A Patient Path to the Nobel Prize

Walk into the science lab of a newly minted Nobel laureate, and you’ll spot the expected and not-so-expected things: pipettes, flasks, syringes, centrifuges, filtration equipment, radioactive-safe refrigerators, disposable gloves, notebooks of data, the journals Nature and Science, books like Molecular Biology of the Gene and The Biology of Cancer, tubes of Elmer’s glue, and a couple of pet guppies in their tanks. Displayed on walls and as computer screen-savers are images pointing to an enduring attachment to New Mexico: a Native American in full Navajo gear, an antelope herd, views of the surrounding mesas, riders in a rodeo, buffalo roaming on Ted Turner’s nearby ranch. Plus some fading photos of a tiger named Camilla that, back in the day, made her second home under a lab bench.

Paul Modrich’s lab is a reflection of the man. Meticulous, observant, and as unassuming as his standard outfit, blue jeans. He hates any hint of sloppiness or carelessness; he hates any trace of bragging or bluster. A James B. Duke Professor of biochemistry and a Howard Hughes Medical Institute investigator, he was awarded one-third of this year’s Nobel Prize in Chemistry. One of his co-winners is Aziz Sancar at the University of North Carolina at Chapel Hill—who had been putting Modrich’s name up for the Nobel for some ten years. The other is Tomas Lindahl of the Francis Crick Institute and Clare Hall Laboratory, near London.

For decades Modrich has studied cell-based mismatch repair, the molecular machinery that detects and corrects errors in DNA replication. The research of the three scientists, who worked independently of each other, “has made a decisive contribution to the under-standing of how the living cell functions,” in the words of the Swedish Academy of Sciences. That research also has contributed knowledge about “the molecular causes of several hereditary diseases and about mechanisms behind both cancer development and aging.”

In early October, Modrich and his wife, lab colleague Vickers Burdett, were on vacation in Rumney, New Hampshire, whose past notable residents include a nineteenth-century Supreme Court justice and an Olympic luger. Their 700-squarefoot cabin sits alongside a small lake where they keep a canoe. The Nobel authorities in Sweden had a hard time coming up with a phone number. He first heard the news of the Nobel from former students who were texting him with congratulations; one of his first calls was to his assistant back at Duke, apologizing in advance for what was sure to be a crazy day on the job. A few days later he found the official announcement somewhere in his Apple Mail “junk” file. There was pressure on Modrich to make a hasty return to North Carolina. He demurred in favor of finishing the long-planned stint away and taking the time to close down the cabin properly.

When he did get back to campus, Modrich was, of course, projected into instant celebrity status. That meant, among much else, being brought to midcourt for a basketball season opener, which happened to be his very first time in Cameron Indoor Stadium since arriving at Duke, as an assistant professor, in 1976. Along with fellow biochemist Robert Lefkowitz, who won the Nobel Prize in Chemistry three years ago (and who joined Modrich on the basketball court), he’s authentically a homegrown Nobel laureate for Duke.

At a campus celebration, Lefkowitz, referring to Modrich, offered a wry commentary on the life of a Nobelist: “Your name has been forever changed. You are now Nobel Laureate Paul Modrich, no matter how inappropriate that title might be, when somebody is introducing you. And you’ll be congratulated everywhere for your Nobel Peace Prize. Or for your Nobel Peace Prize in Chemistry. I hope you can enjoy the hoopla. Knowing you, I don’t think you will.”

Lefkowitz also shared “9 Simple Steps to Winning a Nobel Prize,” a prescription from Michael Brown, the 1985 Nobel Prize winner in Physiology or Medicine: Be curious. Train with a Nobel Prize-winner or equivalent. Find a partner to share the adventure. Find a problem that fascinates you. Find someone to pay for your work. Work very hard. Solve the problem. Be lucky. Pick the right spouse. As Lefkowitz noted, that pretty much outlines the high points for the life and work of Paul Modrich.

About that Nobel-related need to find the right spouse: It happened for Modrich and Burdett when they were both new to Duke. She was trained as a microbiologist and was running her own lab. One day she came by the Modrich lab and asked him the question that sparked a friendship, and then a romance: Could he spare some samples of enzymes for one of her experiments? Since then, she says, “We’ve been together basically twenty-four hours a day.” As lab colleagues, they work in the same space. “We enjoy each other’s company. I’m a sounding-board for him, and he’s a sounding- board for me. But we try not to discuss too much work at home.”

One of their early shared experiences came with the arrival of Camilla the tiger cub. The cub came from Carolina Tiger Rescue in Pittsboro, North Carolina, a wildlife sanctuary devoted to protecting big cats. Modrich was a friend of the organization’s director, who was promoting the idea of having infant tigers—destined for zoos or animal reserves—hand-raised by humans until they were about six months old. Modrich’s photos show the cub, fueled by a meal of chicken parts and playing with a stuffed toy, on Duke’s campus. He brought it to work every day. Also pictured in the scene is Modrich’s first lab technician, who, perhaps showing big-cat influence, went on to become a veterinarian.

As Modrich recalls, “There were two things that our apartment complex prohibited: a water bed and a pet. We had a water bed, a dog, and a tiger.” Modrich was ready to part with the tiger when the time came, and it weighed about sixty pounds. Sure enough, it did tear a hole in the water bed. That didn’t sink Modrich’s spirits, and he managed to repair the bed.

It’s the molecular mechanism of self-repair that put him on the path to the Nobel. Genetic material is maintained and corrected in the face of copying errors, radiation, and inherent DNA instability. Nearly 2 trillion cells divide in the body every day; the more times DNA is copied, the greater the chance that a change, including a change with bad consequences, will be made. As one analysis, in Chemical & Engineering News, described it, without DNA repair, humans would “live short, dark, disease-ridden lives.”

According to the will of Alfred Nobel, the lives singled out for the chemistry prize would recognize “the most important chemical discovery or improvement.” The Australia-based Cosmos magazine noted that over the past decade, half of the chemistry Nobels have been awarded for discoveries in biological systems. The chemistry Nobel going to Modrich, then, points to the permeability of the boundaries that once defined science— and to the chemical underpinnings of our understanding of the human system.

“Paul has an amazing insight into science, almost intuitive,” says Bob Lahue, now professor of molecular genetics at the National University of Ireland in Galway. Lahue was a postdoc in the Modrich lab in the late 1980s. “There might be three explanations for a particular scientific result. And he would unfailingly predict one. Several months later, after doing all the experiments, it turned out he was right.”

Not just right in his scientific speculations. Also steadfast in his analytical approach. A Modrich lab member from the mid- to late 1990s, Dwayne Allen, says Modrich’s career “shows the power of classic biochemistry.” (Allen is now head of the quality-control lab at Ajinomoto North America, an amino-acid manufacturer for pharmaceuticals and medical foods.) Essentially, the idea is to keep purifying things to get at the fundamental understanding of a biological process.

“Sure, things have gotten fancier, with more expensive equipment and exotic methodologies. But Paul is faithful to that classic approach: You take bacteria and grind them up, make some sort of soup or cocktail, and then go fishing for some way to purify it. The way you go fishing is to devise a simple, straightforward, elegant test to isolate bacterial activity. Paul has carried on in that tradition. And he has produced a wealth of information about mutation and how cells correct replication errors.”

That wealth of information from the Modrich lab began with work on bacteria, then fruit flies, and finally human cell lines. Early on, Modrich decided to “work on something fundamental,” says Allen. “When you work on something derivative, you can be pretty sure it’s going to produce something, and that certainty attracts some people who are in academic jobs. When you do that sort of work, extending knowledge about what’s already been proven, there is little risk in terms of the ability to produce scientific papers and get grant money. The major advances in scientific knowledge are a result of asking fundamental questions, as Paul does. But there is never a guarantee that trying to tackle those questions will yield results.”

A world of biological complexity was long familiar to Modrich. He grew up in Raton, in the northeastern corner of New Mexico, about ten miles from the Colorado border. It was not a land of endless opportunity. “Everyone seemed to end up managing a store, working in the coal mines, or becoming a cowboy. That was about it.”

But to the future scientist, there were virtues to life in small-town New Mexico. “I guess life was different in those days,” he says. “My parents and the parents of my friends gave us a great deal of freedom. After school, we were on our own. And we spent a lot of time wandering the hills. I was always impressed by the natural beauty of the environment—the diversity of plant and animal life, the spectacular skies at night. You can go a few miles, and the ecology is completely different. It was just a wonderful place to grow up.”

His father taught high-school biology; over the years, he coached football, basketball, and tennis, and he was among the first inductees into the New Mexico Coaches Hall of Fame. Just about everyone in the town of 7,000 or so seemed to know the elder Modrich. “He was also an excellent biology teacher. In fact he was the only biology teacher in town.” Modrich recalls getting an A in the course. He smiles and adds, “I don’t think it was nepotism.”

“My father was a fairly large man. My brother was built like him, and he was more interested than I was in pursuing athletics. I was interested in other things,” he says. Other things like biology. “When I took my father’s biology course, it was pretty traditional—physiology, taxonomy. There was an experimental biology course being developed that emphasized molecular biology. He was one of the first teachers to participate in that. But it kicked in a year after I had taken biology from him.” Still, his father had discovered a new angle into biology, and Modrich recalls the fatherly advice: “Son, you ought to learn about this DNA stuff. It’s really interesting.”

By the time he was a college sophomore, Modrich, too, was finding the field interesting. At that point, at the Massachusetts Institute of Technology, he was taking a course that explored the work of James Watson and Francis Crick, who would be awarded the Nobel Prize for discovering the structure of DNA. His undergraduate adviser was Salvador Luria. A microbial geneticist, Luria would receive the Nobel Prize the year after Modrich graduated. Modrich landed a job in the lab of Ethan Singer, a pioneer in genetic recombination. He started in a job washing glassware in the lab; eventually he helped out with experiments. As a senior he took a graduate-level course in molecular genetics.

From MIT, Modrich went to Stanford University for graduate work. His Stanford mentor, Robert Lehman, now in his nineties, remembers Modrich as “the most intense graduate student I ever had. He focused on a problem like a laser beam and could not be distracted or diverted until he got a successful conclusion from the experiment. Paul already knew about life in the lab; he knew that much of the time there are frustrations in science, but occasionally something comes out of the work you’ve done. Things worked in his hands. When he set up an experiment, he thought it through very carefully. He didn’t have to be taught. It was innate.”

In their life-after-Stanford conversations, Modrich told Lehman that he wanted to work on gene regulatory mechanisms. It would be his career-long challenge— pursued, Lehman emphasizes, with relentless focus. (Before he was lured to Duke, Modrich went on to a postdoc fellowship at Harvard University and a brief teaching stint at the University of California at Berkeley.)

Farid Kadyrov, a postdoc under Modrich in the early 2000s, says he heard a lot from Modrich about those shaping years. (Modrich was instrumental in getting Kadyrov his current position, associate professor at Southern Illinois University School of Medicine.) As it turned out, another future Nobel laureate would have as his scientific origin point the same Stanford lab. “Senior researchers would treat graduate students as colleagues. They would always be available. Someone like Paul could always walk into a researcher’s office and talk about anything.” And that, Kadyrov says, became the model for the Modrich lab at Duke.

Shin-San (Michael) Su Ph.D. ’87 spent four years in the Modrich lab as a graduate student in biochemistry. Today Su is senior vice president for research and development at Agios, a pharmaceutical company that applies cellular metabolism to the treatment of cancer and genetic diseases. He and other lab veterans look back on the frequent group meetings as basic to their lab experience: People would talk about the hypotheses they came up with, how they might proceed to test those hypotheses, the results they were getting, and how they might interpret those results. All that learning and observing was basic to a scientific education.

“Each individual scientist joining Paul’s lab had his own line of research,” Su recalls. “But by working tougher and brainstorming ideas, they also managed to tackle much more complex problems.” After Su completed his thesis defense, Modrich and Burdett took him out to dinner. “I asked him for any word of advice as I continued my scientific career. He told me to be original in my thinking and to follow my gut, and not to just follow in other people’s footsteps.”

As she has watched him run the lab over the decades, Burdett says she has admired Modrich’s expert balancing act: encouraging lab members to avoid going off on a research tangent, to keep an eye on the overall picture, not to get hopelessly lost in the minutia. “It’s easy to imagine doing work that draws you in at the moment but that leads you to a dead end. Paul has always been good about keeping everyone on track by reminding them that these are pieces of a big puzzle.” And there are always the questions, from Modrich and lab colleagues, driving their science: Could you do this experiment better? Could you get cleaner results? Could you ensure the results you have are reproducible?

“When I look at those I regard as having been the most successful in the lab, and who have proven successful on their own, I think they share several characteristics,” Modrich says. “One is extraordinary interest in and enthusiasm for science. The other is a superb work ethic.”

Those are qualities that another postdoc from the early 2000s, Nicoleta Constantin, says she saw everywhere in the lab. “There wasn’t a strict hierarchy. My feeling was that we were all equal; Paul didn’t favor anybody over anybody else. In that lab you had smart, self-confident, independent people. And there was competition, for sure.”

It was a competition that involved demonstrating ability as an independent scientist, but also as a collaborative researcher who could inspire others into new thinking. Modrich “would show this laser-like ability to isolate a problem, to define a question in the most elegant and simple way,” she says. “And if we landed on a dead end, with results that weren’t reproducible, he would sit us down and we’d troubleshoot or move on to a different project. But it would always come down to doing work of high quality. Paul was impeccable in that regard. If you see a published paper with his name on it, you know it’s of high quality. Otherwise he wouldn’t let it out of his lab.”

The training she got from Modrich’s lab “was not only about DNA repair,” she adds. “It was a way of thinking. It was a way of living. It was the discipline and the motivation to get you to your goals. It was about high expectations and getting results appropriate to those expectations.” She still looks to Modrich for work-related advice, even though she’s veered into a different field: She’s a pediatric nurse in the children’s hospital at the University of North Carolina at Chapel Hill.

Modrich sees his own growth as a scientist tied to his becoming “a little more discriminating” around research questions. “When you’re doing science in a particular problem area, there are many, many different paths that you can follow. Selecting the right path, the right sequence of questions to pursue, can be very important in the success of that project. That’s something I’ve tried to convey to the people who have worked with me. The path that you’re following can be changed dramatically as a consequence of the work of others in the field. Or as a consequence of a serendipitous finding you make in the lab.

“I mean, you write a research grant and you say, ‘I’m going to do A, B, C, D, and E.’ And that’s really not the way science works. It’s more likely that you’re pursuing one thing, and then you find something interesting that may lead you to change your direction. What I think is very important for success in science is making the right choices, because at any point you can take multiple paths.”

Science is grinding work. It doesn’t deliver instant rewards. Modrich has been turned down for grants. And he observes that the “rule of thumb” in science is that 90 percent of experiments don’t work.

Frustration and pressure are “just part of the life of a scientist,” he says. “But it’s a truly wonderful life. You’re essentially your own boss. And you determine what you do, what kind of questions you pursue. Essentially you plot your own future.” His own future, he adds, has him in a better place, temperamentally, after a lot of the Nobel hoopla—the White House receptions, the constant invitations to keynote scientific conferences, the presentation of the Nobel Lecture, the bestowing of the Nobel Medal and the Nobel Diploma by Sweden’s royalty—has exhausted itself this winter.

The lab is much smaller than it was in the past, and Modrich talks about now seeing himself on the path to retirement. There’s less administrative oversight required on his end. And more time at the lab bench. A visitor wonders whether the thought of returning to his scientific roots is pleasing—more pleasing than the hoopla. He smiles broadly. “Exactly.”