Becoming a World-Class Scientist & The Rules of Enzymes with Margaux Pinney

Margaux Pinney is a Sandler Fellow at UCSF and in our conversation we discuss her journey to become a scientist & leader in her field and her work around enzyme evolution. The Pinney Lab studies how enzymes work, how they got there, and how they will adapt in the future. Margaux grew up in a small town outside of Seattle; Black Diamond, WA named after the high quality coal the town used to produce. As someone "obsessed with details," she thrived in chemistry while in high school. Margaux first considered chemistry as a potential career after a teacher told her she was good at chemistry, Margaux then entered community college, leaving her senior year of high school. Taking organic chemistry and physics, she knew she would pursue science and with her community college professor Keith Clay as a major supporter, Margaux entered the University of Washington for college, working in James Mayer’s lab. Where she began her research on enzymes. And coming from chemistry, to Margaux, enzymes are pretty much magical.

Near the end of college, Margaux wrote an NSF proposal around directed evolution, and after getting the fellowship, she went off to graduate school at Stanford. In 2014, Margaux joined Daniel Herschlag's lab. But also did a master's in medicine, concurrently taking the first 2 years of medical school (the hardest 2 years by the way). To her, the master's program felt like an opportunity because she didn't have to pay the medical school tuition. A common theme in her career: taking full advantage of experiences. While at Stanford, she wanted to study enzymes. After a few references and a gut feeling she chose Daniel's lab. In retrospect, Margaux found the best mentors are committed, push you, and have the time. She initially worked on the RNA side. Telling a story she now uses as a proverb in her lab on doing one experiment at a time - Margaux, early-on, ran 9 gels at once, standing a foot tall and wide. Every single gel failed, and she learned to stick to one gel at a time. Margaux also learned she didn't want to work on RNA and moved to protein enzymes.

She began studying the role of hydrogen bonds in enzyme function. "Enzymes have a history" and are actively evolving. Margaux wanted to figure out the rules that drive enzyme adaptation. Starting as a side project, she began studying temperature adaptation. Something Daniel said not to work on but Margaux did anyway (Daniel and Margaux now joke about this). Ketosteroid isomerase (KSI) is a model enzyme system with about 70 years of research. But with just 2 orthologs studied out of 1000s, its evolution was overlooked. By shining a light on old problems with new tools, mainly a large database of enzyme sequences generated over the last ~20 years, Margaux was able to discover a pattern of single amino acid substitutions that are stabilizing at higher temperatures. Publishing her work in Science in 2021.

Throughout her journey, Margaux has learned that a high degree of commitment and flexibility are essential in science because it's both cyclical & a marathon. Around the time when the COVID-19 pandemic began, she started writing her thesis and won a fellowship at UCSF to start her own lab. She deferred to join the labs of Polly Fordyce & Gavin Sherlock as a postdoctoral fellow, learning their high-throughput methods for enzyme screening. In January 2022, Margaux got her lab off-the-ground to combine high-throughput screening and evolutionary analysis, increasing the throughput of enzymology. By bringing quantitative, high-throughput assays to enzymes, the Pinney Lab investigates enzyme function at a scale beyond traditional biochemistry. Work here is just getting started and excited to see the work Margaux & her group put out of the next few years.