Paul Modrich

Paul Modrich
Born	13 6, 1946
Birthplace	Raton, New Mexico, United States
Nationality	American
Occupation	Biochemist, molecular biologist
Title	James B. Duke Professor of Biochemistry
Employer	Duke University, Howard Hughes Medical Institute
Known for	Discovery of DNA mismatch repair mechanisms
Education	PhD, Stanford University
Awards	Nobel Prize in Chemistry (2015)

Paul Lawrence Modrich (born June 13, 1946) is an American biochemist whose research elucidated the molecular mechanisms by which living cells detect and correct errors in DNA, a process known as DNA mismatch repair. For this work, he was awarded the 2015 Nobel Prize in Chemistry, which he shared with Tomas Lindahl and Aziz Sancar, for their collective studies on the mechanisms of DNA repair. Modrich spent the majority of his career at Duke University, where he held the position of James B. Duke Professor of Biochemistry and Chemistry, and was also an investigator of the Howard Hughes Medical Institute (HHMI). His painstaking biochemical work over more than three decades reconstructed the mismatch repair pathway in remarkable detail, demonstrating how cells use a system of molecular proofreading to maintain the integrity of genetic information during DNA replication. This research has had significant implications for understanding the origins of certain cancers and hereditary diseases linked to defects in DNA repair.

Early Life

Paul Modrich was born on June 13, 1946, in Raton, New Mexico, a small town near the Colorado border. He grew up in a modest environment in the American Southwest. His father was a biology teacher, and it was his father's influence that first sparked Modrich's interest in science. In an interview following the announcement of the Nobel Prize, Modrich recalled that his father had told him about the work of James Watson and Francis Crick and encouraged him to learn about DNA, a suggestion that left a lasting impression on the young Modrich. This early exposure to the emerging field of molecular biology set the course for what would become a lifetime of research into the chemistry of DNA.

Growing up in a small New Mexico town, Modrich's pathway into scientific research was not a foregone conclusion, but the encouragement he received from his father and his own curiosity about biological processes proved formative. The story of his father's advice became one that Modrich frequently cited in later years as a pivotal moment in his early development, underscoring the role that mentorship—even informal guidance within a family—can play in shaping a scientific career.

Education

Modrich pursued his undergraduate studies at the Massachusetts Institute of Technology (MIT), where he earned a bachelor's degree in biology in 1968. He then went on to graduate school at Stanford University, where he completed his PhD in biochemistry in 1973. At Stanford, Modrich studied under Robert Lehman, a prominent figure in the field of DNA enzymology. His doctoral work focused on DNA ligase, an enzyme responsible for joining DNA strands, and this early training in the biochemistry of DNA-processing enzymes provided the technical foundation and intellectual orientation that would define his subsequent research career.

Following the completion of his doctorate, Modrich undertook postdoctoral research at Harvard University, further refining his expertise in the molecular biology of DNA before embarking on his independent research career.

Career

Joining Duke University

Modrich joined the faculty of Duke University in Durham, North Carolina, in 1976, beginning what would become a career spanning more than four decades at the institution. He was appointed to the Department of Biochemistry in the Duke University School of Medicine, where he established a laboratory focused on the enzymology of DNA. Over the following years, he rose through the academic ranks to become the James B. Duke Professor of Biochemistry and Chemistry, one of the university's most distinguished professorships. He also became an investigator of the Howard Hughes Medical Institute, a position that provided sustained funding and support for his research program.

Discovery of DNA Mismatch Repair

Modrich's central scientific contribution was the elucidation of the mechanism of DNA mismatch repair, a cellular process that corrects errors introduced during DNA replication. When cells copy their DNA, the replication machinery occasionally incorporates incorrect nucleotide bases, resulting in mismatches between the two strands of the DNA double helix. If left uncorrected, these mismatches can lead to permanent mutations in subsequent rounds of replication. Modrich's research revealed the molecular machinery that cells use to detect and repair these errors, thereby maintaining the fidelity of the genetic code.

The work built on earlier observations by other scientists that cells possessed some form of post-replicative proofreading system. What Modrich achieved was the identification and characterization of the specific proteins involved in this pathway and the reconstruction of the entire mismatch repair process in vitro—that is, outside of living cells, using purified components in a test tube. This was a technically demanding accomplishment that required decades of careful biochemical experimentation.

Modrich's research demonstrated that the mismatch repair system in the bacterium Escherichia coli (E. coli) relies on the protein MutS to recognize mismatches in DNA, the protein MutL to coordinate the repair response, and the protein MutH to introduce a nick in the newly synthesized DNA strand, thereby directing the repair machinery to correct the error on the correct strand. The system distinguishes the newly synthesized strand from the parental template strand through a mechanism involving DNA methylation—specifically, the transient absence of methyl groups on the new strand provides the signal that directs repair to the appropriate strand.

Having elucidated the bacterial system, Modrich and his laboratory went on to characterize the analogous mismatch repair pathway in human cells. While the human system differs in certain details from the bacterial pathway—for example, it does not rely on the same methylation-based strand discrimination mechanism—the core logic of mismatch recognition and directed repair is conserved. Modrich identified the human homologs of the key bacterial repair proteins, including MSH2 and MLH1, and demonstrated their roles in maintaining genomic integrity.

Implications for Cancer Research

One of the most significant outcomes of Modrich's research was the connection between defects in mismatch repair and the development of cancer. Mutations in mismatch repair genes, particularly MSH2 and MLH1, were found to be responsible for hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome, one of the most common forms of inherited cancer predisposition. Modrich's biochemical characterization of the mismatch repair proteins provided the molecular framework for understanding why deficiencies in this pathway lead to a dramatic increase in mutation rates and, consequently, to cancer.

The work demonstrated that mismatch repair is not merely a maintenance function but a critical safeguard against the accumulation of mutations that can drive tumorigenesis. Cells with defective mismatch repair exhibit a "mutator phenotype," accumulating mutations at a rate 100 to 1,000 times higher than normal cells. This insight has had practical implications for the diagnosis and treatment of certain cancers, as tumors with mismatch repair deficiencies exhibit distinctive molecular signatures, including microsatellite instability, that can be detected through clinical testing.

Laboratory and Research Approach

Modrich was known for his meticulous, methodical approach to biochemistry. Rather than pursuing rapid publication of preliminary findings, he characteristically devoted years to the thorough characterization of each component of the mismatch repair pathway. His laboratory reconstructed the entire repair process using purified proteins, an approach that provided definitive mechanistic insights but required extraordinary patience and technical skill.

In an interview with Duke Today in November 2021, conducted approximately one month before Modrich planned to close his laboratory, he reflected on his career and the pathway that had led to the Nobel Prize. He discussed the importance of following one's scientific curiosity and the value of sustained, long-term investment in a single research problem. The closing of his laboratory in late 2021 marked the end of an active research program that had spanned more than 45 years at Duke University.

Conversations and Public Engagement

In addition to his laboratory research, Modrich engaged in public discussions about science and scientific careers. In May 2022, he participated in a conversation with Maya Ajmera, President and CEO of the Society for Science and Publisher of Science News, in which he discussed his career trajectory, his research on DNA mismatch repair, and his perspectives on the scientific enterprise. In October 2025, the University of New Mexico announced that Modrich would be featured as a keynote lecturer during their 2025 Research and Discovery Week, scheduled for November 6–14, 2025, reflecting his continued role as a prominent figure in the scientific community even after the closure of his research laboratory.

Personal Life

Modrich has maintained a relatively private personal life throughout his career. He has been based in Durham, North Carolina, for the duration of his tenure at Duke University. In his 2015 Nobel Prize telephone interview, Modrich spoke warmly about the influence of his family, particularly his father, on his scientific development, but he has generally kept details of his personal life out of public discussion. He has spoken publicly about his connection to his hometown of Raton, New Mexico, and the formative role that growing up in a small town played in shaping his character and work ethic.

In his reflections on his career, Modrich has emphasized the importance of curiosity-driven research and the value of persistence in scientific inquiry. He has described his approach to science as one motivated by genuine interest in understanding biological mechanisms rather than by the pursuit of practical applications, although his work has had profound biomedical implications.

Recognition

Nobel Prize in Chemistry (2015)

On October 7, 2015, the Royal Swedish Academy of Sciences announced that Modrich, together with Tomas Lindahl of the Francis Crick Institute and Aziz Sancar of the University of North Carolina at Chapel Hill, had been awarded the Nobel Prize in Chemistry "for mechanistic studies of DNA repair." Each laureate was recognized for elucidating a distinct DNA repair pathway: Lindahl for base excision repair, Sancar for nucleotide excision repair, and Modrich for mismatch repair. Together, their work provided a comprehensive molecular-level understanding of how cells protect the integrity of their genomes.

The Nobel Prize recognized decades of biochemical research that had collectively mapped the fundamental processes by which living organisms maintain their DNA. In the telephone interview conducted by the Nobel Foundation immediately following the announcement, Modrich described receiving the early-morning phone call informing him of the prize.

Duke University celebrated the award as a milestone for the institution. Modrich was the first Duke faculty member to receive a Nobel Prize while actively working at the university, and the recognition brought significant attention to the university's research programs in the biomedical sciences.

Other Honors

Modrich's work has been recognized by numerous scientific organizations and institutions throughout his career. He has been an investigator of the Howard Hughes Medical Institute, a distinction that is itself a mark of significant scientific achievement and that provided the long-term research support that enabled his sustained investigation of mismatch repair. He is also identified as a 2015 Nobel Laureate on the Duke School of Medicine's official pages, which describe his contributions to the understanding of DNA repair and their implications for human health.

Legacy

Modrich's elucidation of the DNA mismatch repair pathway represents one of the foundational contributions to the field of DNA repair biology. His work provided the molecular framework for understanding how cells maintain the accuracy of their genetic information, a process essential to the prevention of mutations and the diseases they cause. The connection between mismatch repair deficiency and hereditary cancers, particularly Lynch syndrome, established a direct link between Modrich's basic biochemical research and clinical medicine, illustrating the translational potential of fundamental scientific inquiry.

The proteins and pathways that Modrich characterized—MutS, MutL, MutH in bacteria, and their human homologs MSH2, MLH1, and others—are now standard subjects in molecular biology and biochemistry textbooks. The concept of mismatch repair as a guardian of genomic integrity has become a central principle in the understanding of mutagenesis, carcinogenesis, and genome stability.

Modrich's approach to science—characterized by sustained focus on a single biological problem, rigorous biochemical methodology, and the patience to reconstruct complex cellular processes from their individual molecular components—has been cited as a model for how fundamental biological mechanisms can be understood. His career demonstrated that deep, long-term investment in a single research question can yield discoveries of the highest significance.

The decision to close his laboratory in late 2021, after more than four decades of active research at Duke, marked the end of one of the most productive and consequential research programs in the history of DNA biochemistry. However, Modrich's continued engagement with the scientific community through public lectures and conversations, including his participation in events such as the University of New Mexico's Research and Discovery Week in 2025, underscores his ongoing role as an influential figure in the life sciences.