Joshua Lederberg

American geneticist

• Born: May 23, 1925; Montclair, New Jersey
• Died: February 2, 2008; New York City, New York

Joshua Lederberg discovered that genetic material is exchanged between bacteria by both conjugation and transduction. These discoveries were particularly significant for explaining the spread of antibiotic resistance among bacteria.

Primary field: Biology

Specialties: Genetics; molecular biology

Early Life

Joshua Lederberg was born on May 23, 1925, in Montclair, New Jersey, to Zvi Lederberg, a rabbi, and Esther Schulman. His parents were Palestinian immigrants who had arrived in the United States not long before Lederberg was born. A gifted child, he loved to read and was especially interested in science texts. He was accepted to Stuyvesant High School, an elite public high school for gifted boys in New York City, where the teachers encouraged his interests in biology and experimentation.

After graduating from high school at the age of fifteen, Lederberg moved to the American Institute Science Laboratory, which had a program for youths interested in careers in science. In 1941, he received a scholarship to attend Columbia University; once there, he studied with biochemist Francis Ryan, whose research involved the bread mold Neurospora—the model organism that both Lederberg and the team of George Wells Beadle and Edward Tatum would later use for their Nobel Prize–winning research.

During World War II, Lederberg served in the United States Navy. Instead of sending him into combat, the navy trained him as a medical officer. He worked at St. Albans Naval Hospital on Long Island, where he screened returning servicemen for malaria. Lederberg graduated with honors from Columbia in 1944 and entered the College of Physicians and Surgeons at Columbia University to continue his medical studies. He married Esther Zimmer, a colleague’s research assistant, in 1946.

Life’s Work

In 1946, Lederberg temporarily left medical school to investigate bacterial reproduction in collaboration with Edward Tatum, a geneticist at Yale University. Their discoveries would surprise the scientific community and refute many long-standing assumptions. At the time, it was believed that bacteria reproduced only by binary fission, or splitting; Lederberg discovered that while many bacteria do reproduce this way, some actually exchange genetic information through a process that he termed conjugation.

Conjugation is a one-way transfer of DNA (deoxyribonucleic acid, or the nucleic acids associated with the transfer of genetic information) from donor to recipient, in which a donor cell attaches itself to a recipient and sends a strand of DNA through a hollow tubule called a pilus. Lederberg saw the process as analogous to mating, with the donor cell being the male. He dubbed the reproductive trait the fertility factor, or F for short. So-called male cells were labeled F+, while “female” cells—those lacking the fertility factor—were labeled F-. F- cells can be transformed into F+ cells by receiving a set of genes during conjugation.

Many bacteria have DNA both in their main chromosome and in additional ring-shaped, double-stranded pieces called plasmids. Only the plasmid DNA is transferred during conjugation. In the donor cell, a nick is made in one of the strands of a plasmid, allowing the double helix to unwind. One of the two strands of the plasmid is transported to the recipient cell through the hollow pilus. Two strands of double-stranded DNA are held together by complementary base pairings, so each strand can act as the template for a new partner strand. Each cell can synthesize a new partner for its single strand, so the donor does not lose its plasmid when the recipient gains one.

Lederberg demonstrated the process of conjugation using two different mutants of Escherichia coli bacteria. One mutant could not synthesize the amino acid methionine or the vitamin biotin, but it could survive if its media, or food, was supplemented with these nutrients. The second mutant had a normal ability to synthesize methionine and biotin but lacked the ability to make the amino acids proline and threonine. Conjugation between these mutant strains repaired the damage and allowed newly produced cells to live on regular media. Lederberg submitted his conjugation research as his PhD thesis and received his doctorate from Yale in 1947.

His plan to return to medical school was derailed by an offer of an assistant professorship involving full-time research from the University of Wisconsin. Once there, Lederberg and his wife worked with a team of students in genetics research. Their most exciting discovery was viral transduction. Their experiment involved two different mutant strains of Salmonella typhimurium, each of which was unable to synthesize a different amino acid. The strains were placed in different sections of a glass tube and separated by a filter with pores too small for even bacteria to pass through. Despite the filter, which prevented the mutant cells from making contact with one another, a recombinant strain of Salmonella was born—living proof that the two strains had somehow combined their DNA to repair each other’s deficiencies.

Eventually, Lederberg’s team determined that a bacteriophage (a virus that attacks bacteria) had been in the culture all along. Viruses are too small to be seen under light microscopes. They cannot reproduce on their own, so they hijack the reproductive machinery of other cells, forcing them to make more viruses. Accordingly, bacteriophages insert their DNA into bacteria in order to take over the cells. During this process, the genome (all the DNA) of the virus gets inserted into the chromosome of the bacterial cell, so that when the cell replicates, it copies the virus DNA as well. When the bacteriophage is ready, it can remove itself from the bacterial chromosome and attack a new cell. As enzymes cut the phage DNA out of the bacterial chromosome, errors may occur; a bit of the bacterial DNA on each side can be cut out and taken into the chromosome of the new cell. In this way, viruses can accidentally transfer genes between bacteria. This became one of the first tools of genetic engineering.

From 1958 through 1977, Lederberg was involved with the US space program. Before the moon was discovered to be lifeless, he worried that bacteria from the Earth could contaminate the moon’s ecosystem. His concern about the moon turned out to be unwarranted, but if humans were to visit other planets that harbor life, the threat of cross-contamination would be an issue. Lederberg also sat on the National Academy of Sciences Space Science Board and assisted in the search for microbiological life-forms on Mars.

Lederberg’s marriage to Esther ended in divorce. He remarried in 1968 to physician Marguerite Stein Kirsch and became the stepfather of her son, David. The two also had a daughter, Anne. Lederberg died in February 2008 after a struggle with pneumonia.

Impact

For his early research on transduction, Lederberg is considered one of the primary founders of the field of genetic engineering. Throughout his career, he turned his intellect to an array of interests, from public health and artificial intelligence to space life sciences. He was also interested in epidemiology, particularly new and emerging diseases. At Stanford University, Lederberg assembled an undergraduate curriculum in biology and continued to conduct leading research in genetics. He made important breakthroughs in the use of computers in laboratory research, as well as automated equipment for space research. In addition, as an advisor to the US government on issues of science, Lederberg offered counsel to a number of administrations and policies regarding national security and biological warfare. He reported in 2005 that his research interests had turned to determining the fastest rate at which a bacterial cell can multiply.

Lederberg’s work on conjugation remains relevant because of the information carried on bacterial plasmids. The main chromosome of the bacterial cell holds information needed for daily life; plasmids carry additional information, such as the ability to utilize unusual substances for food or the ability to resist antibiotics—the latter of which is a growing problem, as bacteria can rapidly become resistant to antibiotic drugs that take scientists years to develop. When one cell develops a resistance to a new antibiotic, that trait can then spread through the bacteria population by conjugation.

Lederberg received his greatest honor in 1958, when, in recognition of his work on bacterial genetics, he shared the Nobel Prize in Physiology or Medicine with Edward Tatum and George Wells Beadle.

Bibliography

IOM (Institute of Medicine). Microbial Evolution and Co-Adaptation: A Tribute to the Life and Scientific Legacies of Joshua Lederberg. Washington, DC: National Academies, 2009. Print. Summarizes the views represented and the papers presented at a special public workshop of the Forum on Microbial Threats in honor of Lederberg. Covers Lederberg’s career as well as issues relating to antibiotic resistance, infectious diseases, and pathogenic evolution.

Lederberg, Joshua, ed. Biological Weapons: Limiting the Threat. Cambridge, MA: Belfer Center, 1999. Print. Compiles chapters from a variety of specialists on topics of biological warfare. Includes an introduction by Lederberg.

Smolinski, Mark S., Margaret A. Hamburg, and Joshua Lederberg, eds. Microbial Threats to Health: Emergence, Detection, and Response. Washington, DC: National Academies, 2003. Print. Evaluates the threat of microbial pathogens to national security and the state of current knowledge and policy. Includes an extensive section devoted to preventative and defensive recommendations.