“As engineers, we want to create things that don’t necessarily exist on the planet, or may have never existed, but that solve real problems,” said Frances H. Arnold at the 2021 Hoyt C. Hottel Lecture in Chemical Engineering on Oct. 1.

Harnessing the process of evolution to optimize and create enzymes, Arnold, 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).

Her Hottel presentation, Arnold noted at the start, was the first time she had spoken to a live audience in 18 months — a cause for celebration. In the talk, “Bringing New Chemistry to Life,” Arnold recounted the story of her relentless quest to address urgent global challenges by way of better enzymes — the proteins catalyzing chemical reactions in biology and in a vast array of manufactured products and processes. Her narrative described her decades-long effort to, in her words, “compose” with DNA, utilizing the tools of nature to generate enzymes “that work better than what nature has provided.”

The lecture was sponsored by the Department of Chemical Engineering, and was introduced by department head and Institute Professor Paula T. Hammond.

Incomprehensible possibilities

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. “A typical small protein 300 amino acids long with 20 different amino acids — that space of possible sequences is bigger than anything you can comprehend,” said Arnold.

The challenge facing scientists at the time, said Arnold, reminded her of the Jorge Luis Borges 1941 short story, “The Library of Babel.” In this massive collection of books, order and content are completely random, and “librarians despair of ever finding a book that has a meaningful sentence, much less a work of literature,” she said. “So here I am, an assistant professor at Caltech, in this library of all possible proteins, and I have to find ‘Moby Dick.’”

To escape this quagmire, 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 a powerful idea for me,” said Arnold. “If I’m the breeder of molecules, I decide who is fit to go on to the next generation.” This was the spark behind directed enzyme evolution — the process developed by Arnold to engineer better catalysts.

Selectively breeding enzymes

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. (“Four billion years of natural selection has given us proteins you can scrape from the bottom of your shoe,” noted Arnold.) 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.

“It was simple, good engineering, an algorithmic process that led to products like laundry detergent enzymes, and got me the biggest accolade of my life, and an appearance on the set of ‘The Big Bang Theory’ in 2017.”

Emulating nature

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. “We can program bacteria to produce these bonds with a mutant that does the job 50 times better than the best human chemist … and without the environmental devastation,” said Arnold.

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.

By emulating nature “and the powerful process that’s given rise to all life,” she said, “we can use abundant renewable resources to make everything we might want.” Arnold hailed students in the audience: “It’s a wonderful thing to work with; come in with fabulous ideas!” In closing, she said, “If we can learn how to use this process, we can adapt, evolve, and innovate in tandem with our beautiful planet.”

Hoyt C. Hottel served as an MIT faculty member from 1928 to 1968. The Hoyt C. Hottel Lectureship was established in 1985 to recognize his contributions to the Department of Chemical Engineering and its students, and to the establishment and direction of the Fuels Research Laboratory. The lectureship is intended to draw eminent scholars to MIT to stimulate future generations of students. The lectureship resumed this year after a pause in 2020 during the Covid-19 pandemic.