Journey through the Mind: Episode 3 - Featuring Dr. Scott Russo, PhD
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Kelsey
Hello everyone, and welcome to season two of Journey through the Mind, exploring the life of a neuroscientist. My name is Kelsey Lucerne. I'm a neuroscience Ph.D. student at the Icahn School of Medicine at Mount Sinai and co-president of Minds. And I will be your host this season. Today, we're joined by Dr. Scott Russo. Dr. Russo, is a professor of neuroscience, as well as the director of the Center for Affective Neuroscience and the Brain Body Research Center at the Icahn School of Medicine at Mount Sinai.
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Kelsey
Dr. Russo's research has led to new understandings in how the immune system can affect the brain and behavior in stress and depression. His work has paved the way to new perspectives about brain function and mental illness. Dr. Russo, thank you for being with us.
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Scott
Thank you, Kelsey. It's a pleasure to be here.
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Kelsey
So I was hoping we could start with you explaining a little bit about what your lab studies So it takes a more holistic perspective of the brain and mood disorders. Would you mind just explaining a little bit more detail what that looks like?
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Scott
Absolutely. So as you mentioned, we think about CNS or brain disorders and diseases in a very holistic way. It's often thought that the brain is kind of separate from the rest of the body, and it's protected by what we call the blood brain barrier. Thus, treatments and an understanding of the brain must specifically focus only on the brain itself.
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Scott
And we've broken down that general idea about the brain and body being separate and take a much more integrated approach to understanding behavior. So we exploit various fields from within and outside of neurosciences. And our overall goal is to really understand how the brain and body interact in both health and disease, to control both normal behaviors, but also behaviors associated with certain pathologies like depression, anxiety, heightened aggression, etc..
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Kelsey
Yeah, that's a really interesting and really novel perspective on how the brain works. So did you always envision yourself being a neuroscientist or where did this journey to becoming neuroscientist began for you?
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Scott
Not at all. I think I was going to be a pharmacist when I was younger than I was going to be an occupational therapist for a half of the year. I toyed with the idea of medical school and then just really fell in love with neuroscience because of drug addiction class I took as an undergraduate. I then started to work in the laboratory and started applying for programs when I was a senior.
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Kelsey
That's amazing. And at that time, did you know that you wanted to become the principal investigator of your own lab, or were you just pursuing the science.
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Scott
I went back and forth on this question a lot. I mean, I was just talking with one of my trainees earlier today about the decisions we make in academia and how we get to this point. I mean, I was probably going to be an industry scientist for more of the time in my training then, and I wasn't going to be.
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Scott
And sometime in during my post-doc, I just really kind of fell in love with the academic structure And it just never left. So now as I was getting ready to transition, it was really only academia.
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Kelsey
Yeah.
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Scott
But that said, I didn't know that I would be in this particular position, this particular role. I had very little confidence that I'd be an independent P.I. running a successful laboratory so.
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Kelsey
Right. How did you, I guess, maintain the motivation because it's so much work getting to where you are, and it can be very daunting throughout graduate school.
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Scott
Yeah, it is. And I mean, and actually, graduate school for me was the time where I was least decisive about where I wanted to be. And that's why I always tell graduate students kind of, you know, don't put so much pressure on yourself. Think about where you might be five, ten, 15 years from now. But right now is just the period in which you should become the best scientists that you can be.
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Scott
Don't think about exactly where you're going to be post-grad because it might not work out that way. You may change. But yeah, no, I so I think as I hit my postdoctoral fellowship, I just fell in love with what science. I fell in love with the community. I met a great group of partners in my lab at the time who were very supportive.
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Scott
We had friendships inside and out. And, you know, that's what really helped keep me motivated and interested in the science and moving forward.
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Kelsey
Right. So the relationships that you made along the way in academia.
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Scott
Yeah, you know, it's strange, right? Like, you know, I've had lots of jobs over the course of my career that are outside of academia. It's a job. You go in every day, you do your job, you come home, and then you call your friends or your partners and you do what you do. The line there in academia is a little bit more blurred.
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Scott
You know, you're you're kind of a scientific family. And so you have people there that are extraordinarily supportive and are part of your life, kind of both at work, but also personally. And I think those people help you to get through the really challenging times. And I mean, you know, Kelsey, it's it's hard work to finish a Ph.D..
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Scott
Yes. And you need people that are there kind of rooting you on and helping you through it. People that will have a beer with you on a Friday night when an experiment didn't work. Yes. And help you forget about it so that on a Saturday morning, oftentimes you're going back and start that experiment again.
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Kelsey
Right.
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Kelsey
Would you mind explaining a set of experiments or an approach that led to this insight of this brain body interaction?
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Scott
Absolutely. It was a series of experiments or failed experiments, I should say, that started sometime around 2010 maybe. A postdoc in my lab at the time, who now is an assistant professor in Virginia, Dr. Georgia Hotez. We were investigating the impacts of stress on the brain's immune system or microglia as being kind of the predominant immune cell, immune cell within within the brain itself.
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Scott
And every experiment that we did either didn't work, meaning that we found no connection between stress and the activation of these cells, or that it was exactly opposite to our preexisting hypothesis, which was that brain neuroinflammation caused by stress was due to this kind of overactivity of the brain's central microglia And so at one point we just decided that maybe the source of our inflammatory molecules was not coming from these central stores or these central microglia.
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Scott
And we began to formulate a hypothesis around how the peripheral body could, you know, activate and communicate with the brain itself. And so that basically started a decades long investigation into understanding how the immune system might be dysregulated by this by stress, and what that might mean for these stress related disorders like depression and anxiety.
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Kelsey
Yeah, that's really interesting. I guess it must have been quite the transition going from a neuroscientist to kind of becoming sort of having the role of an immunologist in a lot of ways.
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Scott
I borrowed my wife's hematology textbook for medical school and read it because I didn't know what an olucocyte was at the time, and I made some very close collaborations and partnerships with with immunologists here in particular, Miriam Murad, who directs our Precision Immunology Institute and is world famous for her understanding of these interactions. Between brain and periphery.
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Kelsey
Yeah, that's amazing.
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Kelsey
So do you have any advice that you would offer your past or pre science self or anyone who would find themself at that stage?
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Scott
Yeah, you know, to breathe, breathe deeply. Don't be so anxious about where you're going to be. Things work out, work hard, love the science, ask the important questions, but also ask the questions that make you excited. Because if you do all of those things, then it really you've succeeded. At the end of the day, and you will do well if you're in the right mindset, so don't put so much pressure on yourself.
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Scott
Take a deep breath and enjoy what you're doing at the moment that you're doing it. Don't think about, you know, ten or 12 chess moves down right.
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Kelsey
Which can be challenging right,, especially for. I feel like the type of people that enter graduate program are always thinking.
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Scott
Is all.
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Kelsey
Steps ahead.
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Scott
It is. No, I know. But, you know, we end up, I think, putting so much pressure on ourselves, you know, the science will take you the way that it takes you, right? You know, you have to kind of follow that. But it's it's so it's it's hard to plan too far in advance in that way. You know, you have to see what the next experiment brings.
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Kelsey
Very true. I feel like a passion for science is so important, at least in graduate school, to really success, but also enjoying your time.
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Scott
I would also say to I mean, and I hear this now less than I heard it when I was coming up. I think it was more of an issue back when I was in training that you know, academic science is what we do. You know, you're expected to be an academic. You're expected to run an NIH funded laboratory and if you don't, you're somehow selling out.
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Scott
I think that's the wrong way to think about science. You know, this is one facet of what science is there's so many different aspects of science that are important and enriching. And what you should be thinking about as an early and even mid to late trainee is what parts of science get you most excited. And you should do that and just block out the chatter or block out, you know, what others are telling you you should do.
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Scott
You should think about what in science gets you most excited and makes you the most happy and do that.
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Kelsey
Yeah. Science is so collaborative and I feel like what you're saying about this merge between sort of academic and what we might consider like industry, science has become so much more at the forefront of people's minds throughout the pandemic because we see this really incredible collaboration and how it has saved millions of lives and the development of vaccines and other insights.
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Scott
100%. And, you know, it's not even just that it goes even further. You know, I've been really intrigued by these these startups centered around science communication. There's a bunch of them now. You know, some are specific, the brain, but not always. And they're very important. It's a it's a critical part of our ability to not just understand what we're what we're doing, but to help the kind of broader public understand that to sell ourselves and sell the science in a way that's meaningful and that can actually help people.
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Scott
So I think these things that were maybe traditionally outside of the direct paths of academic or industry science are springing up all over the place. And they're super interesting and important.
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Kelsey
Yeah. Where do you see I guess, the segmentations between these two sectors being in the coming years? Because I feel like it is becoming more and more blurred.
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Scott
Yeah. You know, it's I mean, we we all kind of rely on one another now. So I think, you know, it's important to realize that no matter what path you choose, you'll still be able to interact across this broader community between academics, industry, etc., scientific communication. So the lines are definitely blurred. But as this enterprise grows, there's more opportunities to collaborate across those divisions.
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Kelsey
Yeah, kind of coming full circle to your initial collaboration. So that was so important for identifying the brain. Body interaction feel like collaboration is so key.
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Scott
Absolutely. As you know, most of our I would say, oh, and I shouldn't say all of our really important discoveries or collaborative efforts, not just within the lab, but usually across multiple labs Mm hmm.
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Kelsey
Definitely. Especially at Mount Sinai.
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Scott
Yeah. Yeah. No, it's so I was I was at another medical school before I came here. And actually even in I was in a clinical department, and we had very limited interactions with clinicians, very limited interactions across other departments. When I got to Mount Sinai, I was really struck by not just the degree of collaboration within kind of the larger brain institute in neurosciences, but the degree to which clinicians were not just interested but excited to collaborate with basic scientists We've done a lot more clinical work, clinical investigation here at Mount Sinai than I would have dreamed.
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Scott
And I think part of it is because of the environment here fosters these these collaborative approaches to two important kind of translational sciences that don't exist at a lot of other places.
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Kelsey
Yeah, that's definitely really interesting. And I feel like so unique to these research hospital research centers like Mount Sinai the ability to have this clinical aspect to your research. And I feel like that must have been so key to the translational work that you guys do as far as taking this like brain body connection and moving it into models of depression in human patients even.
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Scott
Yeah. Yeah, it's been it's been really great to have that collaborative tie with psychiatry. And I would say now the way that we've moved is that we usually now start in in humans and we do our discovery in humans and then come back to preclinical models afterwards.
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Kelsey
Right.
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Scott
I just I think that having that clinical kind of translational insight on the front end helps you to design in a better experiment on the back end.
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Kelsey
Definitely, because it's so hard the way that we characterize psychiatric conditions is typically self-report. And so you almost need to start in the human model and work your way back to these preclinical models. In order to have something that's relevant to helping people down the line.
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Scott
Absolutely. You know, the, the, the use of the utility of mice and rodents and non-human primates is that we can access questions or we can ask questions and access biological specimens that we can't in human patients. But, you know, I'm not interested in studying and treating and curing mouse depression. Hmm. You know, it is really about finding new treatments for these human psychiatric illnesses.
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Scott
And I think that if you don't have that clinical entry point I think it's really difficult to make meaningful discoveries with with just these other models.
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Kelsey
Right.
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Scott
So that you know, so that's basically the way we've built our pipelines now is that every target we go after typically has come out of a human subjects trial. First.
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Kelsey
I wonder, have you guys just given the increasing reports of depression during the pandemic? And also, we know there's this key link between the immune system and depression. Have you guys made any forays into looking at patients maybe even within the COVID population?
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Scott
Yeah, you know, we're starting to I'm part of a consortium to both recruit and collect immune specimens from patients with long haul COVID. There's a particular increased risk for neuropsychiatric symptoms or results from having this kind of long haul COVID syndrome. And we hypothesized that given what we know about the immune system and how it's dysregulated in depression, that there might be some shared mechanisms.
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Scott
So our goal would be to start to assess the inflammatory status of long haul COVID and then see whether or not we can map out any specific diagnostic features of either depression, anxiety or even psychosis. And if we can do that, I think we could bring it back to some of the preclinical models. Hamsters in particular are an interesting preclinical model because they can get infected with COVID, much like humans can.
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Scott
So, wow, there's yeah, there's some possibilities of coming back and studying COVID infection in a hamster model and testing those causal hypotheses about long haul psychiatric symptoms.
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Kelsey
Yeah, I, I feel that this is something that's going to impact the field of psychiatry extensively. In the coming years. We're just seeing the beginnings of it.
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Scott
I think so. You know, we've for years people have always talked about the link between the immune system and brain diseases, you know, whether neurological or psychiatric in nature. But, you know, my experience that I've been in the field now for probably 15 years is that there's a group of us that really believe and then everybody else kind of is on the periphery and is skeptical You know, there's always a chicken or the egg question that comes up.
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Scott
Was the immune insult resulting from the stress or was it causing the stress disorder? What COVID has done is it's kind of changed the discussion. And people now believe that there is and I think more and more believe that there's a strong link between the immune system and brain disorders. And so I'm hoping that that continues and snowballs, because I do think from a therapeutic perspective, there's a lot of possibilities in targeting the immune system for multiple reasons.
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Scott
You know, it opens up a whole class of therapeutics that we've largely ignored in CNS drug discovery. Those that don't penetrate the brain And it's possible, too, that, you know, there would be fewer behavioral side effects, because if you're targeting things in the periphery and preventing them from getting into the brain, you know, they may not exhibit the types of of of behavioral side effects that we get from other psychosomatic drugs, for example.
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Scott
So I think there's a lot of opportunity there. And I hope that this one good thing that may come out of this is that we start to really interrogate these immune modulatory drugs in treating CNS disorders.
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Kelsey
Do you envision this maybe also being used as potential biomarkers for more personalized treatments against different psychiatric conditions? For example, like a blood test to locate different levels of immune markers? And if you identify one with therapeutic potential, you could target it with a drug.
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Scott
I think Yeah, I think it's a great point. I think you'll have to be very selective in the subtype or the patient that you that you choose to treat for depression. At least I would say about 25 to maybe 30% of the population. If you do laboratory investigation of their immune profile about 30% or so will exhibit this heightened systemic inflammatory state.
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Scott
And I think you'd really want to target that population problem with the immune system is that you're not you're trying to train the immune system to be kind of at an optimal level. You know, you don't want to suppress it too much. You don't want to activate it too much. And so the worry would be is if you select a depressed patient that doesn't suffer from an inflammatory, you know, state, that you would actually do more damage to them by treating it.
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Kelsey
Right.
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Scott
And I think in fact, some of the early data actually shows that to be true data from Andy Miller's group treated unipolar depression, unipolar depressed patients with infliximab, which is the TNF alpha monoclonal antibody. Hmm. And they didn't unfortunately, they didn't design the clinical study in a way to pass this. So they had to do a post-hoc analysis.
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Scott
But it turns out that only the patients that had high inflammation to start with responded well to it in the patients that didn't have high inflammation did worse.
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Kelsey
Interesting.
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Scott
So we really taking that, you know, personalized approach is going to be critical.
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Kelsey
Right. Right. That would definitely be a really interesting avenue, though, for just like future treatments.
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Scott
Yeah. I totally agree.
00:22:05:14 - 00:22:23:05
Kelsey
Dr. Russo, thank you again for joining us today. We really appreciate your time and all that insight you've been able to provide into your research. And the implication of it, but also into kind of what it's like on this career path to becoming a neuroscientist at the top institution like Mount Sinai.
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Scott
Well, Kelsey, thanks for having me. It was fun to chat and I look forward to seeing all the things that you do in your career.
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Kelsey
Thank you.
