As a senior at Cornell University with a double major in chemistry and economics, Brent Stockwell faced a tough decision about which discipline to pursue after he graduated: chemistry or economics? In the end, chemistry won out because it offered him endless opportunities for experimentation.
"With economics, there was only one experiment and it was running all the time," says Stockwell of the global economy. "That problem was hardly amenable to the kind of manipulation that yields new scientific insight."
Today, Stockwell, a chemical biologist at Columbia University, has set out to uncover the mechanisms that govern how cells die. His ultimate goal is to create a global map—a periodic table of sorts—of all the possible routes that lead to cell death, and which ones can be specifically turned on in tumor cells.
"We know a lot about one kind of cell death, apoptosis, in which a cell kills itself," says Stockwell. "And we know something about necrosis, which results from trauma or damage to a cell." There are likely other ways that cells die, but precious little is known about them, he says.
Figuring out how and why cells live or die is essential to revealing vulnerabilities in cancer cells and stopping the damage caused by neurodegenerative conditions. It is also relevant to understanding normal development, Stockwell explains. For example, certain cells must perish on schedule so that the human body can sculpt fingers and toes from the stumpy webbed structures that arise earlier in development.
Stockwell uses natural and synthetic libraries of small chemical molecules to explore cell death. "We test many different kinds of small molecules, which can penetrate the cell and attach to proteins to change their properties, to ramp activity up or down," he says.
Stockwell and his colleagues add chemically tagged small molecules to cells to identify protein targets, which can then be purified and analyzed biochemically and genetically to learn which proteins are involved in cell death. Synthetic analogs of the lethal small molecules can then be developed as drug candidates.
His group’s pioneering studies have helped to open up a type of personalized cancer medicine—the use of synthetic lethal screens to identify new drug compounds that kill cancer cells. Synthetic lethality is defined as a genetic interaction where the combination of mutations in two or more genes leads to cell death. During the last few years, cancer researchers like Stockwell have become increasingly interested in developing synthetic lethality screens as a tool for uncovering genetic dependencies in cancer cells.
To identify compounds that kill cells based on their genetic makeup, Stockwell's group used engineered cells with a specific cancer-causing mutation in a gene known as Ras. Using the engineered cells alongside identical cells lacking the mutation, Stockwell found a small molecule, dubbed erastin, which is selectively lethal to the cells with a Ras gene mutation. A derivative of this compound is now in clinical testing.
In other recent work, Stockwell's lab identified a target protein for compounds that might improve treatment of Huntington's disease by preventing or limiting damage from misfolded proteins. The new protein target seems to initiate the kind of cell death associated with Huntington's disease.
Stockwell has invented several drug discovery technologies, and holds or has applied for 33 patents for such things as drug combinations to treat tumors, a treatment for neurotoxicity in Alzheimer's disease, and identification of genotype selective antitumor agents.
In 1999, after he finished graduate school at Harvard University—but before he began his position as an independent fellow at the Whitehead Institute— Stockwell found the time to indulge his interest in business and economics. He cofounded CombinatoRx, a biotech company that develops combinations of FDA-approved drugs to fight disease. The publicly traded company now has several products in the pipeline, including seven in clinical trials.
"I wanted to have the experience of trying to start a company and see what it was like," Stockwell recalls. "For me, it was an opportunity to see the other side of science."
Although successful as an entrepreneur, Stockwell says the experience reinforced his desire to build a life in an academic lab and not the executive suite. "Following your curiosity is the greatest job in the world."