Genius at Work
Biomedical Engineering Professor Jim Collins's insights have helped improve balance in the elderly, led to advances in genetic engineering — and won him a MacArthur "genius" grant along the way.
By Tricia Brick
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Jim Collins. Photograph by Asia Kepka |
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In Jim Collins's world, time moves faster than it does for us mortals. His slender runner's frame seems always in purposeful motion; he speaks in double time. In his Control Systems in Biomedical Engineering classroom, at just past 10 a.m. on a dreary winter Tuesday, the College of Engineering professor pauses only to make sure everyone is keeping up — and even then his hands dance about, illustrating for his students the movement of a spring or the absorption of medicine into a patient's body.
One minute he's acting out a thirteen-year-old version of himself getting his lone chest hair caught in the spring-based exercise gear he ordered from the Don't be a ninety-pound weakling! ad on the back of a comic book. Five minutes later, he's an astronaut struggling to grab a bottle of Tang while wearing a spacesuit designed to prevent his muscles from atrophying in zero gravity. This is Collins, as a teacher and a scientist: he puts pieces together in crazy new ways that nobody ever thought of before. And he does it with a charisma — and a creativity — that is extraordinarily contagious.
Out of Collins's Applied Biodynamics Laboratory at the BU Center for BioDynamics have come groundbreaking discoveries in wide-ranging areas of bioengineering. His "genetic toggle switch" promises to create programmable cells to fight disease or serve as biological warning systems against environmental toxins. His work in systems biology may lead to a new understanding of the causes of cancer.
And you may have read about his work in footwear: the vibrating insoles he's developed have been shown to greatly improve the balance of elderly people and those whose nerve sensitivity has been damaged by diabetes or stroke, thus potentially reducing the risk of falls.
In the classroom Collins draws on the board the spiraling form of a diagram for a pendulum, discussing how the velocity of the bob changes as it swings through its arc. "Galileo worked this out hundreds of years ago — he was sitting in church, and like you guys, he got bored," he says with a wink, indicating his pendulum diagram on the board. "So he's looking at the priest with his incense swinging back and forth, but instead of thinking about what he's going to have for lunch or his plans for Saturday night, he says, 'I'm gonna solve this.' So you see, there is value even in boredom for a great scientist."
Collins may be looking at a sleepy kid named Raphael as he says this, but his point is taken — inspiration can come from the strangest of places.
"Jim has just a blazing intelligence and an ability to grasp the important aspects of completely new ideas in a split second," says former student Tim Gardner (ENG'00), now an ENG assistant professor of biomedical engineering and a cofounder, with Collins, of the biotech company Cellicon. "You present him with an entirely new idea and he instantly grasps the big picture and the importance of it. And that enables him to navigate new waters and move forward — to make good decisions even when the information isn't completely worked out and when the waters are murky."
Collins's work has been widely recognized. Last year, he was named one of Scientific American's fifty outstanding leaders in science and technology. In 2003 he was awarded a MacArthur Fellowship. In an op-ed in the New York Times last year, Collins wrote of the peculiar challenges of being chosen for the fellowship known as the "genius grant": "After my daughter recently beat me at Candyland, she looked at me, disenchanted, and said, 'Dad, I thought you were supposed to be a genius.' I tried to explain that the MacArthur award was for creativity, not genius, and that my creative work did not encompass the selection of colored cards from a randomly shuffled deck. My daughter just slowly shook her head and walked out of the room."
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| Jim Collins (left) and doctoral student Timothy Gardner (ENG'00) in 2000. Collins's mentoring style "is giving you a very long leash," says Gardner. "Basically, you're on your own to sort things out — which is a difficult thing for some people, but for many gives them a chance to thrive." Photograph by Vernon Doucette |
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Recognition from the MacArthur Foundation, whose grants reward extraordinary creativity across disciplines, is a big deal, financially and professionally. But Collins, a professor of biomedical engineering and a University Professor, says he values his 2000 Metcalf Cup and Prize for Excellence in Teaching — Boston University's highest teaching award — over any other honor he's received.
"I try within my classes to give a sense to students that they do have skills and talents that can make a difference," he says. "I encourage them to do that, to go help people, that it will make for an interesting and enriching life. And it's why many of them get into the subject, but if you focus only on the technical aspects, then they're not reminded, 'Oh, this is why we're doing all these differential equations.'"
A Notion Becomes Reality
Collins doesn't speak lightly of the prospect of helping people through science. It's a central focus of his work and, in fact, the reason he himself first entered the field of biomedical engineering. He was born into a family of engineers and other "quantitatively oriented folks" — his father and uncles were electrical engineers, his mother a math teacher. When Collins was seven years old, one of his grandfathers became blind. Then his other grandfather, a New York City policeman, had several strokes that left him disabled.
"In each of the cases, I was struck as a kid and a high school student at how little was done for these guys in rehab," he says. "And yet I saw marvelous technologies around me, introduced by my dad and others, that were developed for the space industry and the military. And I thought it would be really cool if you could be trained in science and develop devices or techniques that could be applied to the body to restore or enhance function."
He studied physics at the College of the Holy Cross (where he was class valedictorian) and went on to the University of Oxford as a Rhodes scholar. For his doctoral studies there, he researched locomotor biomechanics — essentially, how humans walk and run and jump. He also worked with mathematician Ian Stewart of the University of Warwick, creating mathematical models of the networks of neurons in the spinal cord that control locomotion in humans and animals.
He was hired at BU as a member of the research faculty in 1990, and initially his research focused primarily on human balance control — trying to determine measurements a clinician might take to gain insight into how a patient's balance control system is functioning, and in doing so, to predict whether that person is at high risk of a fall.
But in 1994 he had a breakthrough. Collins met Frank Moss, a physicist from the University of Missouri-St. Louis, at a conference. Moss had recently discovered that a phenomenon called stochastic resonance was at work in the sensory neurons of crayfish, demonstrating that the random signals of noise actually work to strengthen certain neural signals.
"Frank knew I was in a biomedical engineering department, and he pulled me aside and encouraged me to think about medical applications for stochastic resonance," Collins recalls. "He said, more or less, if you come up with an application, you'll never have to write a grant to the NIH again — they'll send a dump truck of money to you every October."
The challenge sparked Collins's interest, and on the flight home to Boston the next day, he considered how Moss's discovery might be applied to human medicine. He wondered whether bioengineers could artificially introduce noise into the body to enhance sensory function.
"I thought, wouldn't it be neat if we could develop vibrating insoles or electrically noisy socks or high-top basketball sneakers that stimulated the ankle," Collins says. "I wrote all this down in a lab notebook on that plane ride home and began to work the next day on the feasibility of these notions."
Conditions like diabetes or stroke — or simply the natural process of aging — can lead to decreased sensitivity in the foot nerves, whose precise signals are necessary to maintain balance. This lack of sensitivity contributes to an increased risk of falls that can be devastating, particularly for the elderly. It's estimated that one in three people over the age of sixty-five falls each year, and 10 to 15 percent suffer serious injuries; the cost to the American health-care system has been estimated at $20 billion a year.
In pursuit of a technology to improve balance, Collins's research progressed from computer modeling to experimental studies of animals' and humans' sensory and motor responses to noise, culminating in tests demonstrating that vibrating insoles could indeed improve elderly people's balance to the level of people fifty years younger. More recently, prototypes of vibrating insoles have been developed through the Afferent Corporation, a company Collins cofounded. Currently his lab is carrying out additional studies of the insoles' effectiveness in activities such as walking and this year completed a study, published in Annals of Neurology, showing that the insoles are also useful for patients whose nerves have been damaged by diabetes or stroke.
But in the years since he first developed his revolutionary insoles, Collins has moved on to molecular and cellular engineering — fields that are light-years away from his work with whole-body mechanics.
"Jim did seminal work in whole-body mechanics," says Charles DeLisi, ENG dean emeritus and Arthur G. B. Metcalf Professor of Science and Engineering. "Then he moved into molecular biology and did seminal work in this area. He has taken the tools of engineering, the mathematics tools, the experimental tools, and applied them at many, many physiological levels — whole-body, whole-organ, cells, all the way down. He had questions he wanted answered, and he wasn't afraid to start a laboratory program to get some of those answers."
"You know, I get bored quickly," Collins says, laughing. "To the good and to the bad, I think. On the noise-enhanced work, I think we've had a very good run for the last ten or twelve years, and we're kind of nearing the end point where I think we as academics can make significant contributions — now other groups can pick it up as it moves toward more clinically oriented problems as well as more commercial applications. I see our efforts increasingly turning toward the molecular side, and there's just a whole host of problems that remain to be tackled there. That will hopefully keep me interested for the next few decades. Although who knows? Who knows what we'll be working on in ten years. I have no idea. And that makes it interesting."
Brilliant or Crazy
Collins had little formal training in molecular and cellular biology, but encouraged by DeLisi's drive toward increasing interdisciplinary work at ENG, he began to consider what a bioengineer might be able to do at the level of genes and proteins.
In 1996, Gardner joined Collins's lab as a doctoral candidate. "He came for his recruiting visit," Collins recalls, "and he initially wanted to develop electronic devices that could be inserted into spinal cords, to provide some therapeutic benefit after injury. I told him that I'd be interested in working with him, but that he needed to know I had no background in that space. And he said, 'No, that's fine! That's great!' He took off down the hall, and I remember thinking, that kid's either brilliant or crazy. And he enrolled and I realized, after I got to work with him, that he's both."
Gardner laughs when he hears this story. "That's probably true," he says. "When I came to his lab I said I wanted to cure paralysis — I think that says it right there." That Collins thought the goal reasonable speaks to a shared belief that a little ingenuity can go a long way toward solving even seemingly impossible problems.
Initially, Collins and Gardner focused on trying to develop artificial materials and devices to try to repair the spinal cord after injury. But after a year or so of research they began to suspect that the available artificial technology wasn't sufficiently flexible to interact with the massively complex biological, chemical, and electrical processes of the human nervous system. Perhaps, they reasoned, rather than introduce an artificial technology into the cells, they might engineer the cells themselves — and, eventually, grow the nerves back. With the support of DeLisi and Charles Cantor, who was chairman of the biomedical engineering department, Collins and Gardner expanded their research into genetic engineering.
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Motors embedded in gel insoles such as these produce vibrations that improve balance for the elderly and patients with nerve damage in their feet. |
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In 2000 they published an article in Nature introducing their genetic toggle switch — a biological circuit that could essentially program a cell to produce a certain protein or turn on or off a certain immune response on demand. Unlike previous genetic switches, which require a steady influx of drugs or other chemicals to keep the cell producing the desired effect, the new switch worked like a light switch within a cell — taking the drug once turns the switch to the "on" state, where it stays until another drug is given to return the switch to the "off" state.
The prospective value of such a switch is monumental. It might be used, for example, to create programmable cells that could serve as biological sensors, designed so that a pathogen in the environment would trigger the switch, alerting observers of the toxin's presence.
The switch could also be used in health care. "The ability to turn genes on and off at will could have a major, major impact in medicine," explains DeLisi, who is now senior associate provost for bioscience. "If you turn off or on certain immune response genes for a period of time, for example, you could avoid tissue-graft rejection while the immune system adapts to the new tissue."
In seeking an application for the toggle switch, the researchers found themselves crossing yet another disciplinary boundary. They came up with the idea of using the switch as a tool to explore the structures of natural large-scale genetic networks by turning genes on and off and examining the consequences on the system. As they pursued the project, they realized that a piece was missing — they needed an engineering approach to work out a map of the system's hidden circuitry. Such an approach didn't exist, so they decided to develop one themselves.
Exploiting Bacteria
About twenty-five members of Collins's Applied Biodynamics Laboratory sit on blue couches, a wooden bench, or the mismatched chairs around the central table. Everybody looks impressed when grad student Mike Driscoll puts a button-down shirt on over his T-shirt — "That's for us?" someone asks, in awe. Driscoll smiles a little sheepishly and leaves the tails untucked as he links his laptop to the room's projector for his presentation. He has Mediterranean blue eyes and brown hair that could use a trim.
Collins sits in a rolling chair at the head of the table. Elbows on knees, he leans forward intently, sneakers planted on the blue tile floor. His lab is organized in teams, with each member — biologist, engineer, physicist, mathematician, or chemist — bringing a unique set of skills to the team's work. "We get risk takers, we get smart people, but first of all, we get nice people," Collins says, "people who are willing to work with each other and to help each other. And it makes a big difference."
A doctoral student in bioinformatics, Driscoll is part of a group working to exploit bacteria for practical applications, using the bacteria themselves as microscopic factories that can synthesize chemicals, produce electricity, generate fuels, or clean up toxic metals in the environment.
Driscoll is presenting his research on the bacterium Shewanella, which has the potential to be used in environmental remediation. The process he has been using to map out the cellular circuitry of the organism was originally developed in Collins's lab.
"What's interesting," Collins notes later, "is the random twists and turns of where our lab has gone. We've been willing to go after what we consider exciting new projects that may be only weakly linked to something that we've done previously."
Thanks to research like the Human Genome Project (of which DeLisi was a founding figure), scientists now know genetic sequences for humans and a number of other organisms. But how exactly do those genes interact with one another and with proteins and other molecules in a cell? To find that out, Collins's lab designed a process by which researchers can establish a kind of wiring diagram for a cell — a map of the different "circuits" that control a given process.
Collins compares the mapping process to an electrical model: imagine that you are trying to figure out the wiring of a house. You might plug a radio into an outlet in the kitchen, turn the volume up high, and then go to the circuit breaker box and flip switches until you hear the radio go off — aha, this switch is connected to the kitchen. You move the radio and return to the circuit breaker to discover which switch is connected to the living room. "You do that, turning things on and off, up or down, until you actually begin to get a first-level map of the wiring of your house," Collins says. "Then you do the next level: you say, 'Okay, now I'm going to try to run the dishwasher, the air conditioner, and the microwave,' and you see, Bam! If I do those three, I blow the circuit, so there's some nonlinearity, or a common connection, that I have to watch out for. That also gives us a representation of the underlying circuitry. And that's essentially what we're doing in the cell."
Thus far, they've created these system maps for bacteria and yeast cells. Eventually, they hope that the maps will help scientists make more effective antibiotics with fewer side effects, as they'll be able to predict exactly what biological components within a cell are affected by a given drug.
The technology also has promise for increasing our understanding of diseases such as prostate cancer, breast cancer, and leukemia: by comparing a disease's effects to its cellular map, scientists may be able to figure out what specific genes or proteins are doing that might be playing a role in the development of the disease. In pursuit of these goals, Collins's group is now studying cells from rats and humans. "You'd think that in science, intellect and ideas are all that matter," Driscoll says, "but it's not true. Energy matters. And Jim is a testament to that."
Daydreaming and Creativity
In recent years, Collins and his wife, Mary McNaughton Collins, a primary care physician at Massachusetts General Hospital and a faculty member at Harvard Medical School, have adjusted their schedules to spend more time with their children, six-year-old Katie and four-year-old Danny. That doesn't mean that there's less time for science, though; in fact, Collins has found that it's given him the chance to look differently at some of the problems he's trying to solve in his working life.
"You know, in this information age, there's both this swamp of information that isn't leading to new insights in a lot of cases and this need for speed that's devalued just spending time reflecting and thinking about cool new ideas," he says. "Now that we've adjusted a bit to spend more time with the kids, we do have more time to reflect on the interesting problems. Kids can also sit and think and daydream, but we don't seem to encourage that anymore, among kids or among ourselves. I think it's underappreciated in the creative process."
Galileo would no doubt approve.
