Upon His Retirement, Modrich Reflects on His Career
Paul Modrich, PhD, James B. Duke Professor of Biochemistry, professor of Chemistry, and member of Duke Cancer Institute, came to Duke in 1976 — when Durham had a small-town feel, the smell of curing tobacco filled the air, and southern accents were the norm.
He grew up in rural New Mexico but had spent time in Boston (MIT for his undergrad and Harvard for his postdoc) and in California (Stanford for his PhD and UC Berkeley's Chemistry Department as an assistant professor for two years).
He was offered the Berkeley position as a graduate student, even though he wasn’t on the job market. Modrich accepted the offer for two reasons — his friend Jim Wang, PhD, who discovered the first DNA topoisomerase, was in the department, and like today, academic jobs were in short supply — but on the condition that he could complete his postdoc at Harvard; delaying the appointment for a year. Berkeley agreed.
Choosing Duke
Modrich hoped for a long-term career at Berkeley Chemistry, but it quickly became apparent that it was not the place for him. So, at the request of Bob Hill, PhD, then chair of Duke Biochemistry, he interviewed for a junior faculty position. Modrich was just 29 and had managed his lab at Berkeley for only one year.
Modrich was impressed by the science and feel of Duke’s Biochemistry Department — it had an intimacy and collegiality similar to what he experienced as a graduate student at Stanford. He was also impressed with the people he met there, including Hill, Bob Webster, PhD, Raj Rajagopalan, PhD, Irwin Fridovich, PhD, Bob Lefkowitz, MD, Bob Bell, PhD, David Richardson, PhD, Walter Guild, PhD, and Sam Gross, MD. When offered the position, he accepted.
Duke proved to be the ideal environment for Modrich’s career development. Duke Biochemistry had a strong reputation in research and research training in multiple areas. He was also fortunate to have excellent graduate students and postdocs come through his lab and to cement many friendships and research relationships in what he calls, “a very healthy environment.”
Most importantly, Modrich had the utmost respect for his colleagues and liked how they thought about their science in areas ranging from molecular biology and genetics to enzymology and structural biology. Modrich describes Duke Biochemistry as "my scientific home and the home of some of my closest friends for 46 years — and a place that allowed my research program to flourish.”
The Nobel
Modrich’s research at Duke emphasized the mechanisms used by enzymes that recognize and process rare sites in DNA. His early work on EcoRI restriction and modification enzymes, and the E. coli DNA adenine methylase clarified how these enzymes work and provided some of the first direct insight into how such enzymes search very long DNA molecules to locate the rare sites that they recognize.
Subsequent work in his laboratory addressed the nature and functions of DNA mismatch repair. Matthew Meselson's laboratory at Harvard had shown that mismatch repair functions as a copy editor in the bacterium E. coli to correct rare mistakes that occur during DNA replication. Modrich's lab identified the proteins and enzymes involved in E. coli mismatch repair and showed how it works. His lab also demonstrated that human cells have a similar mismatch repair system and showed that this pathway is defective in certain cancers, including those from patients with Lynch syndrome — an inherited cancer syndrome that increases cancer risk in a number of cancer types and the most common cause of hereditary colorectal cancer.
In 2015, Modrich (then a Howard Hughes Medical Institute-funded investigator, still based at Duke University School of Medicine), Tomas Lindahl FRS, FMedSci (Francis Crick Institute), and Aziz Sancar, MD, PhD (University of North Carolina at Chapel Hill), were jointly awarded the Nobel Prize in Chemistry "for mechanistic studies of DNA repair."
The three scientists, working independently, revealed how cells repair damaged DNA, which is vital knowledge about how a living cell functions. That knowledge is used for the development of new cancer treatments. Modrich demonstrated the mechanism of mismatch repair. Lindahl discovered the molecular machinery responsible for base excision repair, which repairs genetic damage that has little effect on DNA conformation; and Sancar mapped nucleotide excision repair, which repairs genetic lesions that distort DNA helix structure, like those produced by UV light from the sun. (People born with repair defects will develop skin cancer if they are exposed to sunlight.)
Mentorship and Legacy
Modrich's mentoring style emulated what he experienced as a student in Bob Lehman's lab at Stanford. As Modrich describes it, "Bob asked if I would like to work on the mechanism of DNA ligase. I said yes, and he let me decide what questions I would ask and how I would approach them experimentally, with occasional input from him and others in the lab." He adds, “This approach allows students, especially a less confident student like I was, to realize they can actually do the science themselves."
At its largest, Modrich had a working lab of 23 students, postdocs, and staff, but like all living things, labs have a life cycle. He says, "Scientific careers peak, and for the lucky few, that peak can last for decades. My lab was fortunate in that sense, but due to several health issues and the fact that I regarded our work over the last six years or so as largely incremental, it became clear to me that it was time to think about retirement. My wife Vickers (Burdett), who is also a scientist, and I discussed the possibility of retirement on multiple occasions, and a few years ago we decided that it was time."
He views the end of his career with mixed emotions. He ruminates, “I can do this one thing very well, but will my other interests be sufficient to keep me active?” Bob Lehman, PhD, once told him, "Paul, never retire." But Modrich disagrees. With a scarcity of faculty positions, he says, “It’s important for older scientists to wind down their labs to make way for the next generation.” Sage advice from someone who has received a multitude of scientific honors, including the Nobel Prize in Chemistry.
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In August 2023, a team of volunteers led by Trinitia Cannon, MD (third from left), Leda Scearce, CCC-SLP, MM, MS, and Dina Abouelella, MPH, which also included Tammara Watts, MD, PhD (center) and Katharine Ciarrocca, DMD, MSEd, partnered with North Raleigh International Baptist Church and Duke Raleigh Hospital to offer head and neck cancer screenings. Dozens of families from the Cedar Creek Apartment Complex community came out for the free screenings, education, and games, and Duke Raleigh Hospital donated backpacks full of school supplies.
TheDuke University School of Medicine Department of Head and Neck Surgery & Communication Sciences (HNS&CS) recently launched Project CHECKERS (Community Head and NEck Cancer Knowledge, Engagement, Research and Screening) a Duke Cancer Institute-funded pilot project to bring head and neck cancer resources and education to the broader Durham community.
Led by DCI head and neck surgeon Trinitia Cannon, MD, an associate professor in the Department, the project will be the Department’s first community-based participatory research project and the first such head and neck cancer screening and cancer prevention education project in North Carolina.
Evolving Community Research
The Project CHECKERS team will use a mixed methodology, which includes traditional surveys and screenings as well as interviews and focus groups.
One of their community partners will be the Cedar Creek Apartment Complex community in North Raleigh. Many of these families are refugees — from at least seven different countries in Africa, Asia, and the Middle East — who speak Farsi, French, Swahili, Arabic, and other languages. They are building new lives in North Carolina, in a culture and language that is new to many of them. As is the case with many similar communities, their healthcare needs often go unmet.
The investigators believe that, compared to traditional methods, mixed-method research is an improved way to establish a community partnership, highlight gaps in the community’s knowledge and risk perception, and pave the way for successful future health interventions.
According to co-PI Nosayaba (Nosa) Osazuwa-Peters, BDS, MPH, PhD, an associate professor in the Department of Head and Neck Surgery & Communication Sciences, Project CHECKERS takes an important step in improving community engagement.
“Traditional research is very systematic, very top-down. The researchers have knowledge and decide what they believe the community needs. But these outside scientific experts do not know the values, the culture, the knowledge, or the risks inherent in that community,” he explained.
For example, traditional surveys restrict participants to answering either yes or no; for many people, that binary does not tell a complete story.
“Project CHECKERS will help us understand the lived experiences of people in these communities,” added Osazuwa-Peters. “We’ll learn about context, and we’ll learn to ask questions that allow community members to express themselves. We’ll get responses we would never get based on yes or no.”
Building a Partnership
Project CHECKERS kicked off this fall with focus groups and interviews with community members facilitated by Laura Fish, PhD, MPH, assistant professor in Family Medicine and Community Health, Duke University School of Medicine, and program director for the Behavioral Health and Survey Research Core (a DCI shared resource). An advisory board will provide feedback from both clinical and community perspectives.
Lessons learned from these conversations will help the team develop a knowledge and risk factor survey that will be administered during two head and neck cancer screening events with the community in 2024.
The CHECKERS team will also recruit providers outside the department to participate in these events to address other health concerns in the community such as primary care, mental health, and women’s health.
The long-term goal of Project CHECKERS is to show the benefits of tailoring head and neck cancer screening programs to the communities being served, and how that personalization can improve prevention, early detection, and overall survival in high-risk individuals who have limited access to care.
Noted Osazuwa-Peters, “The mixed-methods framework helps us understand not just whether an intervention works, but how, why, and for whom.”
Community Partners
Another plus to mixed-methods research is its appeal to community partners who might otherwise be hesitant to work with researchers.
“The design places a high value on the stories behind the numbers,” explained Cannon, “so these projects are especially attractive to community partners such as faith-based organizations, whose priority is improving practice and outcomes, more so than research and advancing knowledge.”
Project CHECKERS will provide a valuable bridge between Duke and the North Raleigh International Baptist Church (NRIBC), which ministers to a large immigrant community. NRIBC’s Pastor, Patrick Warutere, invited Duke to participate in the church’s inaugural Health and Dignity for All Fair in Raleigh in 2022. Cannon and CHECKERS co-PI Leda Scearce,CCC-SLP, MM, MS, a Duke speech pathologist and director of Community Engagement for the Department of HNS&CS, recruited nurses, medical students, and resident volunteers to provide HNC screenings for the event.
“We immediately felt a kinship with NRIBC’s Pastor Patrick Warutere and his leadership team,” shared Searce. “By the end of the day, we knew we wanted to continue to work together and set up a meeting the following week.”
Duke HNS&CS and the NRIBC team worked closely to develop the research plan and ensure that the goals and expectations of each group were aligned and transparent.
“That relationship with NRIBC has enabled us to incorporate the community’s perspectives into the development of Project CHECKERS,” said Scearce. “Our aim was to amplify the assets and expertise of the community members themselves.”
Cannon anticipates that Project CHECKERS will become a framework for future projects.
“We are looking forward to similar initiatives in hearing health for older adults, right-hemisphere stroke awareness, and more.”