To describe Jay Groves's lab as cross-disciplinary would be an understatement. A member of the University of California, Berkeley chemistry department, Groves is a biophysicist who straddles several disciplines and uses the tools of materials science, cell biology, and physical chemistry to eavesdrop on communication between living cells.
He focuses on a poorly understood concept: the effect of the spatial organization of proteins and other molecules at the cell surface. Groves, who earned his Ph.D. in biophysics at Stanford University, invented a new approach—coupling synthetic and live cells—to disturb the spatial patterning of cell surface receptors and signaling molecules, and he has observed the surprising impact of spatial changes on cellular discourse.
Groves investigates signaling of the immune system's T cells as a model for understanding how a broad range of cell types communicate with one another. T cells act as scouts for the immune system, communicating with receptors, or antigens, on foreign cells to determine whether they are friend or foe.
He is fascinated with the concept of the "immunological synapse." One of the fundamental principles of the immunological synapse theory is that the proteins engaged in communication at the cell-to-cell junction are precisely arranged in spatial patterns that profoundly affect downstream events.
"The role of spatial patterns in the immunological synapse was very difficult to probe," Groves says. "The classical tools of molecular biology—creating genetic mutations and using drugs to manipulate cells—weren't well equipped to address the question."
But Groves had an idea. In 1997, during his doctoral research at Stanford University, he developed methods to build supported lipid bilayers and used microfabrication techniques to add grids to partition the membrane. Microfabrication technologies originated in the electronics industry and have been refined and adapted for use in exploring biological questions. In 2005, Groves and Michael Dustin (New York University), one of the originators of the concept of the immunological synapse, used those techniques to create a hybrid, half-living/half-artificial cell system. It employs a living T cell but replaces the antigen cell it normally binds with a nanostructure built by Groves. The surrogate antigen attracts the T cell, like a normal antigen would.
"But then," Groves says, "we sneak in constraints," or spatial mutations. Etched onto the manufactured nanostructure are barriers that guide the spatial organization of receptors and signaling molecules. "When a T cell lands, it binds the antigen proteins in the membrane on the artificial cell, and it begins to assemble signaling complexes," he explains. But the synthetic barriers on the artificial antigen cell constrain movement—and thereby change the T cells' behavior. "It's like the members of a marching band milling about on the field, coming together into instrument-specific groups, but then being kept from coordinating into a single unit."
Groves has created an array of these spatial mutants that restrict movement on the cell membrane in specific ways. Using classic cell biology techniques, he characterizes the signals that occur after binding to see how they differ from one spatial mutant to another. These studies indicate that the cell uses spatial organization to regulate the mechanisms of receptor signaling.
His approach may also help explain how certain drugs work. For example, his group has found that large molecules, such as therapeutic antibodies, change the spatial organization of their target receptors on the cell surface. "Maybe," he says, "that's how the drug is working, and we don't know it."
Groves has also begun to use the hybrid cell system to look at how cancer spreads. Much about cancer, for example, can be traced to a breakdown in cell-to-cell signaling that cannot be explained by chemical reactions. Groves recently devised a hybrid live cell-supported membrane system to observe signaling through the Epha2 receptor that shows promise in distinguishing tumor cells in the breast from healthy cells. "Our work has begun to suggest that spatial organization might really have consequences," he says.
As Groves and his students explore cell-to-cell communications, he's witnessing the students learning a new scientific language as they move seamlessly between the physical, chemical, and biological sciences. "If you learn a new language as an adult, you speak the second language with your own accent. But if you begin at an early age, you become fluent in both languages," he says. "We have a new generation of students with an interesting cross-disciplinary bilingualism in science that never existed before."