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"[T]he prepared mind requires unfettered opportunity to recognize and follow unplanned paths . . . when we pursue our passion to master what was once unknowable, we move from a plodding struggle with nature to an ongoing, enlightening conversation."
--Joshua Lederberg, 21stC: Research at Columbia, 1995
Joshua Lederberg's path-breaking research into the molecular mechanisms of gene action made him one of the founders of molecular biology in the 1940s and 1950s. A prodigy who received the Nobel Prize at age 33, he helped lay the groundwork for genetic engineering, modern biotechnology, and genetic approaches to medicine. Interdisciplinary in his scientific interests and methods, Lederberg became a pioneer of space biology, and was instrumental in introducing computers and artificial intelligence into laboratory research and biomedical communication. As a postwar liberal with an abiding faith in the ability of government to improve society, secure peace, and protect the environment with the advice of scientific experts, Lederberg has served for over forty years on advisory commissions on science and health policy, space exploration, national security, and arms control.
Joshua Lederberg was born in Montclair, New Jersey, on May 23, 1925, the oldest of three sons of Zvi Lederberg, an orthodox rabbi, and Esther Schulman, a homemaker and descendent of a long line of rabbinical scholars. His parents had emigrated from Palestine the year before. Lederberg's family moved to the Washington Heights area of upper Manhattan when he was six months old. Zvi Lederberg originally envisioned that his son would pursue a religious calling as well. Despite his Old Testament name, however, Joshua felt drawn to science at an early age, stating in a homework assignment at age seven that his career aspiration was to become "like Einstein," to "discover a few theories in science." Father and son later reached agreement that science, like religious study, offered a path towards enlightenment and truth, and was thus a worthy pursuit.
According to his own recollection, Lederberg has been guided throughout his life by "an unswerving interest in science, as the means by which man could strive for an understanding of his origin, setting and purpose, and for power to forestall his natural fate of hunger, disease and death." Meyer Bodansky's Introduction to Physiological Chemistry (1934) was his most prized Bar-Mitzvah present, the Washington Heights branch of the New York Public Library his sanctuary during adolescent years in which, by his own admission, he was lonely for "intellectual sparring partners." There he read hundreds of works in the sciences, mathematics, history, philosophy, and fiction, among them Paul de Kruif's The Microbe Hunters (1926), a book that portrayed the work of early bacteriologists like Pasteur and Koch as a heroic quest for human betterment. As Lederberg remembers, the book "turned my entire generation toward a career in medical research."
Lederberg finally found academic peers at Stuyvesant High School, a public school that specialized in science and technology and was open by competitive entrance examination to talented students (only male at the time) from all parts of New York City. If he had earlier sought to emulate Einstein, at Stuyvesant he completed his reorientation towards biology. He conducted his first experiments at the school, in cytochemistry, the study of the structural relationships and interactions of cellular components.
After graduation from Stuyvesant at age fifteen, he continued his experiments at the American Institute Science Laboratory, an offspring of the 1939 New York World's Fair and a forerunner of the Westinghouse Science Talent Search, which provided selected high school students (including fellow future Nobel laureate Baruch Blumberg) laboratory space and equipment. In facilities located in the shadow of the Empire State Building Lederberg learned to prepare and stain tissue samples by using formaldehyde, dyes, and other chemicals, techniques required to preserve and make visible the details of cell structure for study under the microscope. During these experiments he became interested in the cytochemistry of the nucleolus in plant cells, part of the cell nucleus rich in ribosomal nucleic acid. This was Lederberg's first foray into the study of the nucleic acids.
Lederberg took advantage of a $400 scholarship to enroll as a zoology major at Columbia University in the fall of 1941, where he met his most important mentor, the biochemist Francis J. Ryan. Ryan, a gifted teacher, encouraged Lederberg in his self-described "passion to learn how to bring the power of chemical analysis to the secrets of life," and introduced him to the red bread mold, Neurospora, as an important new experimental system in the emerging field of biochemical genetics. Ryan also instilled discipline in his precocious student, a trait much needed, as Ryan's widow remembered: "You could tell that Joshua was in the lab because you could hear the tinkle of breaking glass. He was so young, bursting with potential over which he had no control. His mind was far ahead of his hands."
Lederberg's career goal was to bring advances in basic science to medical problems such as cancer and neurological malfunction. At the time, an MD was the conventional pedigree for entry into biomedical research. In pursuit of a medical degree, and to discharge his military service obligation at the same time, Lederberg in 1943 enrolled in the United States Navy's V-12 training program, which combined an accelerated premedical and medical curriculum to fulfill the armed services' projected need for medical officers. He performed his military training duties as a hospital corpsman during periodic stints in the clinical pathology laboratory at St. Albans Naval Hospital on Long Island, where he examined stool and blood specimen of servicemen recently returned from the Guadalcanal campaign for the parasites that cause malaria. His first-hand experience with parasites at St. Albans helped shape his later thinking about the life cycle of bacteria.
After receiving his bachelor's degree in zoology in 1944, Lederberg began his medical training at Columbia University's College of Physicians and Surgeons. Although research was not encouraged among first-year medical students, he continued to do experiments under Ryan's supervision. Columbia's zoology department had been "ignited," said Lederberg, by news of Oswald Avery's discovery that deoxyribonucleic acid (DNA) was the genetic material, in Pneumococcus bacteria. Inspired by Avery, Lederberg decided to investigate further the genetics of bacteria, and specifically to challenge the common but unproven assumption that bacteria were "schizomycetes," primitive organisms that reproduced by cell division and thus produced offspring that were genetically indistinguishable from one another.
After initial failures in his experiments Lederberg proposed a collaboration with Edward L. Tatum at Yale University, who had been Ryan's post-doctoral adviser and who was an expert in bacteriology and the genetics of microorganisms. During a year-long leave of absence from medical school in 1946, Lederberg carried out experiments with the intestinal bacterium Escherichia coli which demonstrated that certain strains of bacteria can undergo a sexual stage, that they mate and exchange genes. This discovery, and the methods used to make it, had far-reaching scientific and medical implications. First, Lederberg demonstrated that successive generations of those bacteria that mate were genetically distinct and therefore suitable for genetic analysis. Secondly, he created a new understanding of how bacteria evolve and acquire new properties, including antibiotic resistance.
Buoyed by his success, Lederberg decided to extend his collaboration with Tatum for another year in order to begin mapping the E. coli chromosome, to show the exact locations of its genes. With Tatum's support he submitted his research on genetic recombination in bacteria as his doctoral thesis. He received his PhD degree from Yale in 1947.
Only days before his scheduled return to medical school at Columbia, Lederberg, then barely 22, received an offer of an assistant professorship in genetics at the University of Wisconsin at Madison, Tatum's alma mater. He accepted, despite misgivings about abandoning medicine, because the appointment offered a unique opportunity to pursue basic genetic research full-time. Over the next twelve years, Lederberg and his wife, Esther Zimmer, a microbiologist herself, together with a handful of postgraduate students, most notably Norton Zinder, published a steady stream of original experimental results from a small laboratory in the genetics department, then part of the university's School of Agriculture. The most important of these was the discovery of viral transduction, the ability of viruses that infect bacteria to transfer snippets of DNA from one infected bacterium to another and insert them into the latter's genome. The use of viruses in manipulating bacterial genomes became the basis of genetic engineering in the 1970s.
Scientific prominence brought with it administrative responsibility. In 1957, Lederberg helped found and became chairman of a new Department of Medical Genetics at the University of Wisconsin, one of the first such departments in the country. Following his early ambition to tie genetics closely to medical research, Lederberg in the fall of 1958 accepted an offer to become the first chairman of the newly-established Department of Genetics at Stanford University's School of Medicine, a medical school more broadly oriented towards research than Wisconsin's. His decision to move to Palo Alto was followed within days by news that he had been awarded a share of the 1958 Nobel Prize in Physiology or Medicine, along with Tatum and George W. Beadle, "for his discoveries concerning genetic recombination and the organization of the genetic material of bacteria."
At Stanford Lederberg continued to lead research in bacterial genetics. He also pursed opportunities his new position provided to relate genetics to the wider context of human health and biology. He helped institute an undergraduate human biology curriculum, and launched investigations into the genetic and neurological basis of mental retardation as director of Stanford's Joseph P. Kennedy Jr. Laboratories for Molecular Medicine.
His fame as a Nobel laureate made it possible for him to broaden his field of scientific interests even further. The launch of the Soviet Sputnik satellite in 1958 prompted him to consider the biological implications and hazards of space exploration. Lederberg gained a place for biologists in the burgeoning U.S. space program when he publicly warned against the dangers of contamination of the moon and of other planets by spacecraft carrying microbes from earth. He explored the possibility of extraterrestrial life as a member of National Academy of Sciences' Space Science Board from 1958 to 1974, and helped develop instruments to detect potential traces of microbes on Mars as part of the National Aeronautic and Space Administration's 1975 Viking mission to the planet.
Lederberg's role in constructing fully automated laboratory equipment for research in space led him in turn to embark on another new pursuit: expanding the role of computers in scientific research. In collaboration with the chairman of Stanford's computer science department, Edward Feigenbaum, Lederberg in the 1960s developed DENDRAL, a computer program designed to generate hypotheses about the atomic composition of unknown chemical compounds from spectrometric and other laboratory data. It was the first expert system for specialized use in science.
Throughout his scientific career Lederberg sought to bring science to bear on matters of public policy, particularly national security and arms control, as a member of several government advisory committees, such as the Pentagon's Defense Science Board, on which he has served since 1979. He worked to bridge the gap between scientists and the public, most prominently by writing a weekly editorial column on science and society for the Washington Post between 1966 and 1971.
In 1978 Lederberg returned to the city of his youth as President of Rockefeller University on Manhattan's Upper East Side. Over the next twelve years he reinvigorated the free-standing, non-departmental laboratories of which the University is made up by refocusing them on molecular biology research with clear medical applications for heart disease, cancer, neurological illness, and infectious diseases. He became University Professor Emeritus and Raymond and Beverly Sackler Foundation Scholar in 1990, when he resumed his own research into the chemistry and evolution of DNA and into computer modeling of scientific reasoning. He continued to advise government and lecture widely about developments in science as they relate to public policy and public health, in particular about the threat of bioterrorism and of both new and reemerging infectious diseases.
Among other honors, Lederberg was elected a member of the National Academy of Sciences in 1957, Foreign Member of the Royal Society of London in 1979, and a fellow of the American Academy of Arts and Sciences in 1982. He received the U.S. National Medal of Science in 1989, and the Allen Newell Award from the Association for Computing Machinery in 1995. He held honorary doctoral degrees in medicine from the University of Turin in Italy and from Tufts University, in law from the University of Pennsylvania, and in philosophy from Tel Aviv University. Lederberg published over 300 scientific and policy-related articles and was the editor of several books, including Papers in Microbial Genetics: Bacteria and Bacterial Viruses (1951), Emerging Infections: Microbial Threats to Health in the United States (1992), and Biological Weapons: Limiting the Threat (1999). His first marriage ended in divorce in 1966. In 1968 he married Dr. Marguerite Stein Kirsch, with whom he had two children, David Kirsch and Anne Lederberg. Dr. Marguerite Lederberg, a psychiatrist specializing in psycho-oncology, is currently an emeritus faculty member at Memorial Sloan Kettering Cancer Center.
Following a battle with pneumonia, Lederberg passed away at New York-Presbyterian Hospital in New York on February 2, 2008 at the age of 82.