Esther Lederberg and the Rise of Microbial Genetics

Oct. 4, 2023

A young E. Lederberg peering through a microscope.
Source: Esther M. Zimmer Lederberg Memorial Website
Anyone who has dipped a toe into the study of bacterial genetics has encountered the work of Esther Lederberg, M.S., Ph.D. (1922-2006), even if they are not aware of it. Her discoveries were central to understanding bacterial gene regulation, recombination and exchange—though you may have a hard time finding a textbook that acknowledges this.

This lack of awareness and recognition is as much a part of Lederberg’s legacy as her scientific contributions. For much of her career, she was snubbed from receiving the professional recognition bestowed upon men whose achievements were intermixed with her own. Nevertheless, through the work of those who knew Lederberg—and those who are just uncovering her story—her legacy is being brought out of the shadows.

Scientific Beginnings

Born and raised in New York City, Lederberg was an avid learner. She had a penchant for studying languages and, as a student at Hunter College in Manhattan, it seemed like a no-brainer that she would pursue language and literature. Instead, Lederberg opted to follow her interest in science and study biochemistry. Her teachers warned her that doing so would lead to career dead ends (she was a woman, after all), yet Lederberg continued down her scientific path. She earned a master’s degree in genetics in 1946 at Stanford University under the tutelage of renowned geneticists Edward Tatum, Ph.D. and George Beadle, Ph.D. 

Shortly before graduating, E. Lederberg met and married Joshua Lederberg, Ph.D., known for, among other things, discovering “a sexual process” in bacteria (i.e., conjugation) in which genetic information (DNA) is directly transferred from a donor to recipient cell. This marriage would have important ramifications for the legacies of both J. and E. Lederberg—often boosting his while obscuring hers.

Lederberg Found a Little Lambda

J. and E. Lederberg standing behind stacks of petri dishes.
J. and E. Lederberg in the lab.
Source: Esther M. Zimmer Lederberg Memorial Website
After their marriage, the Lederbergs moved to the University of Wisconsin-Madison, where J. Lederberg was hired as a professor and E. Lederberg would earn a Ph.D. in 1950. It was during this time that she made some of her most pivotal scientific discoveries. Her first: uncovering lambda phage from cultures of Escherichia coli. This phage (i.e., a virus that infects bacteria) became foundational for understanding bacterial gene regulation and recombination, as well as advancing the broader field of molecular genetics. But what made it so special?

At the time, scientists were already aware that phages destroyed bacteria by lysis. Lambda, E. Lederberg found, was different—it was not only lytic, but also lysogenic. That is, the virus integrates into the host cell genome without killing it; in certain conditions this “prophage” is excised from the genome, leading to production of viral particles and cell lysis. Before E. Lederberg’s work, this 2-part cycle had never been described before—now, lambda is a key model for studying other viruses that exhibit similar lytic-lysogenic life cycles (e.g., herpes simplex virus). J. Lederberg encouraged E. Lederberg to hold off publishing about lambda until she completed her graduate work. As such, she reported on the phage in a brief abstract published in 1951, then more extensively in a paper co-authored by her husband in 1953.

Experiments with lambda paved the way for additional discoveries by E. Lederberg, including the plasmid named bacterial fertility factor (F), which plays a key role in bacterial conjugation. Other findings she reported on with colleagues included transduction, a process whereby host genes are excised along with a prophage during phage replication and production. Those genes are then transferred to a new bacterial cell during phage infection, thus facilitating genetic recombination among bacteria. 

An electron micrograph image of lambda phage.
Source: H.W. Ackermann/Wikimedia Commons
E. Lederberg’s experiments also motivated her development and optimization of replica plating, a revolutionary method for screening thousands of bacterial colonies for diverse phenotypes. The technique involves pressing a sterile velvet cloth onto a plate with bacterial growth and stamping it onto a selective plate (e.g., containing antibiotics), thus maintaining the spatial organization of colonies. Replica plating allowed the Lederbergs to "pound the final nail in the coffin of Lamarckism” (i.e., the idea that genetic traits change in response to the environment), noted Rebecca Ferrell, Ph.D., a professor at Metropolitan State University of Denver who wrote about E. Lederberg for the ASM Press book, Women in Microbiology. They experimentally confirmed that traits like phage or antibiotic resistance don’t develop in response to a specific environmental pressure. Rather, mutation is a random process that can impart some adaptive advantage to an organism under certain circumstances—in other words, adaptive evolution is not a thing.

E. Lederberg reported on replica plating with J. Lederberg. But, according to Ferrell, “that wasn't [J. Lederberg]. No, that was the lady with the knowledge of fabric, [who had been] watching printing presses since she was born,” she said, alluding to the printing press E. Lederberg’s father owned. Yet, “if you go into most microbiology textbooks, [replica plating and the associated discoveries] are credited to [J. Lederberg]."

The lack of—and debate surrounding—the credit E. Lederberg received for her work is a common throughline in her story, especially as it relates to J. Lederberg. Perhaps the most poignant example took place in 1958.

The Nobel Laureate's Wife

That year, J. Lederberg won the Nobel Prize in Physiology or Medicine for his work on genetic recombination in bacteria; the prize was split with Beadle and Tatum for their genetic studies on the mold, Neospora. E. Lederberg, whose work was integral for and/or intermingled with that of her husband, was not included. “There are a couple of photos of the day that the phone calls went out from Stockholm,” Ferrell said. “And she does not look like somebody who's thrilled that this is all going on. It [had] to have been hard.”

E. Lederberg sitting on a stoop next to a large bouquet of roses. She is half-smiling.
E. Lederberg on the day the 1958 Nobel Prizes were announced; the roses mark the occasion.
Source: Esther M. Zimmer Lederberg Memorial Website
For her part, E. Lederberg was relegated to the position of a Nobel laureate’s wife. Her job: don a dress and sit in the audience as J. Lederberg took to the stage to accept his award. He recognized his wife’s “companionship,” with a brief nod to her discovery of lambda phage.

Still, according to Stanley Falkow, Ph.D., who passed away in 2018 and is widely considered the father of the field of microbial pathogenesis, E. Lederberg’s “independent seminal contributions in [J. Lederberg’s] laboratory…surely led, in part, to his Nobel Prize.” The Lederbergs were, for all intents and purposes, a team. While J. Lederberg is often considered the “big thinker” of the duo, E. Lederberg (who no doubt had big thoughts of her own) made the science happen with her notable experimental acumen.

The prestige boost from the Nobel ultimately propelled J. Lederberg to Chair of the Genetics Department at Stanford University; E. Lederberg once again followed and was given a senior scientist position that morphed into a research professorship without tenure (a status not routinely granted to women at the time). She would never be given tenure during her 20-plus years at the institution. In some ways, her teachers at Hunter College were right—being a woman in science, while not necessarily leading to career dead ends, had its fair share of obstacles.

These days, one might ask: why didn’t E. Lederberg stand up for herself? The answer may be, “because smart girls knew what would happen if they did,” Ferrell said. “There weren’t imaginary consequences,” as this was a time when a woman’s value was tied to her role in the home, as a wife—when, for example, a divorced woman was viewed as “damaged goods.” For Ferrell, “[E. Lederberg’s] story reminds us of how many women over the years have only had access to the ability to do science because of a father or a brother or a husband.” 

And Yet, She Persisted

In true E. Lederberg fashion, however, she remained a vigilant and involved scientist, becoming director of the Plasmid Reference Center at Stanford in 1976. There, she diligently named, organized and distributed plasmids to researchers near and far. Ferrell highlighted that E. Lederberg’s dedication to bringing order to the chaos of discovery was no small feat; the enthusiasm she brought to the task reflected who she was as a person. Mark O. Martin, Ph.D., a professor at Puget Sound University who met and formed a friendship with E. Lederberg as a graduate student at Stanford, similarly described her as welcoming and very funny. Throughout their conversations, he came to learn about her history. “She was fairly direct about the things she was involved with,” he said during a discussion about E. Lederberg at ASM Microbe 2017. He noted that she “did not seem angry or embittered about things that, frankly, I would be angry and embittered about.”  

This tracks with other accounts of E. Lederberg’s attitude later in life. She believed that the science speaks for itself; she would be forgotten anyway, so why worry about something like reputation or credit?

Out of the Shadows

The reason to worry is that it is not uncommon for the accomplishments of women scientists to be lost to history, their work swallowed up by the legacies of men. “This kind of stuff happens now. This is people's lived reality. This is not just kind of a cute antique story from the past,” Ferrell said. 

Overcoming this erasure requires deliberate attempts to link scientific discoveries back to the women who made them—and E. Lederberg’s story is a great place to start.

Over time, those close to E. Lederberg have shone a light on her work. Her second husband (E. and J. Lederberg divorced in 1966), an engineer named Matthew Simon, spent years curating photographs and documents about E. Lederberg’s life and scientific legacy for an extensive memorial website. Articles, books and book chapters have been written about her. Martin noted that he makes sure all his students know who E. Lederberg is and what she did. To that end, she has captured the attention of a new generation of scientists, including Morgane Maniveau, M.S., who selected E. Lederberg as her favorite microbiologist during ASM’s 2022 Agar Art Contest. “As a woman scientist in the 1950s, [E. Lederberg] faced many challenges,” Maniveau said. “So it was with all my enthusiasm that I wanted to honor her."

If there’s anything to take away from E. Lederberg’s legacy, it’s her objectivity and pursuit of science amidst a messy mix of societal expectations and barriers. In a time when girls and women were encouraged to keep their intelligence under wraps, especially in a world of scientific discovery dominated by men, E. Lederberg shone bright. 

“This was a smart girl who didn't hide that she was smart,” Ferrell said. “And it turned out okay.” 

E. Lederberg wearing a white lab coat and smiling at the camera.
E. Lederberg in the lab.
Source: Esther M. Zimmer Lederberg Memorial Website

Like Esther Lederberg, Alice Evans—ASM’s first woman president—made critical contributions to advancing the microbial sciences. Check out this next article to learn about her story.

Author: Madeline Barron, Ph.D.

Madeline Barron, Ph.D.
Madeline Barron, Ph.D. is the Science Communications Specialist at ASM. She obtained her Ph.D. from the University of Michigan in the Department of Microbiology and Immunology.