Education

For Paul Modrich, frenzy and failures yield truths

Tar Heels of the Year: Aziz Sancar and Paul Modrich

Tar Heels of the Year Aziz Sancar of the University of North Carolina and Paul Modrich of Duke University share stories of receiving the 2015 Nobel Prize for Chemistry.
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Tar Heels of the Year Aziz Sancar of the University of North Carolina and Paul Modrich of Duke University share stories of receiving the 2015 Nobel Prize for Chemistry.

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The News & Observer’s Tar Heel of the Year

The News & Observer recognizes North Carolina residents who have made significant contributions in the last year and beyond. This year, we asked readers to tell us about people who have made a difference in our state. Here are our stories.

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Paul Lawrence Modrich was an explorer from an early age.

Born in 1946 in Raton, in northern New Mexico, where the foothills of the Rocky Mountains blocked most television signals, Modrich spent much of his childhood outdoors, playing basketball or baseball with friends, or hiking into the hills to look for fossils.

“It was the perfect place to be a child,” he says of his hometown, which had fewer than 7,000 residents. “Completely safe, all this room to explore the natural world. We had to entertain ourselves, and we learned to do that.”

Modrich’s early education about science and nature was more about discovery than disciplined study, he says. “It wasn’t really a directed enterprise. To some extent, you would find something and then take it home to figure out what it was.”

More than five decades later, Modrich has been recognized as one of the top scientists in the world.

I like the day-to-day discoveries. That’s how science moves.

Paul Modrich

Though he conducts regular lectures, most of his teaching, he says, is done at a bench in the lab at Duke University, under the fluorescent lights, amid the glass beakers and tiny test tubes and the humming machines, helping individual students and post-docs design and conduct experiments and interpret results.

He has resisted offers to move into more administrative jobs, he says, because, “I like to work with my hands. I like the physical manipulations we do. I like the day-to-day discoveries. That’s how science moves.”

So, two or three days a week, Modrich comes into the lab to do an experiment, to ask questions, to seek answers, to explore.

‘This DNA stuff’

Modrich’s father, Larry, who taught biology and coached basketball, football and tennis at Raton High School, hoped his son, one of two boys, would play sports but also encouraged his bent toward science. In 1963, a year after a Nobel Prize was awarded for the discovery of the double-helix structure of deoxyribonucleic acid, the molecule that carries the genetic information of every living organism, the prescient elder Modrich told his junior-year son, “You should learn about this DNA stuff.”

After high school, Modrich – pronounced “MAH-dritch” – studied biology at MIT, where he worked in a lab that examined the genetics of viruses that infect bacteria. When he went to Stanford University for his Ph.D. in biochemistry, and during his postdoctoral work at Harvard University, he studied a series of enzymes and their effects on DNA molecules.

His first job was at the University of California, Berkeley, working in a large department and carrying a relatively heavy teaching load.

“Graduate students weren’t really interested in what I was doing” as a researcher, Modrich says, so he left Berkeley in 1976 and came to Duke, where he is the James B. Duke Professor of Biochemistry.

Of slender build, with white hair, a mustache and and a quick, high-pitched laugh, Modrich favors casual clothes to a white lab coat unless he’s working with radioactive chemicals. But Shanen Sherrer, a postdoctoral fellow who came to work in Modrich’s lab in 2011, says there is no mistaking when he’s at work.

“There are stages,” she says. “First, there’s this frenzy as he gets started and everyone moves out of his way and figures out where he wants to go. If he can’t find what he needs, he calls [his wife] to help him find it.”

Once the experiment gets started, Sherrer says, “He loosens up. He talks with the other people in the lab, he checks his email.”

Then, she says, at the end of the day, “There’s another frenzy because he wants to finish up and go home.”

Besides the science that happens there, a research lab can also be a social petri dish, where brilliant people with big egos and different backgrounds have to work closely together. In Modrich’s lab, there are frequent clashes, according to those who work there, usually professional disagreements over the best way to achieve results.

Sometimes, one disgruntled researcher will complain to Modrich about another one.

“I feel like he’s sort of the father of the lab,” Sherrer says of Modrich, who has an adult son and daughter from his first marriage. “And just like children do when they’re fighting behind a parent’s back, you don’t want to tattle because the tattler will get in trouble. He will shine the mirror back on the person tattling and say, ‘Well, you’re no angel either. Cut it out. We’re all adults here.’ ”

Though he is famously shy and somehow manages to always be out of town on his own birthday, Modrich insists on celebrating the birthdays of everyone else in the lab “whether they want to or not,” Sherrer says. He needles them to take time off and to be with their families.

“I know you have heard about people doing 70-plus hours in the lab every week and not knowing what’s going on in their neighborhood,” Sherrer says. “He’s not one of those.”

DNA vulnerable

When he came to Duke, the Research Triangle was not yet known as a center for the study of genetics. That science was being done by relatively few specialists in the U.S. and elsewhere who tended to cluster around promising researchers and labs that had the sophisticated, costly equipment the work required.

Tomas Lindahl of Sweden was one pioneer. In the 1970s, he showed that DNA was inherently vulnerable to mutation and damage, which happens as a result of copying errors and injuries from the time sperm and egg cells form, and through a lifetime of exposure to chemical and environmental assaults. DNA is constantly being damaged – up to 50,000 lesions per day per cell in humans – and so must be constantly repaired to sustain life and minimize disease.

The discovery that DNA undergoes repair had launched a whole new field of study, and Modrich wanted to be a part of it.

Studies in Matthew Meselson’s laboratory at Harvard in the 1970s indicated that mistakes occurring during chromosome replication are corrected by a process called mismatch repair. Modrich was interested in the molecular mechanisms by which mismatched base pairs are recognized and corrected. His laboratory initially determined how mismatch repair works in the bacterium E. coli, and then clarified the mechanism of the reaction in human cells. These studies identified 13 proteins and enzymes involved in E. coli mismatch repair, and eight in the human reaction.

Modrich and his colleagues showed that when the human mismatch repair system does fail, it can lead to cancer, including Lynch syndrome, one of the most common hereditary cancers. With an understanding of why the cells’ repair system fails, science ultimately might be able to prevent the resulting diseases or slow their progress.

Modrich’s lab also found that mismatch repair-deficient cancers are resistant to certain chemotherapeutic drugs, which has implications for treatment protocols.

Today DNA testing is a consumer good available for less than $200 to anyone curious about their ancestry or predisposition to disease. So it may be difficult to imagine how hard it was four decades ago to conduct the kinds of experiments that landed Modrich and Aziz Sancar in the biochemistry and molecular biology textbooks now used around the world.

“You couldn’t just go out and buy these enzymes,” says Vickers Burdett, Modrich’s wife and an accomplished scientist in her own right, who also arrived at Duke in the 1970s. She was in the Department of Microbiology then, and though she was working in an unrelated field of study, she wanted to use some of the materials Modrich was cultivating in his lab in some of her experiments.

“So I came to talk to him about getting a little of his precious enzyme,” she says.

Passion for the work

In some places, says Jack Griffith, who has studied DNA at UNC-Chapel Hill for decades and is friends with both Modrich and Sancar, research is a cutthroat enterprise where colleagues are fierce competitors. But here, maybe because they were trying to establish the Triangle as a center for DNA research, Griffith says, researchers at the universities and at the National Institutes of Health have tended to help one another.

People ask me how it is to spend 24 hours a day with the same person. (With Modrich) It’s not difficult. The compatibility has just always been there.

Vickers Burdett

“People realized that they would have to get together and collaborate and cooperate,” he says.

Modrich shared the enzyme with Burdett, “And we became friends,” she says. “I liked everything about him.”

They married in 1980 and moved into a rural, wooded area outside Chapel Hill. The house where they live now, built in 1976, is a wood-and-stone melding of the clean, uncluttered lines of mid-century style and the warmth of a mountain cabin.

Burdett continued to run her own lab until 1998, when she closed it and joined Modrich in his.

“People ask me how it is to spend 24 hours a day with the same person,” Burdett says. With Modrich, “It’s not difficult. The compatibility has just always been there.”

It helps, she says, that she understands his passion for the work and appreciates the time and devotion required to do it. She once worked with Modrich on an experiment that took five years to set up and complete, only to yield no usable results. In fact, researchers say, most experiments don’t work as hoped.

“Nothing is ever wasted,” Burdett says of such endeavors. “You’re still learning something. You’re learning a technique, or you’re learning different ways of approaching that particular kind of problem.”

Now 69, Modrich has cut back a bit; he has just six people working in his lab now, including post-docs and seasoned researchers, down from a high of about 20. He’s able to take more time away from ongoing experiments than he once could. The couple travel when they can, mostly to a remote cabin in the woods of New Hampshire that Burdett’s father built, and to a home in rural New Mexico the couple built together.

They’re also comfortable spending evenings at home with their playful Weimaraner, Dover, and an old movie they’ve watched a thousand times running in the background. Modrich also is a fan of “Breaking Bad,” the popular but now defunct TV series about a high school chemistry teacher who turns to a life of crime.

Modrich and Burdett were in New Hampshire when they got the news that Modrich had won the Nobel in chemistry, and though he says he did not expect to win and did not intentionally plan to be away, he was relieved not to be at his lab when camera crews and reporters arrived that morning.

“He’s very shy,” Sherrer says. She is, too, and when either one has to make a presentation, she says, each offers the other a little extra support.

Getting it right

As Nobel Week approached, Modrich spent hours culling slides to use in his presentation for an audience mostly of people who read the same dense journals to which he subscribes.

“I’m not a good public speaker,” Modrich says, but in conversation, he patiently, quietly explains the complicated science of DNA mismatch repair as easily as a seasoned cook might describe creating a delicate sauce. In his formal lecture at Stockholm University during Nobel Week, he explained the science and made sure to credit dozens of other researchers whose related work has advanced the field.

More than his presentation to the Nobel VIPs, Modrich was worried about a 15-minute talk he was scheduled to give to a group of Swedish high school students during his trip to Stockholm.

“That’s a little intimidating,” he says. “You don’t want to waste their time.”

In publishing, Modrich takes his time, says Sancar, who has been friends with Modrich since the early 1980s and has collaborated with him on several research papers. Where Sancar is willing to publish when he is 80 percent certain his conclusions are correct, he says, “Paul wants to be 100 percent sure he’s correct.”

Modrich feels the pressure to announce a new discovery, he says. “I can be competitive. But I find it very distracting. It’s better to be right than first.”

You start working on one thing, and it leads you to something else. So it keeps you interested.

Modrich

As much a perfectionist outside the lab as he is in it, Modrich tends to drill deeply into what hobbies he has time for. Those include photography, astronomy and trap shooting.

“I like the physics and the precision of firearms,” Modrich says, but he doesn’t hunt. “I don’t like to kill animals.”

Though he says he was surprised to be named a Nobel winner, Modrich is delighted that DNA repair has finally been recognized by the Royal Swedish Academy of Sciences in the very field – chemistry – in which Alfred Nobel distinguished himself with the invention of dynamite.

But with the Nobel banquet behind him, it’s time for Modrich to get back to the lab.

“There are two wonderful things about science,” he says. One is that, because life in the lab is so intense, the friends made there last for life.

The other, he says excitedly, is that, “You start working on one thing, and it leads you to something else. So it keeps you interested.

“You’re always learning something.”

Paul Lawrence Modrich

Born: June 13, 1946, Raton, N.M.

Family: wife, Vickers Burdett; daughter, Amy Modrich of Oakland, Calif.; son, Adam Modrich of Chapel Hill; brother, David Modrich of Raton.

Education: B.S., biology, Massachusetts Institute of Technology; Ph.D., biochemistry, Stanford University.

Career: Currently the James B. Duke Professor of Biochemistry at Duke University Medical Center, member of the Duke Cancer Institute, investigator with the Howard Hughes Medical Institute.

Extracurricular: Quiet vacations in New Hampshire and New Mexico; amateur photography, astronomy, trap shooting.

Honors: Nobel Prize in chemistry, 2015; fellow, American Academy of Arts and Sciences; member, Institute of Medicine of The National Academies; Investigator, Hughes Medical Institute; member, National Academy of Sciences.

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