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The Synthetic Biologist: An Interview with Howard Salis

By Steve Williams

SW: You’re at a party, what do you tell people when you say you’re a syntheticHoward Salis (photo by Steve Williams) biologist?

HS: I engineer synthetic microbes from the bottom up to make useful stuff. My discipline is very much a cross between that of a chemical engineer and a biological engineer. I know how to engineer biological organisms at the genetic level, and I know kinetics, thermodynamics, and the dynamics of transport processes—basically, how chemicals interact at the molecular level. By applying those fundamental principles, you can engineer the DNA inside microbial systems to make them perform useful tasks, solving humanity’s problems.

For simple biological systems like bacteria, we’ve gotten very good at engineering their DNA so that they can perform complex logic functions, just like a computer. We can also engineer them to manufacture large quantities of useful chemicals.

SW: What kind of chemicals?

HS: All types. Biofuels—of course, everyone is very much interested in biofuels—but also materials, drugs, polymers, and many others. We use so many chemicals in our daily lives. If you pick up a pen, it’s a piece of plastic, right? These chemicals originally come from someplace. Most likely they came from petroleum. What we want to do is make the same stuff, just not from oil.

SW: So, you’re trying to speed up the process. Instead of taking millions of years, you’ll . . .

HS: Right, microbes do not naturally make these types of chemicals. You have to insert the instructions into their DNA, telling them how to make it. And it is a very specific DNA sequence to maximize the production rate of the chemical. You can’t just go in there trying random things and hoping for the best. That doesn’t work well. Evolution might try that, but it takes place over millions of years.

Evolution will also never produce a bacteria that makes gasoline. There is no reason for bacteria to want to make gasoline. Right? Bacteria do not drive cars.

SW: Exactly.

HS: So we need to understand how the genetic code works at the molecular level. And we need to optimize that code toward a desired function—not only in bacteria but also in yeast and more complicated organisms. It’s similar to how engineers build bridges, airplanes, microchips, etc. As my research progresses, we will be able to sit down at the computer and say, “What do we want to build?” Then, using predictive models of gene expression and other cellular processes, we will optimize the microbe’s DNA to obtain a target metabolic behavior. This combination of modeling and optimization is called a design algorithm in the engineering world. It lets you play around with the microbe’s genetic code to see what it will do, all on a computer. We’ve already made significant progress in this area. We then write DNA sequences, turning genes on and off and controlling their expression to a specified amount, to accomplish the goal. So genes have a switch, but also a control knob, too. Sometimes the optimal solution is somewhere in the middle, between very low and very high gene expression. We use predictive modeling to identify the optimal conditions and then apply the control knobs to actually achieve them.

SW: Sounds sort of like science fiction.

HS: Well, the good science fiction is the leading-edge science that happens a few years from now, right?

Interview condensed and edited by Kim Welsch.