Paul Wiggins yanks the mouse cord from his computer and stretches it between his fingers. “Here’s your chromosome, which is about 2 m long.” He twists the cord and squeezes it into a ball. “How”, he questions, “does it get inside a nucleus that’s 10–50 µm long?”

The animated, 32-year-old researcher at the Whitehead Institute of Biomedical Research in Cambridge, Massachusetts, confesses that we do not know the answer. “But we do know its genetic loci don’t end up randomly shuffled. Each ends up at a particular spot. Why?”

Wiggins thinks that tools used in physics can help answer these questions — but that to do so involves researchers jumping in at an uncharted interdisciplinary middle, to measure something that can be linked both to the molecular scale and to the cellular scale, or midway between physics and biology.

Beyond strings

As an undergraduate at Cornell University, Wiggins was entranced by astrophysics and cosmological theories — the grander and more abstract the better. In 2000 he moved to the California Institute of Technology as a graduate student and joined the collective of string-theory pioneer John Swartz, whose work seemed glamorous. “We felt that we were on the threshold of a revolution,” Wiggins recalls. But after 18 months the glamour wore off. “The research felt less like a revolution and more like a small perturbation. There were no predictions.”

Caltech requires first-year students to attend weekly lectures given by outsiders on their research, and Wiggins found the biophysics talks exciting. “Biophysics involved lots of experiments on incredibly interesting phenomena, and nobody had models,” he says. “That appealed to my theoretical instincts.” It also activated previously unsuspected experimental desires. Wiggins switched fields, and in 2005 finished a thesis on the statistical mechanics of biomolecules.

His research was so promising that he was named one of five fellows at Whitehead — a prestigious independent research institute that employs about a dozen permanent faculty members affiliated with the Massachusetts Institute of Technology. The institute’s fellows programme fast-tracks promising young researchers, putting them in charge of their own labs and bypassing the postdoc phase in which they would have had to labour in someone else’s group.

Island-hopping

At Whitehead, Wiggins was free to pursue what my Stony Brook colleague Fred Goldhaber calls “island-hopping” research. The analogy comes from the Second World War, when the Allies swept across the Pacific towards Japan. They advanced more rapidly not by conquering islands in sequence, but by skipping over several at a time, leaving them to be liberated afterwards. In a similar fashion, effective research programmes often do not proceed outward in safe steps from thoroughly understood terrain, but in ambitious leaps that skip terrain for other researchers to explore later.

Wiggins’ island-hopping has involved taking biological information about cellular structures and applying methods of physics to explore the mechanisms giving rise to these structures. He and some Caltech colleagues, for instance, did experiments to see if physics could shed light on the intricate shapes of the membranes surrounding the cellular subunits known as organelles. The team used optical tweezers to tweak such membranes in various ways, measuring the forces it took to drag membranes into different shapes (2008 Proc. Natl Acad. Sci. 105 19257). Wiggins admits that the researchers have so far made only limited progress. “But,” he says, “we have shown that, in a controlled environment at least, we can quantitatively compute the forces involved based on mechanics and structure.”

Wiggins’ latest research — which he was using his mouse cord to explain — involves studying the chromosomes of the bacterium E. coli. These chromosomes are circular, but two key sites are the “origin”, where replication begins, and the “terminus”, or the opposite point, where replication ends. To explain why E. coli always manages to locate genetic sequences in the right place, a physicist naturally thinks of two possible explanations, involving external and internal interactions. The genetic material may be bonding to some external scaffolding, or its position may be determined by internal interactions between the DNA strands themselves.

What Wiggins is doing is using conventional fluorescence-microscopic techniques to determine the precision by which the different sequences end up in their particular places. The width of this distribution — the precision — measures the strength of the coupling between sequence and location, which provides clues to the mechanism tethering it in place. Wiggins’ preliminary measurements suggest that external interactions prevail at the terminus, but that internal interactions prevail throughout the remainder of the chromosome. “We seem to know where the biological action is,” he says.

The critical point

Island-hopping faces well-known obstacles. As Wiggins points out, everyone likes the idea of interdisciplinary research, but it requires effort to make it work. “You spend a lot of time being an ambassador,” he says, “explaining to colleagues and potential collaborators why your problems are relevant and interesting, which takes you away from the lab bench.” Indeed, cultural differences are an obstacle even after a collaboration is formed. As Wiggins puts it, “Physicists always tend to think that they know how to do other people’s problems better, while biologists often place little value in mathematical models.” In his eyes, both physicists and biologists think that they know how to ask the interesting questions, and tend to treat members of the other culture as mere technicians.

Wiggins has largely been shielded from these problems at the small and biomedically oriented Whitehead Institute, but his five-year stint is drawing to a close. “Next year I have to look for a real job,” he says. And although Wiggins does not think that he can sell himself as a biologist yet, for him the move into biology has been worth the risk. “String theory lost its glamour for me when it didn’t have achievable targets. What turned me on to biophysics were the interesting measurements and predictions you can make, and the urgent need for models. It is a field that is wide open.”