Nobel Prize Goes to Work that is Essential for Life

“Without these mechanisms we would probably not exist and would certainly all die young,” said Mark Downs, Chief Executive of the Royal Society of Biology in regards to the 2015 Nobel Prize in Chemistry awarded on October 7, 2015 to Tomas Lindahl, Aziz Sancar, and Paul Modrich for their studies on DNA repair.

DNA requires faithful replication to ensure its message is properly transmitted from generation to generation. When mutations in DNA occur, whether by UV radiation from the sun, toxic chemicals, or random chance, cells need a mechanism to fix the mistake.

When DNA repair goes awry, mutations can lead to a slew of diseases including cancer and neurodegenerative diseases. Lindahl, Sancar, and Modrich have each devoted a life of work to understanding how DNA works.

Since 1961, over 82,000 articles have been published on PubMed on this topic. With such a huge field of research Lindahl said there are “10, 15 excellent people you could choose from, and you can’t give the Nobel Prize to more than three people. So I feel very lucky and privileged to be included in the top class that was awarded.”

Tomas Lindahl in the lab at Cancer Research UK Image credit: Cancer Research UK
Tomas Lindahl in the lab at Cancer Research UK
Image credit: Cancer Research UK

Born in Stockholm, Sweden, Lindahl first began thinking about the stability of DNA in the 1960s at a time when nearly everyone presumed DNA to be quite stable. But Lindahl knew that one base in DNA known as cytosine could undergo a spontaneous chemical modification into another base known as uracil. In 1974 he published a paper describing a bacterial enzyme that removes the misplaced uracil, allowing the cell to fix the mistake. This process became known as base excision repair. Lindahl continued studying this process and in 1996 replicated human base excision repair in the lab.

“This is wonderful news!” Sir Tim Hunt said, a Nobel Laureate for the 2001 Medicine prize. “Tomas was my boss for almost 20 years, a real scientists’ scientist,” calling him a “pioneer in the study of DNA decay and its repair.

Sancar, who was born in Turkey, worked on another DNA repair mechanism called nucleotide excision repair. This process repairs damage following UV radiation, which causes two thymine bases to inappropriately bind, resulting in a mutation. Sancar isolated three bacterial enzymes (known as uvrA, uvrB, and uvC) that recognize and cut out the mutated DNA, allowing for natural repairs to occur. His paper published in 1983 led to his professorship at the University of North Carolina at Chapel Hill, where he remains today.

Modrich was on vacation in a New Hampshire cabin when he first heard the news. “The field, for many years, didn’t receive the attention I think that it really deserved,” he said.

Although currently at the Duke University School of Medicine, Modrich is from New Mexico where the natural landscape spurred his interest in science. In 1963, the year that James Watson and Francis Crick won the Nobel Prize for their discovery of the structure of DNA, Modrich’s father, who happened to be a biology teacher said, “You should learn about this DNA stuff.”

Paul Modrich at Duke University Image credit: Duke photography
Paul Modrich at Duke University
Image credit: Duke photography

Fortunately for Modrich, he took this advice to heart. Throughout the 1980s, Modrich worked on a third kind of DNA repair. Sometimes mistakes are made when DNA is copied as cells divide. A system known as mismatch repair fixes 99.9% of these mistakes. In bacteria, the original DNA strand that has no mistakes is recognized by a chemical signal known as methylation. This allows the mismatch repair machinery to know what DNA strand is the template, and which one is in need of proofreading and correction. Modrich published his work that recreates this process in the lab in 1989. But in humans, methylation serves a different purpose unrelated to mismatch repair, and scientists are unsure how the template strand is recognized.

Lindahl, Sancar, and Modrich’s initial work all fell under the category of “basic science,” but medical applications of this research are underway, as is evidenced by the large number of people currently working in the field.

Tom Brown from the University of Oxford, commented on the Prize saying, “Importantly, the field is ripe for exploitation in the therapeutic context.”

For more information on the 2015 Nobel Prize in Chemistry, visit these links from Nobelprize.org:

Press-release

Non-technical explanation of DNA repair research

Technical explanation of DNA repair research

Note: This piece was originally written as a deadline-writing exercise for one of my Science Journalism classes at Boston University the morning of Friday, October 9, 2015.

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