Massachusetts Institute of Technology
A Network Biology Approach to Antibiotic Action and Bacterial Defense Mechanisms
In the business world, it's not uncommon to dismantle a rival's popular high-tech gizmo to discover what makes it tick. This approach, known as reverse engineering, has been brought to life—literally—by James Collins as a strategy for understanding how biological systems operate.
Collins is a leader in systems biology, a relatively new field in which researchers are gleaning the basic rules for how cells and their components are assembled and what shapes their behavior. Systems biologists work with the "part lists"—genomes, proteins, signaling pathways, and so on—but their ultimate goal is to understand how all these elements interact.
He is also a founder of the even newer field of synthetic biology, which exploits findings from systems biology to "forward engineer" novel biological circuits. These visionaries are assembling laboratory-made genes, proteins, and DNA and RNA fragments and plugging them into bacteria. On these researchers' drawing boards are miniature drug or chemical factories, devices that sense hostile germs, and microbes that could generate alternative forms of energy. Currently, Collins is tinkering with the circuits of bacteria that are activated when the bugs are exposed to antibiotics and are either killed or deploy protective measures against the drugs.
"This is where some of the interesting problems in biology are going to lie—at the interface of mathematics, physics, and bioengineering," says Collins, who feels his selection as an HHMI investigator is a sign of growing acceptance for such interdisciplinary work by the molecular cell biology community.
After all, his career path has been far from conventional. "I started in physics," he says, "and then studied medical engineering as a graduate student, focusing on whole-body dynamics and problems like balance control. Only a few years ago did I make the transition to molecular biology, and from there to systems and synthetic biology."
Engineering and math were the common currency of the Collins family, and their basement contained an electronics lab in which Collins's father, an electrical engineer, tinkered. "I was brought up in an environment where people were always designing things," he says. He studied physics at the College of the Holy Cross in Worcester, Massachusetts. He then won a Rhodes Scholarship and spent three years at Oxford University, where he earned a Ph.D. in medical engineering in 1990; that year he joined Boston University (BU) as a research assistant professor.
When Collins was in his teens, one of his grandfathers lost his sight and the other had a series of disabling strokes; it was this "formative experience" that spurred an interest in rehabilitation medicine. At BU, he channeled his interest in nonlinear dynamics—a branch of mathematics that deals with how systems change over time—to develop a new class of medical devices. In studying how people maintain balance while standing, he found that applying randomly varying signals—"noise"—to the feet of elderly people actually enhanced their sensation of touch signals and improved their balance. Collins helped launch a company that develops vibrating insoles and similarly inspired devices aimed at the rehabilitation medicine market.
Moving into the engineering of biocircuitry, Collins and his colleagues in his Applied Biodynamics Laboratory at BU built the first genetic "toggle switch," a step toward designer living cells that can be programmed for desired functions. Over the next few years, Collins will continue dissecting the signaling pathways in bacteria that regulate their responses to drugs. "Many of the direct drug targets in bacteria are known," he explains, "but we want to get a better understanding of what else is going on in the microbe, so that we have a foundation for developing more effective antibiotics."
Other projects include engineering bacteriophage viruses that could be administered with antibiotics to treat infections and using reverse bioengineering to probe the workings of stubborn "persister bacteria" that cause chronic infections by hibernating to escape drug attacks.
Collins has balanced his drive to innovate with a love of teaching—for which he has been recognized frequently. In 2000, he received BU's highest teaching award, the Metcalf Cup and Prize for Excellence in Teaching.
While he has no magic formula for motivating young people to pursue science careers, he emphasizes real-world relevance no matter which subject he's teaching. And he believes students should be allowed—even encouraged—to fail as a necessary preparation for this kind of work.
"After all, I spend most of my days failing," observes Collins. "I want to succeed, of course, but I feel very comfortable putting eight months' worth of work in the garbage can."
In December 2014 Collins moved to the Massachusetts Institute of Technology.