Esther Lederberg: The Invisible Scientist Researching The Unseen

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Esther Lederberg In Wisconsin (1958) ©The Esther M. Zimmer Lederberg Trust.

Esther Lederberg is often regarded as one of the greatest female American microbiologists. She not only pioneered the field of microbial genetics (before DNA was even discovered!), she also discovered 2 vital pieces of information that laid the groundwork for bacterial genetics ultimately changing microbiology and immunology forever! So why haven’t you heard of her? Probably because she was a humble girl married, for the majority of her career, to her male collaborator who took her for granted too many times.

The Life of Esther Lederberg

Esther Lederberg was born on December 18, 1922, a product of David Zimmer and Pauline Geller Zimmer who were immigrants from the Austro-Hungarian Empire. They settled in the Bronx, New York in the United States, where David found work in textiles (keep this in mind as it will become important later on in our story).

Her early years were during the roaring ‘20s; Babe Ruth was hitting home runs for the Yankees, the speakeasies were in full swing and Charleston was all the rage. Esther would be too young to ever become a flapper and, instead, spent the majority of her childhood living through the Great Depression. Even from an early age, Esther was always challenging herself in different ways like learning Hebrew from her grandfather in the Bronx, New York.

When she decided to pursue a degree in biochemistry. Her teachers at Hunter College were mortified. A degree in biochemistry was “too difficult for women” in their eyes. They tried very hard to convince her not to study biochemistry. Most women of the time were expected to pursue degrees in French or Literature, but Esther decided to pursue her passion; she went and studied biochemistry. Her hard work began to pay off when she won a fellowship to obtain a master’s degree in Genetics from Stanford University. Like so many other aspiring researchers, the fellowship was not enough to pay the bills and she not only had to become a teaching assistant but also had to wash her land lady’s clothes to make rent. Esther even recalls having to eat frog legs from the anatomy dissection rooms a few times so she wouldn’t go hungry. I highly doubt these were prepared like the French dish!

One day a dashing young man sent Esther a love letter….well not really. It was a letter about her research on Neurospora (which is a fungus). And come on ladies, is there anything sexier than a man courting you with science and validating your intelligence?! Esther thought so, and she married Joshua Lederberg 5 months after receiving that letter.

Esther and her husband Joshua Lederberg moved to the University of Wisconsin where Esther would get her Ph.D. And so began a long-term relationship in marriage, science, and collaboration.

Lambda Phage, Replicate Plating, And Bacterial Sex

Throughout their relationship, Joshua was known for his big ideas while Esther was known for her exquisite experimental design and techniques. For a while, it was a perfect partnership and led to Esther Lederberg playing a crucial role in 3 major discoveries in microbial genetics.

1. Lambda Phage - An ‘enduring symbiosis’ virus

The first would be the discovery of the lambda phage. Lambda phage is not someone pledging to a fraternity, but a bacterial virus. Bacteria viruses come in several basic shapes: one that looks like a worm (filamentous), one that looks like a 20 sided dice for those that enjoy some tabletop games (icosahedral), and one with a tail and little legs which makes it looks like some sort of space spider, looking at you Mando (this is what a Lambda phage is).

But back to Esther's discovery, she found that this virus was able to take its DNA and put it into the bacteria’s DNA. This allows the viral DNA to be present in the bacteria as it replicates. The viral DNA will lie dormant until conditions are no longer favorable. This dormancy is due to a protein the virus makes that prevents the rest of its genes from becoming active.

These viral genes become active when a stressor (ex. ultraviolet light) affects the bacteria. In response to the stress, the viral DNA pops out of the bacterial DNA, causing many viruses to be made. Sometimes though, the viral DNA will accidentally take some bacterial DNA with it which will then be inserted into a different bacterium’s genome when that virus infects it (this could be something that could give the bacteria resistance to antibiotics!). This was all discovered because Esther spotted an irregularity in a few E. coli colonies. The lambda phage has become an important tool in learning about how genes are controlled and the exchange of DNA between organisms.

2. Replica Plating - The Bacterial Stamp

The second groundbreaking discovery made by Esther was replica plating. When working with microbial genetics, it is sometimes necessary to screen thousands of microbial colonies for a particular trait due to the bacterial colonies either gaining or losing a particular gene/function. At one point this was done by carefully picking up a single colony and placing it on a new media plate with some sort of selective force that only a bacteria with the desired trait can grow on (either an antibiotic or the absence of a nutrient). There is actually a very low rate for microbes to pick up and incorporate DNA into their genome, so microbiologists would have to repeat this task hundreds, or thousands of times to find the few successful microbes. Coming from a family of textile workers (see I told you it was important), Esther thought of velvet. This material was not smooth and the little fibers would act as 100s of tiny inoculating needles making her able to quickly and accurately screen thousands of colonies for the desired trait in just one action.

This method she developed works like a stamp; you take the velvet and press it on the “master plate” that has all the bacterial colonies. You then press it, in succession, onto 3 plates: general media (everything should grow), selective (like antibiotic- only microbes with desired traits will grow), and another general media with the last as a control to make sure you are not losing the microbes by accident during the stamping process. By comparing the plates you can now tell which ones have the phenotype you are looking for. This simple process streamlined bacterial genetics and would save countless microbiologists hours or even days of work, even to this day!

3. Fertility Factor - Bacterial Sex

Her final contribution to science was in bacterial sex. Now, bacteria don’t have sex like humans or animals. They do not combine two individual genomes into a third unique individual. Rather, they are capable of passing or sharing genes from one bacterium to another. One bacterium can be like “What if I was to tell you I have this gene that protects you against antibiotics. Is that something you might be interested in?” And the other bacterium says “Yeah, I think I would.” So they seal the deal in a handshake, except their hands are called pili, and the deal is called a horizontal gene transfer.

Esther identified what she called the fertility factor, or the f-factor, which are genes that can be transferred between bacteria. Bacteria are categorized as either F+ (male), or F- (female) and the f-factor allows the “males” to connect to the “female” (remember that handshake). The male can then transfer these genes, which can include antibiotic resistance, to the female which now has “become” a male and the cycle continues. This was the start of understanding horizontal gene transfer between bacteria and the first time anyone proved that bacteria do not create exact clones of themselves.

Nobel Prize and Legacy

Esther Lederberg and Joshua Lederberg at the Nobel Prize award ceremony ©The Esther M. Zimmer Lederberg Trust.

Esther had worked with Alexander Hollaender and Milislav Demerec in the US public health services (PHS) in trying to increase penicillin production. She would also work with George W. Beadle, Edward Tatum, and her husband at Stanford University on researching gene regulation. Her husband, Joshua, would become the head of the department of genetics at Stanford. She’s connected to so many microbe moments that revolutionized microbiology in the 20th century, yet she was not regarded as a significant scientist in her time.

Joshua Lederberg, George W. Beadle, and Edward Tatum would receive the Nobel Prize in 1958 for “their discovery that genes act by regulating definite chemical events” and “discoveries concerning genetic recombination and the organization of the genetic material of bacteria”. These men won a Nobel Prize in 1958 for their (& Esther’s) work.

You would think, “after all this Esther would have gotten a Nobel Prize? A tenure track position? Anything?!” Unfortunately, she was always viewed as a lab assistant, capable of following orders from her male collaborators. Now, with any prize, there are always a handful of people who help the recipient rise to stardom but are largely unrecognized during award ceremonies. But Esther played more than a supporting role in the discovery that led to the Nobel Prize.

She collaborated with Joshua for 10 years, made the lambda phage discovery, invented replica plating, and helped identify the ‘f-factor’. Yet, at the Nobel Prize ceremony, she got all dolled up to sit on the stage, watching the men take all the credit for what they collectively built. As a final blow to Esther, Joshua made two Nobel Prize speeches, neither addressed his wife by name nor acknowledged her contributions to the project.

By 1966, Esther and Joshua were divorced and she struggled to keep her job at Stanford after her affiliation with Joshua was over. She eventually did get a faculty position, but this was a non-tenured track position. She would end up leaving this position to found the Plasmid Reference Center as well as being the director until her retirement in 1985. Throughout her life, she published over 20 papers, and 50 academic works including conferences, abstracts, and proposals.

I like to think that Esther still got her happily ever after. She found love again and remarried when she was 70 to Matthew Simon. The two of them shared a love for baroque and renaissance music. Esther Lederberg died November 11, 2006, from pneumonia and congestive heart failure. She was 83 years old. Her husband Matthew Simon even created a website in her honor!

But her legacy lives on and a lot of that has to do with her supportive husband Matthew Simon! But we also use so many of her techniques in the labs today! The lambda system is still very much used as one of the tools to modify E. coli. There are different ways (one still using the virus, cool!) to use this system, but all use the virus’s DNA to add or remove a gene or genes from the bacteria's genome. So, if you take a genetics class, or go into a bacterial research lab, it is likely you will at least learn about this useful tool and, if you do, make sure to thank Esther for it!

What do you think? Was Esther’s contributions great enough to have received the Nobel Prize?