When the Nobel Prize in Chemistry was awarded last month to Tomas Lindahl, Paul Modrich, and Aziz Sancar for their “mechanistic studies of DNA repair,” the usual mix of congratulatory messages and “oh, biology won again” laments appeared online. Among those messages, however, appeared other, less routine sentiments: regrets that some pioneering scientists were skipped over and confusion as to how and why the prizewinners were selected.
Many in the research community pointed out that the DNA repair field is a large one whose original discoveries were made more than 50 years ago, before even the eldest winner—Lindahl—had earned his Ph.D. Others complained that some press materials released by the Nobel Committee implied that the three awardees had “discovered” DNA repair, an error propagated in news stories written about the prize.
To be sure, this year’s Nobel Prize in Chemistry rewards actual chemistry: DNA repair describes the molecular mechanisms by which life’s genetic material is maintained and corrected in the face of internal mistakes such as copy errors, external insults such as ultraviolet radiation, and inherent DNA instability. Without DNA repair, humans would live short, dark, disease-ridden lives. Lindahl, Modrich, and Sancar built on earlier discoveries to dissect how three important types of DNA repair occur: base excision, mismatch repair, and nucleotide excision, respectively (C&EN, Oct. 12, page 6).
DNA repair “is certainly in chemistry’s strike zone,” wrote Paul Bracher while live-blogging the chemistry prize announcement on Oct. 7. At the same time, Bracher, a chemistry professor at Saint Louis University and author of the blog ChemBark, said, “I’d love to know how the committee arrived at these three scientists out of the many possibilities. This one is sure to be controversial.”
Writing on his Sandwalk blog the same day, University of Toronto biochemist Laurence A. Moran expressed displeasure that in its press release and popular science summary, the Nobel Committee ignored some seminal discoveries in the field of DNA repair and, in particular, ignored the contributions of Philip Hanawalt, currently a professor of biology at Stanford University.
In two different posts, Moran cited reviews published in 2013 in the Yale Journal of Biology & Medicine describing critical experiments carried out during the 1960s by Paul Howard-Flanders at Yale University and Richard Setlow at Oak Ridge National Laboratory that revealed how a repair system in bacteria could excise DNA bases damaged by UV light. It also describes research conducted by Hanawalt and his student David Pettijohn showing that the repair in UV-irradiated cells occurs via the synthesis of short patches of DNA. One of the reviews was written by Hanawalt himself and recounts work he did as a Ph.D. student at Yale during the late ’50s in the lab of Setlow (who later moved to Oak Ridge).
At 84, Hanawalt is the only surviving senior author of that original elite group of DNA repair researchers and therefore would have been eligible to win the chemistry prize this year. He’s not as bothered as colleagues and supporters such as Moran that he was not among this year’s Chemistry Nobel recipients. Instead, he’s more interested that the full story be told of how our understanding of DNA repair evolved from the interactions of “bright, naive students with their experienced but sometimesopinionated mentors.”
In truth, the DNA repair field began before Hanawalt and his contemporaries were on the scene and before scientists even had a clear picture of DNA. Around 1927, Hermann Muller of the University of Texas, Austin, demonstrated that X-rays can cause mutations in fruit flies that the insects pass along to their offspring. Similarly, in 1949, Albert Kelner at Cold Spring Harbor Laboratory showed that UV light could cause damage to bacterial cells from which some cells would then recover.
But it wasn’t until after the structure of DNA was characterized in the early 1950s that scientists figured out how radiation was damaging the genetic material. That mystery was solved—at least for UV radiation—in 1960 by Rob Beukers and Wouter Berends, Dutch scientists at the Technological University of Delft. They showed that UV light causes thymine bases in DNA to form cyclobutane dimers. Hanawalt says the identification of this chemical entity provided one of the tools critical to demonstrating how enzymes repair DNA because the dimers’ removal from DNA’s double helix could be measured.
In 1957, Sen. Prescott Bush of Connecticut (father and grandfather to the well-known U.S. Presidents) gave a boost to the DNA repair field when he approached researchers at Yale, including Setlow, to investigate the health hazards of nuclear testing. The federal interest—and accompanying funding—in understanding the effects of radiation that began with the Manhattan Project led to a concentration of research and training at Yale that set the stage for the first identification of DNA repair processes.
Independent of the Yale group, Claud (Stan) Rupert at Johns Hopkins University was studying how UV light kills bacteria in the late ’50s. He was trying to understand why a lethal dose of UV radiation could be partially “reversed” when the irradiated bacteria were subsequently exposed to regular, visible light. By 1960, Rupert reported that an enzyme, which he dubbed photolyase, was responsible for this photoreactivation process and could reverse thymine dimers in bacterial DNA.
Just three years later, Yale’s Howard-Flanders; Setlow, who had by then left Yale; and Hanawalt, three years into his faculty appointment at Stanford separately published papers on another type of DNA repair—one that happens without the aid of visible light. Howard-Flanders and Setlow used different Escherichia coli mutants to prove that removal of thymine dimers from bacterial DNA is required for cells to survive UV exposure. Hanawalt and Pettijohn went further to demonstrate that short patches of newly synthesized DNA replaced tracts of bases, which include dimers, during repair. They called this process repair replication, now known as nucleotide excision repair.
By 1974, Hanawalt had organized the first conference on DNA repair, drawing 200 participants, including Lindahl. Modrich and Sancar were not yet working in the field. Modrich earned his Ph.D. in 1973. Sancar would get his in 1977.
The Turkish-born Sancar would eventually—in the early 1980s—isolate, clone, and synthesize the protein components of the nucleotide excision repair system, demonstrating a working error-repair machine in E. coli. Now 69, Sancar continues research at the University of North Carolina, Chapel Hill.
Modrich would also eventually dissect and reconstitute a distinct DNA repair pathway. The newly minted Nobel Laureate, now 69 and working as a Howard Hughes Medical Institute investigator at Duke University, isolated and defined the components of the DNA mismatch repair system, which fixes errors that infrequently occur during the DNA replication process. Modrich’s seminal work, published in 1989, built on the discovery of mismatch repair by Harvard University’s Robert Wagner Jr. and Matthew Meselson in 1976.
C&EN would need many pages to fully recount the story of DNA repair research. Here are some high points.
1949: Albert Kelner shows that UV light impairs bacterial cells and that some cells recover.
1960: Claud (Stan) Rupert reports that an enzyme, photolyase, enables light-activated DNA repair in bacteria and yeast.
1960: Rob Beukers and Wouter Berends prove that UV light causes a type of DNA damage known as a thymine dimer.
1964: Philip Hanawalt, Paul Howard-Flanders, and Richard Setlow publish papers describing nucleotide excision repair.
1974: Tomas Lindahl discovers spontaneous cytosine deamination and, subsequently, base excision repair.
1974: The first conference on DNA repair takes place in Squaw Valley, Calif.
1976: Matthew Meselson and Robert Wagner Jr. uncover DNA mismatch repair.
1983: Aziz Sancar dissects and reconstructs the nucleotide excision repair system in E. coli.
1989: Paul Modrich reconstitutes the DNA mismatch repair system in E. coli.
Of this year’s three winners, the Swedish-born Lindahl actually did discover a type of DNA repair. Now 77, Lindahl seized on studies conducted in the early 1960s that showed DNA bases could spontaneously degrade. The most serious form of this degradation, a cytosine base getting deaminated and converted to uracil, led Lindahl to discover base excision repair while he was at the Karolinska Institute in the mid-1970s.
Yet all of these details—or at least the fact that DNA repair had been known since 1964—were absent from the press release and popular science summary posted at nobelprize.org after the announcement on Oct. 7.
The advanced scientific information on DNA repair released by the Nobel Chemistry Committee later in the day did mention the work of Rupert, Setlow, Howard-Flanders, and Hanawalt. Yet the Nobel’s popular science summary describing the prize still states that the field began in the 1970s: “The story begins with Tomas Lindahl, born in the same country as Alfred Nobel.”
When contacted by C&EN about why some DNA repair pioneers were not honored with this year’s prize, Nobel Chemistry Committee chair Sara Snogerup Linse pointed only to the will of Alfred Nobel, which states that the prize should be awarded “to the person who shall have made the most important chemical discovery or improvement.” Claes Gustafsson of the University of Gothenburg, the committee member who authored the advanced scientific summary did make clear in an Oct. 7 nobelprize.org interview that this year’s Nobel Laureates were not the original discoverers of DNA repair, however.
DNA repair was on the minds of major scientific prize committees this year. The 2015 Albert Lasker Basic Medical Research Award was given to Evelyn Witkin and Stephen Elledge for their work on how cells sense that their genome has been damaged.
Another pioneering DNA repair researcher who might have been honored is Sancar’s doctoral adviser, Rupert, now 96. Sancar says that Rupert, whom he calls “the father of DNA repair” because of Rupert’s discovery of photolyase and subsequent work on photoreactivation, was the second person he called after the prize announcement. “He was ecstatic,” Sancar says.
The conundrum of restricting Nobel Prizes to a maximum of three recipients, who also must still be alive, often leads to second-guessing and concerns over who has been left out. For example, Hanawalt might have been considered for this year’s Nobel with his mentor, Setlow. But Setlow passed away in April.
Still, Hanawalt objects to the characterization that he was overlooked by Nobel. He says he learned a lesson from Erwin Chargaff, a Columbia University biochemist whose experiments on DNA base pair ratios in nature proved key to solving the structure of DNA. Chargaff was not recognized along with James Watson, Francis Crick, and Maurice Wilkins in 1962 with the Nobel Prize in Physiology or Medicine. “He was a very bitter man when I met him some years later,” Hanawalt says. “That’s sad both because he was overlooked and because he let that oversight affect his ongoing life so severely.”
“The Nobel Prize is hardly a measure of a human’s net worth over their lifetime,” Hanawalt continues.
But he also wants to be clear on this year’s prize: “I stand by my position that the three selected Nobel Laureates in Chemistry are completely deserving of this timely recognition for their seminal contributions and that they are appropriate models for success in our important field of DNA repair.”
David Kroll is a freelance science writer based in North Carolina. He holds an unpaid adjunct professor appointment at Duke University School of Medicine.