Genetics: Fast Forward

By Cassandra Nelson

It’s the kind of opportunity that comes along only once in a lifetime—and for biomedical engineer James Collins, once may be enough. As the first BU researcher to be named a Howard Hughes Medical Institute (HHMI) Investigator, Collins will receive several million dollars over the next five years and the possibility of renewed funding for postdoctoral researchers and other lab assistance in the future. “This money will allow me to go after cutting-edge, innovative, and long-term investigations that would be difficult to get funded through normal mechanisms,” he says.

Collins was one of 56 HHMI Investigators chosen this May, from a pool of more than 1,000 applicants nationwide. He sees his selection as evidence of a paradigm shift in molecular cell biology toward research that crosses traditional disciplinary boundaries. A physicist and medical engineer by training, his own career has followed an increasingly interdisciplinary path in recent years.

A transition to molecular biology led Collins to systems biology, where he applied a reverse engineering approach to genomes, proteins, and signaling pathways to develop a method of identifying the targets of drug compounds, which can reduce the costs of developing new drugs and vaccines. From there, he helped found the field of synthetic biology, which builds on systems biology to “forward engineer” genes, proteins, and DNA and RNA fragments, creating novel biological circuits in the lab. Among Collins’s creations was the first “genetic toggle switch”—a molecular device that can turn specific genes off and on, revealing how they interact with different cells throughout the body.

“Now you can imagine a small molecule that could be added to Cipro to make super-Cipro, or to ampicillin to make super-ampicillin, and so forth. All with one molecule.”

There are no signs that Collins, who received a MacArthur Fellowship in 2003, plans to narrow his focus any time soon. Looking ahead, he tells HHMI that the interesting problems in biology will lie “at the interface of mathematics, physics, and bioengineering.”

Right now, the problem Collins finds most fascinating has to do with the specific mechanisms by which bacteria respond to antibiotics. A better understanding of how antibiotics work is a prerequisite for developing much-needed, more effective ways to fight infections. Already, he and his colleagues at BU’s Applied BioDynamics Laboratory have begun to lay the groundwork for increasing antibiotics’ potency.

“Our platform and our discoveries give a nice base for extending the life of existing antibiotics,” Collins says, “enhancing their effectiveness while restricting the emergence of resistance.”

He and two graduate students, Daniel Dwyer and Michael Kohanski, began by discovering a previously unknown cell death pathway triggered in response to bactericidal antibiotics. Cell death pathways are mechanisms that tell a cell to shut down—in this case by producing oxidative agents called hydroxy radicals, which damage lipids, DNA, proteins, and other parts of the cell. (Hydroxy radicals are also the reason why antioxidants are touted as ingredients in everything from pomegranate juice to wrinkle cream.)

Collins’s lab then identified several targets related to this oxidative cell death pathway, providing a good basis for medicinal chemists to develop a compound that could be added to existing antibiotics to enhance their killing power. The result would be a more efficient antibiotic that can be given in smaller doses.

“Now you can imagine a small molecule that could be added to Cipro to make super-Cipro, or to ampicillin to make super-ampicillin, and so forth,” says Collins. “All with one molecule.”

In addition to cell death pathways, bactericidal antibiotics stimulate a common defense pathway in cells—called an SOS pathway, after the distress call used by ships at sea—which helps repair the microbe’s DNA. Because errors in DNA replication are what cause new strains of antibiotic-resistant bacteria to emerge, Collins and his team have also identified a way to shut off this SOS pathway genetically by knocking out one of its on switches. “We get the second whammy by shutting off the SOS pathway,” he says. “We reduce the emergence of resistance.”