Researcher

Paul Modrich

Profile

Paul Modrich is an American biochemist at Duke University and Howard Hughes Medical Institute Investigator who shared the 2015 Nobel Prize in Chemistry with Thomas Lindahl and Aziz Sancar for their mechanistic studies of DNA repair. Modrich's specific contribution was the elucidation of the mechanism of mismatch repair (MMR), the cellular surveillance system that corrects base-pairing errors introduced during DNA replication. Working with E. coli and later human cell extracts, Modrich reconstituted the complete MMR reaction in vitro, identifying the key protein components (MutS, MutL, MutH and their human homologs MSH2, MSH6, MLH1, PMS2). Defects in MMR cause Lynch syndrome—the most common hereditary colorectal cancer syndrome—and MMR deficiency (dMMR) is now used as a biomarker for immunotherapy response. The FDA has approved pembrolizumab (Keytruda) for any MMR-deficient solid tumor, making Modrich's mechanistic work directly clinically actionable. Pharmaceutical companies developing immunotherapy combinations and diagnostic companies developing MMR status assays rely heavily on the mechanistic framework Modrich established.

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