David Baker’s parents were both scientists at the University of Washington, and growing up, he figured that was the last thing he’d ever want to be. Yet after a couple of intriguing detours, his life path has led him right back to the UW campus. It’s there that he has carved out his own path as a world leader in understanding proteins, and how these complex 3-D structures carry out all the biological functions that DNA tells them to do in the body.
“I wasn’t really interested in science much as a kid because my parents were in science,” Baker says. “I didn’t really listen to people very much.”
Baker, 46, now has a lot of people who want to listen to him, like graduate students, faculty, big drugmakers, industrial corporations, and venture capitalists. Baker, a UW biochemistry professor and investigator for the Howard Hughes Medical Institute, is leading an effort to design new enzymes on computers from scratch that Mother Nature never created through evolution. His dream, which is beginning to take shape in a pair of Seattle-based startup companies—Arzeda and Bio Architecture Lab—is to craft enzymes that might break down stubborn proteins so entire plants can be used for biofuels, or crops can be made resistant to herbicides.
This is all gaining momentum in the wake of the Human Genome Project, as scientists have gained access to the sequence of the entire 3-billion-letter string of human DNA, and many other organisms. But the genes are really just an instruction manual, or a parts list, for the real work in biology that gets done by proteins. And while DNA comes in a linear, digital string of chemical units known as A,C, G, and T, proteins that arise from the code are chaotic, spaghetti-like 3-D structures that carry out all the business in the body, forming everything from muscles, nerves, and blood, to the stomach enzymes you produce to digest your meals.
Scientists have long used tedious, expensive crystallography or nuclear magnetic resonance spectroscopy technologies to characterize proteins. Over the past 15 years, Baker’s lab has pioneered new ways to make it so distributed computer networks can be used to perform complex calculations that predict how a gene sequence will turn into a precisely folded protein structure. Now that Baker’s team has made significant strides there—and gotten more than 200,000 people around the world to contribute their computer downtime to the cause—Baker is pursuing the kinds of applications that get entrepreneurs and VCs excited. He says it’s now becoming possible to create new proteins from scratch to do all kinds of useful things.
“David possesses the rare combination of having a strong scientific mind with the creativity and foresight to stay on the cutting edge of significant trends in terms of the Internet and networked computing,” says Nikesh Parekh, CEO of Bio Architecture Lab and an angel investor. “He has vision in terms of pushing the envelope of science.”
Daniela Grabs, a former student of Baker’s and co-founder of Arzeda, adds: “David is very smart and he is genuinely interested in understanding science (and not in becoming rich or famous). He truly believes that only by sharing and exchanging ideas and experiences we can advance the most.”
I sought to learn more about how Baker got on this track during a visit to his UW lab a couple of weeks ago.
He showed up like a man in a hurry, a little after 10 am, when he usually gets to the lab each day. Baker has brown eyes, and brown curly hair that fans out over his ears. He has a slight, wiry, and athletic frame that is a giveaway of one of his favorite hobbies—hiking and climbing in the Cascades. He wore a flannel shirt, black pants, and trail runner shoes, which he casually put up on a coffee table in his office, next to a stack of books and scientific papers as we sat down to talk. The place gives off the irreverent vibe of many labs, with yellowed clippings taped to the wall from the satirical newspaper The Onion, and photos of lab members climbing some picturesque peaks.
Baker grew up not far from his current-day office, in Seattle’s Montlake neighborhood. His parents were professors at the UW, in physics and atmospheric sciences. Baker didn’t take much interest in science as a kid, although he got good enough grades at Garfield High School to get into Harvard University. He concentrated there on social studies, particularly philosophy, until he got bored his senior year.
“It seemed like a lot of talk,” Baker says. “I decided it was just talk and there wasn’t a lot of content to it.” Biology, in contrast “seemed like something you could really learn.”
Still, he had no idea of his career path when he graduated. He took off to see the world, and spent about six months in 1984, when he was 22, traveling through China, India, and Nepal. It was the first year China was opened up to individual outside visitors, and he called the experience “exhiliarating, but not really constructive.” He met other Westerners who would teach English for a while, make some money, and pursue their next travel adventure. “By the end of that time I was eager to do something that was actually going to contribute to the world,” Baker says.
On his return, Baker entered UC Berkeley for graduate school in biochemistry. He dabbled in various fields, from brain science to developmental biology. During graduate school, he met his wife, Hannele Ruohola-Baker, then a biochemistry grad student at Yale. (She has gone on to become an accomplished scientist in her own right, as a UW stem cell researcher at the new South Lake Union labs.)
Baker got his doctorate in 1989, and did a five-year postdoctoral stint at UC San Francisco. He says he used that time to “learn as many things as possible” and didn’t particularly focus on protein structure.
By 1994, when he was 31, he took a faculty job in the biochemistry department at the UW. All the stars aligned for him. His wife got a job at the UW, he got to come back to Seattle where he could enjoy skiing and hiking mountains, and it enabled his kids to be close to their grandparents. But there was more to it than that—the UW allowed him the freedom to sink his teeth into his emerging interest in protein folding.
“I like living in Seattle, and I’ve always felt the people here let me do the kinds of things I wanted to do,” Baker says. “Basically, everybody left me alone, which is what I wanted. I was able to pursue the things I was interested in.”
Protein structure and folding soon captured his interest at the UW. Baker and his students did experiments unraveling proteins and watching how they go back together again.
Baker was intrigued by how proteins obey the laws of physics, and like to settle into the lowest energy state possible. One analogy he uses to help people envision this is if balls were dropped onto the planet from high in the atmosphere, they’d want to settle in the lowest place above sea level, like a ditch in the Dead Sea. Scientists have long used imaging techniques to analyze protein structure, but it’s time-consuming and expensive, and there is a vast and unknown number of proteins in nature—maybe 10 million to 100 million, Baker says. The way to get a handle on the structure of a large number would be through computer models that can run algorithms that predict the 3-D structure based solely on an amino acid sequence.
“The DNA sequence alone doesn’t tell you anything about what the protein does, or how it does it. It’s just like the instructions for making a 3-D structure,” Baker says. “You need to be able to go from the genome sequence to proteins and their structure and how they work as machines to really understand how biology works.”
This requires a lot of calculating, on the level of supercomputing, and even then, many efforts to predict structure have been plagued by inaccuracies. One big step forward came in 2003, when the Baker lab showed, in a paper in Science, that it could create a protein that didn’t exist in nature. It won an award for the best paper in that leading scientific journal that year, he says.
Protein structure might sound hopelessly theoretical to the man on the street, but Baker has worked for years to engage the public in this science. The most visible way has been through Rosetta@Home. This is the distributed computing project that emerged from beta mode in October 2005, in which people around the world download some software that uses their computer to run calculations when it’s not in normal use.
The fruits of this labor are provided free to academic and nonprofit researchers, and cost a $35,000 license fee to companies. Baker—in keeping with what Grabs said about not wanting to become rich—takes the license income and uses it for an all-expenses paid annual retreat for the former students and other academic developers who work on the project at Sleeping Lady Mountain Retreat near Leavenworth, WA (selected for its many great hiking trails nearby).
As the power of the computers to characterize proteins has grown, Baker has gravitated toward the next challenge of creating new proteins and enzymes for all sorts of industrial purposes. The first protein created in 2003 didn’t really do anything, Baker says. Since then, the lab has gotten better at it, creating more than 60 different enzymes using the technique, and had its work published in further articles in Science and Nature, which has grabbed the attention of more than a few industrial biotech companies.
Last year, several companies approached Baker, offering to sponsor particular projects of theirs in his lab. He had to say no, because his funding from the Howard Hughes Medical Institute stipulates that he stick to basic research, and not do applied work for companies. That prompted three members of his lab—Eric Althoff, Alexandre Zanghellini, and Grabs—to get Arzeda established. They’ve recently won committed venture financing from OVP Venture Partners and WRF Capital.
Baker has a limited role as a scientific advisor to the company, but he says he doesn’t have entrepreneurial dreams of his own. He says he’s excited about the potential for applications, and that it provides another career path for his students and postdocs, as an alternative to faculty jobs at a university.
As for his management style, Baker likes to walk around the lab, which is a relatively big academic group of about 40 people. He says he tries to talk to people in the lab every day. Unlike a lot of faculty, he avoids travel, heading to the East Coast only once a year to deliver a series of talks on his work. “My job is here to push the research along. I travel much less than most people. I’ve heard myself talk before,” he says.
So what makes him stand out? Parekh, the CEO of Bio Architecture Lab, says Baker is “very competitive and drives people in his lab to achieve excellence.” Althoff adds that Baker is open to new ideas, and is collaborative in the academic community. “He shares his results publicly very early on in order to get people outside of his lab’s opinions and thoughts on how to best go forward,” Althoff says. “He continually insists on using the best control experiments to verify that results are real.”
Baker relished talking about applications during our conversation, particularly ones with broad societal implications—like vaccines for HIV, or a genetically modified banana that might protect people from getting sick with cholera. But when I asked about where all this work is headed, and what his ultimate goals are, he chose not to get carried away with a promise that he might not be able to deliver, or that is at least decades away.
“We can’t predict protein structures perfectly now,” Baker says. “We’d like to design active catalysts, proteins that bind tightly to other proteins, drugs useful for diseases, vaccines that work. A lot of problems we work on are really hard. For the short-term, it’s really about being better at what we’re doing than we are now.”
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