Switched on Science

From Basketball to Balance

If the MacArthur fellowship allowed him to pursue his varied interests, it may be the Rhodes scholarship that helped foster those interests in the first place. After completing an undergraduate degree in physics from the College of Holy Cross in 1987, Collins was one of four students in New England chosen to continue his education across the pond. "Going to Oxford was a life-changing experience," he says. First off, it made his modest skills on the basketball court seem extraordinary. "If you could dribble with one hand you were good enough to get on the basketball team in Oxford," he laughs. "We were the top-ranked University team in the UK, but let's face it, we were not that good. Any decent high school team over here could have beaten us."

More importantly, Collins took full advantage of the fervent intellectual climate. "At any time of day, there were a handful of graduate students hanging out in the common room, talking about their areas of study or about other disciplines or other topics," he says. "It's something I haven't seen in the States, because we've really Balkanized departmental boundaries. But it broadened my interests and expanded my ability to talk to people outside my field."

One of those people was Ian Stewart, a mathematician at the nearby University of Warwick. In 1989, Stewart wrote a book review for New Scientist in which he mused about the similarities he'd seen between patterns produced by coupled oscillators and by four-legged animals trotting, galloping, or otherwise getting about. "I got a phone call from Jim - I think it was within about 24 hours of the magazine appearing - saying, 'Can we talk?'" says Stewart. That meeting resulted in four papers on animal locomotion published through the 1990s. "It's one of the most interesting pieces of mathematical work I've done," says Stewart, "and it's all because Jim was bright and adaptable and spotted something that looked interesting and was willing to move out of his scientific comfort zone to pursue it."

With a PhD in medical engineering from Oxford, Collins returned to the US in 1990 and accepted a position at Boston University (BU), a school that was strong in bioengineering and close to where his wife was finishing her medical training. There he went from working on the biomechanics of locomotion to looking at how we maintain balance, and how those systems break down as we age. The challenge was to generate technologies that could enhance sensation in the lower extremities, thereby enhancing balance. His first animal studies, conducted in rats, were a success. In collaboration with Peter Grigg at the University of Massachusetts Medical School, Collins showed that random, low-level stimulation boosted the response of touch-sensitive neurons in the skin of rats. They published the work in 1996.

That was just the beginning. "When I die I don't want my obit to say that the rat community in Boston is devastated by the loss of Professor Collins." So he started work on people: first on BU students and eventually on older subjects, including diabetic and stroke patients. Again, Collins and his colleagues found that tickling mechanically sensitive neurons (this time in the feet) with vibrations too subtle to consciously feel could improve sensation and balance. In 2000 Collins cofounded the company Afferent to help develop a product for delivering these stimulating vibrations. At the same time, Collins was about to publish the Nature paper that would help usher in the era of synthetic biology.

Switching on Synthetic Biology

In 1996, the Whitaker Foundation was looking to create a new program to train engineers to go from working with genes and cells to tissues, organs, and eventually the whole body. Charles Cantor, who was then chair of BU's department of biomedical engineering, asked Collins to prepare a presentation. "Then he says, 'Oh, I forgot to tell you, you have four days to come up with something. The site visit is on Friday,'" recalls Collins. "So they wheeled me out with some four-day-old, half-baked ideas about what an engineer could do. Well, we didn't get the grant."

Nonetheless, the experience made Collins and his graduate student, Tim Gardner, think about what an engineer could do in a cell. "We started thinking, wouldn't it be neat if we could take molecular components, like genes and promoters and proteins, and engineer circuits like an electrical engineer would, using biological components instead of transistors and resistors and capacitors, and we came up with the idea of a toggle switch."

The switch itself was simple in design: Collins and Gardner sketched out a circuit in which the product of gene A would shut down gene B and vice versa. When protein A is abundant, gene B is off. The switch can be flipped by transiently suppressing expression of A, so that protein B can accumulate and keep gene A off. The components they would use were borrowed from well-studied gene regulatory networks, such as the lac repressor and tetracycline inducible system.

Putting it together wasn't necessarily easy; although the modeling looked good, molecular biologists were somewhat dubious. "Invariably they'd kind of pat us on the head and say, 'Guys, biology is really complicated. Why don't you go back to engineering?' " says Collins. When Gardner presented the work at an Office of Naval Research (ONR) meeting, "he was completely assaulted by the card-carrying molecular biologists," says Eric Eisenstadt, who was the ONR program officer who'd funded them.

"It was a little discouraging," says Gardner, now at Amyris Biotechnologies in Emeryville, Calif., "but Jim was not at all deterred. He just figured they were being pointy-headed academics who are quick to criticize." He was right. With the help of Cantor, who offered his lab space and expertise, Gardner was able to build the switch and get it to work in Escherichia coli. Their accomplishment was published in Nature in 2000, in the same issue in which Michael Elowitz and Stan Leibler, then at Princeton, described their engineering of a synthetic oscillator in E. coli.

"It seems elementary now, but back then it was a big step forward because it was a biological system that was completely designed. The engineers specified what they wanted in terms of behavior, and then they went ahead and built it. And that's not the way biology normally works. Or at least we don't think it works that way," says Eisenstadt, now at the J. Craig Venter Institute. "So I will forever think of Jim as one of the pioneers in the whole synthetic biology movement."

"What makes him a good scientist is he's a good engineer," notes George Church of Harvard Medical School. "He's rigorous without getting bogged down in details. He knows the details, but he also knows how to get his team to build something new and get it to work."

To succeed in a project like that, says Cantor, now chief scientific officer of Sequenom in San Diego, Calif., "you need two things: You need to be imaginative, and you need to be rigorous enough to take your fantasies and make them work. Jim has both."

Collins also has good timing. "He understands where research is going and what are the hottest topics," says former postdoc Diego di Bernardo of the Telethon Institute of Genetics and Medicine in Napoli. "In research, like in everything else in human life, things go in and out of fashion. Jim somehow knows when the time is mature to do something."

Tight Control, and Tight Scheduling

Since then, Collins has continued to apply engineering techniques to designing useful biological devices. Last year, he and his colleagues designed a switch they could use to control expression of a desired protein in mammalian cells. "The switch is so tight, they can express some of the most toxic proteins known," says Cantor. Then, when the switch is thrown and the toxin is expressed, he says, "the cells drop dead." Such a system could allow researchers to eliminate a single cell or a subset of cells in a developing embryo and observe the effects.

The Collins team also generated a bacteriocidal phage that can break up a biofilm to get at the harmful microbes hiding within it. That work was "interesting," says Church, because "rather than just doing systems biology, where you're trying to learn about the natural world, this was making something that works a little bit better than the natural world. I mean, why don't regular phage do this?"

He's also found that different classes of antibiotics appear to kill bacteria by a common mechanism that involves production of free radicals, a discovery that MIT's Graham Walker hails as "potentially paradigm shifting. This is incredibly creative and original work. Jim has a real feel for biology that, along with his engineering skills, is a really potent combination."

Plus he operates at high speed. "He has this amazing ability to walk in the main lab door - he's always moving at a very brisk pace - and zoom through the lab on the way to his office. But he always knows exactly what you're doing," says Priplata.

"He talks very fast and thinks very fast, so his lab is going very fast," says di Bernardo, who estimates that he accomplished in his one year in Collins' lab "work that probably would have taken me three years somewhere else."

"His energy rubs off on you," says Priplata. "He gets you excited and motivated."

And he does it all between the hours of 9 and 5. "He has everything organized down to the minute and he uses that time to the most," says di Bernardo. "He should write a book on time management, because I think he has devised a lot of tricks that could be useful to other people. I don't know how he does it."