Joshua Lederberg

Joshua Lederberg

The geneticist Joshua Lederberg (born 1925) was a pioneer in the study of bacteria and viruses to determine the chemical and molecular basis of genetics. He shared the 1958 Nobel Prize for physiology or medicine with two associates. His work on genetic recombination propelled the field of molecular genetics to the forefront.

Joshua Lederberg is a Nobel Prize-winning geneticist whose pioneering work on genetic recombination in bacteria helped propel the field of molecular genetics into the forefront of biological and medical research. During the first four decades of the 20th century the study of heredity focused largely on the problem of transmission of genetic elements from parent to offspring. The organisms most commonly studied were higher animals and plants, in particular the small fruit fly Drosophila melanogaster and the domesticated corn Zea mays. In the period just preceding and following World War II, however, geneticists' attention began to shift to investigation of the structure and function of genes themselves. Higher organisms being less suitable for such studies, geneticists turned to much simpler forms such as bacteria and viruses. As a pioneer in this new line of research, Joshua Lederberg's studies on both bacteria and viruses paved the way for the modern-day understanding of the chemical and molecular bases of genetics.

Joshua Lederberg was born on May 23, 1925, in Montclair, New Jersey, the son of Rabbi Zwih H. and Esther (Goldenbaum) Lederberg. After his family moved to New York City he attended Stuyvesant High School, where early on he was introduced to biology. Through a program known as the American Institute Science laboratory, Lederberg was given the opportunity to conduct research in cytochemistry (chemistry of cells) after school hours and on weekends. He was influenced early on by reading the works of science oriented writers such as H.G. Wells, Bernard Jaffe and Paul De Kruif. For his Bar Mitzvah he received a copy of Meyer Bodansky's Introduction to Physiological Chemistry. He enrolled at Columbia University in New York in the premedical curriculum in 1941. He received a tuition scholarship from the Hayden Trust in order to afford the university. Serving as a laboratory assistant to Professor F. J. Ryan of the Zoology Department, Lederberg carried out several experiments on the mutation of the bread mold Neurospora, just then becoming an important organism for the study of biochemical genetics (that is, how genes control biochemical reactions in cells).

After receiving his B.A. with honors in 1944, at the age of 19, Lederberg entered the College of Physicians and Surgeons at Columbia University to pursue a medical career. He had enlisted in the US Navy V-12 college training program which featured a condensed pre-med and medical curriculum to produce medical officers for the armed services during World War II. While an undergraduate, Lederberg was assigned duty at the US Naval Hospital at St. Albans in Long Island. Two years into the medical curriculum however, he took a leave of absence from Columbia to pursue graduate research at Yale in the laboratory of Edward L. Tatum, who had pioneered in the use of Neurospora for the study of biochemical genetics. Although he had intended to work in Tatum's laboratory for only a few months, Lederberg remained at Yale for two years, receiving his Ph.D. in 1946. Working with Tatum, Lederberg studied the newly-discovered phenomenon of sexual reproduction in bacteria, particularly the species Escherichia coli. At Tatum's laboratory in New Haven, Lederberg had met his future wife Esther, who became an important geneticist in her own right, obtaining her Ph.D. from the University of Wisconsin.

In 1948 Lederberg accepted an appointment as assistant professor of genetics at the University of Wisconsin; he was named associate professor in 1950 and full professor in 1954. In 1957 he organized the Department of Medical Genetics and became its first chairman. Two years later, in 1959, Lederberg assumed the chairmanship of the newly formed Department of Genetics at Stanford University Medical School in Palo Alto, California. In 1962 he became director of the university's Kennedy Laboratories for Molecular Medicine. In 1978 he was appointed President of Rockefeller University.

Lederberg was most noted for two major discoveries. First, he showed that sex and regularized genetic exchange occurs in bacteria, just as in higher animals and plants (though by a different cellular mechanism). Second, he demonstrated that genetic exchange can also occur between bacteria through the agency of viruses, which carry portions of genes from one bacterial host cell to another. These two discoveries were pivotal in laying the methodological foundation for the study of the molecular organization and function of genes. He also discovered that penicillin's ability to kill bacteria was due to its preventing synthesis of the bacteria's cell walls.

Up until 1940, biologists generally accepted the apparent fact that bacteria reproduce solely by asexual means— that is, by the fission of one cell into two. Thus, in contrast to sexual reproduction, asexual reproduction produces genetically identical descendants; by definition there is no possibility of genetic exchange and recombination. By the end of his first year at Yale, however, Lederberg was convinced that bacteria have a sex life of sorts involving the process of conjugation, in which two cells of opposite ("male" and "female") mating strains come together and apparently exchange genetic information. In studying this process, Lederberg found that genes are transferred in an orderly fashion from one of the bacterial cells to the other during the conjugation process. Moreover, he found that the exchange was directly related to time, suggesting that the donor cell transferred a single linear chromosome at a uniform rate to the recipient. Lederberg immediately saw that if this were true, it provided a means of mapping the bacterial chromosome. He found that he could disrupt the mating process at regular intervals and then determine, by biochemical analysis, the various physiological deficiencies and new capabilities of recipient cells. Thus, it became possible to study the organization of genetic material in bacteria just as in higher animals and plants.

In 1952, in collaboration with his graduate student Norton D. Zinder, Lederberg discovered a second process of gene exchange between bacteria involving a bacterial virus (bacteriophage) as a carrier agent. Known as transduction, this process occurs when a bacteriophage infects one bacterial cell, reproducing itself inside using the bacteria's cell machinery. During this process the bacterial DNA (deoxyribonucleic acid) is degraded. Occasionally, bacterial DNA fragments become enclosed in a bacteriophage shell in place of the virus's DNA. These "pseudophages" are able to infect another host cell but cannot replicate bacteriophage (since they have no bacteriophage DNA). The fragment of bacterial DNA, however, can become incorporated into the second bacterium's genome and even function in its new host cell.

The significance of Lederberg's discoveries was far-reaching. In general, his methods opened up a whole new procedure for studying the structure and organization of the genetic material in both bacteria and viruses. It suggested— for the distant future—the possibility of engineering genetic exchanges so as to produce bacteria with particular desired genetic makeup. More immediately, it provided methods for studying gene function by making possible the isolation of particular genes, and thus made possible the study of their biochemical effects. It also provided the basis for understanding the mechanism of viral and bacterial disease in animals and plants, since in many cases viral genes become incorporated into host cell DNA, producing long-term, even hereditary, effects. Indeed, much of the subsequent work in the development of molecular biology in the 1950s and 1960s was based on the methods developed by Lederberg and his associates. With George W. Beadle and Edward L. Tatum, Lederberg shared the 1958 Nobel Prize in physiology or medicine for, in the words of the committee, "his discoveries concerning genetic recombination and the organization of the genetic material of bacteria." Lederberg's work in genetics eventually proved to be one of the foundations of gene mapping which eventually led to efforts to genetically treat disease and identify those at risk of developing certain diseases.

In addition to his outstanding contributions as a laboratory scientist and technician Lederberg was also concerned about the role of science in society and the far reaching effects of genetics research. He saw that the biological revolution was a "philosophical one" that was to bring new depth of scientific understanding about the nature of life. He foresaw scientific advancements in the treatment of cancer, organ transplants and geriatric medicine developing into a whole new set of ethical and social problems.

After divorcing his first wife, Lederberg married Marguerite Stein Kirsh in 1968 with whom he had two children, a daughter and son. While Lederberg was made very aware throughout his life of the stiffness of personal competition, he remained firm in his belief that scientific discoveries, no matter how slight, were beneficial to the world. "The shared interests of scientists in the pursuit of a universal truth," Lederberg said in The Excitement and Fascination of Science, "remain among the rare bonds that can transcend bitter personal, national, ethnic, and sectarian rivalries." He was a member of the National Academy of Sciences, the Royal Society, London, and has received eleven honorary degrees. Lederberg still considered chemical and biological weapons to be a matter of the gravest concern in today's society, and provided an extensive scientific consulting service to the United States government, which earned Lederberg the National Medal of Science in 1989. In the summer of 1997, Lederberg was studying the deadly 1918 flu virus, found in preserved tissue, in an attempt to find a vaccine against the disease that killed over 20 million people in Europe alone.

Further Reading

Biographical information on Lederberg may be found in the McGraw-Hill Modern Men of Science (Vol. 1, 1960). A general discussion of the significance of Lederberg's work, in conjunction with that of Beadle and Tatum, is in the New York Times (October 31, 1958). Also available are works by Lederber himself Papers in Microbial Genetics: Bacteria and Bacterial Viruses, University of Wisconsin Press, 1951; Man and his Future, Little, Brown, 1963, pp. 263-273; Health in the World Tomorrow, Third PAHO/WHO lecture on Biomedical sciences, PAHO/WHO Scientific Publications no. 175, 1968, pp. 5-15; The Excitement and Fascination of Science: reflections by Eminent Scientists, Vol. 3, Part 1, Rockefeller University, 1990, pp. 893-915. □