From Literature to Lab: An Interdisciplinary Path into Neurodegenerative Research

00:08 Dr. Alice Chen-Plotkin

I had never seen science as a creative process when I was in college, because when you're in college and you're taking classes, science classes feel kind of boring sometimes, right? You're just memorizing things. But I think there I was in the lab, and I suddenly understood that everything you learn in a book, somebody had to figure out this way.

00:34 Charles Shen

Hello, everyone. This is Charles, and you're listening to Ever Thought About…?, created by undergraduates at the University of Pennsylvania. We hope to bring to you exciting episodes about the diverse research undertaken around campus. Sit down with us as we chat with Penn professors about the work they've dedicated their lives to. In this episode, we explore research on neurodegenerative disease with Professor Alice Chen-Plotkin. Dr. Chen-Plotkin is a Parker Family Professor of Neurology at Penn and a physician-scientist whose work focuses on uncovering the molecular mechanisms underlying neurodegeneration. Dr. Chen-Plotkin has been trained in the humanities as an English major, in the sciences as a Rhodes Scholar at Oxford, and in medicine at Harvard Medical School. She has been recognized with national honors from the American Academy of Neurology and the American Neurological Association. She now leads a translational neuroscience lab in the Perelman School of Medicine while also caring for patients with movement disorders. We're very excited to have you here today, Professor Chen-Plotkin.

01:34 Dr. C-P

Oh, thanks for having me.

01:36 Charles

Thank you so much for being here. We just heard about your work just now, but I wanted to go back to kind of the start of your academic journey. You were an English major in college, which isn't exactly the most obvious path to neuroscience. How'd you find yourself into this field?

01:53 Dr. C-P

As an undergrad, I wasn't sure exactly what I wanted to do at all, but I think that maybe the unifying theme when I was an English major and now is that I'm really interested in why people behave the way they do. I think just back when I was in English, and I was actually a creative writer. That's what I did. I was going about trying to understand human behavior sort of humanistically, right? And I think kind of because I trained in medicine along the way, I was always really fascinated by the diseases that kind of take away your sense of yourself, right? It's one thing if you break your leg or if you have asthma or something like that. It's another thing if your brain stops working the way you thought it should, right? And so I think I was drawn to those diseases again because of this strong interest in human behavior. Then over time, because I have a practice of patients with Parkinson's disease primarily, I became really interested in whether I could figure out not only how sort of a brain region works from a, you know, like “this is kind of interesting” perspective, but also what can a gene and protein do that causes one person to, you know, develop a disease and do really poorly versus some people develop the same disease, they don't do very poorly, or some people don't develop disease at all. So I think that was the evolution over time, but probably the root was an interest in human behavior.

03:32 Charles

Wow, that's honestly quite amazing. Like, is there a specific moment that you remember, maybe in undergrad, where it really felt like neuroscience could be the next step?

03:43 Dr. C-P

Not in undergrad. So I think in undergrad, I got a little bit, it’s funny, I got a little interested in science. And it's like, so I was very, very much embedded in being, you know, in the creative writing, English, literature, kind of world at that time. And I'm an immigrant. I was born in Taiwan. I came to the US when I was three. And my parents are both doctors, and they were very interested in my becoming a doctor. I think there are probably other immigrant kids you know that have experienced this phenomenon. And so essentially, there I was doing my English major stuff. And my parents were just convinced that I was definitely going to become a doctor no matter what. And so they eventually convinced me to work in a lab between my junior and senior year of college. And you got to understand, Charles, like I had not worked in a lab before. Like the previous summer, I was like, teaching poetry writing to high school kids. That's what I was doing. So it's shocking to me that a lab took me. And in any case, I agreed to do this because I felt with my parents, I was like, well, you know, I'll just write my collection of poetry on the side, make my parents happy. I can't fight all the battles all at one time. And so maybe the most, one of the kind of really difficult things for me to admit, because when you're 21, you really don't want to admit this kind of thing, is that I actually loved being in the lab. I thought it was really, really fun. You know, I was, it was actually a T-cell immunology lab. I was in charge of growing the cell lines. We were trying to figure out a receptor-ligand interaction. I was doing a lot of flow cytometry. And I don't know, I think it was just kind of, I had never seen science as a creative process when I was in college, because when you're in college and you're taking classes, science classes feel kind of boring sometimes, right? You're just memorizing things. But I think there I was in the lab, and I suddenly understood that everything you learn in a book, somebody had to figure out this way, right? And also, it turns out I kind of like to cook, I like to just do stuff with my hands. I take pride in kind of, having good techniques, so on and so forth. And so that summer, which was really before my last year of college, I suddenly had this niggling concern that, here I am, I like being in a lab. What does this mean for me? I've never done this before. I don't have any other skills. And also, of course, I just did not like admitting that any part of what my parents thought was going to be correct. So that was kind of how I got a little interested in science. And that's also actually why I have undergrads in the lab always. It's because I think that, as an undergrad, it's really hard to understand this creative aspect of science, unless you're actually doing research and having to be that creative person. You can't really figure that out from taking classes.

07:22 Charles

Going on that last part about undergrads, I feel like you really see yourself in a lot of the undergrads who come into your lab and work a lot. You work with students in many different stages. How do you think about specifically mentoring these students in a research-intensive lab, and what do you hope that they really take away from that experience?

07:42 Dr. C-P

Yeah, I think for me, as I said, I would never have gone down a scientific path if someone hadn't been willing to just take me into their lab. And it's kind of shocking. As I said, I'd never worked in a lab before but by the end of the summer, I was in charge of managing all the cell lines. And I've told you before, Charles, like when I think about this, like would I ever take an undergrad who'd never been in a research environment before and put them in charge of our cell lines? No! I'd be afraid they would mess it up, right? But I had a lot of trust from my PI. She was a young PI at the time. You know, she really just had half a technician's time and me. So I think, you know, I got a lot of trust and attention, right? And so I think that…I'm very grateful for that experience. It changed how my life went. And so that's why one of the reasons the lab has undergrads. The other reason is that the lab has had undergrads who were incredible, who've done incredible things. And there's no reason to think that you can't make huge discoveries when you're 18, 19, 20, 21, your brain is working very, very well. Probably better than my brain, right? That's just scientifically true. You just need the opportunity and maybe the drive. I think one of the things that's really fun about being a professor is that you always know people from, we've even had high schoolers sometimes, but from their teens up until their age, and you relate to them not as their boss, right, but as if they are all younger versions of yourself. That's the relationship. And I think that there are very few like jobs that are like that. There are jobs where people are your trainees or there are younger people who work for you, but it's not a given that the relationship is that these people are all sort of younger versions of you yourself, right?

09:56 Charles

So, yeah, that's very well said, and just going off of that further, for the Penn students who might be listening to this podcast, what is one piece of advice you would give them as they're figuring out what comes next? For some, like they might be freshmen who have never touched research at all before. Others, like they might have been in a biomedical lab for like two or three years. So, like going into research or going from college into the world beyond, what is one piece of advice you would give?

10:30 Dr. C-P

I think piece number one is that if you are scientifically oriented, if you want to do research scientifically, it's probably a good idea not to hop around too much. Because basically, you see students who kind of spend each summer in a different lab or something like that. And I think that does not allow you to really get the in-depth expertise, either technically or in the subject matter, to develop intellectually. And I think that's the goal, to develop intellectually, not to like run 10 Western blots, right? And so I think that's one thing for people in the sciences. The other thing I think about a lot, and I think, Charles this is probably okay for your podcast listeners to know – you were in my lab for a little period of time, so you and I have had a lot of these conversations. I think that it's really hard in your environment, to get into college and kind of get into grad school beyond that. The competition is starting really, really early, much earlier than when I was a teenager. And people feel this great need not to be behind, to kind of keep up and to do a million things. And it starts really young. And the reason I keep emphasizing this starting really young is because I actually think the fact that it starts really young may affect how your brain develops too, you know? And I'm very worried about that. So what I'd say is that as much as possible, spend some time trying to figure out who you really are. What things you really enjoy doing. Not what you think you ought to enjoy doing or what somebody else thinks you should be doing. Like as I said, I did go to this lab because my parents thought I should be in this scientific environment. But I think that ultimately, for example, my choosing to spend most of my time doing scientific research as opposed to seeing patients, that was a hard decision for me and it was hard because it went against what almost everyone around me did, right? I went to medical school, everybody became a doctor. I kind of got off that ramp and was like bottom of the scientific totem pole trying to do a postdoctoral fellowship at some point because that's what I really wanted to do. And so I think kind of just being in touch with who you are, trying to kind of close off those sources of distraction and noise if you can. I think that's really important. both because you'll be happier, and I also think ultimately you'll be more successful by kind of figuring out what it is you're really meant to do yourself.

13:51 Charles

I think like for many of us in undergrad right now, like we're trying to figure out like what is our passion. And then like for some of us, it really takes like not just months, not a semester, but years to develop. And we might not even figure it out until we've graduated.

14:08 Dr. C-P

Yeah, I mean, I didn't enter neuroscience until I was in medical school. I almost dropped out of medical school because I was like, maybe I shouldn't be a doctor. And then the thing that saved me is that there's the Brain and Behavior class that all early medical students have to take. And this professor literally kind of got up and started talking about the diffusely projecting systems of the brain. I still remember this lecture. And of course, one of the diffusely projecting systems of the brain is the dopaminergic system, our system that's in charge of kind of a lot of our, how the brain perceives reward, right? It's also incidentally the system I spend like all my medical life manipulating because the thing that Parkinson's patients are treated with is dopaminergic medications. But it was a really kind of striking moment to me. And I thought, wow, this is like a really interesting thing that I could spend a very long time thinking about. And it's been now like probably almost 30 years still thinking about those problems, which is cool, right?

15:16 Charles

Yeah. And then just going like a bit further into talking about like what makes, what is your passion, right? Like, it sounds like you have a lot of things you've previously juggled and then now currently balance to a very efficient degree. So you've been quite open that your primary passion is with research. And then, but you're also a practicing physician. So how do you exactly balance the relationship between your clinical and scientific work?

15:46 Dr. C-P

Yeah, I would say that kind of in the long arc of my life, what I'm trying to do is, as I said, maybe understand being a human better and also hopefully help some humans along the way. Those are just the two things, right? And I would say that kind of this interest in, as I said, what makes us human, why we behave the way we do, that's the abiding sort of thing that courses through my life. It guides what I like to read outside of work, you know, guides a lot of my friendships, things like that. But I would say that in my professional life, the current goal is very straightforward. It's, these are really bad diseases. They affect tens of millions of people. We can't do anything about them. You know, is it going to be possible in the lifetime of my lab and my activities in it to take something we discover, make it into essentially a treatment for patients and at least try out whether it works. Very few things have ever worked in neurodegeneration, so I don't know if I can fix Parkinson's, but I do think I can get some things from the lab into human clinical trials. And so that's the near-term goal right now.

17:08 Charles

I mean, as someone, I think, to the listeners of the podcast, I've worked with Dr. Chen Plotkin for some time, and I'm confident that we will be seeing quite beautiful things. Just to give the audience a bit more kind of background, what is exactly your specific research projects right now and what is going on in your lab?

17:32 Dr. C-P

Yeah, So, and this maybe relates a little bit to how my clinical life and my science life kind of intersect too. So what I think most people already know is that we live in an age where it's actually incredible how much data you can get, right? But I think there's a gap in many ways between the amount of data you can get and the amount of meaning, in a biological sense there is, right? And so this is very true for a lot of human science, right? Because we have technologies that let you get quote unquote “omic” level data, right? Meaning all the genes in your genome, all the proteins in your proteome, right? All the metabolites in your metabolome, those are the omics, right? But so you can measure everything. How does that then help you understand anything, right? So the lab was founded in 2010. And in 2005, just five years beforehand, the first genome-wide association study had been done. So that was kind of the event that heralded this coming of this omic age. So I was part of a very early genome-wide association study in one of the neurodegenerative diseases. And I thought at the time, either kind of being able to profile people and human-derived materials in this way is going to be huge, or it's just going to be a lot of hoo-ha. And it was unknown which way it was going to go. So what I tried to do when we first started the lab is I actually followed that first genome-wide association study signal. It's in a disease called frontotemporal dementia. And I wanted to figure out, can you get from a signal, like a location in the genome, to the gene that's involved, to what that gene is doing, to how that gene's function, you know, ends up causing some neurons to die, which then ends up causing, you know, people to have this like behavioral problem in how they kind of can manage their ability to inhibit behaviors that they really shouldn't express, right? And so that was kind of how the lab started, and that's still what it does. You know, we use human materials collected from patients. It's blood, CSF, the fluid around your spine and your brain. It's brain tissue for the people who donate their brains after they die. We use these technologies that kind of allow us to profile them at this omic scale. We then try to figure out what are key drivers as opposed to, here are the 90 genes that have risk variants for Parkinson's disease. What's unifying, what's kind of driving, right? And then we take the things we think are the best guesses for these key hub genes and proteins and we change them in cells or in animals in order to see if we're right. Because like if you have perturbed the central gene in a hub, right, and you think that's actually really important to the whole pathological process, you should be able to see an effect in a disease model, right? And so this last part I think is very important, like being able to be proven wrong, right? And so that's what we've done largely in Parkinson's disease, but in the other neurodegenerations as well. And so, you know, like the project you worked on when you were in the lab came from a biomarker screen. We were looking in the blood for proteins that predicted who with Parkinson's disease would have a mild course versus have a very severe steep decline, who seemed more protected. And that protein gene, we identified over 10 years ago and kind of at that time you couldn't do the thousand, 10,000 protein screens. So it's like a few 100 proteins that we screened. And that this was basically a protein called apolipoprotein A1, which is your good cholesterol. And I was very intrigued by the fact that higher levels seem to be protective in Parkinson's disease. So rather than just leave it at that, as you know, we tried to figure out how. We wanted to figure out is it actually touching, you know, the disease protein in Parkinson's disease? So does it kind of keep that disease protein in Parkinson's disease from being able to wreak havoc by sequestering it? And so the experiments in the lab were designed to test that.

22:22 Charles

Yeah, that's honestly awesome. Just going to more so the bigger picture, what do you think is one of the greatest challenges in neurodegenerative research right now? And how are these challenges impacting kind of the lab?

22:36 Dr. C-P

Well, so I think there's sort of the... basic difficulty of the problem. And then there's the time we live in right now, right? So the basic difficulty of the problem is that these are diseases that are associated with aging, right? And so it is possible that maybe as organisms age, entropy increases. There’s a reason that new construction houses have less problems than historic 200 years old houses, right? So it could be that these diseases are at least partially the result of a lot of systems failing a little bit, right? And so from the perspective of that, that's going to be hard to solve, right? Because it's like as soon as you plug up a little leak in the ceiling, another leak could happen, right? So that's the basic kind of question I think about. Overall, I think though that for most of the neurodegenerative diseases, there are key driver forces. And if there are key driver forces, there should be key kind of places you can block that driving force, right? The difficulty right now is we're in a crazy age, right? I mean, we have a lot of uncertainty for biomedical research funding, at the governmental level, right? And It's making a lot of people anxious. It's basically making it unclear exactly where the goalposts are. And so that's quite difficult. And I am very worried, not for my lab. My lab's been around for, you know, 16 years now, right? I'm worried for the baby labs, you know, right? If you're just trying to start up right now and you can't be sure that you'll be able to sustain funding, you know, like sustain anything, and just also just the morale of it, then I think that's worrisome to me.

24:40 Charles

Because from my experience in the lab, research is a very time-intensive process. It takes a lot of patience and it takes time and a lot more effort that goes unseen behind the scenes.

24:54 Dr. C-P

Yeah, 100%. And I think that's why the morale piece is such a problem, right? Because I think that in order to be able to be patient enough and to deal with all the times your data are going to look weird or negative or whatever, you need to have a certain good morale in any research group. And I think that becomes really tough when there are so many uncertainties, right?

25:19 Charles

Yeah, exactly. Well, let's look at more so like the positive end. Like what do you look forward to in the field right now? And what do you think is really achievable in say the next decade or so?

25:34 Dr. C-P

Yeah, so when I think about kind of, if we just take just Parkinson's disease, right? When I think about like what was known, about how kind of the disease proceeds, how it progresses. When I was first training in neurology, which was, the early 2000s, right? I'm amazed. I forget that we didn't know all sorts of things. We didn't know that alpha-synuclein pathology could spread from cell to cell. We certainly couldn't model that, you know. We didn't know kind of that alpha-synuclein, which is the disease protein in Parkinson's disease, that the shape, the conformation seems to matter, that basically the kind of pathological information is probably contained within the shape, right? We didn't know about like how different host genetic factors interacted with this kind of spread of synuclein pathology, right? So we know a lot of things we didn't used to know about the process. And I also think that there's a lot of will in both the kind of general community, right, and public and private sectors to kind of make sure that there is a research effort here.

26:56 Charles 

Thank you so much, Dr. Chen-Plotkin, for taking your time today, and then see you in the next episode.

27:03 Dr. C-P

Okay, thanks, Charles.