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.

Cells replicate by dividing in two, but with each replication, small variations creep into the DNA sequence. Rather than waiting for natural mutations, Arnold causes small mistakes to be made when DNA is copied in the test tube. Then she inserts all the mutated copies into living microbes, which translate the genes into proteins. At that point, she combs through the different proteins to find the ones she likes.

Arnold opted for this brute-force approach, running hundreds—even thousands—of experiments with random mutations in the proteins, selecting those with the characteristics she wanted to breed in the second generation and so on over multiple generations. And because microbes reproduce every 20 minutes, it didn’t take billions of years to see the results. “All you have to do is look at antibiotic resistance to understand how quickly biology can adapt,” she says.

She published her first papers on evolutionary protein engineering in the early 1990s in the face of considerable skepticism. A bit of intellectual snobbery may have been in the mix. There is an unspoken hierarchy in academia. It’s a culture that favors curiosity-driven basic research over practical applications, and it draws a fine distinction between science and engineering. “Some people looked down their noses at it,” Arnold admits. “They might say ‘It’s not science’ or that ‘Gentlemen don’t do random muto-genesis.’ But I’m not a scientist, and I’m not a gentleman, so it didn’t bother me at all. I laughed all the way to the bank, because it works.”

More than one senior colleague over the years has accused her of being arrogant, a charge she cops to readily and does not apologize for. It’s a quality that has helped her stay on top in a highly competitive research environment. “I’ve always been confident,” she says, describing herself as “honestly arrogant—I wasn’t pretending. I never had any doubt about the utility and importance of what I was doing.”

Among the many intriguing results from her research were new proteins that don’t break down under high temperatures, making them ideal for everything from laundry detergents to developing new drugs. Merck drew on her techniques to develop a process for manufacturing the diabetes drug Januvia.

She also developed new kinds of enzymes that help convert cellulose in plants into sugars and then into useful fuels and chemicals. That work, and a passion for building a green chemicals industry based on renewable resources, led to Arnold co-founding in 2005 a biofuels company called Gevo, which went public a few years later. But she didn’t become the CEO—the job she’d envisioned for herself as an undergraduate. By then she knew it wasn’t her forte. “I know how to do science. I know how to make things,” she says. “I don’t know how to run a company. Now that’s a really tough job.”

Arnold’s scientific gamble back in the 1980s to jump into biotechnology and engineer the biological world has paid off in hundreds of publications, dozens of patents, and countless professional accolades. She is one of only a few people with membership in all three of America’s national academies: the National Academy of Sciences, the Institute of Medicine, and the National Academy of Engineering. In January, she went to the White House to receive the National Medal of Technology and Innovation.

Many academic researchers take a sabbatical break every seven years or so, but Arnold has taken just one in her 27 years at Caltech. She spent that time traveling with her family through Australia, Madagascar, Namibia, South Africa, and Egypt.

She has faced plenty of challenges. Right after she returned from her sabbatical, she was diagnosed with breast cancer and spent two years battling it into remission. She lost her husband, Caltech physicist Andrew Lang, in 2010. Today she is cancer-free, focused on her work, and getting her three sons through high school. “I don’t sit around feeling sorry for myself,” she says. “There’s always somebody who’s a lot worse off than you. I love what I do, and I’m grateful for every day I can do it.”

Arnold may have a pragmatic bent, but ultimately she’s just as eager as her colleagues to decipher nature’s code when it comes to how genetic sequence dictates function—she’s simply realistic about the unlikelihood of this happening in her lifetime. “We can do all this manipulation, but we don’t understand the rules of composition for DNA,” she says. “So the best we can do is cut and paste pieces from compositions that nature has already written.” If she can’t compose, she’ll go right on breeding. Maybe she hasn’t been doing this for 4 billion years, but Arnold just might give nature a run for its money yet.