Our Scientists

Ed Chapman likes to work with his hands. He's been a mechanic, carpenter, rope maker, and a combine operator harvesting peas. He's also currently restoring all the windows in his 1930s-era house in Madison, Wisconsin. He brings this mechanical penchant to his laboratory's studies of how neuronal cells traffic molecules, release their chemical messengers, and connect with the next cell to, ultimately, determine how we think, feel, and move.

"I like to figure out how stuff works," says Chapman. His lab has concentrated in part on piecing together the molecular-scale nanomechanics of the reaction that happens when the synaptic vesicle fuses with neuron's plasma membrane. This fusion reaction is necessary for the nerve cell to release its neurotransmitter or hormone signals that regulate how neighboring nerve cells respond.

"Understanding membrane fusion is similar to understanding the structure of the double-helix—it's a topological thing," Chapman says, referring to the study of three-dimensional structures that are continually reshaped. "The lipid bilayers have to fuse and rearrangements have to take place. To this day, nobody knows how that works." For instance, it's unknown exactly which components make up the fusion pore that marks the beginning stage of melding membranes.

As a postoctoral fellow with Reinhard Jahn at Yale University, he studied the presynaptic nerve terminal, where neurotransmitters are released. All the various protein players had been identified, but no one had figured out how they worked together to cause fusion. "It was like a puzzle with all the pieces laid out before me. Figuring out how they fit together has been the rate-limiting step."

For almost two decades, Chapman's own lab has been chipping away at that, using the latest optical probe molecular techniques and reconstituting membrane fusion in the test tube to determine the minimum puzzle pieces needed. But fitting together the nuts and bolts of the membrane fusion machinery is just a starting point for his lab. They take those molecular findings and translate them up the chain to genetic and electrophysiology experiments using mouse models.

The optical probes, for instance, let his group move back and forth between fusion experiments in the test tube and mouse neurons cultured in the lab dish. His group solved a 20-year-old conundrum about the synaptic vesicle protein, synaptophysin, showing it is involved in endocytosis rather than exocytosis. Kinetics studies have also revealed the specific trafficking functions of the large family of synaptotagmin proteins, as well as a key role for the DOC2 protein during the slow phase of synaptic transmission.

Chapman relies on a strong background in chemistry and physics to help his lab straddle the intersection of biophysics, electrophysiology, and genetics. He says working in such diverse fields is a bit like mixing the worlds of performance art and sculpture. But it allows his group to do things like use "old-fashioned chemistry" to measure the kinetics of fusion, or exocytosis, on the order of a millisecond. "Exocytosis is one of the fastest things that animal cells do," he says. "We wanted to study it in real-time." So, his team adds back specific proteins or lipids to the minimum fusion recipe to find a mix that reacts at biological speeds.

He's now turning the lab toward higher-level cellular mechanics—the connections between neurons that build circuits. His group grows neurons on diversely patterned surfaces to see how that changes their connectivity. He's also studying a process called reverberation, which results when a multi-connected circuit of neurons persistently fire nerve transmissions. It's a process that is thought to play a role in memory.

"What are the rules? How much recurrent connectivity do you need?  What if you grow the neurons in discrete nodes rather than mass culture? There's all this crazy stuff you can do," he says, knowing he'll be getting his hands dirty again.