Denis Malyshev

The DNA Amplifier

Synthetic biologist is expanding the genetic alphabet to create unnatural proteins

Earthly life-forms, from microbes to whales, all share the same DNA structure, with ladder rungs that pair the amino acids adenine with thymine and cytosine with guanine. Or at least they did until 2014, when grad student Denis Malyshev and colleagues at Scripps Research Institute California revealed they had inserted functional DNA, expanded with a third, man-made base pair, into living Escherichia coli bacteria.

Synthetic biologists manipulate the genes of bacteria every day, but they are limited to using nature’s four-letter DNA alphabet. By giving bacteria more letters to work with, Malyshev and his colleagues greatly expanded the number of products they can manufacture.

Malyshev, who grew up in Russia, began his scientific training very young; he attended a chemistry-focused high school in Moscow that emphasized research. As an undergraduate at the Higher Chemical College of the Russian Academy of Sciences, Malyshev was a coauthor on eight research articles, including one in the Journal of the American Chemical Society.

At Scripps, Malyshev landed in the lab of Floyd E. Romesberg, whose team was working with man-made nucleotides. “I was so thrilled with the idea of tinkering with the most important thing in nature,” Malyshev recalls.

Malyshev coaxed the expanded DNA into replicating in a polymerase chain reaction. But it was his work in living cells that brought worldwide attention to the research. He created the first semisynthetic organism, with a six-letter genetic alphabet and the potential to make entirely new types of proteins.

Malyshev is now a scientist at La Jolla, Calif.-based Synthorx, a start-up founded by Romesberg to translate the potential of those unnatural proteins into actual products. “I want to see this impact biotechnology, drug discovery, and vaccine development,” Malyshev says. “We have a chance to disrupt how medical biology is done today.” -Melody M. Bomgardner

Vital Stats

Current Affiliation: Synthorx

Age: 29

Ph.D. alma mater: Scripps Research Institute California

Talent: Engineering DNA with unnatural base pairs and inserting it into living cells to make never-before-seen proteins.

Scientific role model: Elon Musk. He challenges conventional wisdom, goes against the flow, and backs his ideas with his own money, Malyshev says.

Three Most Important Papers By Malyshev:

“A Semi-Synthetic Organism with an Expanded Genetic Alphabet” (Nature 2014, DOI:10.1038/nature13314)

“PCR with an Expanded Genetic Alphabet” (J. Am. Chem. Soc. 2009, DOI: 10.1021/ja906186f)

“Palladium and Platinum Catalyzed Hydroselenation of Alkynes: Se–H vs SE–SE Addition to C=C Bond” (J. Organomet. Chem. 2003, DOI: 10.1016/s0022-328x(03)00546-1)

Research At A Glance

As a grad student, Malyshev added a man-made base pair (X-Y, shown) to DNA and then inserted the genetic material into living bacteria. The work opens the possibility of building never-before-seen proteins with novel amino acids.
As a grad student, Malyshev added a man-made base pair (X-Y, shown) to DNA and then inserted the genetic material into living bacteria. The work opens the possibility of building never-before-seen proteins with novel amino acids.

Credit: Synthorx

Matt MacDonald
Hosea Nelson
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