Profiles in Science
Frances Arnold Turns Microbes Into Living Factories
Instead of synthesizing new biochemicals from scratch, the Nobel Prize-winning chemist puts nature to the task — with astonishing results.
By Natalie Angier
May 28, 2019
PASADENA, Calif. — The engineer’s mantra, said Frances Arnold, a professor of chemical engineering at the California Institute of Technology, is: “Keep it simple, stupid.” But Dr. Arnold, who last year became just the fifth woman in history to win the Nobel Prize in Chemistry, is the opposite of stupid, and her stories sometimes turn rococo.
Take the happy images on her office Wall of Triumph. Here’s a picture of a beaming President Obama, congratulating Dr. Arnold in 2013 for winning the National Medal of Technology and Innovation.
That must have been a fun event! Sure, Dr. Arnold said. Except for the part where the minibus that delivered the medal recipients to the event caught fire as it pulled up to the White House door. The cabin filled with smoke, passengers were gasping and crying and staggering toward the exit, the younger ones carrying the older ones — and all were greeted by a phalanx of Secret Service agents, guns aimed at the medalists’ heads.
“They must have thought we were terrorists,” Dr. Arnold said. “We were convinced they were going to shoot us.”
Okay. How about this charming picture of Dr. Arnold with the Queen of England in 2015?
Another fun story! When Dr. Arnold and her 16-year-old son, Joe Lange, landed in London after a 12-hour flight from California, the border agent asked what brought them to the United Kingdom. Dr. Arnold, who was “feeling very hot-stuff,” announced she was going to a reception that evening to meet the Queen.
Is that so? the agent said skeptically, eyeing her slightly disheveled appearance. And you are?
A chemical engineer.
And what, pray tell, is next on your agenda?
Next I’m off to an awards ceremony at the president’s palace in Italy, Dr. Arnold replied.
Madam, the agent said, if you are going to Buckingham Palace, you must have an invitation. May I see it, please?
Oh, I don’t have it on me, Dr. Arnold said. It’s packed away in my suitcase.
That’s it, the agent said, shutting his ledger book and grabbing her and Joe’s passports. Come with me, please.
‘I Quickly Turned the Tie Around to Show Her the Manufacturer’s Name’
Mother and son spent the next two and a half hours in detention while their story was verified and barely made it to the reception on time.
“They thought I was a kook,” Dr. Arnold said. “Apparently a lot of 60-year-old women say they’re going to meet the Queen.”
Both stories encapsulate another of Dr. Arnold’s maxims: “Give up the thought that you have control. You don’t. The best you can do is adapt, anticipate, be flexible, sense the environment and respond.”
Or maybe not respond. “Joe said to me afterward, ‘Mom, next time why don’t you keep your mouth shut.’”
d of state: evolution.
Dr. Arnold won fame and the Nobel Prize for developing a technique called directed evolution, a way of generating a host of novel enzymes and other biomolecules that can be put to any number of uses — detoxifying a chemical spill, or example, or disrupting the mating dance of an agricultural pest. Or removing laundry stains in eco-friendly cold water, or making drugs without relying on eco-hostile metal catalysts.
Rather than seeking to design new proteins rationally, piece by carefully calculated piece — as many protein chemists have tried and mostly failed to do — the Arnold approach lets basic evolutionary algorithms do the work of protein composition and protein upgrades.
The recipe is indeed an engineer’s dream: simple.
You start with a protein that already has some features you’re interested in, such as stability in high heat or a knack for clipping apart fats. Using a standard lab trick such as polymerase chain reaction, you randomly mutate the gene that encodes the protein.
Then you look for slight improvements in the resulting protein — a quickened pace of activity, say, or a vague inclination to carry out a task it wasn’t performing before, or a willingness to operate under conditions it deplored in the past.
You mutate the improved version again and screen the output for even better performance. Repeat as needed. You do your experiments with the help of a bacterial workhorse such as E. coli, or with an exotic microbe isolated from hot springs in Iceland where temperatures can exceed 175 degrees F.
You consciously treat proteins and their carrier microbes exactly as people unconsciously treat disease microbes when blasting them willy-nilly with antibiotics: You encourage the microbes to rise to the challenge, adapt, survive.
Through directed evolution, Dr. Arnold’s lab has generated microbes that do what organisms in nature have never been known to do. Some of them, for instance, stitch together carbon, the element that defines life, and silicon, the stuff of sand, glass and computer chips but heretofore not of life (unless you are a Horta, the rock-shaped beings who famously mind-melded with Mr. Spock on “Star Trek”).
All it took were a few mutational tweaks to a bacterial protein called cytochrome c.
“We showed for the first time that living organisms can use their own machinery to bring carbon and silicon together to form a bond,” said Jennifer Kan, a postdoctoral scholar in Dr. Arnold’s lab who performed the experiments. “We didn’t even have to nag the protein too hard to get it to do it.”
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Or how about a mind-meld between carbon and boron, or super-bent carbon rings packed with energy like coiled springs — chemical bonds that had never, or rarely, been seen in living organisms until directed evolution showed them the way?
“In the lab, we’re discovering that nature can do chemistry we never dreamed was possible,” Dr. Arnold said. “We’re adding whole swathes of the periodic table to the chemistry of the biological world.”
Diana Kormos-Buchwald, who directs the Einstein Papers Project at Caltech and is a close friend of Dr. Arnold, said, “Frances essentially invented the field of evolutionary chemistry. Instead of analyzing materials and trying to produce them through standard chemical synthesis, she found a way to use nature itself to populate the landscape of all possible variants of biologically or chemically important molecules.”
Dr. Arnold has another favorite mantra: “Nature doesn’t care about your calculations.” Analyzing the evolved mutations that proved most effective at tweaking a protein’s performance, the Arnold team found the changes in all sorts of unpredictable places.
“It was far from the active site of the protein, or it was on the surface,” she said. “It was where everybody said it wouldn’t matter but it did matter. I gleefully took the results to the biochemists and said, ‘Nyeh nyeh nyeh, you can’t predict that but I found it, and I’ll do it over and over again.’ That really pissed them off.”
In exploring the outer realms of biochemical bondage, Dr. Arnold is driven by more than intellectual curiosity. (Really, why didn’t nature take advantage of our planet’s abundance of silicon to gin up an earthly version of the Horta?)
As a “card-carrying engineer” with an undergraduate degree in mechanical and aerospace engineering from Princeton, and a doctorate in chemical engineering from the University of California, Berkeley, Dr. Arnold also is motivated by a desire to make useful things.
And because she is an ardent environmentalist, useful means good for the planet.
Directed evolution methods can yield specialized enzymes that will carry out desired reactions far more cleanly and efficiently compared to standard chemical processes, with their reliance on solvents, plastics and precious metals.
“All my projects are about sustainability, bioremediation, making things in a cleaner fashion,” Dr. Arnold said. “I get these students who come in and say, I want to help people. I say, people get plenty of help. Why don’t you help the planet?”
She has started a number of companies, including a business heartily endorsed by Jane Goodall called Provivi, which is devising techniques for synthesizing insect mating pheromones cleanly, cheaply and on an industrial scale, with the goal of fending off agricultural pests through confusion rather than extermination.
In April, Dr. Arnold and three of her former postdocs filed the papers for a start-up called Aralez Bio, which will apply the principles of directed evolution to produce customized amino acids for drug companies.
As currently configured, the pharmaceutical industry is astonishingly “not green,” said Christina Boville, the chief scientific officer of the new venture.
“They produce 100 times more waste than product,” she said. “We think we can do much better, and our technology actually works.”
Dr. Arnold is sui generis. She projects a charismatic self-confidence rare in anybody, especially a woman — the legacy, perhaps, of growing up as the only daughter among five children.
“I was more of a boy than the boys,” she said.
And smart, to the point of taking high school courses while she was still in grade school. But Dr. Arnold somehow manages to stay on the right side of swaggering.
“She is a unique combination of warm and caring, while also rigorous and no b.s.,” said Mikhail Shapiro, a Caltech professor of chemical engineering who has known Dr. Arnold since 2005, when he sought her help as a first-year graduate student. “I consider her a role model.”
She has notes of both the military and the counterculture. Her grandfather was a three-star general, and her father was a nuclear physicist and in the reserves. But she rebelled against her parents so ferociously that she moved out on her own in Pittsburgh when she was 14, supporting herself by working as a waitress, a taxi driver, in jazz clubs and in pizza parlors.
“You name it, I’ve done it,” she said. Her parents were thrilled when she told them she wanted to go to Princeton, and they happily paid the bills. For all their political and philosophical arguments, Dr. Arnold and her father remained close until his death in 2015.
“We fought all the time,” she said. “But he understood me.”
She has traveled and lived around the world, crisscrossed South America and Indonesia on her own, motorcycled through Europe and Turkey. She speaks five languages and plays guitar, piano and pipe organ.
Dr. Arnold is fast becoming a celebrity. In November she’ll join boldfaced types such as Lin-Manuel Miranda and Jeff Bezos for a Portraits of America ceremony at the Smithsonian’s National Portrait Gallery.
In her office, she has crates overflowing with awards and “literally a thousand invitations” to give talks around the world.
Caltech, where Dr. Arnold has worked for nearly her entire career, has 38 Nobel laureates to its credit, but she is the first woman among them.
“I don’t mind being a celebrity,” she said, because “I photograph better than I look in reality,” which is a lie.
Her friends say she is an outstanding cook. In the acre of garden surrounding her elegantly comfortable 1948 California ranch house near Pasadena, she grows enough food not only for herself but for the local food banks, too: tangerines, oranges, blueberries, lemons, kumquats, artichokes, kale, cucumbers, tomatoes, herbs and spices.
Yes, a charmed life, except — terrible things have happened to her.
Her first marriage, to biochemical engineer Jay Bailey, fell apart in the early 1990s, and he died of colon cancer in 2001. In 2004, Dr. Arnold was diagnosed with breast cancer that had spread to her lymph nodes, and she underwent 18 months of grueling surgery, radiation and chemotherapy, all while raising three young boys and working 60-hour weeks.
“I used to have a photographic memory,” she said. “Chemo knocked that out.”
In 2010, Dr. Arnold’s common-law husband, the cosmologist Andrew Lange, committed suicide, leaving behind a crater of emotional devastation so deep that Dr. Arnold still struggles to forgive him.
Worse by far was the accidental death in 2016 of her middle son, William Lange, at the age of 20, an event that Dr. Arnold says she is not yet ready to talk about.
“Frances did not have an easy life,” said Viviana Gradinaru, a Caltech neuroscientist and close friend of Dr. Arnold. “But despite everything, she got the Nobel Prize.”
Dr. Arnold grows impatient when people express awe at the strength of her spine.
“Nobody is guaranteed an easy life,” she said. “Look at the people in Syria. I have friends who are Holocaust survivors. What was I supposed to do — give up, say I can’t go on? No. I had other children. I had a group of young people in the lab. Why would I give up?”
First, you learn that you have no control. And then you straighten up, fetch your invitation, and go to meet the Queen.