daughter, Anne who attends Hunter High School. When he arrived at Rockefeller in the fall of 1978 many members of the University community had their first glimpse of the new president as he accompanied four-year-old Anne each morning to the University's childrens' school. BACK TO THE FUTURE The move to New York brought Dr. Lederberg back to the city where he grew up. Ivin Prince, a grade-school chum, now a prominent New York dentist, remembers the "Josh" with whom he climbed cliffs above the old Polo Grounds in the Bronx (until "Josh fell off and broke his collarbone"), and the boy who once tried to hypnotize his whole class. His precocity was early apparent--he asked questions his teachers couldn't answer. Dr. Prince remarks, smiling, "He was a little guy then, with a rather large head. We kids just assumed it was big because it had a lot of brains in it." The distinctive Lederberg style of debate was honed in "quasi-Talmudic argumentation" with his rabbi father. 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 resolved with his admission to Stuyvesant High School, one of the city's renowned training grounds for budding Nobelists. Like many of New York's children of immigrant parents, his passage to higher education was made on scholarships and the subway. The venerable institution he returned to preside over had undergone some changes since Oswald Avery's day. The 1950s and 1960s brought extensive physical expansion and intellectual revitalization after the war years, including the establishment of the graduate degree program. From among Rockefeller's Ph.D. alumni have come a number of the University's current laboratory leaders and two Nobel laureates. The financial recession of the mid-1970s necessitated some belt-tightening and reassessments. "We began asking ourselves," says Rodney Nichols, executive vice president and a member of the University's administration since 1970, "What is the appropriate future direction for this place? As it turned out, Josh, who had not been involved in these discussions, arrived with his own ideas, which pretty much coincided with what the board of trustees had been deciding: that we needed to re-emphasize the University's traditional strengths. It was symbolic that one of Josh's first acts as president was to have a sign put up on the main gate, under the one that says 'The Rockefeller University.' It reads 'Founded in 1901 as The Rockefeller Institute for Medical Research.'" Almost all of the new laboratories that have been established during Dr. Lederberg's administration concentrate on biomedical investigations and lean heavily on the insights and methods of molecular biology. Their leaders have been recruited from across the country and the world, as well as from the University's own ranks. While Rockefeller retains its long-standing commitment to basic research in the biological and physical sciences, the new groups have expanded the University's thrust in such areas as heart disease, cancer, mental and neurological illness, and infectious diseases, including diseases of the Third World, which ravage and kill more people than any others and which have been of particular concern to Dr. Lederberg as an area that has been sadly underattended to by Western science. Building new laboratories, renovating old ones, not to mention trying to resolve the problem of attracting promising young investigators to a city of astronomical housing costs, has required a lot of planning and vigorous fund-raising. "It may be," says Dr. Lederberg, "that in New York you have to work twice as hard to make things happen. So we work twice as hard." This spring the University's new apartment building, Scholar's Residence, opened next to the existing Faculty House. A superb new laboratory building will soon be under construction. Part of it will house the investigators who share joint appointments as Rockefeller faculty and investigators of the Howard Hughes Medical Institute that was established at Rockefeller in 1986, in which the University takes justifiable pride. Next year, Joshua Lederberg will reach mandatory retirement age as president of The Rockefeller University. He plans to remain on campus as professor emeritus. He anticipates further writing and continuation of his participation in public policy activities, e.g. in arms control discussions with Soviet scientists, and as a member of the United States Defense Science Board. He is also co-chairman of the Carnegie Corporation's blue-ribbon commission, appointed in 1988 to assess and advise the federal and state government on issues of science and technology. He is eager to pick up on his work with computers and their applications to reasoning in molecular biology. "And," he says, "if some lab will let me borrow a bench, there are still some interesting things left to do in bacterial genetics."