Meet our Speakers: Dr. Edwin Chapman

Making the invisible, visible: the creative core of scientific discovery.

Meet our Speaker: Edwin Chapman, PhD

By: Emma Watson Roberts

Edwin Chapman is a professor of Neuroscience at the University of Wisconsin-Madison and an HHMI Investigator. The Chapman lab has spent the last 28 years studying the molecular mechanisms that mediate calcium-triggered exocytosis and their effects on synaptic function, as well as a variety of associated membrane trafficking events. Ahead of his talk on Tuesday, April 29^th, I had the opportunity to chat with Dr. Chapman about his work, his approach to science, and what he takes away from all his years in the lab. This interview has been edited for length and clarity.

Was there any event or person that inspired you to pursue a career as a scientist?

Yeah, my origin story. I have two things I'd say about that—and these change as you age, I have a different perspective as an old gray-haired guy —I mean one thing that's really clear was when I was in college in Bellingham, Washington, where I'm from, I really admired my professors, and I thought they had an incredible lifestyle—learning and doing science, teaching and disseminating science in an academic setting where you get to do stuff in laboratories with equipment and chemicals. This is something I always liked through childhood. And I thought “boy, it'd really be great to be one of those people”. So that was kind of planted in the back of my mind, but coming from a blue-collar family, was that practical? I didn't know. One professor at my local college, Western Washington University (WWU), a physical chemist named Wilson, was talking to me in a way where he's kind of assuming I would go to graduate school. He didn't ask me. He didn't suggest it; he sort of behaved in a way like he saw something, and he treated me differently. There was an assumption like, “yeah, you have these abilities, so you're going to do something with them. And, you know, what exactly is it going to be?” That planted a seed because now I had a grown-up saying: you could be one of us.

Then in grad school I had my first rotation with Bill Catterall, who worked on ion channels. So, I rotated with this lab and then I had classwork, and in my classwork I learned about ion channels from Bertil Hille. He wrote the major work Ion Channels of Excitable Membranes and was a thought leader in ion channels. And then the first time I heard the word “fusion pore” was the same class Bertil taught in an AP-bio class in Seattle. And Wolfhard Almers taught me about fusion pores in that class. So, I worked on ion channels in Bill Catterall's lab as my first rotation, learned about ion channels and fusion pores in AP bio class that Bertil Hille and Wolfhard Almers were lecturers in, and Peter Detwiler taught us the Hodgkin-Huxley Model and action potentials and stuff. Well, I look back over that and I'm like, “wow, you know, these were luminaries and that I was working with some of the best people ever in these fields”. I didn't know that at the time. I was just some cocky kid and so it really didn’t sink in until later. So, I'd say that those were pretty formative things early in my development as a scientist.

And then I guess the last thing I'd say is that I owe Reinhard Jahn a debt of gratitude. I continue to work on the problems that drew me to his lab 30 years ago all the way back in 1992. The last, last thing I should mention is when I came to the University of Wisconsin, Meyer Jackson was a big influence on me because he was older and he was still into the details. This is a guy who still did experiments. He did really deep, rigorous analysis. He still published his single author papers. I think it had a pretty strong influence on me.

What are the big questions that you are pursuing in your lab?

So… I mean, I would argue despite the discoveries of Jim Rothman and others, that we really don't know atom by atom how proteins catalyze the merger of two lipid bilayers. So, I still think that's a deep but also detailed kind of question because we kind of know the players, we kind of know they do it. We just don't really know how they do it. Not everyone may agree with that, but I feel like I can make that argument. So that's a big question.

The other thing I'd say on that question is one of the longest running projects in my lab. It's been going seven years and we're not even halfway to reconstituting fusion pores and determine their structure. And I think that's really the only way to get sort of an atom-by-atom, blow-by-blow account of the catalysis of the merger. So, my fantasy—I can go on about this forever—but my fantasy would be to reconstitute the fusion machinery, for example, in nanodiscs of increasing diameter. To let the fusion pore go from trans-SNARE, to pore, to dilated pore, and to solve the structures of each of these along a reaction coordinate. And then I would see how proteins can catalyze the merger of two lipid bilayers. So that's something, you know, I mean, I have a hundred things I want to do, but I think that's probably a big broad general one.

If you discovered a completely new protein, what would you name it?

My instinct would be to name it functionally. But if I'm going to be cute, I would find a way to work in something I love like a dog or a family member or something like that. What I wouldn't do is come up with some really complex multi-syllable name you know, like synaptotagmin. The interviewer notes that Dr. Chapman has spent the majority of his career working on the synaptotagmin family of proteins and refers to them affectionately as “syt” to save time as he says it hundreds of times on the average day.

Where do you see your lab in 10 years?

The real answer is I have no idea at all. None. What we're doing now, I didn't know I'd be doing 10 years ago, so it's difficult to predict in the future. You know, I started my lab working on molecules. Then we worked on molecules and cultured neurons. Now we're working on molecules, cultured neurons, and brain slice preparations. And we've begun to use AAV in brain to modify things before we make slices. We do super resolution imaging, we use nanodiscs and black lipid membranes. We couldn't do these things until those techniques were invented. There are a lot of questions I have; I just don't have technical ways of addressing them. I never would have guessed that microscopists would have broken the light resolution limit, but they did in a few different ways. And so, one thing I do know is that sometimes we have to create technology, or we wait till someone else creates it. So, the real answer here is that it will depend on our rate, and the rate of other labs, in technology development.

Do you have any hobbies outside of the lab?

My favorite thing in the world are dogs. My dog Zoey in particular. I'm also a very passionate weightlifter. Weightlifting is the only thing in my entire life I do at a predetermined day and time. Day in and day out through my whole adulthood—going to sleep, waking up, eating—nothing is regimented except for weightlifting. I’d say lifting is my main passion and art is my main interest. If I was more talented, I would have been an artist, but I was better at science, so I do science. The interviewer notes that the wall of Dr. Chapman’s office is papered with art—some from various lab members, some from his favorite artists, and some, his own original sketches and photographs.

What is your favorite experiment that you or your lab has done?

Oh, boy. That's a tough one. That's a really hard one.

One thing I knew I wanted to do when I entered the field was to reconstitute calcium-triggered fusion. Now, Ward Tucker did that paper in 2004, which is a pretty good start. But I think that our 2018 and 2020 papers on nanodiscs and bilayers really raised the bar for what we study. Because one of the things that excites me about what we do is, and people to phrase this in a lot of different ways, it's making things that aren't visible, visible. You know, the first fully reconstituted system with microsecond time resolution to really look at dynamics that no one had ever seen. I feel like that work really stood out. I remember seeing the first traces for all those papers and seeing those first experiments and like that eureka moment, like this idea was true, or this was right, or this worked.

But there are other really exciting things like—I will say a couple more things and I won't go on forever—when you start your lab you have to generate papers. You don't know if you're going to be successful. In our very first paper, Chapman and Davis 1998, it was the first paper to ever show how a C2-domain binds membranes and showed that these side chains actually penetrate bilayers. I think that was very meaningful for me; my very first paper turned out to be a step in excitation secretion coupling that goes in the textbooks, you know, and it's reproducible, and it came entirely out of an idea I came up with while riding my bike home. I just thought of scanning the surface of the C2-domain and trying to find the surface that touches the bilayer by fluorescence. So I was really proud of that. I think one more I would mention is it was really fun working with Min Dong to find the botulinum neurotoxin receptor. That was really satisfying because it was a simple approach we used, and it worked. When you get something simple that works beautifully, it becomes more elegant. I mean, E=mc² is an incredibly simple equation. It's also one of the deepest things that human minds ever come up with. So, I'm not saying that our work was equal to E=mc², but it's not always the fanciest thing that you're proudest of.

What is your favorite part of being a PI and what makes you excited to get up in the morning and do research?

Well, that's complicated. Underneath all of it is the excitement of discovery; seeing stuff that no one's seen. That's underneath all of it, but as you age it changes a little bit because you see people start their training, say as a graduate student, and I'm old enough now where they did a postdoc, they became PIs, they became senior PIs. And as I've aged, while I still kind of live for the new findings and I can still get excited and lose sleep, I'm thinking about all the life paths that have been affected. From the people I've worked with that maybe passed through my lab and, in many cases, use it as a springboard. I'll spend more time now thinking about the people, more than what they did, especially when they go off and do well in the future, like during a postdoc or when they get an independent position, or they move into industry. It brings a tremendous amount of satisfaction because you really start to feel like you made a difference in people's lives. Maybe that sounds a little grandiose, but it’s true.

Any last thoughts or advice?

So, I think it's good to always have a product in mind, make papers. You have to be productive. But just as important is, you know, really, what are you trying to figure out? What are you trying to say with your papers? For me, it wasn't a conscious thing. I sort of naturally gravitated toward biophysics, not formally trained. Maybe I'm formally trained in pharmacology and biochemistry and some spectroscopy but, you know, the real questions in neuroscience to me were 1) neuronal cell biology questions, 2) protein biophysics questions and 3) synaptic transmission questions.

So, I think that depending on what kind of scientist you are, you have to figure out what gets you excited. I think of science as a combination of a blue-collar job but also a pretty incredible artistic endeavor, because I think you really are limited only by your creativity. And like we talked about before, sometimes you can invent methods but, sometimes, someone who's better at that invents a method that you can capitalize on. So, your creativity will now be expressed by how you capitalize on that invention rather than having been the person who created that invention. And I personally get enormous satisfaction when you think of some weird idea and then a few experiments later, it turns out to work. So, try to figure out other ways of seeing things—ways that other people don't do—that come to you so you can make a unique contribution.

Hear more from Dr. Chapman at his seminar on April 29^th in SHM-C 4^th floor conference room. Interested in the work the Chapman lab is doing? Check them out at https://chapman.neuro.wisc.edu/