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Arnold speaks at U. about Nobel-winning research on ‘promiscuous’ enzymes

Frances Arnold ’79 speaks to packed crowd

Frances Arnold ’79 spoke to hundreds of undergraduates, graduate students, and faculty on Friday, Oct. 26 in Frick’s Taylor Auditorium. Photo courtesy of Albert Jiang.

From mechanical and aerospace engineering to chemistry, Nobel laureate Frances Arnold ’79 said her mindset was to “keep it simple, stupid.” 

On Friday, Oct. 26, Arnold returned to the University for an intimate reception in the morning and a seminar in the afternoon in front of hundreds of undergraduates, graduate students, and faculty members.

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Arnold is a co-recipient of the 2018 Nobel Prize in Chemistry and is the first University alumna to win a Nobel Prize. Her achievement also makes her the fifth woman chemistry laureate and the only U.S. woman winner. She is also the first woman to be a member in all three U.S. national academies of science: the National Academy of Engineering, the Institute of Medicine of the National Academies, and the National Academy of Sciences. Arnold is currently the Linus Pauling Professor of Chemical Engineering at the California Institute of Technology.

Arnold spoke briefly at the reception, citing how crucial the University was in establishing her foundation as a scientist — and more importantly, a thinker.

“I learned how to read and write here. It’s a remarkable thing that an engineer is given the time to explore lots of opportunities,” she said. “Think[ing] broadly has enabled me to go into many different areas in my career — to make connections that I wouldn’t have been able to do otherwise.”

She emphasized the values of classes that were outside her concentration, as well as the research opportunities she had, explaining, “It was the advice, the leadership, and the mentorship that taught me that engineers could have a big impact — by being engineers — but also by thinking about the bigger policy issues and impact that technology has on society overall.”

Arnold described how, as a “student of evolution and adaptation in a rapidly changing world,” remaining flexible and creative was essential to “putting crazy new ideas together.” She credited her computational and qualitative background and described how jobs are beginning to go to bioengineers instead of pure biological scientists. She urged students to fill their thoughts with ventures outside the laboratory and to learn to read, write, and think broadly.

Later that afternoon, a standing-room only seminar was held in Frick Chemistry Laboratory. Assistant professor of chemistry Todd Hyster, a former student of Arnold, greeted the more than 250 students and faculty present before introducing his former mentor.

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Arnold then took the stage, discussing the work that won her the Nobel Prize. Her research involves using an optimization process to direct enzymatic evolution for catalyzing chemical processes that do not occur in the natural world.

A self-proclaimed “engineer inspired by the biological world,” Arnold described how the “Keep it simple, stupid” mindset was essential to developing solutions and driving technology out into the world. “Get one idea and beat it totally into the ground,” she said.

Arnold said that as a mechanical and aerospace engineering student at the University, she initially wanted to build rocket ships — “the most complicated things on the planet.” However, she credited her brother for catalyzing her love for biochemistry and helping her recognize that enzymes — a product of 4 billion years of evolution — are in fact the most complicated things in the world.

These complex proteins are built using about 450 combinations of 20 naturally-occurring amino acids, providing more possible combinations than atoms in the universe. Because it is far too difficult to build these enzymes from scratch, Arnold instead took parent proteins — with quadrillions of possible recombinations — evolved them, and screens them into mere thousands of candidates.

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She described directed evolution as a sort of molecular optimization process, which can be visualized as a topographical map of a multidimensional fitness landscape. After deciding upon the desirable traits of the molecules, Arnold was then able to exploit smooth paths on this landscape to allow for adaptation, one mutation at a time. In fact, after just 2 percent of a sequence has been changed, the enzymes will demonstrate radically different functions.

This leads to the central question of her research: How can you create not just a better enzyme, but a whole new enzyme? In order to solve the problem, Arnold referenced research observing the natural evolution of enzymes to break down man-made compounds such as atrazine.

Arnold described enzymes as being “promiscuous” with a multitude of inherent capabilities that are not necessarily selected for at a given time. “Enzymes are just like graduate students,” she jokingly remarked, referencing both groups’ propensity for sugar. The enzymes’ nonselective capabilities are similar to the graduate students’ diverse interests and talents that extend beyond the lab, she added. 

Arnold’s lab’s research focused on the heme, a metal-containing, self-assembling, DNA-encoded structure that can be tuned by mutation. Using bacteria such as E. coli and Rhodothermus marinus, her lab evolved heme-protein compounds called cytochromes that cycloproponate — that is, generate and insert three-carbon rings — or create new carbon-metal bonds entirely. 

While it was simple to observe the functions of enzymes, Arnold explained how difficult it was to measure and analyze the structure of these enzymes. In one case, she found that the total volume of an active site was zero, which made no sense. “Nature doesn’t care about your calculations,” she said. “Obviously, your calculations are not capturing the capability of the protein to adapt to this chemistry.”

Despite these difficulties, Arnold’s team was able to create cytochromes that can synthesize unique bonds (specifically, carbon-boron and carbon-silicon), which have never been observed in nature. In doing so, Arnold’s team simplified processes that normally require five to seven complex chemical steps to a single enzymatic process hundreds of times more efficient than any human-made chemical process.

By coupling bacteria and yeast — which Arnold considers to be the best chemists and engineers in the world — with the most advanced engineering design process in the world, evolution, scientists will no longer be bounded in their advancements in agriculture, pharmaceuticals, and countless other industries, Arnold said.

“It’s a lot of fun to do this work, because we’re in a goldmine pulling chunks of gold off the wall. Sooner or later, others will see the gold too and [begin] doing this, I hope,” she concluded.

The reception was sponsored by the School of Engineering and Applied Science and took place in the Fields Center Multipurpose Room. The seminar, entitled “Innovation by Evolution: Bringing New Chemistry to Life,” took place in Frick’s Taylor Auditorium at 3 p.m.