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Paul Modrich Shares Nobel Prize in Chemistry

Biochemist has spent four decades researching how mistakes in the DNA code are repaired

Part of the Paul Modrich Shares Nobel Prize in Chemistry Series

Paul Modrich

Paul Modrich's research has explained how the body repairs DNA mismatches, preventing disease. Photo: Duke Photography

Paul Modrich, the James B. Duke professor in the Department of Biochemistry in the Duke Medical School, will share this year’s Nobel Prize in Chemistry for his four decades of work on how mistakes in the DNA code are repaired.

The finding underlies the most common form of colon cancer and about 20 to 30 percent of other spontaneous tumors, as well as Huntington’s Disease and other neurodegenerative disorders.

The Royal Swedish Academy of Sciences announced today (Wednesday) that Modrich, 69, who is also a Howard Hughes Medical Institute (HHMI) investigator, will share the award with Aziz Sancar, the Sarah Graham Kenan Professor of Biochemistry and Biophysics at the University of North Carolina at Chapel Hill, and Tomas Lindahl of the Francis Crick Institute and Clare Hall Laboratory in the UK.

“We’re on vacation in New Hampshire, so this was sort of a shock” Modrich (pronounced MOD-rich) told the Nobel Prize press office on Wednesday morning as his wife, Vickers Burdett, also a Duke biochemist, answered another phone in the background.

DNA’s fidelity is crucial to our well-being, for when it goes wrong, cancer and other diseases can occur. Misspellings in the genetic code are constantly happening due to ultraviolet radiation, free radicals of oxygen and carcinogenic substances of all kinds. Thousands of these errors are estimated to occur each day across the human body’s 10 trillion cells.

So the cell has built-in machinery to detect errors and correct them, and that has been the focus of the work being recognized by this year’s prize.

Starting on the question of DNA repair in the late 1970s, Modrich’s key contribution has been the identification of the mismatch repair (MMR) system, a key proofreading mechanism of proteins that identifies and corrects the errors that occur in the DNA code during chromosome replication.

"In human cells, MMR reduces the error rate by a factor of a thousand," Modrich told the HHMI website. In healthy cells, approximately one mutation occurs per cell division among the 3 billion letters of DNA being copied. MMR serves as a “copy editor” to catch and repair these misspellings, which would increase to about 1,000 in its absence.  

Modrich’s work also has shown that inactivation of this mismatch repair system is the cause of the most common form of hereditary colon cancer, and that repair errors also play an important role in the development of a number of neurodegenerative diseases and 20 to 30 percent of sporadic tumors found in many tissues.

“Paul’s discoveries about mechanisms of mismatch repair transformed our understanding of this important guardian of our DNA,” said Michael B. Kastan, M.D., Ph.D., executive director of the Duke Cancer Institute. “DNA repair pathways are critical determinants of whether cancers arise, how cancers respond to therapies, and many of the side effects of cancer treatments. It is difficult to get more important than that combination of effects.”

Modrich told the HHMI website that growing up in a small town in northern New Mexico instilled him with a love of the natural world.

"There was huge biological diversity around me," he said. "Within five miles, the ecology can change dramatically -- it was very thought provoking."

His father, the local high school biology teacher, encouraged his curiosity. In 1963, when he was a junior in high school and the DNA double helix discovery was only 10 years old, Modrich remembers his dad giving him very important advice: "You should learn about this DNA stuff."

Modrich earned his bachelor’s degree at the Massachusetts Institute of Technology in 1968, and a Ph.D. at Stanford University in 1973. He arrived at Duke in 1976 and is a fellow of the American Academy of Arts and Sciences and a member of the Institute of Medicine and the National Academy of Science.

Paul Modrich reacts to being awarded the 2015 Nobel Prize in Chemistry.

“He always struck me as being very brilliant,” said research technician Elisabeth Penland who has worked in the Modrich lab since 1994. “Back then, one of his postdocs said ‘I expect Paul to get the Nobel prize one day.’ We’ve been waiting for this for 20 years. I knew this was coming. He’s brilliant. He never lets go. He is 10 steps ahead of everybody in his head.”

“He’s worked on this his entire career -- identifying the activities and characterizing the enzymes that carry out mismatch repair and contributing to understanding the biomedical importance of the system,” said colleague Lorena Beese, Ph.D, also a James B. Duke professor of biochemistry. “This prize speaks to the importance of fundamental basic science discoveries. Paul is an advocate for basic research and funding to support basic science.”

"I’m a basic scientist,” Modrich said by phone this morning. “Understanding how living things function is intrinsically valuable. Many of the major health-related implications of science have been directly derived from basic science investigation -- understanding how things work.”

"I must say I am so thrilled for Duke to have another laureate,” said Robert Lefkowitz, the 2012 Nobel laureate in Chemistry and James B. Duke professor of biochemistry at Duke. (See video of Lefkowitz visiting the Modrich lab Wednesday.) “Mine was first in the history of the institution, which seems strange, but then you wonder if we are going to have anyone else in the near future, and it's so great that we do, and that it's Paul. Paul is so worthy."

Modrich will receive a medal and meet the Swedish royal family in Stockholm on Dec. 10 as part of a week-long celebration of the prizes in chemistry, physics and medicine or physiology. He also will share one-third of a $960,000 prize.