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October 26, 2021 Tuesday 11:20:11 AM IST

Frances Arnold-Engineering Better Enzymes at MIT

Stories of Life

In the Hoyt C. Hottel Lecture conducted at MIT, Arnold opens up her story of path-breaking research to engineer better enzymes for critical applications. She is the Pauling Professor of Chemical Engineering, Bioengineering and Biochemistry at Caltech, launched a field of engineering with applications in alternative energy, medicine, and diverse industries. Her research earned her the 2018 Nobel Prize in Chemistry, as well as the Charles Stark Draper Prize of the U.S. National Academy of Engineering (2011), the U.S. National Medal of Technology and Innovation (2011), and the Millennium Technology Prize (2016). 

Arnold was in the vanguard of scientists in the late 1980s eager to leverage the latest innovations in genetics. Researchers had figured out how DNA coded for proteins, and how to edit DNA. But in an era before high throughput computing and massive databases for cataloging proteins, no lab could manipulate genetic sequences to select for desired properties on a realistic time scale. Arnold drew inspiration from the British biologist John Maynard Smith, who laid out the workings of natural selection in molecules. Mutations that routinely pop up in DNA sequences can either lead to protein failure and the end of the line, or to a fitter protein variant that survives and can engender future generations. This was the spark behind directed enzyme evolution which is the process developed by Arnold to engineer better catalysts.

To realize her vision, Arnold created a factory in her lab guided by a rigorous methodology. She sampled enzymes of interest, and identified DNA sequences that could lead to enhanced functions. Then she generated mutations in these sequences and, using host bacteria, created enzymes whose properties she would evaluate. Arnold repeated this process again and again until she arrived at an enzyme with the properties she sought. The result of her first years pursuing directed enzyme evolution was a new breed of subtilisin, an enzyme that can be found in dirt. The engineered subtilisin could function in a harsh solvent, a property that made it extremely useful for chemical applications. This version also satisfied an overarching goal of Arnold’s research: making biologically based enzymes to replace those synthesized by chemists, which often involve environmentally destructive materials. Directed enzyme evolution unleashed a flood of activity on optimized and repurposed enzymes from Arnold’s lab, as well as from labs around the world. Biocatalysis is becoming a transformative industry, with the proliferation of biologically based enzymes to coax the formation of chemical bonds in molecules containing such elements as halogen, fluorine, or chlorine. 

In 2016, Arnold’s lab designed an enzyme that normally catalyzes important biological reactions in living things to forge a carbon-silicon bond. It was a first. Molecules built around such chemical bonds are in high demand in the pharmaceutical, agricultural, semiconductor, and renewable energy industries. To meet the need, conventional synthetic chemistry relies on hazardous materials, harsh and often costly manufacturing conditions. Arnold believes her methods offer an environmentally friendlier and less expensive alternative.