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Brains, Black Holes, and Beyond (B Cubed) is a collaborative project between The Daily Princetonian and Princeton Insights. The show releases 3 episodes monthly: one longer episode as part of the Insights partnership, and two shorter episodes independently created by the 'Prince.' This show is produced by Senna Aldoubosh '25 under the 147th Board of the 'Prince.' Insights producers are Crystal Lee, Addie Minerva, and Thiago Tarraf Varella. This show is a reimagined version of the show formerly produced as Princeton Insights: The Highlights under the 145th Board of the 'Prince.'
Please direct pitches and questions to podcast@dailyprincetonian.com, and any corrections to corrections@dailyprincetonian.com.
Senna Aldoubosh 0:15
Hi everyone, welcome to brains black holes and beyond a collaboration podcast between the Princeton Insights newsletter and the Daily Princetonian. From the Prince, my name is Senna Aldoubosh.
Ketevan Shavdia 0:25
And Ketevan Shavdia.
SA 0:26
Today's guest on the show is Alec Downey, a final year grad student and PhD candidate in the Ecology and Evolutionary Biology Department. Alec got his bachelor's in Ecology and Evolutionary Biology at Yale University and his masters of philosophy at the University of Cambridge, and his Masters of Science at Princeton University. He now works at the Graham lab and researches mice to better understand human immunology. Alec, welcome to the show.
KS 0:49
As a first question, I would like you to introduce yourself. What got you interested in Ecology and Evolutionary Biology? And why did you choose to start working at Graham lab and pursue their research about mouse human immunology?
Alec Downey 1:01
Sure. So I sort of always been interested in ecology and evolution and sort of, I wasn't like a wild nature child as a kid, but I did always like animals. So that was always what I wanted to do in undergrad. When I, when I started started, I knew that was what I wanted to major in. But you still don't really have a concept of like, what research is and what topics are actually particularly exciting to you. So I kind of bounced around and did a bunch of different things, dabbled in sort of plant ecology and human genetics. But I sort of became interested in infectious disease through taking a seminar series in evolutionary medicine. So sort of understanding how evolution gives us better insight into the health challenges that people face. And so because of that, I sort of realized that immunology or disease in general was a topic of a lot of interest to me. And in my master's, as well as the year I spent working at the National Institutes of Health, I worked on sort of, not not the host side of sort of infectious disease, but the parasites side. So trying to understand how parasites infect and sort of what are the dynamics of it had this inkling that but that wasn't quite satisfactory to me. And I'd heard about Andrea as like a really wonderful researcher, I'd actually seen her give a seminar at Yale in my senior year, and knew that she was someone who is like a really great person to work with. And so and I thought, well, she'll sort of she's done a lot of interesting work on this host parasite interface, and sort of thinking about the ecology and how the ecology affects what sort of the outcome of that interaction. And so that was what got me excited to work with Andrea, and sort of to come to Princeton, EB in general, which is a wonderful place to be a graduate student in which has a nice cluster of people who really think, an exciting and sort of groundbreaking ways about the sort of host parasite interaction. And so that was sort of what what got me here. And I was still sort of thinking, oh, I want to do parasites when I started. But pretty quickly, Andrea sort of properly assessed that what I'm actually interested in really is the host, and I'm sort of interested in the host biology, like, what is the host doing? How was the host's strategy, right? How does it handle the fact that it gets exposed to a bunch of parasites? And how does that interface with other aspects of the host biology? And so working with Andrew has really been a wonderful fit for that, because we we use sort of methods from immunology, we work on ideas from immunology, but we also work in ideas from what sometimes called evolutionary ecology, which is like a very vague term, but basically just sort of means like, basic aspects of organismal sort of biology in terms of what are their what are their lifespan patterns, where they're sort of reproductive patterns? So like, sort of what are the sort of basic outlines of organismal biology and the organismal strategy? And so that's been a really profitable sort of space for me to work in. And the mice are a particularly exciting part of that, although not the only part of that for my dissertation.
SA 4:02
Gotcha. And talking about your dissertation, as a final year grad student, you're likely preparing to present your dissertation. Could you give us an overview about what your dissertation is about? And what you've been able to learn about immunology?
AD 4:14
Yeah so, my dissertation has been a couple of different aspects of immunology and has used a couple different techniques. So the basic sort of overview concept that I sort of work with, and that I used when I was out on the trail looking for postdocs was sort of the question of why is there so much variation that we observe in the immune system, right? It's not the case that there is a single optimal immune phenotype, but rather, there's a variety of autoimmune strategies. And when you sort of assess the immune systems of a bunch of humans, they're all going to look very different from each other. And this isn't necessarily like a bad thing, per se. It's just a thing. And so why do we observe that thing? So that was sort of kind of the organizing principle and you can sort of attack this from a couple of different ways. So one of the ways that they started actually was with a little mathematical model. So one thing that a lot of people in Princeton EB do is theoretical biology and theoretical ecology. And so trying to understand sort of, based on an organism's, you know, projected lifespan and the epidemiological risks that it faces, how is its optimal immune strategy going to vary. And so that's like a very abstract way of doing things. But then we also spend the Graham lab, we do a lot of empirical work, we get our hands dirty. And so one of the main projects that I've been working on is this project, that Andrea has been running my advisor for a long time, studying the immune phenotypes of rewild, at laboratory mice. So these are laboratory mice that you sort of are raised in these indoor settings. But then after four to six weeks, we put them into outdoor enclosures. And we basically allow them to sort of run around in these outdoor enclosures. And that's a very different environment outdoors, from what they experienced indoors, there's a much richer sort of environment in terms of microbes in terms of the food they can eat, they experienced natural weather patterns, we do try to keep predators away from them. And we're, we think we're pretty successful with that. But still, you know, it's a very different setting from what a lab mouse experiences indoors. And so we can sort of get a sense of what does that outdoor environment and that sort of that richness, that chaos, contribute to the immune system, right. So you guys may be familiar with this idea of the old friends hypothesis that, you know, the exposures that we have early in life to, you know, dirt or whatever, really matter for what our immune system looks like. And that's why there's sort of one thought as to why there's this increasing presence of sort of chronic sort of gastrointestinal diseases in developed countries. And so it turns out that this exposure to the outdoor setting or sort of taking this advice, appointment doors really dramatically changes their immune systems. And so there's these big differences, which are really cool. And sort of understanding, okay, what exactly contributes to those differences? And what do those mean for the outcome of infections? What does those mean for the sort of parasites that we're interested in as well as the host? Yep, trying to get a sense of that is, I think, really useful. And so I've been working on a couple different aspects of that project, including some of these things like taking different mouse strains and sort of infecting them and seeing how the rewilding affects the parasite response differently. And my sort of biggest project has been using some data we have from RFID tags that each mouse gets to track the activity of the mice in these enclosures. And to see, okay, who are they interacting with? Or who do they tend to, like sort of appear in a location with? And does that at all sort of relate to what their immune systems look like? And it turns out, basically, that individuals that more frequently sort of interact, roughly speaking, have more similar immune systems, because they're probably encountering the same microbes. We're not totally sure exactly why. But that's our best hypothesis. And so this is this, this rewiring system is really wonderful, because it both enables us to really better understand the immune system in the natural setting in which it would have evolved, as well as to get a sense of what factors shape what the immune system looks like. So we get this nice, granular thing to be able to say like, oh, okay, alright, all this exposure to stuff really matters for their immune system. And by the way, some of the variation that you then observed among these mice is going to be determined by who they are, like, interacting with. And so that's been one of the main parts. And there's one other part which we're kind of still working on, but we're getting there where, so we don't just study mice in the Graham lab, that's kind of one of our main things. But people in the lab have done things like insect immune systems and have done things like sort of antibody dynamics in humans. And what, what I am also working on is the immune systems of Northern Elephant Seals, which are just huge seals. And there's a lot of really cool stuff that we can learn from that, which I don't want to bore you all with the details, but I am happy to talk about.
KS 8:58
So speaking of wild mice, something very exciting is that Graham lab was actually interviewed by the New Yorker. In the article, it was mentioned that mice share a large majority of their genes with humans, and even suffer many of the same illnesses. Would you be able to briefly elaborate on the similarities and immune function between humans and mice, as well as the similarities and differences between lab mice and your wild eyed mice?
AD 9:20
Sure, yeah. So there are a lot of differences, but there are also a lot of similarities and precisely what these are is kind of complex. I don't know, it's definitely debated and not something I'm super familiar with, but I have some some degree of familiarity. So the basic structure of our immune systems are pretty similar. So we have a lot of the same sort of types of immune cells which are serving broadly similar functions and sort of, in analogous ways so like, and there's like certain specific molecules, right, a lot of specific molecules do broadly speaking the same thing. So for example, if you get infected by a virus of some sort, our immune systems are going to produce a lot of the signaling molecule called interferon gamma. A mouse is also going to produce a lot of the signaling molecule called interferon gamma. And it's going to coordinate the immune response in broadly similar ways. And so the dynamics of an immune response, and a lot of the sort of cell types that get used are going to be very similar. So in terms of the broad outlines, the immune responses between mice and humans are very, sort of our sort of work well as sort of, you can, you can, you can sort of draw a lot of good information from a mouse to apply to a human, but not all the information. And there's a number of reasons for this. So some things just to do with the fact there are still some basic evolved differences. I don't exactly remember the divergence time between rodents and primates, but it's something maybe around 50 million years ago. So that's a lot of evolutionary time in which molecules might change and functions might change, the selection might work in particular ways or drift. So you can still get a lot of differences. And we do see plenty of differences. But then some of those differences are also going to be because we are very different organisms, in terms of what we do, right? We are huge compared to a mouse mass might weigh, I don't know, a healthy mouse might weigh 20 grams, something along those lines, right, which is going to be a couple orders of magnitude less than human ways. So that's going to be a big difference, the lifespan is very different, the sort of reproductive dynamics very different, the sort of basic aspects of the ecology are quite different. And so those are going to be sort of affecting how the immune system operates. And the strength of a response may be that it puts out in different circumstances. And then an additional complication is actually in that lab rewild, that distinction that that you highlighted, because we're really we're not comparing, we're generally not comparing humans who have been sort of relatively dirty environments, right? Like we sort of, you know, we experience a lot of stuff, a lot of mouse waves in sort of stainless steel, sort of, or like plastic kind of environment where like, they don't experience anything, because we really don't want them to experience anything. That's the theory. We want them to be like, pure so that they can sort of be easily replicable. And we can sort of determine exactly what's going on. And so that's not only are you comparing two different organs, but you're also comparing them in two different environments. And so figuring out which one of those actually matters for the differences that we see between mice and humans, is really challenging. And that's one of the reasons why rewilding, like what we do in the Graham lab. And there are some other groups that do this as well, is so useful, because rewilding enables us to sort of say, Okay, we're not, you know, we can sort of observe what the environment does to the immune phenotype, right, we can get a sense of that by taking mice that are basically genetically identical, and sort of comparing what they look like in the lab versus what they look like the wild. And when they rewire that, they look quite different. So their immune systems are a lot more experienced, they have a lot more immune memory, they also seem to produce a lot more antibodies, there are still some things that seem to be somewhat similar in terms of some aspects of the production of sort of immune signaling molecules, or maybe similar, but there's, there's a lot of things that just through the aggregate experience change. And what that means, actually, is that you get these very different sort of presentations of disease burden. So a classic example is that it's extremely hard to infect a lab mouse with some sort of gut worm. But gut worms are quite prevalent in humans. And this is something that we really would like to know more about. It's just you just have to give them a truly ludicrous number of larvae in order to establish an infection. And it's usually just not very large. And we'll have mice, when you give them to rewilded the mice, they get a whole lot, they get them a lot more easily. And that's a really cool result that we've observed just in the summer of 2021. That sort of difference because of the sort of rewilding, and actually what that seems to be doing to the immune system, we think it's basically interfering them from producing an effective anti worm response. And so that sort of difference, right? Not only does it make it sort of matter, is it showing what the environment does, but also the rewilding ones, you could say because worms are relatively common in humans, right? They're becoming a better model. These rewilding mice for human helminth infections for humans gut worm infections, compared to the lab mice as a model. And so this might be a really promising way forward to understand better what infection sort of looks like. Because we can see in this one instance that like hey, actually, the infection is going to, you know, we can better model the infection if we take a rewild and mouse. And so you know, who's to say if that's something that's really durable, it's kind of hard to do these experiments, but it'd be super exciting to be able to really figure out some sort of way to make rewilding more of a default for the purposes of comparison with humans.
SA 14:32
That sounds really exciting and really interesting. Like rewelded mice are a lot more related in a way to humans like in the sense of like immune function and everything. But I guess before we get to our last question, if there's anything that we haven't mentioned yet, is there anything you want to plug into the podcast or anything that you also want to add about your research?
AD14:51
I mean, not in particular. So I think that, you know, there's a lot of, you know, it is sort of an exciting topic to be working on right now in terms of sort of understanding, sort of trying to get a better sense of how the immune system operates. And one thing that I think is really interesting in general about the immune system, and that my adviser sort of spent a lot of time thinking about and sort of pioneering, right is understanding the extent to which the immune system is obviously incredibly sort of helpful in in preventing sort of parasite infections, but also, that can sort of have its own costs to the self, right? It's mounting an immune response is really sort of energetically expensive, you've probably feel really dragged out if you're sick, right? And that's one of the reasons why because your immune system is like, actually, we would like all the resources now, please. So that's sort of one thing that is sort of interesting, right, is that the immune system is really sort of draining to us. And also, an overly aggressive immune system can damage the self. Right? This is something that is sort of, maybe not in previously not been so well appreciated. And sometimes I still sort of see like, when I sort of see stuff in sort of popular press, it's like, I don't, I don't know about that, you know, like this idea that like, you can't really have like an immune system, which like, operates perfectly and super powerful and super efficiently against parasites, without it also damaging yourself in some way. And so, obviously, we know about sort of classic examples of autoimmune diseases are things like lupus, rheumatoid arthritis, and there's lots of diseases of this nature. And so sort of that kind of balancing act is really interesting, and sort of understanding how the environment and the genotype can sort of shift the positions of like, what is the optimal balance is, I think, something really exciting to think about. And so that's something that, you know, I think, is also relevant here, right? Understanding like, okay, the immune system is better becomes better at this or is operates better in this way, when you're outdoors, like maybe it's better at dealing with, I don't know, bacterial infections, but it becomes worse at dealing with worm infections, because there are a lot more worms. And so understanding like those trade offs is, I think, a really foundational thing, actually, to the study of the immune system. And it's something that we're sort of constantly thinking about, like, Okay, what got better? And what got worse, like got better, what got worse?
KS 17:03
As a final question, what advice would you give to students listening right now that you would give to your younger self?
AD 17:09
Well, honestly, actually, the piece of advice that I give to people who want to do grad school, most often, is to go work with someone who is a really good advisor, you're going to spend, you know, five plus years working in one place, I think it is relatively rare that people have like a truly strong sense, like, like, truly, like perfectly strong sense of like, I want to work on this topic precisely. And only this topic. And if you sort of have that approach, right, there's, there's a relatively limited number of people who can really help you do that. So you, maybe you got one or two people who can help you do that. Or you may just have constructed yourself. But if you sort of go someplace where you find someone who you can work with for an extended period of time, right, and who is going to be supportive, and who is going to help you with whatever it is that you're that you're doing, you're going to have a happy grad school experience or have, you know, for the given value of grad school, right, like, you know, it's going to go well. And so I think I often sort of emphasize to people like you should go someplace where you are enthusiastic about working with the person who is going to be your advisor, and working with people who are going to be your collaborators. And so that's actually a thing that I sort of often tell people about, like, why I really like Princeton EEB is that it's a wonderful department, my advisor, Andrea has a wonderful person, I'm really fortunate to work with, and it's a, it does have a strong community aspect to it. And so like, yeah, there are going to be days where I'm like, nothing seems to be working, you know, I can't come up with a good idea, whatever. And there's people around who can help me sort through that. And there's people around who can, you know, help me make the next day, a better day, right. And having those sorts of things is, I think, actually really important. And you're going through the process of sort of working with people who are fun to work with, and sort of interacting with people who are sort of intellectually sort of exciting for you, you're gonna figure out what you what you, you know what you're happy doing. But you're, even if you think like, Ooh, this is the perfect topic for me, if you're unhappy doing it, it's not, it's not really gonna work out terribly well for you. So that's sort of I know, that's not really about like, the science per se, but I do think that's something that's incredibly important is being in, like, the right environment for doing whatever scientific research you're going to be doing.
SA 19:17
I think regardless, that's great advice to hear, even if somebody doesn't necessarily choose grad school, it's like the idea of, you know, having that open mind, looking for an advisor that's very supportive, and in a collaborative environment, and all those are really important in all fields.
AD 19:31
I hope so, you know, I don't really know, you know, like, I've not done things other than scientific research, but like, I imagined it's true. So, yeah, I'm gonna keep dispensing it as advice, and then maybe people will tell me actually, it doesn't matter. For now. For now. It seems okay.
SA 19:45
For now. It does. Yes. So that's what matters. But Alec, thank you so much for being on the show. It was really great learning about your research, and best of luck with your dissertation and becoming Dr. Downey.
DA 19:54
Thank you so much. I really appreciate it. It was great to be here.
SA 19:59
This episode of B cube was hosted by Ketevan Shavida and me, sound engineered by me and produced under the 147th Managing Board of the Prince. To learn more about the Graham lab, visit the links in the description below. From the Prince. My name is Senna Aldoubosh and have a great rest of your day.
Transcribed by https://otter.ai