Directed Evolution: How to Turn Mutations Into Green Fuel

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March 8 2013 11:19 AM

The Director of Evolution

How Frances Arnold mutates DNA and breeds strange, new, and useful creatures.

Frances Arnold in her laboratory.
Frances Arnold in her laboratory

Courtesy of Frances Arnold.

Charles Darwin spent a lot of time with pigeon breeders and was fascinated by how they selectively bred individual birds to produce offspring with neck ruffles or other distinctive traits. It was one more piece of evidence for his theory of evolution through natural selection: the notion that nature preferentially selects those organisms best suited to a given environment and ensures that the fittest reproduce and survive.

Frances Arnold designed a way to direct evolution—to take over the wheel from nature. In her lab at Caltech, she can essentially rewrite DNA then use it to change the way organisms behave, creating new proteins for renewable energy—“green” chemistry. Her methods revolutionized the field of protein engineering and are now used in hundreds of labs around the world.

Arnold came up with her plan to override natural selection in the late 1980s, when she was a young, untenured chemical engineer at Caltech. Protein engineering was still in its infancy. Progress was slow, and she was impatient. Most of her colleagues were designing elegant, small-scale experiments to discover the rules underlying how DNA sequence and structure translate into proteins that carry out key functions—a noble endeavor but one that continues to elude the best scientific minds in the world. Arnold wanted to solve real-world problems, and she thought she could use nature’s own method—evolution—to speed things up.

“I thought, ‘Why on earth would you try to design something you don’t understand?’ ” she recalls. “Evolution is the only molecular optimization method we know, so why not use it? Human beings have been manipulating the biological world for thousands of years without understanding how DNA codes function.”

Arnold grew up in Pittsburgh. Her father was a nuclear physicist who assured his daughter she could do anything, and she believed him. Fiercely independent, she lived on her own in high school, and worked as a cab driver and a cocktail waitress at a local jazz club to pay the rent, and protested the Vietnam War. Her grades suffered, and she wasn’t sure how easily she would get into a good college. But she did, perhaps benefiting because she was one of the only women to apply for a major in mechanical engineering. 

Since her chosen major had relatively few requirements, she spent much of her time studying economics, Russian, and Italian—not to mention dalliances with the occasional Italian post-doc. After her sophomore year, she spent a year working in a factory outside Milan that builds nuclear power-plant components. Arnold remembers the 1970s as “believe nothing, protest everything, try everything” times, and that’s what she was determined to do.

Arnold never intended to go into science; she envisioned a bright future as a diplomat or the CEO of a multinational corporation, perhaps earning an advanced degree in international affairs. But the oil crisis of the 1970s and growing concerns over nuclear energy in the wake of the Three Mile Island disaster piqued her interest in alternative energy. She realized how critical renewable energy would be to resolving the global energy crisis, and she threw herself into the cause.

After graduating from Princeton, Arnold went to work for the Solar Energy Research Institute (now the National Renewable Energy Laboratory), writing United Nations position papers and designing solar energy facilities for remote locations with few resources. But national priorities on energy shifted with the election of Ronald Reagan, and Arnold decided to go back to school. She earned a Ph.D. in chemical engineering from the University of California–Berkeley and initially intended to work on biofuels. But excitement about the burgeoning new field of biotechnology caused her to rethink her options. She ended up at Caltech as a biochemical engineer, and she’s been there ever since, manipulating evolutionary selection to her own ends.

In one sense, her ability to direct evolution is nothing new: People have engaged in artificial selection for centuries by choosing to breed only those organisms that exhibit the most desirable traits, whether it be ruffles in pigeons, speed in horses, bright colors in orchids, or herding behavior in dogs. The only difference is that Arnold is using cutting-edge biotechnology to manipulate DNA and selectively breed molecules. To some extent, it’s easier to breed outrageous, surprising, or useful new things at the molecular level. It’s not possible to cross a cat with a fungus and produce a functioning organism, but you can cross fungal proteins and cat proteins successfully. And the progeny aren’t as strange as you might think.

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