Joshua Lederberg
Pioneer of microbial genetics: Joshua Lederberg (1925-)
by King-Thom Chung, Department of Biology, The University of Memphis
Joshua Lederberg was awarded the 1958 Nobel Prize in medicine and physiology for his discovery of "sexual recombination" in bacteria (bacterial conjugation). This award was shared with Drs. George Wells Beadle (1903-1989) (1) and Edward Lawrie Tatum (1909-1975) (3). Conjugation is mediated by the presence of the F+ factor (fertility factor or plasmid) and requires cell to cell contact. The plasmid can reside inside the donor bacterium as an extrachromosomal element with its own origin of replication or it can be integrated into the bacterial chromosome. When integrated in the chromosome, replicative transfer begins within the F plasmid region at the oriT region and continues into the chromosomal region. Thus the chromosomal genes as well as F plasmid genes are transferred to the recipient cell during conjugation. Via a process of recombination (Hfr high frequency recombination), the newly acquired DNA is incorporated into the recipient’s chromosome and the recipient cell in turn becomes a donor cell provided an intact F plasmid is present. When the plasmid DNA is maintained as an extrachromosomal element, the F plasmids transferred at a high frequency. Dr. Lederberg made the distinction between Hfr and F+ and coined the term plasmid in 1950 to describe extrachromosomal genetic elements. However, the term was not widely accepted until the 1970s when bacterial drug resistance was shown to be mediated by self-transmissible plasmids and became a major medical problem.
Joshua Lederberg was born on May 23, 1925, in Montclair, New Jersey. His father was called Zwi H. Lederberg, an orthodox Jewish rabbi, and his mother Esther Goldenbaum, a housewife; both of them immigrated from Israel in 1924. They moved to New York City when Joshua was only 6 months old and the settled in the Washington Heights neighborhood. Joshua spoke proudly of his parents; he considered his father an idealistic person and his mother "a heroic soul" who had to work extremely hard to keep the family together during his father’s prolonged illness. Joshua has two brothers. One of them, Seymore, is a professor of biology at Brown University. The other brother, 16 years younger, lives in Jerusalem and is with the Lubaviche rabbi’s group of the Hassidem.
The young Joshua was a "precocious youngster" who developed a keen interest in science as early as 6 or 7 years of age. This interest was inspired as a result of "sublimation of his father’s and family traditions, religious impulses, but within a secular framework" as described by Dr. Lederberg at a later day. Young Joshua was an extremely intelligent, active, inquisitive, and optimistic person with a strong desire to learn. Later, he developed an analytical mind that gave him the power to look at subject matter with an unusual insight and an amazing capability for innovative thought. This could be seen during his early school days when he constantly confronted his teachers with questions that they could not answer. This was so annoying to some of the teachers that they made a deal with him: "if you (Joshua) do not ask too many disruptive questions, you can sit and do your own work in the back of the classroom." He began to read Bodansky’s Introduction to Physiological Chemistry at the age of 11, which impacted his scientific development greatly.
He attended Stuyvesant High School (a high school for budding Nobelists) and graduated with top grades in 1941. Young Joshua was an avid reader of science books during his high school years. Among the books he read were Eddington and Jeans’ Physics, Jaffe’s Crucibles in Chemistry, and Wells, Huxley & Wells encyclopedia The Science of Life. The popular culture in those days that idealized scientists with novels and movies like Arrow-Smith, The Magic Bullet, The Life of Louis Pasteur, and The Symphony of Six Million also inspired this young man’s desire for a career in medical research.
Joshua then enrolled at the nearby Columbia College as a student of the premedical curriculum, the main reason for enrollment being that he had obtained a scholarship. He worked as a laboratory assistant to Professor Francis J. Ryan (1916-1963) of the Zoology Department and helped to conduct experiments on the mutation and adaptation of the bread mold, Neurospora.
Professor Ryan had a great influence on Lederberg and went far beyond his duty to encourage Joshua. Ryan became his life-long mentor.
Joshua obtained his bachelor’s degree with honors in 1944. He continued his education at the College of Physicians and Surgeons at Columbia University while working for Professor Ryan. In 1944, he read papers published by Oswald T. Avery (1877-1955), Colin Mac Leod (1909-1972), and Maclyn McCarty (1911-) and learned that deoxyribonucleic acid (DNA) was the genetic material. These papers inspired Joshua greatly. In 1946, with Professor Ryan’s encouragement, he was able to work for three months with Dr. Edward L. Tatum at Yale University. His research with Dr. Tatum was so interesting that he never went back to Columbia. Instead, he continued his graduate studies with Dr. Tatum.
At Yale University, Joshua Lederberg and Dr. Tatum studied the reproduction of E. coli and discovered that certain strains of E. coli possessed the mechanism for transfer of genetic material with subsequent recombination in the recipient host. Lederberg showed that genetic material was exchanged by conjugation, a process by which cell to cell contact is required and which may result in the transfer of an entire complement of the bacterial chromosome.
In 1947, Joshua received his Ph.D. degree in Microbiology from Yale University and accepted an appointment as an assistant professor and in 1954, to the rank of full professor at the age of 29. In 1957, Joshua organized the department of medical genetics and served as its first chairman. In the same year, Dr. Lederberg was a Fulbright Visiting Professor of Bacteriology in the laboratory of the eminent immunologist Sir Frank MacFarland Burnet (1899-1985) (2) at Melbourne University in Australia.
Upon his return to the University of Wisconsin, Dr. Lederberg was involved in research projects involving bacterial genetics. He had two great associates; one was his wife, Esther Marilyn Lederberg. They had met and married in 1946 when both of them had served as assistants to Dr. Tatum. Esther had obtained a bachelor’s degree from Hunter College, a master’s degree from Stanford University, and her Ph.D. from the University of Wisconsin where she also had received a United States Public Health Service Fellowship for research. In 1956, Joshua and Esther Lederberg were named joint recipients of the Pasteur Award of the Society of Illinois Bacteriologists.
Esther Lederberg helped in the development of the technique of replica plating in 1952. This technique was essential in the study of bacterial genetics, more specifically in the selection of mutants from among hundreds and hundreds of bacterial colonies on a plate. Joshua and Ester devised sterile velveteen pads that facilitate picking up a few bacteria from each colony. In their original replica plating studies, organisms from a liquid culture were evenly spread on an agar plate and allowed to grow for 4 to 5 hours. Then sterile velveteen pads were gently pressed against the surface of the plate to pick up organisms from each colony. The tiny fibers of velveteen act like hundreds of tiny inoculating needles. The pad was carefully kept in the same orientation and used to inoculate a series of agar plates containing different media supplemented with essential nutrients such as amino acids and vitamins. Esther and Joshua used this technique as an indirect selective method to prove the spontaneous origin of mutants with adaptive advantages. This is a significant contribution to the process of microbial genetics. The technique of replica plating is still widely used in genetic laboratories today.
Another contribution Esther provided to the Lederberg laboratory was her discovery of lambda-phage (l -phage) in E. coli in 1953 and her initial observation of F factor, at a time during which Joshua and Esther exemplified the importance of team work.
Joshua Lederberg’s other great assistant at the University of Wisconsin was Norton D. Zinder (1928-), then a doctoral candidate. Dr. Zinder, now at the Rockefeller University, also became a great bacterial geneticist. Between 1951 to 1952, Joshua Lederberg and Zinder together discovered that bacterial viruses could carry hereditary material from one cell to another by transduction. This is accomplished as follows. After a virus has absorbed to a host cell and caused lysis of a bacterium with the release of some 100 copies of phage particles, occasionally a bacterial gene(s) is packaged into the head of the viral particle. When this "defective" phage particle starts the infection over again, the bacterial gene is transferred into the new host bacterium with subsequent incorporation into the chromosome via recombination.
In 1959, the Lederbergs moved to Stanford University where Joshua assumed the chairmanship of the newly created department of genetics in the medical school. Unfortunately, Joshua and Esther’s marriage did not last. They were separated in 1966.
Joshua remarried in 1968 to Marguerite, who was an attending psychiatrist at the hospital. She was born in Paris and was hidden as a child during World War II in Southern France. She came to the United States after the war. Dr. Lederberg has one daughter born in 1974. Marguerite also has a son David Kirsch who was born in 1964 from her first marriage.
Dr. Lederberg enjoyed working in the environment of the Stanford medical school because he could relate genetics to a wider context of human health and biology, particularly neurobiology and mental illness. He oversaw a large and diverse research group and helped institute a human biology curriculum for undergraduates. He was also interested in computer sciences. He formed a collaboration with Dr. Edward Feigenbaum, chairman of computer science at Stanford, Professor Bruce Buchnan, computer scientist, and Dr. Carl Djerassi (1923-) professor of chemistry. Together, they created DENDRAL, a computer program to generate structures of organic molecules and to explore how molecules exist in nature. In 1974, with support from the National Institute of Health, they established Stanford University Medical Experimental Computer (SUMEX) to provide hardware for research projects all over the country.
Additionally, he was interested in extracurricular activities. He served as a panel member for the President’s Science Advisory Committee. He served on President John F. Kennedy’s Panel on Mental Retardation and directed research on the genetics, development, and neurobiology of retardation at the Kennedy Laboratories for Molecular Genetics at Stanford University.
Since 1957, Dr. Lederberg has also been concerned with the contamination of the moon by lunar rockets. He and biophysicist Dr. Dean B. Cowie (1913-1977) from the Carnegie Institute of Washington were seriously concerned about the use of earth satellites for moon missions. They were particularly concerned that non-sterile rockets reaching the moon could destroy or distort the picture of potential biochemical evolution of life on the moon. As a consequence, Dr. Lederberg served on the National Academy of Science’s committee for the space biology program from 1958 to 1977, and on the National Aeronautics and Space Administration’s (NASA) lunar and planetary missions from 1960 to 1971.
Dr. Lederberg was a great advocate for having a public well informed about science issues. In 1966, he initiated and wrote a weekly column for The Washington Post over a period of six years. He commented on everything from gene cloning, to manipulating weather, science ethics, education, the environment, the history of medicine and the state of science reporting itself.
In 1978, Lederberg was appointed President of the Rockefeller University, New York City. This brought him back to the place where he grew up. During his administration, he built many new laboratories and renovated old ones. Research projects conducted at most of these laboratories concentrated on biomedical investigations and lean heavily on the insight and methods of molecular biology. He also established the Howard Hughes Medical Institute. He added new university apartment buildings and residences for scholars from around the world. The university’s thrust was expanded to include research in such areas as heart disease, cancer, mental and neurological illnesses, and infectious diseases, including diseases of the Third World.
In 1989, Dr. Lederberg retired from administration, but he still keeps an active research program and remains involved in public affairs. His current research interest is to find out how mutagenesis varies with the conformational changes that DNA undergoes during the cell cycle or under the conditions of transcription. As a member of the National Academy of Science Committee on International Security and Arms Control, he maintains his participation in public activities. He is deeply concerned about the threats to humanity from naturally emerging viruses. In addition, as co-chairman of the Carnegies Corporation’s blue-ribbon commission he advises federal and state governments on issues of science and technology. He is also an adjunct professor at his alma mater, Columbia University, and serves as a mentor to undergraduate students.
Dr. Lederberg has been the recipient of many awards, most notably the Eli Lilly award in 1953 for being an outstanding youth bacteriologist at the annual meeting of the Society of American Bacteriologists (now called the American Society for Microbiology) in San Francisco; the Nobel Prize in Medicine and Physiology in 1958; and in 1989 he received the National Medal of Science, the nation’s highest scientific award.
As a multitalented man of wisdom, Dr. Lederberg is considered the father of microbial genetics. His insight, compassion, motivation, integrity and scores of other wonderful qualities make him a shining star and role model for many scientists. This author has been fortunate to have had the opportunity of meeting him at a scientific meeting. Before then, Dr. Lederberg was just a legendary figure in textbooks. With Dr. Lederberg actively involved in public appearances, it seems highly likely that many more individuals will have a chance to personally meet this legendary figure.
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