Tinkering With Cells Listen to HHMI investigator Jim Collins talk about synthetic biology while getting an inside glimpse at his Boston University lab.

HHMI: TELL US ABOUT A CIRCUIT YOU'VE ACTUALLY CREATED.

JJC: In terms of a cell, a network or circuit means a set of proteins and genes interacting with each other. One circuit we've engineered is the genetic toggle switch. It's made of two genes; each wants to be on and shut the other one off. The circuit can exist in two stable states: in state 1, gene A is on and gene B is off; in state 2, gene B is on and gene A is off. The circuit can be switched between the states when we deliver an inducer—a chemical or environmental stimulus that shuts off the currently “on” gene. It's a relatively simple example of what we do. Toggle switches and related synthetic gene networks can be used to endow cells with the programmable ability to sense and adapt to their environment.

HHMI: YOU WORK IN BOTH SYSTEMS BIOLOGY AND SYNTHETIC BIOLOGY. HOW ARE THEY RELATED?

JJC: In systems biology, researchers are taking computational approaches to studying the natural pathways and circuits inside cells. Whereas in synthetic biology we're trying to put together a new radio, in systems biology we're trying to figure out how an existing radio is wired up. It's like basic electrical engineering classes: students are given circuit boards and told to figure out how they work. They have to go through each component of the board, turn it on or off, measure its effects, and infer the underlying wiring. In systems biology, that's what we're doing inside the cell.

HHMI: WHAT QUESTIONS CAN SYSTEMS BIOLOGY ANSWER?

JJC: I'm excited about using systems biology to reveal how drugs work. Researchers are very good at testing whether a drug hits a target. But they don't know what else it hits inside the cell. We can take a systems biology approach: screen all the genes, proteins, and some metabolites in the cell to identify a drug's target. We've used our approach on antibiotics and shown that they target and activate many more cellular networks in bacteria than we thought. By understanding the inside wiring of the cells, and how circuits respond to a perturbation like an antibiotic, we can come up with better therapies.

We can use this same approach to understand how diseases affect different pathways. We can take someone with prostate cancer or breast cancer, look at the expression of genes in their tumors, and analyze which pathways have been affected. We're just beginning studies like that.

HHMI: WHAT'S MOST CHALLENGING ABOUT WORKING IN THESE NEW FIELDS?

JJC: There are a lot of cool synthetic biology ideas out there. It's pretty easy to come up with a circuit diagram and increasingly straightforward to build the cellular components you'll need. But it's really hard to get the constructed biological circuit to behave the way your schematic or model indicated. We've recently developed an approach that allows us to put together a number of well-characterized parts—genes, promoter, and proteins—and predict with some accuracy how they'll behave together in different circuits. But our synthetic biology toolkit is still relatively small. We're playing around with circuits that consist of two, three, maybe six genes that give cells rudimentary functions. We're expanding our understanding of cellular networks, but the cell is incredibly complicated and it's going to take a long time to figure it out. I'd be surprised if we ever develop a full understanding of every single network in the cell, which is partly why this field is so fascinating to be in. I think we'll be in business for a long time.

James J. Collins is a professor of bioengineering at Boston University and codirector of the Boston University Center for BioDynamics.

Interview by Sarah C.P. Williams.

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