This Year’s Nobel Prize In Chemistry Sparks Questions About How Winners Are Selected | November 11, 2015 Issue - Vol. 93 Issue 45 | Chemical & Engineering News
Volume 93 Issue 45 | pp. 35-36 | Latest News
Web Date: November 11, 2015

This Year’s Nobel Prize In Chemistry Sparks Questions About How Winners Are Selected

The three scientists honored for their work in DNA repair made crucial contributions, but critics wonder about those left off the list
By David Kroll
Department: Science & Technology
News Channels: Biological SCENE
Keywords: Nobel Prize, DNA repair, Laureates, chemistry, base excision repair, nucleotide excision repair, DNA mismatch repair, Philip Hanawalt
[+]Enlarge
Credit: Shutterstock/C&EN
Illustration of noble prize.
 
Credit: Shutterstock/C&EN

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.

[+]Enlarge
Lindahl
Credit: AP
This is a picture of Tomas Lindahl.
 
Lindahl
Credit: AP
[+]Enlarge
Hanawalt
Credit: Linda Cicero/Stanford News
This is a picture of Philip Hanawalt.
 
Hanawalt
Credit: Linda Cicero/Stanford News

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.

 
[+]Enlarge
Modrich
Credit: Kevin wolf/AP images for HHMI
This is a picture of Paul Modrich.
 
Modrich
Credit: Kevin wolf/AP images for HHMI
[+]Enlarge
Sancar
Credit: Max Englund/UNC Health Care
This is a picture of Aziz Sancar.
 
Sancar
Credit: Max Englund/UNC Health Care

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.

DNA Repair, A History

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.

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.

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.

 
Chemical & Engineering News
ISSN 0009-2347
Copyright © American Chemical Society
Comments
Lynn Silver (November 18, 2015 1:52 PM)
And what about Evelyn Witkin? She did get the Lasker - but why not the Nobel?
David Kroll (November 19, 2015 10:04 PM)
Dr. Silver, you raise an interesting question for which I can only speculate. My guess is because this year's Lasker and Nobel for DNA repair researchers recognize two distinct areas of the general field. Witkin and Stephen Elledge received the 2015 Lasker Award for Basic Medical Research for elucidating the cellular response program to DNA damage and other stressors, while the Nobel was given for mechanistic dissection of the biochemistry of the DNA repair enzymes themselves. Dr. Hanawalt also told me he was delighted that Witkin and Elledge received the Lasker for their distinct contributions, calling them "deserving awardees and good friends."

The Lasker Foundation does not offer a chemistry prize, however, Their awards are presented annually to up to five individuals in each category: basic medical research, clinical medical research, and public service. A special achievement award in medical science is presented every other year. That 2014 award went to Mary Claire-King for her work on hereditary breast cancer driven by mutations in BRCA genes.

The Lasker Foundation notes that their prizes are popularly known as "America's Nobel" as 87 Lasker winners have gone on to win the Nobel Prize, 43 in the last decade alone. On some occasions, the same group of Lasker winners later receive the Nobel Prize: The 2006 Lasker laureates – Elizabeth Blackburn, Carol Greider, and Jack Szostak – later won the 2009 medicine Nobel for their work on how chromosomes are protected by the enzyme telomerase.
Thomas P. Farrell (November 18, 2015 2:12 PM)
Dr. Hanawalt is clearly a role model for any aspiring scientist - putting scientific discovery ahead of personal accolades. It is very refreshing to hear his perspective. I am sure his peers will continue to recognize the seminal and significant contributions he has made to the field, and all will admire him as a great human being who is unencumbered by ego.
Paul Yu (November 18, 2015 2:23 PM)
Dr. Hanawalt has wise words to live by not just in the elite domain of Nobel / Lasker contenders but in science in general. I would have liked to have seen him recognized being that he was an influential teacher to me three decades ago, but his attitude and his accomplishments speak for themselves. A class act.
E.G. Meyer (November 18, 2015 3:25 PM)
This is an extremely well written summary if DNA repair and evaluation of the contributions of all the scientists who worked in the Field
P. Shing Ho (November 18, 2015 4:03 PM)
First, congratulations to the three Nobel Laureates. Although DNA repair is an important biological process, their mechanisms are clearly very much chemical and, therefore, entirely appropriate for the prize in chemistry. This story probably reflects best on Prof. P. Hanawalt, whose commentary on this year's Nobel Prize is both gracious and insightful (in regards to its measure of actual scientific impact).
John Hatten (November 19, 2015 2:58 AM)
I think everyone needs to remember that the awarding of a Nobel prize is a very subjective matter, and as we've seen in awards given past, the Nobel committee have displayed their own agenda. The work of MOST scientists will languish in obscurity, while the great contributions, such as all of the scientists named above, will find permanence on the merits of the work alone. These scientists will be referenced in theses and dissertations for probably the next century, and some maybe even longer. So raise a toast and give thanks that our own work can be built on the foundations of these giants. And may we always remember the army of countless scientists who have come before us and hope we may also contribute to the understanding of mankind.
David Mendenhall (November 19, 2015 10:38 PM)
Everyone seems to overlook the purpose of the prize to fund scientific research. Nowadays it goes to people who are already successfully funded.
Robert Buntrock (November 21, 2015 2:08 PM)
Another reason that Lindahl is cited as making the first major contribution is that he's Swedish. For decades, many Nobel Prizes have included a Scandinavian and a Swede in particular, causing much raising of eyebrows.
Carlos Frederico Martins Menck (December 2, 2015 7:04 AM)
The three Nobel Winners on DNA repair have to be congratulated, as they did a great job for this late recognition of the whole field of DNA repair. By dissecting three of the mechanisms, many other discoveries could be made, revealing the high relevance of DNA repair for cells, for evolution, and for human being. However, for his contribution during more than 50 years to the field (which includes the discovery of excision repair, but not only), Phil Hanawalt should be in the list, and I am sure most of the researchers on DNA repair recognize that. As Phil is a nobleman, his comments and attitudes only confirm this. Those that had the opportunity to work or simply talk to him, know that. Unfortunately, among the mistakes, the Nobel committee mentions the work of Phil as only confirmatory, not citing his seminal paper of 1963. Interestingly, the committee also did not give the appropriate value to the roles of DNA repair for the organisms, that is, protecting us from cancer (only mentioning that) and aging (not a word). But many discoveries are still open for those who work on DNA repair, and this will probably be acknowledged sooner or later.
Steve West (December 5, 2015 10:19 AM)
The recipients of the Nobel Prize for Chemistry deserve their accolades, but it is a pity that the prize committee takes so long to reward a key area of research such as this. If the prize had been awarded a few years earlier, then the committee could have chosen between Paul Howard-Flanders, Dick Setlow, Tomas Lindahl, Phil Hanawalt, Matt Meselson, Evelyn Witkin, Miro Radman, Paul Modrich or others who were the true pioneers of the DNA repair field.

Leave A Comment

*Required to comment