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Esther Lederberg, 83; helped unlock mysteries of bacteria and viruses

November 30, 2006|Thomas H. Maugh II | Times Staff Writer

Esther Lederberg, the pioneering microbial geneticist whose crucial discoveries were overshadowed by those of her Nobel Prize-winning husband, Joshua Lederberg, died Nov. 11 at Stanford Hospital of pneumonia and congestive heart failure. She was 83.

She discovered the lambda phage, a parasite of bacteria that became a key tool for the laboratory study of viruses and genetics, and was the co-developer with her husband of replica plating, a technique for rapid screening of bacteria for desired mutations.

"She developed lab procedures that all of us have used in research," said cancer researcher Stanley Falkow of the Stanford University School of Medicine.

She was also a pioneer of women's rights, becoming a full professor at a time when women were rare on the faculties of Stanford and other major universities. "She was a real legend," said Dr. Lucy Tompkins of Stanford.

A phage is a virus that infects only bacteria. Before Esther Lederberg's work, the only known phages were so-called lytic phages that invade the bacterium, multiply rapidly and kill the host.

As a graduate student at the University of Wisconsin in 1950, she accidentally discovered the lambda phage -- the first known "temperate" phage. Temperate phages invade bacteria, but they insinuate themselves into the host's DNA where they can persist as long as the cell is alive. The genetic information is stored in rings of DNA called plasmids.

Only when the cell is stressed, such as by a lack of nutrients, does the phage replicate, killing the host bacterium.

She was growing the common bacterium Escherichia coli in petri dishes when she noticed that some colonies had a "nibbled" appearance, like something had been chewing on them. Puzzled, she retrieved material from the gaps and found that it could produce the same phenomenon in other bacteria. The retrieved material proved to be the lambda phage.

The lambda phage became a laboratory model for more complicated animal viruses that have a similar life cycle, including some tumor viruses and herpes virus.

She laid the groundwork for demonstrating how phages can transfer genes between bacteria, and her findings were crucial to advancing the understanding of how genes are regulated, how pieces of DNA break apart and recombine to make new genes, and how the process of making RNA from DNA is started and stopped.

Building on her work, Joshua Lederberg won the 1958 Nobel Prize for Physiology or Medicine for his discoveries on how bacteria swap genes.

The couple working together also developed the technique known as replica plating.

Before their work, screening bacteria for a desired mutation was a straightforward but tedious procedure that might involve testing as many as 10,000 individual bacteria colonies. Their procedure had the simplicity of a rubber stamp.

Colonies of bacteria are typically grown in a petri dish or "plate" holding a medium that contains everything needed for their growth. The Lederbergs discovered that they could place a piece of velvet on the original plate, then place it on other sterile plates to transfer bacteria from each colony.

If such a replica plate lacks a nutrient critical for the bacterium's growth, only mutants able to make the nutrient themselves will flourish. Alternatively, if the replica plate contains an antibiotic, then only those colonies resistant to it will flourish. The original antibiotic-sensitive bacterium can then be isolated from the original plate.

The discovery not only provided a rapid way to identify mutants, but it also proved that the mutations, such as antibiotic resistance, were already present in the original colonies and were not, as many scientists believed, developed upon exposure to the antibiotic.

Although the team eventually settled on sterile velvet cloth for the transfer, the original experiments were performed using the makeup applicator from Esther's compact.

In her later years, Esther Lederberg was a seemingly limitless repository of information about the bacteria and phage strains she worked with, according to biochemist Dale Kaiser of Stanford.

Countless researchers worldwide reaped the benefits of her methodical records and near-photographic memory of the details of her strains, he said. From 1976 to 1986, she directed the Plasmid Reference Center at Stanford -- a repository of genetic information about phage genes.

She retired in 1985.

Esther Miriam Zimmer was born to a poor family in the Bronx, N.Y., on Dec. 18, 1922. She enrolled at Hunter College of the City University of New York, intending to study French or literature. But to the horror of her instructors, who thought science was for men only, she got diverted to biochemistry and received her bachelor's degree in 1942.

She then went to Stanford to study genetics. She became a teaching assistant but was still so pressed for money, she later told her husband, that she took the frogs that were dissected in the lab and ate their legs for dinner.

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