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A large thrust of your research is molecular switches. What are these switches and why do you focus on them?
WADE: Molecular switches sense environmental stimuli and turn them into cellular responses. They are molecules or systems of molecules that can switch from one form to another—for example from being inactive, or “off,” to being active, or “on.”
They’re important because they’re how biological systems talk to one another. They’re at the center of everything. They’re key to development, for example. Circulating hormones and some small molecules and proteins will flip on the molecular switches that induce a group of cells to differentiate into specialized tissues. And when a switch doesn’t act properly, it can lead to a disease.
When might that happen?
WADE: In a way, you can say that cancer is a result of malfunctioning molecular switches. A family of genes called Ras is one example. Ras proteins are required for cell growth, and normally, after a cell has grown for a while, Ras switches off. But in cancer, the switch malfunctions and continues to stimulate the cell’s growth. So the cell does not die.
How does this model of molecular switches apply to multiple-drug resistance?
WADE: The proteins in bacterial cells that are responsible for multiple-drug resistance are biological switches. Certain drugs can flip these switches, “turning on” the mechanisms that confer resistance.
Did you set out, when you first became interested in science, intending to focus on this area of biology?
WADE: In high school, I was always good in math and science (although I got a C in chemistry class). A nearby college offered me a chance to do research in an inorganic chemistry lab. I loved it.
I like thinking about how to solve a problem, how to simplify a complex problem into its basic components and understand how it works.
But you didn’t stick with inorganic chemistry.
WADE: No. In grad school, I got interested in catalysis. Catalytic antibodies were in vogue at the time. People thought that they had the potential to bind to almost anything, which would give them huge therapeutic implications. Then as a postdoc at the University of Pennsylvania, I worked with Bill DeGrado. We were designing proteins from scratch—de novo—to learn their structure and function. That research led to my working on some of the MerR proteins.
MerR proteins comprise a really cool family of switches. They are activated by a wide range of different signals—small organic molecules, heat, metals and others. I became interested in how you can have one protein activated by so many different things.
Does your current research relate to that theme?
WADE: We are now studying one of the mer proteins, which is called BmrR. Specifically, we’re interested in how it can recognize and possibly be “turned on” by a variety of drugs, a process that appears to lead to multiple-drug resistance. More and more of our research has focused on this area.
Why have you narrowed your focus?
WADE: BmrR and other proteins involved in multiple-drug resistance are sort of a paradox. Everything we learn about molecular switches has to do with specificity. Most switches are turned on by a specific thing. But these switches do not discriminate.
--Interviewed by Melissa Hendricks