Episode 24: Chinfei Chen, MD PhD

The following interview was conducted in-class, during the Spring 2024 session of Hidden Figures: Brain Science through Diversity, taught by Dr. Adema Ribic at the University of Virginia. What follows is an edited transcript of the interview, transcribed by Gigi Adkhamovna Toirova, Marina M Kamal, Andrew Mason Williams, Sapphira Nguyen Thompson, Aishwarya Sivasubramanian, Goutham Baiju, Kariman M Eitta, Annabelle Grace MacTaggart, Katie Marie Manley, Gianna Lynne Latorre, Olivia G Allen, Camille Hou, Izah Zainab Qureshi and Braden W Ciszek , who also drafted Dr. Chen’s biography. The final editing was by Dr. Adema Ribic.

Dr. Chinfei Chen is a professor of neurology and neurobiology at Harvard Medical School and a research associate in neurology at the Boston Children's Hospital. She earned her M.D. and Ph.D. from Harvard Medical School and completed her residency in adult neurology at Massachusetts General Hospital. She studies synapse and circuit plasticity in the brain with a special interest in environmental impacts and influences on the thalamus. Dr. Chen’s lab has been funded by the NIH and SFARI, and Dr. Chen is a Pew Biomedical Scholar. Her research aims to help increase understanding of various neurodevelopmental conditions such as epilepsy and autism.

Can you tell us a little bit about how you grew up?

My father came to the U.S. from Taiwan to go to grad school. He arrived in LA with $200 to his name and managed to make his way to the University of Illinois, where he got his graduate degree in architecture. I was born when he got a job in Delaware and then we moved to New York City (before I was conscious) and I grew up there.

What was your education like?

I went through the New York Public School system, including Stuyvesant High School, which they called an exam school-I loved that school. I went to the University of Pennsylvania for college. I had no idea what I wanted to do. I had a propensity to science and math and I think I ended up majoring in engineering. After that, I applied to medical school and went to Harvard Med. 

What was your college experience like?

After my freshman year, I really did not want to go back home to stay with my parents over the summer. I had cast a wide net of summer jobs that included finance jobs in Wall Street, publishing jobs in New York City, and one of them that I applied to was a laboratory job and I think that was the only job I got. The laboratory was under Britton Chance. He has now passed away, but he was a biochemist and studied the mitochondrial pathway. He was a bit of an inventor who won the Olympic gold medal in sailing one year. He loved to create instruments, and he was very interested in studying the activity of cells and mitochondria. 

Was that your first research experience?

Yes. Some components of mitochondria, NAD and the flavoproteins, fluoresce when they change states. Britton was interested in measuring fluorescent changes as a reporter for activity. He wanted me to use this approach to look at the metabolic activity of the brain. It was a tissue that he thought might be useful because he was also doing it in the liver, heart and muscle. He modified a milling machine usually used to cut plexiglass, and hooked it up to a computer that could control XY movements of a stage positioned below the mill. You would take a frozen block of brain tissue from a rat, glue it down on a platform on the stage, and then immerse it in liquid nitrogen so it was completely cold. Low temperatures enhance mitochondrial fluorescence signals. There was a light guide that also moved across the tissue block collecting fluorescent signal pixel by pixel. After acquisition of fluorescence from the one plane of the tissue block, the mill would grind away the surface of the brain. And then you would just repeat the imaging of the next section.

 And so for the entire summer, I sat in this dark room just watching these pictures of the rat brain come up on the screen and I thought, Wow, the brain is really beautiful. That's how I got interested in neuroscience!

Would you call that experience a formative one?

Yes. The laboratory environment was a nice home away from home, where you get to know people who are of different ages and different stages of training. You kind of become part of a second family. I would go into the lab, even if I wasn't doing an experiment, just to be around those people. I had a desk there so I could work and study there too. I ended up spending a lot of time in the lab. It was a relatively big lab, so I didn't get to see the PI that often. But I got to meet people who were around the same age as I was, and interested in different things, which was very nice.

I mentioned I applied to medical school because at that time I thought–– if you are good at science and math, you go to medical school. There wasn't really a preconceived notion that you could be a scientist when I was an undergrad. But back then, during the first 2 years of medical school, you were sitting in class for 8 or 9 hours a day listening to lecturers, so I liked the lab better. 

Was there anyone in your field that you looked up to or idolized? 

At Harvard I met many role models. One of these people who was very influential is named Edward Kravitz (Ed). He was the head of the graduate program in neuroscience at the time. He was the most welcoming person that you could ever meet. He made science a lot of fun. Medical school has a herd mentality as you are sitting in an auditorium with 270 students. Ed made me feel like an individual. 

Did you work with him during your career?

Yes. I decided to do a PhD on top of the MD and I started working in Ed’s lab. At the time, he studied behavior in lobsters. If you put a bunch of lobsters together in a tank, it creates a social dominance hierarchy where one lobster becomes dominant and all of the other lobsters are submissive. You can watch them in Chinese food restaurants that have lobster tanks. The dominant lobster will rear on its tail and stand up with its claws up and the submissive lobsters will flatten out on the bottom of the tank. Ed went on to show that there were specific neurotransmitters that drove the two behaviors. One was serotonin which increased dominance. Octopamine was the other neurotransmitter, which, if you inject it into a lobster, would induce a submissive posture. I thought that this was very interesting and I told Ed I wanted to join his lab. He said, you can't just do one rotation, you have to try out different things and see what you like. However, I had no idea which lab to go to. Ed then told me about this new PI, Peter Hess, who just arrived and was setting up his lab in patch clamp electrophysiology. Ed  suggested I rotate with him during summer. So I went to Peter’s lab to do a quick rotation, figuring that I would return to Ed’s lab in the fall. But I fell in love with patch clamp electrophysiology, and I ended up doing my Ph.D. with Peter in calcium channel biophysics. 

What are some of the biggest challenges going for an M.D.-Ph.D., and what advice would you give to people interested in an M.D.-Ph.D. program?

The one common thing in people who do either one is that they're good at math and science. But that's the only thing that the two careers have in common. They are completely different fields, and a person who's good at medicine may not be good at science, and vice versa.

In medical school, you are in a class of 270 people. You all do the same thing. You take the same classes. You take the same tests. Many people like being part of a group that is doing the same thing. And in medicine, when you treat a patient, there's a set standard protocol to follow. If you don't follow it, you can get into a lot of trouble.

 In contrast, in science you are discovering something new, something that's never been known before. A science career is more attractive for someone with a loner or pioneer type of personality, where you go out and you're trying to be different from everyone else. The personalities of people who do medicine and Ph.D. are very different, so when you do M.D.-Ph.D., you basically have a split personality. In one context, you have to follow all the rules. You can't question a superior physician and say, “Well, why are we doing that this way? Why don't we do it another way?” You'll get into a lot of trouble. Whereas in science, if you do it the same way, you’ll do the same thing that everyone else does, and nobody's gonna care.

I'm an advisor for M.D.-Ph.D. students. They often have trouble flipping back and forth between the two fields, and in the end, most people choose one field or the other for the majority of their time.

Did you know at the time of graduation that you wanted to pursue medical school, or did you take a gap year?

I went straight through. Back then it wasn't that common to do a post-bacc. Now it's much more common, and probably a good idea. Given all the options I had at the time, I decided to do medicine, because that seemed to be what you do if you're good at math and science. But then I sat down and started thinking to myself: Is this really what you want to do? Is this what interests you? 

 You have to choose a career that every day you wake up to and you want to go to work. You don't want to be thinking: Oh, no, not another day. You have to listen to your own heart about what really gets you going. But the good news is that you have time to figure that out. If you don't decide now, it's not “do or die.” You have time to decide.

Was there any point in your journey that made you feel like it was a turning point, like something that ignited your career? Can you pinpoint one moment that you that made you feel like that? Or was it never like that, never just one moment?

I would say there wasn't ever a eureka moment. There are points in one’s life when you have to choose to go in one direction or another. You're always terrified that you're going to make the wrong decision, and then that will be it for the rest of your life. But this is not true. When I chose to go to Medical school, it was more of a default choice. My parents wanted me to go to Medical school because they were immigrants. They felt that medicine offered a secure and stable job. Choosing to do a PhD instead of just going straight through with medicine was a  big decision point for me. At the time, it felt like holding your breath and jumping from a plane, and just hoping things would work out.

 After my PhD, I finished my MD. I decided to do a Residency in adult neurology at Mass General Hospital. After that came another big decision point where I had to decide whether I would just continue with medicine, see patients, and have a little bit of a lab, or to just commit to the PhD path. I chose to follow the research path.

What was the most challenging moment in your research career, and how did you overcome it?

There are always challenges in research, they’re big and small. The most challenging moment for me was when I started my own lab. I think that is one of the hardest things to do. This is because you feel like you're on your own, and you're all alone. Before you start having students and trainees in your lab that you can converse with, you are all alone. Additionally, you can be friends with other scientists, but you can't be doing the same thing as the other scientist. Starting your own lab is a period where you have to decide who you are as a scientist. 

What do you think is the greatest accomplishment of your career?

Well, I hope it's still coming. When I was a resident, I had a 20 year old patient who had a small stroke. It was a tiny, tiny little stroke and if it were anywhere else in the brain she wouldn't have even noticed it. But, she had a stroke in the medial dorsal and anterior thalamus and she could not make new memories. She was completely devastated. It was as if she was the patient H.M. and it made me realize how important the thalamus was. I've made a career of studying the thalamus, which, when I first started, was not thought to be particularly interesting. All the textbooks call it a relay; information goes in, and then it's sent out to the cortex. I've spent my career showing that there's a lot more plasticity in the thalamus that previously assumed and that it's really important for sensory processing. I chose the visual system for my preparation, and initially, I was met with a lot of resistance. Everyone thought I was either crazy or that I was studying a blind animal, the mouse. But gradually, I think there's been a little bit more acceptance that the thalamus is an important structure. I feel proud about that and eventually, hopefully, people will appreciate this subcortical region for what it is.

What made you interested in studying synaptic plasticity in the brain? And how did you and your research team get to finalize that research question for your lab?

Coming out of my residency at Mass General, I was keen on studying the thalamus, so I opted for a postdoctoral fellowship focusing on synapses. I approached my post-doctoral PI, Wade Regehr, and expressed my desire to explore the thalamus while he was focused on the cerebellum. Therefore, I embarked on studying the thalamus, working on it during his absence, mostly at night. I initially pondered which area of the thalamus to investigate. The stroke case I encountered involved the limbic thalamus. However, it is important to have a tractable system, something controllable, so I chose the visual system. I've always been intrigued by plasticity, as it's fundamental to how the brain operates. A static circuit between neurons leads to no changes; everyone would be the same, which isn't true. The reason for our differences lies in plasticity. It's a significant question with much to explore and learn.

What does the typical day in your lab look like? What are the parts that you enjoy the most? And does your daily routine change often?

What happens in my lab is not what happens in my office. In my lab, people come in and they do an experiment. They talk to other people who are doing other experiments, they exchange ideas, and you get this very very rich intellectual exchange that doesn't depend on your seniority. It doesn't depend on what background you come from-it just depends on your ideas. That's what I really like about science. I come into my office, and when I have a chance, I go out to the lab and I talk to people and we exchange ideas. In my own office I have a lot of meetings with people and administrative committees. I’Il try to write papers and grants. What I like the most is actually doing an experiment. And for the longest time I was able to do my own experiments, but it's gotten very busy and harder to do now.

Synaptic plasticity is implicated in various neurological disorders.  How do you envision your research contributing to our understanding of these disorders, and potentially informing therapeutic strategies?

People study synaptic plasticity in different areas of the brain with the goal of understanding how the normal brain is formed. How can the brain adapt to change and how does disrupted adaptation lead to neurologic disorders? We've been studying plasticity that comes with visual experience, and we think that's relevant because there is clinical evidence that patients with visual cortical strokes can be trained to detect motion in the damaged visual field. Our hypothesis is that this plasticity is coming from the thalamus because the cortex is damaged. There could be plasticity mechanisms that are dormant, meaning that they're not used all the time, but in cases of disease they can be reactivated to help the person function.

Do you think that your experience in medical school and residency as a doctor has given you a unique perspective for creating research questions, as compared to others who would do only a Ph.D.? 

I’ll never regret doing an M.D. I didn't get to see much (of the world) because immigrant parents are very protective. During medical training, I was thrown into the emergency room where there's people from all over the world coming in. They're people from all parts of life, people that are very well off and people who are very poor, who have very different experiences. As an intern and resident, I got to know these people and learn where they came from. That is an experience I would have never gotten otherwise. I learned about life.  Additionally, the experience I had in medicine sparked my interest in a certain area of the brain. 

What are some of the biggest unanswered questions or areas of mystery in your field that you hope to address through your research or see research by other labs.

I hope to understand the underlying mechanisms of synaptic plasticity and the potential to harness plasticity to repair disorders. To understand the underlying synaptic pathology of certain disorders. Quite honestly, the brain is a large organ and we're still learning so much about it. That is why it's a huge frontier to explore. I'm very positive about neuroscience right now, and also for decades to come.

What ultimately led you to pursue a career as a scientist instead of a medical doctor?

I felt like I could do what I wanted as a scientist, whereas in medicine you're very much limited to what the standard is. It's very hard to try out new therapies. Usually it takes 10 years, and you have to write protocols and recruit patients, whereas in science you can test an idea immediately.  It's just more spontaneous, which I like. 

What advice can you give to students looking at Ph.D. and M.D. programs? How can you successfully approach and go through the process? What is that one trait that characterizes your trainees?

Curiosity. In science, you're always active. You never stop learning. My medical school classmates didn’t have that. They're happy to have a good life. Honestly, they looked bored, and a lot of them went into industry to work on drug discovery. 

Do you communicate with other neuroscientists around the country and even the world? Have there been any particular collaborations that you've enjoyed the most or found the most fruitful?

I have a lot of collaboration here locally as well as across the country. Zoom made long-distance collaborations easier, but sometimes experiments need to be done on the same mouse. It's hard to collaborate with someone in California in these situations. I’ve been blessed with wonderful colleagues and collaborators.

Are there topics of research that you're interested in outside of your current work?

I've been working in the visual system all these years, but now I'm interested in going back and looking at the limbic thalamus.

What would this ideal project be?

To watch plasticity happen, live, in real time and watch how a cell changes its function in real time, and how that affects behavior. 

As a professor of neurology and an advisor for students at Harvard Medical School, do you teach neuroscience topics?

I teach in my field, so I teach plasticity and development. I'm also an advisor and the associate director of the Program in Neuroscience-the same program that Ed was the head of many years ago when I was a student. I do a lot of advising for the students and am on the steering and advising committees of the M.D.-Ph.D. program. I would say that I always tell the students  to try more than one thing. You cannot come in with this idea that you want to do X, and just do X. You've got to do X, Y, and Z, because that's what Ed made me do, and look what happened. I initially came in (to Harvard) interested in biomechanics of joints! 

Were any moments when you thought things weren’t progressing the way you wish the would or that things just went wrong in general?

All the time! Things are always too slow. There are certain moments when you think that your current approach may not be the best. I think an important skill, especially in science, is knowing when to pull out— because once you invest a lot of time and money and effort into an idea or hypothesis, you don't want to give it all up. However, sometimes that's the correct decision. Plus there's always self-doubt. The issue is when to listen to it, and when not to.

Did you have any regrets?

No, I don't have any regrets, because I think you learn something from everything. You learn from failures too. 

What characteristics make a great physician? 

A great physician is someone who listens to the patient. This is not done enough anymore, but you can actually do a lot of diagnosing by just taking the time to listen to the whole story. The problem is that doctors are so busy they don't have the time, and so they'll cut the patients off. They want the main points, and they don't hear the whole story. And without that whole story, you're at a disadvantage of diagnosing. A great physician is someone who actually takes the time. The best advice I ever got was to sit down when you talk to the patient, because it conveys to the patient that “I have the time to listen to you. I’m not in a rush.” The patient is going to be much more willing to tell you what's going on. They may not be able to tell you exactly what the problem is, but if you give them time it will come out. And the physician and the scientist need to be very observant of everything, even the minor details, because those often lead to something really interesting. 

What is something you would tell your younger self?

Don't spend all this time worrying about if you made the right decision-that’s a waste of time.

Historically, at least in the field of visual development and plasticity, women have always been leading the way in transformative science. Is it simply because they had to do a lot more homework and control experiments, just to make everything so much more solid because they're women, or is it something else? 

I think there's a little bit of both. There's a higher proportion of women who are interested in neuroscience and development. Perhaps it’s because they're often interested in children, nurturing and growth. Women also have an affinity towards medicine because they tend to focus more on personal interactions. Science in the past was a really tough world. When I was deciding to do a Ph. D. and I spoke to the head of my M.D. Program, he said, Why don't you just marry a nice guy?”.  At some point you have to decide whether you're going to let that guy decide what you want to do with your life. I did marry a nice guy btw. 

How did the graduate students change from back then to now, especially in light of the recent unionization?

Over the past decade or two, students are anxious about what their life will be like. Part of it may have to do with a lot of anxiety about what's happening in the world. When we were grad students, we did not actually have a high salary. We always had to share rooms. I lived on instant noodles for many years-they're really good and I still like them. We thought of it as a certain phase in our life that we would eventually grow out of and then get to what we wanted to do. I think that that's still true, but there is a lot more anxiety about the future now.  Graduate students feel less sure of where they will be 10 years from now. 

We've talked a lot with other scientists about the importance of having a creative outlet or a non-scientific hobby outside of your lab work, whether that be cooking, hiking, painting, etc. Before we delve into your research, I'm curious to hear about any hobbies you may have, and your thoughts about creativity and science.

I like to garden. I enjoy things that flower a lot in the summer, so I use a lot of creativity to put together arrangements of flowers.

One of my biggest pastimes, having been in Boston for a while, is watching their sports teams. I'm a huge Red Sox fan. My lab is a few blocks away from Fenway Park, so we can walk over for a game – until they got really good, and then it was impossible to get tickets. I also learned how to play ice hockey for exercise. My husband is from Minnesota, and one year for my birthday he got me a full set of hockey gear. I'm from an immigrant family – you give me something and I feel like I can't waste it, so I learned how to play hockey.

Did you play pick-up hockey?

I had never played hockey before, although I did ice skate when I was young in New York. So I joined a Women's League, and the name of our team was “Chicks with Sticks.” It was introductory hockey where they would teach you how to do certain moves, and then you would play scrimmages. It was more organized (than pick-up), and it was very introductory. Very good exercise.