บทถอดความฉบับเต็มของ Don’t Give Up on Basic Science with Soren Emerson

is no longer able to have that effect. We don’t do this within the center directly. We’re kind of earlier in the target and mechanism development, particularly because this is an academic center, not a drug development company. But, we need to find that causal evidence so that therapies can be built on top. Interesting. Can you talk a little bit about how you got interested in this specific niche area of research? My interest in science came from losing my mom to cancer. That was over 10 years ago now- I was pretty young. But that is what got me interested in how we can use science to help people- that’s how I got interested basically in translational research. And the reason that I ended up in addiction neuroscience is that in part, it was an area that felt like there was no treatment option. Cancer is still pretty difficult to treat, similar to when my mom was going through it. But substance use disorder had the same sort of feeling to me in that there’s, in some ways, nothing you can do, in terms of a direct treatment strategy. So when I first started out, that’s what made it feel like something that was important for me. And then the other aspect of it is that I just found it really interesting. Because when you give a drug, if you’re just studying basically neuropharmacology, there are so many different parts of science that come into that. You are studying how cells work. You’re studying how behavior is controlled by the brain. You’re studying what different brain regions do. There are all of these different things that come together. And I have a genetics angle in there. Neuroscience is this incredibly interdisciplinary field already. You add in neuropharmacology and you’re basically able to study everything about the brain. Very interesting. If you could explain translational research to our audience. Everybody’s coming at this from different areas and disciplines. Talk about what is translational research and why is it important? There are two big buckets in biomedical research. One of them is called basic research because it helps us understand translational research. Basic research essentially asks, how does the universe work? So: our body is made of cells. Each of those cells do different things. And if we’re not trying to understand how they work in a disease context, that’s what we would call basic biomedical research. If we wanted to understand, though, what those cells do in a disease context, that’s where we start moving into translational research. Often what we’re doing in translational research is trying to understand: how do we take these basic mechanisms that we’ve characterized and understand how they are dysregulated or how they go badly, if you will, in a disease state so that we can make new treatment interventions? Gotcha. So would you say in basic science, you’re asking maybe more broad questions and translational research, you’re getting more specific with your questions? In some ways, yes. In some ways, no. The goal is more broad to understand how does, in this case, more broadly, how does the universe work? In this case, how does biology work? But, in basic research, you often are actually getting even more specific because you’re trying to understand these very precise processes. Whereas a disease, it has a more specific general focus. How do we cure a disease? But any disease tends to bring in a lot of different mechanisms. It’s usually not just one. Whereas basic research, you’re kind of drilling on one very specific thing. Gotcha. Was there a reason that you were more interested in translational research? Yeah, yeah. That, in some ways, was the same thing that brought me to addiction research in the beginning. I was experienced with my mom’s treatment and then just the interest in how we can study the effects of different drugs on behavior in the brain. Well, I know you won’t be the last scientist talking to us, and so I think pulling back the curtain to explain that is helpful. What have you discovered so far in your research since coming here? The most broad thing I can say (and then we’ll get more specific), is that where I started was trying to understand- kind of how I said at the outset- how does the brain change following drug consumption or drug exposure? When I first started working on this project, what we knew is that there were these changes in a specific region of the brain called the nucleus accumbens. This is at the center of the reward neurocircuitry. So we know that this is a very important region. Whenever you take a drug or whenever you have some sort of rewarding experience, dopamine levels will be increased in the nucleus accumbens. We’ve been studying this region for a very long time. But in my research, I wanted to understand how does it change as a result of drug history? Because someone doesn’t just wake up with a substance use disorder. Of course, there are genetic risk factors that predispose it, but it results from a history of drug use. And so, what we’re trying to do is understand mechanistically, how does that occur? Basically, we identified an enzyme that’s responsible for, we thought, enabling cocaine-induced changes in the nucleus accumbens. What we found after years of work, is that it seems to work a little bit in the opposite. It actually seems to act as a brake, if you will, on changes that are induced, in this case, by cocaine exposure or self-administration. But that’s equally important, because it allows for a very strong stimulus- and here I’m really speculating, I don’t know this part for sure- is that a very strong stimulus like cocaine might be able to push back- kind of a brake- on the brain changing. Which we think this enzyme- called CAT2A- which is what we think it might do. So basically it allows these very salient, potent stimuli, like a drug of abuse, to actually change the brain more so than something like a less salient stimulus. But this is speculation on my point,

that last part. We don’t know for sure. Fair. When you’re studying addiction, there are so many things that folks are addicted to these days. Why choose cocaine? Cocaine- aside from the epidemiology of it- it hurts a lot of people, just in terms of its abuse liability and also overdose deaths. It is studied a lot in addiction, in part because it’s a very clean drug. Now, what I mean by clean is that it has a very well-defined target, which is a protein called the “dopamine transporter”. This is a protein that is expressed on cells that release dopamine into the nucleus accumbens, for example, the brain region that I study. Cocaine blocks the transporter. Dopamine is released, and normally the transporter acts kind of like a vacuum cleaner: it sucks the dopamine in, and then it can be recycled or degraded to be released again. But the effect of this is that dopamine levels are elevated because cocaine blocks the dopamine transporter. Some other drugs don’t have as much of a specific target. They’ll hit a lot of different things. In studying cocaine, are you able to make general inferences about other addictions as well? In general you can. Because all drugs of abuse through different mechanisms ultimately, with some narrow exceptions, will possess their addictive effects because they are leading to an increase in dopamine levels. Gotcha. As you think about your research, what do you hope the impact of it is on our society? I would hope most directly of course, that it would lead to being able to create new treatments for substance use disorder. I also recognize that I’m in the translational pipeline, right? We’re trying to understand a disease state, but we’re also studying basic mechanisms. Like what happens when you elevate dopamine at a higher level than normal for some of these sustained periods, like you might get with cocaine? What does that do to the brain? And so to some degree, some of the discoveries that we might make may actually be applicable to more basic neurobiology. That is important because you never really know what the ultimate impact of basic research will be. They’re not clearly assigned discoveries that lead to like a product or something. Of course, this is translational. It could lead to the identification of a target, but it also could have more broad implications that I might not know. Circling back to our conversation earlier, would you say most of the time when you’re doing translational research, there’s still some basic science that’s happening as well? Yeah, I would say both things are happening at the same time. Great. As you think about this journey, what have you enjoyed most about being a graduate student? I have enjoyed- and this kind of surprised me I would say- how social it is, like how fun it is to work with other people trying to answer difficult questions. That has been probably the most rewarding part of this, I would say. That has been a very good way for me to spend my early- to now mid- approaching late-20s. I was 22 when I got here. I’m now 27. But that surprised me. I think being able to develop as a person during that time with people at different life stages. You have postdocs that are older than you. There’s undergrads that are younger than you. It’s been a good way to spend this period of my life. Then it’s really rewarding to do the science. And I don’t just mean making discoveries or being the first person to know something, which I think is often what the answer to that kind of question is. But I just find the process really fun, to be able to ask questions. Yeah, I obviously also love asking questions, which is why I do this. Tell me about that social aspect. How big is your lab in terms of your ability to connect there? How have you tried to connect socially outside of the lab? I should know the answer to how big the lab is. It has grown a lot in the five years that I’ve been here. I want to say it was maybe eight people when I first started. I think it’s 18 now. Wow. But those numbers could be completely wrong. They’re ballpark numbers. Okay, fair. People are moving on. People are getting hired all the time, which is a good thing. You want people coming in and coming out. That’s a sign of a good lab. I would say that in terms of connections, a lot of it, which also has surprised me, has been connecting with the broader community at conferences. Because when I was an undergrad researcher, I didn’t really have that same type of experience. That was very new to me. So, you know, you get to meet people whose papers you read and you think, wow, this person is… you don’t really think of them as a person. Like, they just do this great science. Yeah, up on this pedestal. Yeah, and then you’ll just be, like, you’ll be at a bar after a conference. They’re just there. What do you say is your biggest challenge in terms of graduate school? I would say, and this is both a good thing and a bad thing, is that it does take some time to get used to being constantly criticized. And to recognize… its odd because academic science tends to be very personal- the way that it’s organized. All of the different labs, usually they’re named after the person who runs them. So I work in Erin Calipari’s lab- I work in the Calipari lab. And so by nature, it is just so personal. And so it can feel like anytime you are discussing a scientific idea and someone is pushing back or even just asking a question of like, are you sure this is the way that it works? Which, by the way, is the question you should ask because the whole point of science is to identify different truths. That does take some getting used to, though, because it’s happening all the time. What do you do for yourself to help separate criticism that you might receive- between this is not me personally, this is just the work that I’ve done? I try to disconnect myself from it. I have not succeeded in doing that completely. I don’t think anyone can. I would

say over time, I’ve created different narratives that allow me to buy into this is a good thing that’s happening right now. This is one strange example to give, but there was a scientist named Santiago Ramón y Cajal. He was a Spanish neuroscientist who basically made some really good guesses. It’s not like he knew everything that was happening, but he made some good guesses: the brain is made of neurons and they communicate to each other. So, he is historically viewed as what we call the father of neuroscience because those good guesses generally were true and we’ve really just been living in the implications of what he was writing 110 years ago. He has a book- it’s called “Advice to the Young Investigator”. One thing he says in there is that science needs to be aggressively self-correcting. He gives this example of how should someone be successful in science? How should a young scientist be successful? What they need to do is identify the most understood concept in science, and then they need to just attack it relentlessly. That’s good for your career. You’ll get notoriety. People will yell at you. You’ll yell at them. People will notice that you’re yelling, and that can be good for your career. But that’s also just how science needs to work. And so I tell myself, not comparing myself to Santiago Ramon y Cajal or anything, but I tell my… Nice to have role models. Yeah, sure. Well, he’s a little weird in someways, so I don’t want him to be a full role model, just for the record, if anyone listened to this. Very important for science, some odd things going on too. But yeah, I just tell myself, this is the scientific process and I’m part of it. And it’s fun and this is one part that needs to happen and that’s okay. That’s great. So as you think about the resources at Vanderbilt, what are some that you’ve discovered that have been particularly helpful? There is actually one resource that I would say has been particularly important for me, and that’s something called the Lacey Fisher Interdisciplinary Research Grants. This is a program at Vanderbilt where basically there is some money available for graduate students to do collaborative research. I was able to get connected with some students in Dario Englot’s lab. In particular, their names are Ghassan, Bruno, and Anas. And then another student in Erin’s lab, Thomas, he’s the one who made the connection. We’ve been working on this project together where we got a Lacey Fisher grant. What we’re doing is taking some of the molecular biology in Erin’s lab- this is understanding what is happening in a tissue in a disease state, and combining it with their clinical epilepsy program. What they’re doing is they are resecting tissue from people with what’s called focal epilepsy. Basically, uncontrolled seizures result from hyperactivity in a small region of the brain. In this case, they’re all in a region of the hippocampus. And what they’ve been doing is when someone doesn’t respond to pharmacotherapy for epilepsy, they actually remove the sub-region. We call it the seizure onset zone because that’s what’s causing the seizures. Normally that tissue just gets thrown away. This is a treatment. But what we proposed was, hey, we’ll get someone. They’ll stand next to the trash can. And they’ll intercept the tissue, and then we’ll freeze it, and we’ll actually sequence it, which means we’ll be able to look at all of the genes that are being expressed. You can use that to get an idea of: how is the function of this brain region being kind of aberrantly altered in a disease state? Anyway, that’s the kind of thing that’s pretty high risk, and it wouldn’t just happen probably in either of our labs independently. By giving students like me and like the NGLAT group the opportunity to collaborate and have our own financial resources to produce something more high risk. I think that’s a very special thing that Vanderbilt supports. Absolutely. How did you even hear about what they were doing and think to make that connection? It really is one of those spirit of collaboration- things just coming together. I have a friend in Erin’s lab, Thomas, who’s an MSTP, and that stands for Medical Scientist Training Program. I’m just a regular PhD person, but there are some people who get both an MD and a PhD. Overachievers. So they have a lot more, like, you know, they go to medical school together. They’re interacting all the time in a non-laboratory context. One day, he just called me and said, hey, do you want to do something with human tissue? And I really had no context for it. But we all got lunch together, came up with this project idea. I mean, they had the overall idea for how we could study epilepsy, but we kind of came in with this molecular angle. It was just the opportunity of: we know we could get a grant for this and we just want to try something new. Yeah- basically taking something that would have otherwise not been utilized in any way and using it towards more research. Great. I know you’re somewhat early in this project, but what have you learned so far there? I have learned that it is a lot of work to get the approvals to work with human tissue. Which makes a lot of sense. Absolutely. It shouldn’t be easy. This was my first time working in any sort of context with human samples. We’ve had to go through a lot of different biosafety training for me and then for actually processing the samples and, of course, IRB approval. Luckily, the IRB covered most of this anyway. But for me, it’s really been about the safety training. Now, I’m used to doing that kind of stuff, working in an environment where you need to be careful. But that is primarily what I’ve learned at this point. We haven’t actually started sequencing yet. The reason for that is we’ve been collecting tissue samples for a while. However, we need to do clinical follow-up to see how people respond to the surgery. So that means that we have to wait a minimum of

six weeks. And this is not a very common procedure. My understanding is that there are only around 500 of these procedures that happen a year. Vanderbilt actually has a pretty high rate. We seem to be getting maybe 10 to 20 a year. 20 would be the high end. 10 seems like it’ll be on the lower end. But we’re close. Biosafety is going to meet soon. Then we’ll know if we need to adapt or if we are ready to go. And then sometime in the summer, we’ll have results. But the hope here is that we’d be able to actually have a way of identifying: was the surgery successful? Like, did we get the right brain region out? (I mean, they’re pretty sure, I should say, that they got the right brain region out- they’re not doing this willy-nilly.) But there currently isn’t any way to really verify that molecularly. So this would be kind of filling that need. And also in the future could help us subtype different patients afterwards. Say that someone responded very well to having this brain region removed, they might still need additional follow-up pharmacotherapy. This could help in some way stratify patients later on, or be a different confirmation of the kind of epilepsy that they have. Soren, I am now fascinated by how does one store brain tissue? Much the way you might store (well, I shouldn’t say that), I would just say something in your freezer. I mean, okay, not really. The freezer is much colder. A typical freezer in your house is like negative 20 degrees Celsius. By the way, I don’t have good heuristics for what Celsius temperatures mean outside of a research environment. It’s very odd, right? We’re all in Fahrenheit most of the time. And in a lab, we just go to Celsius. But very cold is my understanding. So we are working at negative 20 degrees Celsius. We’ll take the tissue and freeze it in a very cold- we use something called isopentane- so it does not interact with water. You can chill it to a very cold temperature just with dry ice. The reason it’s important that it doesn’t interact with water is that water will create ice, and ice expands. It’ll damage the tissue, and we really just want to have a tissue specimen by itself. So, we’ll freeze it in isopentane, and then we store it in an air-sealed container, and then it stays at negative 80 degrees Celsius in a giant freezer. Thank you for going on that tangent with me. Can you talk a little bit about any other Vanderbilt resources that you found helpful? One that is very important is the core facilities at Vanderbilt. What a core facility refers to is a part of a university research center where there is very specialized equipment or procedures that can be performed by experts. Because the purpose of a lab is to identify specific questions that the lab focuses on. So in Erin’s lab, what we focus on is how do drugs of abuse, for example, alter brain function really broadly? That’s what we’re trying to do. But sometimes we might need a very particular procedure to be performed. For example, some of the steps of doing what’s called RNA sequencing, where you want to measure all the RNA in a sample. We might do some sort of procedure with the mouse, for example, give it drugs. We can collect the brain region. We can measure behavior. But some of the more specialized processes really require an expert who’s doing it all of the time. So I could probably figure it out myself, but better that it’s done by someone who is doing this all of the time. Vanderbilt has given- some of the cores have their own NIH funding- but Vanderbilt also gives a lot of support to different core facilities. So, we have different cores for just measuring RNA. We have cores for measuring protein. There’s some that make behavioral apparatuses available for basically studying different animal behaviors. There’s a ton of them that I’m not mentioning right now, but that kind of thing is extremely important for making science happen. I think you make a great point of, yeah, I could eventually figure this out myself and do it, but from a time cost analysis, from a precision analysis, it makes sense to have these experts that you can just kind of offload some of the things on so you can focus on what you do best. It really, I would say, is important in terms of the cost benefit because if someone does it right the first time, that will be at least half the cost of what is the more realistic scenario, which is that it fails the first time. Failure is very common in science. It happens all the time because you’re trying to do things that have never been done before if you’re asking good questions. If you’re not asking good questions, it’s important to repeat experiments. But generally, in the cases where really good science is happening, you’re trying to figure out something that is no one understands. You’re becoming the expert on it through experience. And so, cores make that much more efficient. I think that’s a great example of, you know, earlier you talked about academia is full of criticism and question asking. I think it’s also full of failure. Can you talk a little bit about how you got more comfortable with that and use it as learning experiences? So we’re going to come back to Santiago Ramon y Cajal, who didn’t write anything about failure. Well, he wrote some things about failure, but he blamed a lot of other people for his own failure, so that’s not really applicable to this. But the way that I do this is I try to make sure at least I learn something every single time. And if I do an experiment and technically it fails, I like to at least have some sense of why. Sometimes I don’t. Sometimes you try something like five times and give up on it. But I try to make sure that I think every single time I do an experiment, and if it doesn’t work, what can I do to improve next time? Yeah, which is another great shout out for the Journal of Failure, which does not exist. Someone needs to go ahead and become the editor of that. It would be good. There are

some journals that exist to publish what’s called negative data. Negative data means (negative data versus positive data) negative data means that, so say you have a hypothesis. This is a strange example, but like if I give some sort of chemical to a tomato plant, I think there’s going to be more tomatoes. I find that there’s no change in anything about the tomato plant or the tomatoes. That would be called negative data. So my hypothesis was wrong, and also there was nothing even interesting about this. But it’s still important, you know, whatever my chemical happened to be, it would be good that someone else didn’t use it. Right. They don’t have to waste their time doing the same thing and realizing there was no result. Yeah, unfortunately, there is this bias toward not publishing negative data. And it’s inefficient. It also, though, is bad for the process of science overall, because science is supposed to be the self-correcting process. And so if you think about it, the implications of this kind of bias are that, going back to this tomato plant, (I don’t know a ton about tomatoes, I’m not sure why I’m using this example), but if, let’s say, a thousand people do this experiment with this chemical, it is totally plausible that maybe three people… will find that actually you do grow twice as many tomatoes. And only those results will be published. So what you would see in the literature is: “this chemical makes tomatoes grow really well”. But in reality, it definitely doesn’t. There are some anomalies that happen a very small percentage of the time. So we really do need the journal of failure, I think, to help us out. Great. Well, Soren, can you talk a little bit about what you’ve discovered about yourself since beginning the PhD journey? I have discovered that I’m more comfortable with public speaking than I realized. And some of that is through just practice, getting in front of people. But I was going to say maybe it’s also an innate characteristic, but it’s definitely not. I definitely learned how to do this kind of from being criticized all of the time and having to stand up in front of people and get, not yelled at, but you know. People are like at a conference or something, people are really like asking you like, what are you saying? Explain it more. And you got to just think on your feet. And so that has made public speaking a lot easier, I would say. Yeah. I think a lot of times when we think about a scientist, we think about somebody who is very analytical, who can be precise with experiments at the bench, but a great scientist has the ability to communicate. What were some ways that you were able to better your communication style for other folks? I would say the primary thing is practice. And I would actually say there is some inspiration that I get from my graduate mentor, Erin Calipari. Erin is very comfortable speaking to lots of different audiences about science. And that comes in part because her dad is John Calipari,

my understanding, a very important college basketball coach- I really don’t know much about college basketball, but I understand that he’s very important in that area. And so there’s a lot of media attention there. I think because she grew up around it, she’s comfortable doing it. She has a lot of things with the university in that regard and is constantly speaking to different audiences. And in this case, it tends to be about neuroscience. And so that has been something that surprised me in terms of how important it is. Because like you say, you don’t think of broad communication- I think when you’re learning how to do science- as being the most important part. It’s like, how do I design an experiment? How do I analyze it? And how do I present it to a scientific audience? And so, I think being around someone who is constantly working on how do we present this? How do we make sure that the story makes sense to not just you, but everyone? That, I would say, is how I’ve been able to build that. Well, and as you bring up Dr. Calipari, thinking about mentorship, what has been helpful in the mentorship process? How have you built your network of mentors over time? In Erin’s case, what Erin does is, she gives all of her trainees the opportunity to think independently, of course, with some guidance. But the most important part of doing science- like there’s this technical aspect which is critical- but it’s also being able to think about: how do I present my data? How do I ask the next question in a way that is efficient and makes sense? And then she also gives space for you to figure things out on your own and to, in some cases, fail. And that ends up, that’s kind of difficult, but it’s extremely important to have the opportunity to do that. In some contexts, the PI will be very demanding in the sense that this experiment needs to work. And hey, this is science. It’s completely unguaranteed that anything will work at any given time- ever. And so that is one thing that I think she does very well. That’s great. And Soren, to close us out, can you talk a little bit about something you wish you had known when you started, that you think will be helpful for others? I wish I had maybe more mental preparation for the failure aspect of it. Unless you’ve experienced it before, it’s kind of difficult to explain- to get used to something not working repeatedly. You just have to build this resiliency and faith that through the scientific process, eventually things are going to work out. What do you think an aspiring scientist could do to build this armor towards failure? Well, what you have to do is build some perspective. So maybe go read some memoirs from famous scientists and try to see how their failures that they’ve written about are actually good things. Yeah, that’s a great one. Anything else you’d like to share with the audience before we close today? I would just like to thank everyone for listening to this. And I would hope that one thing that we touched on earlier was the importance of basic research. We’re kind of, I feel like, at a time and place where basic research is not being appreciated, partially because we live in this world where everyone wants immediate results or they want something to be immediately applicable or for something to be a good story. And oftentimes the best science- the most important science that allows new treatments for people like my mom for cancer- those often come from studies in basic research. We won’t see the importance of it until later. And so I would hope that broadly, if anyone takes anything away from this, it’s don’t give up on science and don’t give up on basic research. That’s great. Thanks so much for joining us today, Soren. I really appreciate your time. Yeah, thank you. Thanks for joining us on another episode of Discovery Dialogues. Stay connected with the Vanderbilt Graduate School as we continue exploring ideas, innovations, and people shaping our academic community. Until next time, keep asking questions, stay curious, and continue discovering what inspires you. This podcast was recorded in Studio 608 at Vanderbilt University with the assistance of JT Spangler. This podcast is produced by Anna Thomas, Nick Hyer, and Stacey Satchell in the Graduate School at Vanderbilt University with audio editing by Ben Hill. The perspectives shared in this episode are those of the speakers and do not necessarily represent the views of Vanderbilt University.