June 2011

Gary Felsenfeld: untangling chromatin’s mysteries

Returning stateside

Felsenfeld had a productive year with Coulson, predicting one of the earliest molecular structures using crystal field theory (the chlorocuprate anion CuCl42-) and completing what would be his last purely theoretical work.

He returned to the United States in 1956 and took up a post at the NIH, following an arrangement he had made prior to departing for Oxford. His draft board (the Korean War was over, but the draft was still active) had told Felsenfeld to obtain an officer's commission while in England or he would be serving in the infantry when he returned. Fortunately, Alexander Rich, whom Felsenfeld had befriended at Caltech, invited him to join the NIH as an officer in the Public Health Service.

Together with Rich and David Davies, another former Caltech colleague, Felsenfeld began working with synthetic polynucleotides, in vitro synthesized RNA segments of defined sequence, that in a few years would prove instrumental in cracking the genetic code.

Felsenfeld, Davies and Rich, though, were using these building blocks to understand how nucleic acids formed stable ordered structures like the recently solved DNA double helix. This was his first project with nucleic acids – and it proved to be an auspicious start.

While analyzing the salt requirements for double helix formation using complementary strands of poly-adenine and poly-uracil, Felsenfeld noticed that his spectrophotometer readings displayed some unusual absorption data at certain salt concentrations. Initially he tried to ignore it – perhaps he had made some experimental errors – but eventually he accepted that the data, which suggested a helix with twice as many U's as A's, was real. He remembers asking Davies, "Is there any way to fit a second poly-U into the structure?"

At the NIH, Felsenfeld, Davies and Rich uncovered the formation of a triple nucleotide helix.

What they had uncovered was the formation of a triple nucleotide helix. "It was a wonderful, wonderful moment, exhilarating. You're so lucky to have something like that when you're just starting out."

To be young and in science

After three years at the NIH, Felsenfeld was offered a faculty position in the biophysics department at the University of Pittsburgh. Biophysics was still emerging as a distinct field, and it was an unusual opportunity to join a discrete biophysics department. Recently married and ready to set out on a new endeavor, he accepted their offer. While continuing his biochemical characterizations of synthetic polynucleotides, Felsenfeld also was given leeway to start working on the copper protein hemocyanin, which he felt would be an ideal project to weave together his scientific interests in quantum chemistry and biology.

However, only two years later, the NIH brought Felsenfeld back to Bethesda with an offer he couldn't refuse. The intramural research director of the Institute of Arthritis and Metabolic Diseases (now NIDDK), DeWitt Stetten, had been persuaded to form a new laboratory of molecular biology. In a twist from the norm, this new group would be composed entirely of young, rising investigators rather than established scientists.

Felsenfeld recalls those early years as a marvelous time, and the lab was full of energy and enthusiasm. The only downside was that Felsenfeld quickly realized that his studies with nucleic acids would be all-consuming; after a few years, the work with hemocyanin fell by the wayside.

He continued investigating the stabilization of multistranded nucleic acid structures by counter ions; this soon led to studies using polylysine and polyarginine as models to examine the interaction of DNA with basic proteins in the nucleus. Eventually, though, he got tired of saying they were good models, "because they weren't good models!"

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