Interviewer: Maggie Sui

Trivia

• Favorite book: Slaughterhouse Five. I found the author Kurt Vonnegut’s works at specific, formative point in my life and it very much resonated with me. It’s this blend of sci-fi and commentary on human nature, the need to challenge orthodoxy, and the absurdity of it all. It’s always reminded to think about how the grand plans laid out by the ‘people in charge’ affect ordinary people, and to have some humility about what the role of good leaders should be.
• Favorite place: New Hampshire. I think some of my best memories are from vacationing in the small towns of New Hampshire like Lincoln or Conway when my kids were young. I’ve never been in the wintertime, but in the summer it’s just so beautiful and peaceful. There are beautiful hikes, fun swimming holes, bouldering, and lots of good fishing.
• Favorite food: Hot pot. Around LA, I’ve gotten really into hot pot places. There are just so many of them, and it’s a great meal where everyone can get what they want.
• Favorite protein molecule: ATP synthase. It’s such a beautiful structure and an incredibly elegant molecular machine. I remember being blown away when I learned about its structure and how that relates to its function. It’s also a protein complex that is essential to life.

Can you provide an overview of your research?

I am a sensory physiologist. My lab studies the synaptic and circuit mechanisms of how the brain makes internal representations of the world around us, and we investigate this in the context of chemical information in insects, mostly in the fruit fly. Chemical communication underlies all of life on Earth. Our experience as humans is dominated by sight and sound. But, for the vast majority of organisms on the planet, their main mode for interacting with the world is through chemical signals, so I view olfaction as the language of life. Olfaction also serves as a particularly compelling system for studying questions concerning how sensory information can be translated into useful behaviors and actions in the animal. In the smell circuit, high level representations of sensory objects are constructed in very few steps of neural processing, so this circuit is a particularly tractable system to study questions like how the brain generates behavior.

What are some possible applications of your research?

Our research provides insight into basic neuroscience inquiries, such as how does the brain translate environmental stimuli into behavior? How does the brain generate internal representations of the world? Such questions have important implications for understanding how to help people with neuropsychiatric or neurodevelopmental disorders who struggle with normal sensory processing. Understanding our sense of smell also has a huge potential for changing the way we live. We all walk around with little machines in our pockets that can capture visual and auditory stimuli, and then also play those back to us, but nothing comparable exists for chemical signals. Enabling machines to sense, encode, and decode chemical signals would be significant for applications as wide ranging as search and rescue in natural disasters, environmental monitoring, and medical diagnostics – there is a chemical signature for many diseases.

What are some exciting recent developments in your field?

Just in the last few years, we’ve finally seen the first protein structures for the odor receptors. The first insect odorant receptor structure was published about four years ago, and, just a month ago, the first human odorant receptor structure was published by a collaborative research group from UCSF, Duke, and City of Hope, just a few miles away. These structures are beautiful because they show the mechanistic basis of how these receptors detect their odorant ligands. One of the most intriguing aspects of this work is that, so far, the solutions for how odor ligands are recognized by insect vs mammalian odorant receptors are quite different. In one case, binding is quite promiscuous and appears to be mediated by many, very weak interactions, whereas in the other case, binding appears more selective and mediated by a lock-and-key-like mechanism. However, we just have the structure for one odorant receptor for each case, and each is somewhat of a special case. Most olfactory systems have dozens to up to more than a thousand odorant receptors, and the structures of more receptors will undoubtedly be soon solved, so in the next decade or so, it should become clear what is the more “typical” mechanism for odor recognition, or if different odorant receptor families from different parts of the evolutionary tree solve the same overall problem with distinct mechanisms. Either would be fascinating!

What aspects of research do you most enjoy?

There are so many things. I think working with students is probably at the top of the list – the back and forth, brainstorming and puzzling, getting stuck and both thinking hard and then suddenly gleaning insight and being able to move ahead – I enjoy the starts and stops. It’s not a steady process.

I also really love doing experiments and being at the bench. I think something that’s the most disappointing about progressing in science is that you get to do fewer and fewer experiments. You work so hard to be able to run a lab, and you’re excited that you can because you finally have the platform to try out all these ideas that you’ve had for years, but then you don’t really have time to do the actual experiments yourself anymore because you have to be writing all the time. So I spend more time in front of the computer than I would like, honestly, but that’s just the nature of things. But watching a student learn and grow, seeing the quality of their data and analyses steadily improve, and guiding them to discovery – that is really what I enjoy the most.

What do you most like about running experiments?

I find beauty in the biological specimens themselves. There’s a structure to everything – from what a neuron looks like to how they’re organized in layers or compartments or bundles. There’s a physical beauty to biology. I also really enjoy pushing the boundaries of what can be done working in a very small brain, so there’s also that technical aspect of pushing the envelope and trying to see something that nobody else has seen. The first time you record something, and you realize it’s the first time anyone has seen this particular phenomenon – it’s pretty amazing.

What influenced you to pursue neuroscience, and more generally, scientific research?

I was very motivated by disease and wanting to understand things like neurodegenerative disease and mental diseases of the brain. Neuroscience in the past 20 years has definitely become more dominated by circuits and systems neuroscience research, but, initially, being very motivated to try to understand the basis of diseases, I started on the molecular side. During my PhD, I worked on the biochemical pathways and the transcriptional events that occur downstream of calcium entry triggered by neural activity and how those things might go wrong in different types of genetically based neurodevelopmental diseases. We would take neurons out of animal brains, dissociate them which destroys all their connections, and regrow them in a petri dish. This allows us to have enough biological material to study the biochemical events that are happening in those neurons, but unfortunately, then we must study them outside their native context in the brain. Eventually, I became more attracted to studying neurons in their endogenous circuit context and that led me more into the systems neuroscience side of things. Ultimately, in many areas of biology, the goal is to bridge scales of explanation. I think we will eventually get back to the molecular level and how it affects circuit behavior, but tracing the etiology of a disease through multiple biological levels is a technically and conceptually challenging thing to do, but I still am very motivated to make headway on this problem and try to contribute to understanding disease states.

What are some of the challenges you’ve recently faced? How did you overcome them?

Well, I mean, there’s always the everyday scientific challenges. We usually cope by pivoting to a different but still interesting aspect of the problem if we hit a technical wall. Often we can make some progress in another area, and, in the meantime, new tools or methods will emerge that can allow us to return to the original approach. One personal challenge that I’m coming up against is realizing my kids are growing up very quickly. My older child is a sophomore in high school. So I’m realizing I just have two years left with him before he’s off and living his adult life. I’ve realized, okay, I need to balance my job with spending as much time as I can with my children. There is this perpetual work-life balance challenge that you have to deal with.

What advice would you give to Caltech students and other young students interested in research?

The most important things are things you’ll learn outside your classes. Classes are important. They give you a foundation. But a lot of times I see students killing themselves to get in that fifth class or over-uniting. However, when I look back on the things that helped me to crystallize what I was interested in, they came from outside the classroom. The key thing to figure out is what is the level of explanation in science that you find satisfying. One person’s mechanism can be the next person’s phenomenology. I consider myself mechanistic, but I don’t study things down to electrons moving in the orbitals of atoms. Each person has a level of explanation that they find compelling and that they’re excited about. For a psychologist that could be behavioral, and for a structural biologist, that’s atomic, so figuring that out is important, and you can’t figure that out without a lot of exposure to different kinds of science, lectures, papers, and people who work across all these different scales – see how they think about things. All that kind of stuff is really hard to get from a classroom, so it’s possible to have students who are very, very well prepared on paper based on their coursework, but they’re not intellectually ready to pick a problem to focus on for their thesis in graduate school. Honestly, the reason to come to a place like Caltech is the people you’ll meet. Bug people and ask them about their work. Ask them how they decided what they were interested in. Go to lectures and ask the lecturer questions. In the grand scheme of things, that is what will have a much bigger impact on the development of your thinking and the range of creativity you’ll have.