Ed Chapman’s tenacious approach to the “most important” problems in biology

“It’s really simple,” says Chapman — a professor in the Department of Neuroscience at the University of Wisconsin School of Medicine and Public Health — although his explanation resembles a master class on the finding, its context, and how it builds the understanding of communication between nerve cells.

Given the intricacy of what he and a legion of other investigators are finding, the effort does not always succeed with outsiders to the field. But Chapman’s name is known and respected among colleagues and competitors who explore the transfer of neurotransmitters from neuron A to neuron B.

In fall 2022, Chapman, who holds a doctorate in pharmacology and is one of two Howard Hughes Medical Institute (HHMI) investigators at UW–Madison, received an “A” grade from the nation’s largest private funder of medical research. The HHMI review described Chapman as “fearless,” with a broad and scientifically aggressive approach that is “unique in the field.” The organization provides steady, reliable support, with an emphasis on new frontiers of medicine, for its seven-year engagement.

Chapman concentrates on research questions that are big, bad, and basic. Many of them concern the release of neurotransmitters at the synapse — the tiny gap between two neurons. He works mainly at the level of molecules, cells, and artificial models of cellular structures.

The multi-faceted approach has propelled Chapman to the forefront of a highly competitive effort to unravel the ground-level secrets of the nervous system. Thirty years ago, he began to work out how a specific protein, in the presence of calcium ions, releases a neurotransmitter into the synapse by triggering the opening of a structure called the fusion pore.

The pore’s formation is the first step in the membrane fusion reaction. When the pore dilates, the membrane that encases the sac of neurotransmitters, called a vesicle, undergoes a complete merger with the plasma membrane around the cell. It’s a complicated process, even though it happens in neurons on micro- or milli-second timescales, and it’s a major focus of the Chapman lab.

In 2018, Chapman used a gadget developed in his lab to demonstrate that the number of proteins in a fusion pore governs how it opens. The lab-built pore did not simply open, flush its cargo into the synapse, and close. Sometimes it opened briefly, and sometimes much longer. Sometimes it opened completely, and other times, partially. And sometimes it even trilled like a flute.

“The experiments are very challenging,” Chapman admits. “And [our results] have been confirmed by others. We could still be wrong — up to 99 percent of neuroscientists believe that, in neurons, the fusion pore expands and releases its entire contents when it opens.”

Why do researchers care? Because this release is the home of neural chit-chat. For example, Chapman speculates that the process could overturn the signal from glutamate, the brain’s major excitatory neurotransmitter. The glutamate receptor, he notes, “requires a quick, big dose of glutamate to activate, but if you apply the same number of glutamate molecules slowly, it will be desensitized.”

So, a trickle of glutamate could convert the classic excitatory neurotransmitter into an inhibitory one.

The result was characteristic of Chapman’s approach. It focused on the speed of a process. And it was basement-level basic: neurotransmitter releases occur countless times a minute in a person, and they are critical to kicking a football, typing a word, remembering your aunt’s name, and smelling the roses.

Basic science matters, says Chapman, who is not shy about being considered a type of mechanic who delights in asking, “Can you fully understand a car without knowing how its components work?”

Growing up in Bellingham, north of Seattle, Chapman played the trumpet and baritone and was interested in chemistry, biology, and oceanography. Educated at Western Washington University, the University of Washington, and Yale University, he eventually settled on biochemistry.

“I always wanted to know how everything worked. I think that most human beings do,” he says.

Why focus on the nervous system? According to Chapman, it’s because “nerves do all the interesting stuff” and they do it faster than any other tissue.

Understanding the mechanism that allows a neuron to blab with a neighbor is one pillar of a remarkable research career. Chapman, who leads a research group of about 18 people located in the Wisconsin Institutes for Medical Research, has explored other aspects of neuronal biology including the mechanism of action of botulinum toxin and the movements, dynamics, and fusion of other organelles in neurons.

One goal of his work on the formation and recycling of synaptic vesicles is to understand how synapses can vary their reactivity. Again, basic mechanics have fundamental implications.

“We know neuronal function has to change with experience, or else you could not remember or do anything,” Chapman says.

His work centers on some deceptively simple questions: How do neurons create and control fusion pores? What molecules and mechanisms are involved in the fusion of membranes—the ubiquitous “containers” housing every animal cell?

The process of membrane fusion, which enables neurotransmitter release, evolved two to three billion years ago, long before neurons, and it underlies the functions of all eukaryotic cells.

“Membrane fusion is as fundamental to life as DNA and genes,” Chapman notes. “Some people think fertilization is the most important case of membrane fusion. Some people feel viral entry into the cell, perhaps because a loved one died of a viral infection, is the most important fusion event. I can understand that. But to me, the most interesting fusion process, by far, is the one we think with and feel with. It’s the fusion of the membranes that results in the release of neurotransmitters. Overall, I think fusion pores and the mechanics of membrane fusion are among the biggest unsolved problems in all of cell biology.”

The lab’s results have been published in top scientific journals, and Chapman mentions several of them as his greatest hits, but when asked about memorable moments from his research career he sometimes returns with completely different answers.

“My proudest achievement is the success of my trainees,” he says. “Everything else is a distant second.”

The extent of his influence, Chapman says, was driven home at the traditional 60th birthday symposium, held in July 2022.

“When people go off and are incredibly successful in their careers and lives, and they come back and explain your role in that. … It’s something I did not think about very often, but it was incredibly emotional, hit me pretty deep, pretty hard,” he shares.

An example of such a person, Jihong Bai, PhD, is now a professor at Fred Hutchinson Cancer Center in Seattle. In 1998, Bai became Chapman’s first graduate student.

“I trained in the Chinese system, [where] your professor is well dressed, soft spoken,” says Bai. “I met Ed. He has a ponytail, it’s summer, he’s wearing flip flops. It was shocking, but we remain friends to this day, after 24 years. I still pick his brain about my research and career.”

Jeremy Dittman, MD, PhD, associate professor of biochemistry at Weill-Cornell Medicine in New York, met Chapman during a seminar at the University of California, Berkeley. In a one-to-one talk afterward, Dittman says, “I thought, why is Ed even paying attention to a random post-doc? He was really engaging, asked me difficult questions. … He was super nice, listening to what I had to say.”

Noting that the two remain in touch 22 years later, Dittman says. “He was a mentor, a guardian angel. He’s always someone I can count on, but he seeks out my advice too. He can be extremely humble, and his science is bold, but he does not have the attitude typical of people who have reached his status in science.”

Min Dong, PhD ’04, now an associate professor at Harvard Medical School, arrived in Madison in 1999. He says his decade in the Chapman lab “were really the best 10 years of my life. He’s very good at encouraging people, leading people, discovering people’s strengths. After all these years, he’s still helping me.”

Chapman’s gravitational attraction to big questions was obvious when he interviewed for a professorship at the school in 1996.

Meyer Jackson, PhD, the Kenneth S. Cole Professor of Neuroscience, recalls, “It was shocking how totally he was able to answer the questions. He would run through the prior studies, had almost a photographic memory of an enormous amount of prior work, and showed exactly where his work fit in. He really did blow everybody away in the job interview.”

Jackson, who’s now a friend and collaborator, adds, “Ed has a special flair for biochemical, in vitro studies of proteins. There is a large community that follows the basic strategy of working in the test tube, but he has done that exceptionally well [and] has made the big breakthroughs in important areas. I think we made a good choice in hiring!”