Alexis Komor

Our genomes—the vast collections of DNA that provide our underlying biochemical code—differ from person to person in millions of ways. But we know how only a fraction of those variations in DNA sequences affect health—for example, giving some people genetically low cholesterol or harboring a mutation that could lead to a deadly cancer. Alexis Komor thinks there’s much more we can learn from the differences in our genomes.

“Over 99% of the genetic variants that we’ve identified through sequencing, we have no idea what they actually do, how they’re impacting our health, whether positively or negatively or neutrally,” Komor says.

Komor, an assistant professor at the University of California San Diego, uses techniques she developed as a postdoc to introduce targeted changes to DNA in lab animals and cells and studies how those changes affect biological systems.

Throughout her career, Komor has used a molecular approach to get a detailed understanding of DNA. As a graduate student with Jacqueline K. Barton at the California Institute of Technology, Komor synthesized molecules that target DNA base mismatches, which often result in cancer-causing mutations.

“In my lab, she worked on designing molecules that bound preferentially to DNA mismatches as a first step toward designing new selective anticancer agents,” Barton says. “Her generation of molecules took us a whole quantum step further in terms of potency and selectivity.”

Komor then went to work as a postdoc with David R. Liu at Harvard University. “She’s one of the most determined people I’ve ever known. She is intellectually very rigorous and unforgiving in a really good way. Alexis is never tempted to trade off rigor for convenience,” Liu says. “As a result, she’s a brilliant scientist.”

In Liu’s lab, Komor developed the first DNA base editor—a tool that can target a desired location of the genome and chemically alter a specific base. It was an elegant idea, but it could have easily failed. Liu says that because of Komor’s rigor, it was clear the approach was going to work from the very first set of experiments.

Because of the therapeutic promise of DNA base editors, people have approached Liu about turning the sequencing gel from Komor’s first successful base-editing experiment into a nonfungible token, or NFT, he says. She agreed on the condition that any proceeds go to a charity supporting women in science or science education for underrepresented groups.

Now, at UC San Diego, Komor is combining her work in Barton’s and Liu’s labs to forge a new research direction. She’s using base editing to understand how mutations in the genes that code for our cells’ DNA-repair machinery can lead to disease. Komor is developing tools to introduce variants into DNA at will so she can study how they affect cells and animals.

Her team changes a DNA base and then watches to see what proteins the cell sends to deal with the resulting modified base pair. Sometimes proteins from one DNA-repair pathway appear; other times, proteins from multiple repair pathways work together. What the researchers have started to observe can get weird, Komor says. “It’s pretty exciting, actually.”

Research at a glance

Alexis Komor uses DNA base editors to introduce mutations in DNA so she can study DNA-repair processes. Base editors consist of a portion—usually a modified Cas9 combined with a guide RNA—that recognizes a specific DNA sequence, and an enzymatic portion—cytidine deaminase, in this example—that chemically alters a DNA base at the targeted sequence.

Credit: Adapted from Nature 2016, DOI: 10.1038/nature17946/Yang H. Ku/C&EN/Shutterstock

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