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The traditional four-letter DNA alphabet wasn’t good enough for Denis A. Malyshev and Floyd E. Romesberg, Malyshev’sgraduate adviser at Scripps Research Institute, La Jolla, Calif. “What happens if you add two more letters to the natural genetic alphabet?” Malyshev asks.
What they found “has profound implications and has revolutionized efforts to express and evolve proteins with unnatural amino acids,” says Dale L. Boger, chair of the chemistry department at Scripps. That is why the work earned Malyshev, 28, the Nobel Laureate Signature Award for Graduate Education in Chemistry, which comes with accolades for Romesberg, 48, as well.
Malyshev already had significant lab experience and multiple publications before he got to Scripps. He went to a chemistry-focused high school, the Moscow Chemical Lyceum, in his native Russia, and his work there won him a best-of-chemistry prize from the Intel International Science & Engineering Fair in Cleveland. Then he studied chemistry at Mendeleev University of Chemical Technology of Russia. “I was doing hardcore organic chemistry and organic synthesis, and I was a little afraid of how far I wanted to step outside of that,” he says.
But he had developed an interest in biology and wanted to turn his chemical background toward biological questions. Malyshev had intended to rotate between labs to find the best biological fit—rotations were one reason he chose to go to graduate school at Scripps.
Instead, Malyshev quickly got hooked by his first rotation in Romesberg’s lab working on the synthetic DNA project. The unexpected choice made him ask a lot of questions. “I felt like I was being interviewed for the job of mentoring him,” Romesberg jokes.
Previous graduate students in the lab had already created a new pair of synthetic letters, but they had not yet really attempted to use them, Romesberg explains. He could quickly tell that Malyshev would be a good fit for the delicate project, which would inevitably require a lot of troubleshooting and great hands. “A lot of students aren’t good at that, but Denis was very good,” he says.
The next step was to show that the synthetic DNA letters could be copied in DNA, transcribed into RNA, and then amplified with polymerase chain reaction technology. While successfully completing those steps, Malyshev and Romesberg also demonstrated that the unnatural base pair made from the two new letters was functionally equivalent to a natural base pair. That alone might have been enough for a top-rate thesis.
But then Romesberg and Malyshev decided to take the work to the next level. “I wanted him to do something that was significant,” Romesberg says. They inserted the unnatural base pair into an Escherichia coli bacterium, where it was replicated along with natural DNA and was maintained for nearly a week. “When I started up my lab 15 years ago, this was the goal,” says Romesberg, who got his Ph.D. at Cornell University and did a postdoc at the University of California, Berkeley.
The breakthrough promises to revolutionize the ability to make proteins containing new amino acids outside the 20 natural ones. And that could lead to a wide range of useful proteins and drugs translated from the unnatural DNA to treat specific ailments. Malyshev graduated in late 2013, and he was the first employee of Romesberg’s new company, Synthorx, which is working to commercialize the technology.
Malyshev says he has always dreamed of doing something big—designing a next-generation computer or launching a rocket or creating a breakthrough drug. “I always wanted to do something that makes a difference and that other people care about,” he says. “I can see a lot of potential in this.”
Romesberg and Malyshev will present the award address before the Division of Biological Chemistry.