Correcting the Blueprint of Life

A Historical Account of the Discovery of DNA Repair Mechanisms1

Several decades have passed since Jim Watson and Francis Crick first described the double-helical structure of DNA. The unshakeable dogmas that preceded and postdated the discovery of DNA were that genes were made of proteins and that DNA was inherently a stable molecule. Friedberg takes us on a worthwhile trip down memory lane to examine the personalities and experiments of the scientists responsible for refuting these dogmas and unraveling the mysteries of DNA damage and repair. New York institutions feature prominently in this book, along with anecdotes regarding the eccentricities of known and unknown scientific pathbreakers. Rockefeller University students will immediately recognize the story of Oswald Avery et al, providing experimental proof that DNA was the transforming principle responsible for the reactivation of the pneumococcus bacteria (first observed by the British physician, Frederick Griffith, in the 1920s). Avery, a Canadian-born American medical researcher, was described by others as "the most deserving scientist to not receive the Nobel Prize for his work."

Ruth Hill’s (Columbia University, New York) discovery of a UV-sensitive E.coli mutant inaugurated an era emphasizing genetic analysis of mutations. The first UV-resistant E.coli mutant was isolated by then-Columbia University graduate student, Evelyn Witkin. She gained fame in later years as a leader in the field of DNA damage and repair, eg, by first identifying the SOS response, an E.coli system triggered by DNA damage. Together with NY-born scientist, Seymour Benzer (who, along with Sydney Brenner, inferred an instructional relationship between genes and proteins) and others, these scientists paved the way for the development of key concepts in DNA single and double strand-break repair.

It seems that great discoveries inevitably provide fodder for good stories. The famous Salvador Luria-Max Delbruck fluctuation experiment, demonstrating that mutations were stochastic events in bacteria, is no exception. Friedberg relates how Luria was observing a slot machine when he hit upon the idea that mutations occurring early on in small bacterial cultures would yield large payouts or “jackpots” in the population. Hence, the title of Luria’s 1984 autobiography is A Slot Machine, A Broken Test Tube. Another scientist, Albert Kelner, received his payoff only after tremendous perseverance. Of humble beginnings, he joined a Cold Spring Harbor Laboratory research initiative geared towards mutating bacteria into antibiotic-producing variants. His years of failure and frustration were finally rewarded when Kelner showed that exposure to visible light influenced the recovery of UV-irradiated Streptomyces griseus spores. Renato Dulbecco, one of Luria’s students, subsequently demonstrated the same phenomenon, photoreactivation, using irradiated phages.

The stories describing Meselson’s identification of DNA methylation in strand discrimination during mismatch repair and the famous Meselson-Stahl experiment are only touched upon here. So are accounts of Richard Setlow’s work on the excision of UV-induced lesions in E.coli DNA and Jane Setlow’s work on a bacterium first discovered in irradiated meat, Deinococcus radiodurans. Subsequent reviews and books have discussed the work of Setlow and others in more elaborate detail. What sets this tome apart from later writings is the fact that the author (a scientist and educator) has infused the early history of DNA repair with personal stories that will resonate with the current generation of scientists.

Reference:

1 Correcting the Blueprint of Life—A Historical Account of the Discovery of DNA Repair Mechanisms, E. Friedberg, CSHL Press, 1997, Plainview, NY