How Cold War nuclear testing launched the field of DNA repair at Yale

In the 1950s, U.S. Senator Prescott Bush, a Republican from Connecticut and father and grandfather to future presidents, approached Yale’s biophysics faculty with a request. Could they determine whether radiation causes irreparable damage to human DNA?

World War II had just ended with the first strategic use of atomic weapons. The Soviet Union and the United States were locked in a Cold War arms race. Scientists and the public alike feared that radiation from nuclear testing would cause irreparable DNA damage and cancer—a belief that grew out of the illness and death in the aftermath of the atomic bomb blasts in Japan.

The Atomic Energy Commission (AEC) countered that people exposed to equivalent doses of radiation exhibited different outcomes; while some developed cancers, others didn’t. It was premature, the AEC concluded, to say that the effects of radiation were irreversible.

The search for answers was on. Yale biophysics and radiobiology researchers began to study the effects of radiation on living cells. “The time was ripe and the situation was ideal,” recalled Philip Hanawalt, Ph.D. ’59, then a graduate student in the biophysics department. “Watson and Crick had just reported the structure of DNA, and biophysicists at Yale decided it was important to learn what radiation did to DNA.”

Hanawalt and other re-searchers reflected upon those heady times in May, when the Department of Therapeutic Radiology hosted a symposium to commemorate 50 years of DNA repair research at Yale.

Hanawalt, who holds the Dr. Morris Herzstein Professorship in Biology at Stanford, recalled an all-hands-on-deck mentality among the biophysics faculty. “We met weekly for informal research discussions. We were like a large family sitting around the table discussing science. We were all focused on a common goal, figuring out what radiation did to cells, and particularly to DNA.”

In their search for answers Yale scientists made many of the pioneering discoveries in the field of DNA repair. Researchers in the Radiology Department, a precursor to the Department of Therapeutic Radiology, and in biophysics discovered not only DNA repair mechanisms but also their genetic control. The research that began at Yale led, Hanawalt said, “to an understanding of the multiple DNA repair mechanisms required for the maintenance of genomic stability in all living cells.”

The formal discovery of DNA repair occurred in three laboratories simultaneously. Hanawalt’s graduate research with Richard Setlow, Ph.D. ’47, initiated studies on the inhibition and recovery of DNA synthesis in bacteria following irradiation with ultraviolet light. Then Setlow subsequently found, mutant cells that were sensitive to ultraviolet light retained damage in their DNA, while normal cells cut out the damage. Hanawalt had moved to Stanford, where he showed that repair patches were inserted into DNA, presumably replacing the damaged parts that had been removed. At Yale, Paul Howard-Flanders, Ph.D., isolated mutant bacteria sensitive to ultraviolet light and reported that while normal bacteria removed the damage, the mutant bacteria could not. Damage in DNA, the researchers concluded, can be cut out and the missing parts replaced correctly through a process called nucleotide excision repair.

Joann Sweasy, Ph.D., professor of therapeutic radiology and of genetics, pointed out that DNA repair occurs naturally in our cells every day. “But if the repair isn’t good, or there’s a faulty gene, that’s when you get suboptimal mutations that lead to cancer,” she said.

Peter Glazer, M.D. ’87, Ph.D. ’87, chair and Robert E. Hunter Professor of Therapeutic Radiology, professor of genetics, and member of the faculty advisory committee of the Cancer Biology Institute at West Campus, has overseen a $9 million grant from the National Cancer Institute titled “DNA repair in cancer biology and therapy.” The title suggests an important goal for the field of DNA repair. The grant, which ended June 30, was to take advantage of knowledge of DNA repair pathways in order to treat cancer. The interdisciplinary effort brought together more than a dozen investigators to focus on fundamental and translational cancer biology.

“The DNA repair field is getting more and more exciting in its complexity and its relevance to human health,” said Hanawalt. “If you Google DNA repair, you’ll get more than 18 million hits. It’s alive and well, and the early insights of radiation biologists at Yale got it started, while current scientists at Yale help to keep it in orbit.”