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Nobel laureate Modrich excited to get back in the lab

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Nobel laureates Paul Modrich and Dr. Robert Lefkowitz were honored at Countdown to Craziness Saturday. The Chronicle recently spoke with Modrich about his recent award.

Paul Modrich—James B. Duke professor of biochemistry, member of the Duke Cancer Institute and Howard Hughes Medical Institute investigator—became the second standing faculty member in Duke’s history to win a Nobel Prize Oct. 7. He was awarded the 2015 Nobel Prize in Chemistry for his research on DNA repair, which has potential applications for fighting cancer and other diseases. The Chronicle’s Neelesh Moorthy recently spoke with Modrich about the award, his work and the importance of basic research.

The Chronicle: How did you react to winning the Nobel Prize? Did you have any idea ahead of time that you would receive this award?

Paul Modrich: I was extremely surprised. They didn’t have our number because we have a vacation cabin in New Hampshire. My cellphone started beeping around 6 [a.m.]. I got a text message, and it was “Congratulations for your Nobel Prize” from a former post-doc. And then I started getting a bunch of emails. I hadn’t heard from Stockholm, so I looked up the Nobel Prize website, and there it was.

TC: Could you explain your recent research on DNA repair?

PM: There are multiple DNA repair systems in the cells. We’ve worked on the pathway that recognizes base pairing errors—non-Watson-Crick base pairs—in the DNA helix.

The enzymes that copy DNA are incredibly accurate. DNA polymerase, as it copies DNA, makes about one mistake for every 1 million to 10 million bases copied. Each of your cells has 6 billion base pairs, or 12 billion bases, so this still corresponds to 1,000 errors per cell division. Our interest was how such a reaction could happen biochemically. To address this, we grew cells, broke them open to make a cell extract and added DNA with a mismatch to see if it might be repaired. This worked, and we then found that the reaction was defective in extracts prepared from cells with genetic defects in several mutator genes—genes shown by others to play a role in mismatch repair in the cell. This permitted us to purify the protein products of these genes and determine what they do. We then identified nine additional proteins required for the reaction and reproduced this replication error correction process using purified proteins.

Those studies were done in bacteria, and we were interested if a similar pathway existed in higher cells. So, we approached this problem using similar kinds of DNA substrates and showed that, yes, human cells have a similar reaction. Because we knew that the bacterial reaction plays a very important role in controlling mutation rate, the question was: Does this human reaction also have a role in genetic stability?

About this time, a paper appeared in Science from the de la Chapelle and Vogelstein Labs showing that tumor cells from patients with Lynch syndrome—the most common hereditary cancer—had frequent mutations in simple DNA repeat sequences that non-tumor cells from the same patients did not. When we saw that paper, the nature of the tumor mutations suggested to us that it was extremely likely that these cells were mismatch repair mutants. I called Bert Vogelstein with these thoughts, and he sent us cell lines derived from Lynch tumors. We looked at these biochemically, and we found that they were biochemically defective in mismatch repair. In terms of clinical implications, that’s one of the most significant consequences of the work.

Availability of these mismatch repair-deficient cancer cells also allowed us to identify and isolate the missing components, and this has recently culminated in our reconstitution of human mismatch repair in the test tube.

TC: What do you think have been some of the most impactful scientific discoveries in the past five to 10 years?

PM: There’s been tremendous progress in the area of neurobiology. It’s an area I’ve always regretted not going into—in fact, one I considered when I was in graduate school.

A second example is the recent isolation and characterization of CRISPR/Cas systems by Jennifer Doudna, Emmanuelle Charpentier and others. These systems arguably represent the most powerful genetic tool for the manipulation of the genomes of complex organisms. This technology is already raising serious ethical questions because it provides, in principle, for the ready modification of the human genome.

TC: Why is basic research important?

PM: Without this basic research by the mismatch repair community, when the Lynch syndrome mutations were identified, there would have been no knowledge base on which to speculate about the nature of the cause of that disease. But this is just one example. In my view, the bulk of the major advances in clinical medicine derive from our advances in our basic understanding of biological processes.

TC: Do you think basic research faces any challenges?

PM: I think that there are many. One of the most serious is availability of funds, particularly for young scientists. The scientific future of this and other countries depends on the successful nurturing of young scientists, and if they can’t get the funding to get their labs going, the future of science will be compromised. A lot of funding agencies are trying to address this, but it’s still a significant problem.

Why is this a problem? I think there are two issues. Funding has remained relatively flat or has decreased slightly in terms of real dollars. There’s also been an increase in the pipeline of the number of young people. It’s not clear to me what the answers to this are, but as I said, I think it’s a significant problem.

TC: What do you think scientists’ and science’s role in the media ought to be?

PM: The bulk of science done in this country is paid for by the public. I think that the public needs to know whether they’re getting their money’s worth, and probably the simplest way to do that is through the media and the Internet. That said, I think there are some cases when scientific findings are hyped in the media, but I’m not sure what can be done about that.

TC: How do you think receiving this award is going to affect your career at Duke moving forward?

PM: I have no idea. My interests are in experimental research. My lab is quite small now, and this has permitted me to go back and do experiments myself, which I enjoy tremendously. My intent is not to let this impact my ability to get back in the lab. I’d like to get back as soon as possible.

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