December 2012

The road well traveled together

A joint “Reflections” by Leonore and Leonard Herzenberg

The wedding of Leonore and Leonard Herzenberg 
Lee Herzenberg recalls fondly the purchase of her wedding dress. She bought it for $10 off a sample rack in a shop on New York’s 14th Street. “It was a tiny size but could have been made to order for me except for being too long,” she says. “I made the headdress and veil myself by salvaging applique flowers from the part we cut off the hem. Money was in short supply in those days.”

Sometimes the road not taken intersects with the road you are on.

In their joint “Reflections” article in The Journal of Biological Chemistry, “Our NIH Years: A Confluence of Beginnings,” Leonore and Leonard Herzenberg describe their scientific journey from the laboratory of Nobel laureate Jacques Monod in Paris in 1957 to the National Institutes of Health in 1959 and finally to a joint laboratory at Stanford University School of Medicine, where they have been for more than 50 years.

Their formative years at the NIH turned out to be an important stop on their journey. Leonard Herzenberg, who goes by Len, remarks, “I am continually aware of how valuable my NIH roots really are.”

The couple’s “Reflections” article begins with an unexpected plot twist. Leonore Herzenberg, who goes by Lee, describes finally starting to feel that their life was stable: finding appropriate child care and enjoying what they thought would be a long-term appointment in Monod’s laboratory in Paris studying transcriptional regulation and the LacZ operon.

One day, they received a letter that had been mailed to Len’s former address. As a result, it was four months late. This important and very tardy letter was calling Len to report to service in the U.S. Army! The couple thought because he was doing a fellowship overseas, he would be exempt from being drafted until its completion. This was not the case. “There was no appeal at this point. Len was a fugitive, plain and simple,” Lee writes.

Monod was able to pull a few strings and set up Len to join the laboratory of Harry Eagle at the NIH as a Public Health Service appointee. The couple returned to the United States, and Len “was on his way to a new life and career ‘carrying a pipette for his country’ at the NIH (instead of carrying a gun in the army).”

The Eagle lab was at the forefront of mammalian cell culture and was the first to develop the proper media and growth conditions to cultivate, most famously, HeLa cells as well as other tumor-derived cells. This work eventually led to the President’s National Medal of Science for Eagle.

When Len joined the lab, he helped improve growth conditions for different kinds of cells. This work later led to one of his greatest accomplishments: the development of the fluorescence-activated cell sorter, or FACS, for which Herzenberg won the Kyoto Prize in 2006.

FACS is an automated cell-sorting system that allows separation of different cell types from a heterogeneous cell mixture. The cells are sorted one at a time and quantitated based on the light-scattering and fluorescence characteristics of each particular cell. This has been a powerful tool in the field of immunology and cancer biology. While Len’s place at the Eagle lab had been prearranged, Lee wasn’t so sure what the next step was for her. She writes, “NIH was not so welcoming for husband-wife teams … I was basically cut adrift.” Luckily, Bruce Ames, a former colleague of Len’s who later would develop what is now known as the Ames test, was at the time just embarking on his independent career at the NIH. Lee successfully obtained a permanent position in the Ames lab.

Ames’ research focused on bacterial genetics and the histidine biosynthesis pathway in Salmonella. This work was similar to the work Lee had conducted in the Monod laboratory, so it was a smooth transition. Interestingly, Len and Lee’s bacterial gene regulation work in Paris with the LacZ operon had many parallels to the histidine operon Lee worked on in the Ames lab. Both systems were examples of bi-stable systems. She explains, “They operated either in an ‘on’ or the ‘off’ position – they could not and did not operate for any length of time in the middle.”

The Herzenbergs describe the NIH in those days as a wonderful environment. Scientists who had made great discoveries within their fields were often right down the hall or across the campus. Many fruitful conversations and collaborations grew from corridor and cafeteria conversations. One such collaboration, with Mike Potter, became an important cornerstone of Len’s career. He always had wanted to study a cell line that could be used to determine cell-surface antigens and suspected that these antigens could be used as markers for genetic studies in cell culture. He needed a “cell line that was close to a normal, accessible cell type.” Potter’s laboratory had the answer. Potter had a cell line, P388, derived from mouse lymphocytes from chemically induced tumors. Len’s group used the cell line for many years after the initial collaboration.

Toward the end of Len’s Public Health Service appointment, the couple decided it was time for him to negotiate for a permanent position. Len was successful in securing a local offer, and the couple was happily ready to settle at the NIH. But again fate stepped in.

In a twist that may make current job-seekers green with envy, Len received a letter that contained a job offer for a position he never had applied for. Future Nobel laureate Joshua Lederberg had been tasked with starting the genetics department at the Stanford University School of Medicine. Lederberg wanted Leonard to be his first faculty appointment. The two had met briefly in Paris and at the NIH, but nothing foreshadowed the job offer, Len recalls. The Herzenbergs mulled it over and decided this was too good an opportunity to pass up, so they packed up and moved to California, where they have had a joint laboratory since.

Though they left the NIH many years ago, the Herzenbergs have continued work that relates to their time there. The couple writes, “We recently realized how important it now is to protect cultured cells against mutagenesis while they are being cultured.” Len’s work in improving cell-culture growth conditions in Eagle’s lab has made an indelible mark on their research trajectory. One member of their group, Kondala Atkuri, gives an informative summary in the “Reflections” article of their current efforts to grow mammalian stem and other therapeutically useful cells at oxygen concentrations that more closely mimic levels found in vivo and that are much less likely to induce dangerous mutations.

Although the Herzenbergs have been away from the NIH for many decades, it is a cherished part of their history. Len writes, “As I look back, I realize that the people I met and the focus on mammalian biology, genetics and human disease that they transmitted to me is really the enduring legacy of our NIH years.”
 

Photo of Pumtiwitt McCarthyPumtiwitt C. McCarthy (pumtiwitt.mccarthy@fda.hhs.gov) is a postdoctoral fellow at the U.S. Food and Drug Administration.
 
 
 


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