Chemical Biology, Pharmacology
University of Illinois at Urbana-Champaign
Dr. Burke is also an assistant professor of chemistry at the University of Illinois at Urbana-Champaign.
Marty Burke harnesses the power of synthetic organic chemistry to understand and maximize the capacity for small molecules to perform protein-like functions in the context of living systems. His research aims to enable the utilization of such small molecules as molecular prosthetics, i.e., replacements for proteins that are missing or dysfunctional in currently incurable human diseases.
Growing up in Manchester, Maryland, then a one-traffic-light town, Marty Burke wanted to be either a baseball player or a doctor. In the end, he decided to attend college at nearby Johns Hopkins University—an experience that, for someone who had never met a scientist before, was nothing short of “revolutionary.”
As an undergraduate at Hopkins, Burke started blending research in organic chemistry with medicine by incorporating novel compounds into large molecules, called polymers, to treat human disease. Inspired by his undergraduate research project with Henry Brem, a neurosurgeon who pioneered new treatments for brain tumors, Burke decided to pursue a joint M.D./Ph.D. degree at Harvard University.
“I started asking myself, ‘What else is out there in modern medicine that we don’t have a good solution for?’” recalls Burke. The answer came to him when, in the course of his medical training, he treated a young woman with cystic fibrosis. He could explain to her parents exactly what was wrong with their daughter: her body was missing a key protein, called CFTR, that serves as a channel in a cell’s membrane for the passage of chloride ions. But he had no answer for how to cure the fatal disease. It was a hard lesson in the realities of bedside medicine and a pivotal moment in Burke’s career.
“It occurred to me quite strikingly that this is an area of unmet need in modern medicine,” says Burke, now a chemical biologist at the University of Illinois at Urbana-Champaign. “A missing protein is the underlying defect in many diseases and it’s one where the classic drug model fails.” Most drugs either improve or inhibit a protein’s function, but they cannot substitute for a protein that is altogether absent from cells.
Burke began to think about this “missing protein” problem from the perspective of a chemist, by asking: “Could you design small compounds that function like the missing proteins?” The idea, he says, is to synthesize molecules small enough to be easily taken up by cells in the body. The molecules could cure disease by functioning in place of a missing protein—just like a prosthetic hand replaces the function of a hand lost to injury or disease. Burke admits he is now obsessed with this concept of “molecular prosthetics.”
To tackle this problem, Burke realized he would need to gain expertise in organic synthesis, an area in which he had little experience. He joined the lab of HHMI investigator Stuart Schreiber, a leader in the synthesis and study of small molecules. “I'm grateful,”says Burke, “that Stuart decided to take a chance on me.”Burke describes his time in Schreibers lab as transformational. “Stuart not only taught me how to make molecules, but perhaps more importantly, he also taught me how to explore the limits of what they can do.”
Some small molecules that occur in nature have already shown promise as molecular prosthetics. For example, amphotericin B, a small molecule produced by bacteria, can insert itself into cellular membranes and act like an ion channel that transports potassium ions across the membrane. It's nature's way of screaming out that this approach is possible, says Burke. Now in his own lab, Burke and colleagues have already made some progress in tweaking the structure of amphotericin B to understand how it forms a channel—key information for designing an amphotericin-like molecule that could replace CFTR to treat cystic fibrosis.
For molecular prosthetics to become a reality, Burke and his laboratory must overcome two huge challenges. First, it can take many years to synthesize just one molecule. Burke’s goal is to develop an automated process that could be completed in a few days. The second challenge is to understand the general mechanism by which small molecules are able to operate like proteins in living systems. That understanding is critical to being able to design the most effective molecules.
Burke is so driven to see molecular prosthetics become a reality that he devotes 100 percent of his time to research. Although he sometimes misses treating patients, he believes he has found his place bringing chemistry research to bear on curing human disease. He also managed to find a way to help kids back in Manchester get an early exposure to the wonders of science. He sends his mom giant chemistry model sets so that her preschool class can now make new molecules of their own.