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Episode Transcript

Tan Deleon
On behalf of the members of the Connecticut Academy of Science and Engineering, welcome to this inaugural edition of Learning & Living STEMM in Connecticut, the podcast of the Connecticut Academy of Science and Engineering. My name is Tan Deleon. I’m an elected member of the Academy, and in 2020, was elected to the Academy’s Governing Council, and I’m pleased to serve as host for this podcast. The Academy is a nonprofit created by a special act of the Connecticut General Assembly in 1976, with key areas of work including advising and informing the people and the state of Connecticut, on science, technology, engineering, mathematics, and medicine, collectively known as STEMM. This podcast is key to sharing, with the residents of our state, interesting STEMM developments, and increasing visibility for the state’s innovators and entrepreneurs, businesses and industries, academics, our talented workforce, and those doing STEMM-related work in public service.

For today, I’m pleased to have as our guests fellow member, Daniel Bolnick, professor of ecology, and Evolutionary Biology at the University of Connecticut, and Dan’s former postdoc, Jesse Weber, now assistant professor for Integrative Biology at the University of Wisconsin Madison. We’ll talk a bit about their research, and some about what led them to where they are in their now careers. Dan first, then Jesse, can you tell me a bit about yourselves?

Daniel Bolnick
Sure. So I’ve been fascinated by biology ever since I was a kid. I grew up in a family that were hikers and canoers, and spending a lot of time outdoors. And I had the privilege of traveling a great deal as a kid, my father was both an academic and a consultant, who worked with countries around the world to come to advise them on economic policy. And so we traveled to and lived in Southeast Asia, lived in Central Africa. And that experience exposed me to a wide variety of biological diversity around the world and made me really fascinated in the origins of biological diversity as we see it today, and how that diversity is sustained, and motivated me to become an evolutionary biologist. And to this day, I get the opportunity to spend a lot of my time thinking about why the world is such a diverse place.

Tan Deleon
That’s fantastic. Jesse?

Jesse Weber
Sure. Not quite as exciting as Dan’s, but I grew up in a suburb of Denver, where I wasn’t necessarily convinced I was going to be a biologist early on. But going toward college, I realized that I really did love molecular biology in particular. And so I went on to an undergraduate degree at the University of Colorado Boulder, aiming for that kind of a degree. But about three-quarters of the way along, I had an advisor that recommended to study abroad. And so I went to Botswana and studied in the Okavango Delta looking at large herbivore migrations, and realized that this was a lot more fun than sitting at the bench pipetting things all day long. And so I made a major career decision that I was going to go to graduate school and try to understand the genetics that led to all the diversity that I was seeing out there and the kinds of adaptations that allow animals to fit into their environments. And so I’ve been super lucky since to go to a Ph.D. and work on mouse behavior, then go do a postdoc with Dan working on fish immunology, then go to another postdoc working on rhinoceros beetle horn evolution. And now I’m just super excited to be running a lab continuing some of the stuff that I did early on with Dan in new and I think really fun directions.

Tan Deleon
Thank you for that. That’s it’s very interesting because it seems like there may be a common thread between the both of you. Dan – is Botswana part of your past as well? Or is that is that I guess like what makes that place so special because it seems like Jesse has a tie there as well.

Daniel Bolnick
Yeah. Well, I lived in Zambia for the tail end of high school in Lusaka and I did visit Botswana during that time for a family vacation trip. And then I also lived in Tanzania for a couple of years after grad after my undergraduate degree. I taught high school biology and math and a small public school in northern Tanzania. But I did spend one summer in Botswana as well. During college, I spent a summer helping a botanist, doing plant surveys and plant ecology work in the Okavango Delta in Botswana. So actually, Jesse and I coincidentally overlap in that regard. I won’t say that all evolutionary ecologist in the world get their start because of the Okavango Delta. It certainly helps.

Tan Deleon
Certainly, certainly, I find that fascinating. Like, it’s like, you know, years apart, and yet still, there’s still that common thread. But so the focus for today is on the topic of Resistance is Futile: Evolution of Tolerance when Immunity and Parasites isn’t Worth the Cost. Please explain what you mean by this. Dan, then Jesse.

Daniel Bolnick
Yeah, so I started out in graduate school, interested in the origin of species and how one species splits into two genetically different and ecologically different populations that are then eventually different enough that they’re considered separate species. And to do that, I started working with a small fish called Three-Ppined Stickleback. It’s a widely studied species, there are probably 100 laboratory groups around the world that work on Stickleback this every couple of years is an international Stickleback meeting. So although it’s not well known as like a household name, in the US, it is a well-known fish and widely researched. And I started out interested in this to understand population differences and adaptation and evolution. And along the way, a lab tech in my lab on the LAOs started, I had her dissecting thousands of wild-caught fish to understand what they eat and how they’re evolving to eat different foods. And she started noting down when she saw certain parasites.

And what came out of that years later, a graduate student of mine – Will Stutz – analyzed those data, which again, were coincidentally collected, and realized that there’s some lakes in British Columbia, Vancouver Island in Canada, where the Stickleback are heavily infested by certain parasites 80% of the individuals are carrying around these enormous tapeworms. So, for reference, one of these tapeworms can grow to be half the body mass of the fish. That’s like me – I’m 155 pounds – that’s like me carrying around right a 75-pound tapeworm. It’s, it’s brutal, right? And yet, 80% of the fish are carrying these things. And then you drive two kilometers, three kilometers away to a different lake on Vancouver Island, and nobody has this parasite, not one fish that we found. And so how is that variation maintained? So I became really interested in that. And there were two branches of thought that I started out with. I’m an evolutionary psychologist by training. So my instinct is to think is it about their ecology, their ecological niche. And in this case, the parasite is acquired when a fish eats an infected crustacean, a little zooplankton in the water. And if individual fish eat the plankton, then they’re at risk of getting the parasite. And if they don’t eat the plankton, if they eat other foods, then they’re not at risk at all. So maybe it’s all about their diet and their ecology. Or maybe it’s about their immune system, is it maybe it’s a genetic feature. Maybe some populations are resistant to the tapeworm. And they just can’t get it, they kill it. And other populations maybe are vulnerable, susceptible, or easily infected. So is this about ecology, or is this about immune genetics? And so that was really my motive to try and understand the relative roles of ecology and immune genetics. And so I brought in a few people to work with me, Jesse included, and maybe I’ll hand it off to Jesse to tackle the resistance and futile bit…

Jesse Weber
Sure, yeah. It wasn’t a hard pitch when I was looking for postdocs that I was leaving mouse world and looking for a new model to work on that was out in the wild and Vancouver Island is a wonderful place to go. But Dan is just this wonderful ecologist that thinks so broadly that he samples everything and has these enormous datasets. And when he showed me this picture of infection variation across Vancouver Island, basically like 50, lakes and streams, where Dan had gone in and measured, like, which ones have parasites and which ones don’t. And it was this huge spectrum, a lot of them that didn’t have it to a few that headed at really high levels. And as someone trained in genetics and quantitative genetics, I mean, that’s, that’s gold. It’s the idea that you can go out and look at these, what we would often call like a high line and a low line, and a lab suit. Usually, you can do artificial selection to increase a trade or decrease a trade, but it might take years and years to do it. Nature’s already done it. But it gave us the opportunity to ask well, yeah, let’s first figure out what’s going on in each of these populations, using a really nice approach called a common garden, which we kind of steal from plant biology, where we bring animals into the lab, and then raise them under the same environment and ask if their traits differ. If they do, that means that it’s probably due to genetics, because we’ve controlled for any environmental variation that’s there. So we didn’t necessarily know at the start that there were going to be these kinds of trade-offs between maybe a resistant fish or a non-resistant fish, all we knew is that we’re going to look for genetic differences in their infection.

But once we started piecing apart what was going on with these things, we started to find some really, I think, profound, you might call disease traits that were associated with infection. Some of these fish, when they would get exposed to a tapeworm, their entire body cavity, like the internal area that holds the organs together, would fibrosis into this tough, like a mass of tissue, which looks terrible for the fish. And we weren’t exactly sure what was going on with it at first, but it certainly seemed to us to stunt the growth of tapeworms too. And so this started us thinking in different ways about, well, what are the benefits here, it will share, you’re probably protecting yourself in some ways from a tapeworm, but in other ways, you’re really hurting yourself. So Dan went and followed that up with a bunch of other people in the lab to ask about the consequences of when this fibrosis happened. And I have people in my lab, looking at some aspects of it now, too. But it turns out that if you are able to lose that trait, you then get other benefits. So it’s the idea that fish are constantly trying to decide do I defend myself? Or do I just feed this tapeworm and grow as fast as I can? And so there are the like, resistance isn’t always going to be the best outcome depending on what kind of environment you live. I think this is a growing story. So we don’t have all the pieces yet. But it’s a neat idea that we can go into these systems where we know there must be something there. That’s the hypothesis. But then by digging into the genetics and breaking apart all these different combinations of genes and seeing how they work together, we can start to unravel the evolutionary history of how organisms really adapt to their parasites.

Tan Deleon
Hmm, that’s that is very fascinating. And I have to say, I didn’t know what a Stickleback actually looked like, because obviously I’m not an Evolutionary Biologist, but they’re, they’re cute little fish, I have to say so with their with the spines and stuff, but so, as you said, there is a balance that the fish has to achieve. And I mean, balance is part of nature as a natural phenomenon. So does this fibrosis the fish’s immune response to tapeworms? Does that have an analog to humans health and how does this potentially translate going forward?

Daniel Bolnick
Absolutely. So it’s estimated that about 40% of mortalities in the US involve diseases that have an element of fibrosis in them. fibrosis isn’t always the least central cause of death. But heart disease can involve a buildup of scar tissue in the heart. Cancers often involve a buildup of scar tissue associated with the tumor. So fibrosis, to clarify, is the buildup of a web of protein outside of the cells. And scar tissue is arguably the most familiar version of that. But cirrhosis of the liver with alcoholism is a fibrotic disease. Cystic fibrosis is a familiar disease to many people. So there are a lot of human diseases and when you talk about fibrosis, to somebody involved in biomedical professions, they think it’s bad. You know, they think that’s a disease. It’s a pathology. It’s a bad thing. And it’s the result of an overactive inflammatory response. So if you have chronic inflammation, you build up scar tissue. Now, we think that’s a bad thing. And yet here we have evidence from the Stickleback, that they’re actively evolving to do fibrosis.

So why is that? Well, turns out it’s two because it has a protective effect against tapeworms. It helps reduce the size of the tapeworm, it often helps them actually encapsulate the tapeworm in this web of scar tissue and kill them. But it’s not an unalloyed good thing, right? We often think about immunology and immunity as good for us, right? We want to be immune to diseases. And we assume that more immunity and more defense is better. It’s sort of analogous to the military philosophy. You know, the more you invest in your military, the better defended you are, the better you are. But of course, those investments have costs, you’re not putting resources into something else, and there are side effects. And so in the case of Stickleback, and in general, we think well, more immunity is good. Well, not necessarily more immunity can mean that you gum up your whole body cavity, all of your organs stick together, you can’t move as well, you can’t grow as well, you can’t reproduce as well, you’re burning energy that you could put towards other things. So much like humans, this fibrosis in the fish is a pathology, it is a bad thing, all else being equal, but it’s also a good thing because it protects. So then the question is how do those costs and benefits balance? You can approach this like an economist, almost any investment in an economic human sense, involves costs and benefits. So you can put your resources into this thing, and it has side effects that can be damaging, or you can put your resources into something else. And you want to think about the balance of those marginal costs and marginal benefits is sort of the same thing. Organisms have trade-offs that they have to face. Do they put resources into this? Do they put into that this thing has benefits and costs? How do you balance that? And it’s not always more is better.

Tan Deleon
Yeah, that’s a no, that’s a very, very valid point. Just Jesse, anything, anything to add to that?

Jesse Weber
Yeah. The idea is that your choice isn’t always constant either, right? So I think one of the really neat things from our study was that we could learn that in the history of the Stickleback, they might initially evolve resistance to the tapeworms that use this fibrosis. But then later on sometime farther down in their evolutionary lineage, after they move over to a different league, or something else happens, they choose to lose it and not choose to I’m gonna say choose Evolve is the word that’s happening is that they, they evolved to turn off his response because systems have changed. And so it’s this, this plasticity, this flexibility of this decision that really makes these things fun, too, because in stickleback, it’s not just one lake or one stream that we’re looking at. It’s dozens and dozens and dozens where we can start to ask, well, why is it happening here and not here? What are the consequences of this for the rest of the biology of the fish?

Tan Deleon
So if you were to, I mean, I’m, again, pardon my ignorance here. But if you were to take the Stickleback that you’d said, was, you know, in one, one ecosystem, it didn’t have fibrosis in another ecosystem it did. If I took the one in the ecosystem that didn’t have fibrosis into this ecosystem, where it did, would it automatically turn it on? Or is that something that you need a certain amount of time in order for it to evolve too?

Daniel Bolnick
It’s a great question. As Jesse mentioned, we use what’s called, in the parlance, a common garden experiment where you bring animals into a shared environment to try and control for the environmental effect. Okay, and what we find is that there’s clearly a genetic element there’s this inherent genetic difference and the way that you do this is really kind of a fun experiment. And this is what Jesse brought into the lab, it wasn’t something that I was an expert in originally, it was the process of taking, say, a population with lots of fibrosis and no tapeworms and a population with very little fibrosis and big happy tapeworms. And we brought them into the laboratory as eggs. We made hybrids between them. We made another generation of hybrids after that. And when you do that, think about the genome of one lake as a deck of cards with blue backing on the cards. You know, the decorative face of the cards is blue, and the other is a deck of cards that are red. Right? And when you make a first-generation hybrid, you sort of just put the two decks of cards on top of each other. But then when you make that second generation of hybrids, you shuffle those decks and now you’ve mixed up the cards. And then what you do is in our case, we experimentally infected the fish and measured how well the tapeworms grew, measured how much fibrosis there was measured other aspects of the immune response of the fish. And then you scan through the deck of cards, so to speak of their genome. And you’ll look for where you see statistical correlations between what, whether you had a red or a blue card at this spot in the deck, and whether or not they had fibrosis or whether or not they had a big tapeworm. And by doing this, you can localize, okay, chromosome two, has something that influences fibrosis, and chromosome 11, or 12 has something else that influences how well the tapeworms are growing above and beyond the fibrosis effect. And so we can really localize not only that it is genetic, but we can say, oh, something on chromosome two is doing something on chromosome 12 is doing this.

Now, the environment can still matter – the environment could switch off the thing on chromosome two, potentially. Okay. And, then what we can do to narrow it down further, is look inside chromosome two, and say what genes in this window of the genome show a fingerprint of historical natural selection, natural selection leaves its fingerprints, or its footprints in the signature of the genome. And so you can look for that. And we see that there’s the gene with the strongest evidence of natural selection inside chromosome two is a gene that in mice regulates fibrosis, and you oh, wow, couldn’t be any better than that. And the expression of this gene, how it’s turned on, or turned off, is different between fish with higher lower fibrosis, perfect. Then we do genetic manipulations experimentally, we reach in and we mutate that gene, and it changes the amount of fibrosis. And we’ve now used a drug that blocks the protein that the gene produces, we changed the fibrosis. So we now have multiple layers of evidence that this particular gene SPI1B, controls, have controls, or at least contributes to differences in fibrosis.

So clearly, it is genetic, which means that’s going to last no matter where you put these organisms. And, the most surprising bit in all of this was that we would have expected this well-defended population, strong fibrosis, to kill tapeworms and makes them tiny. Sure, we would have expected that’s where the natural selection was, when we look for that fingerprint, we can tell which population the selection happened in. And I would have guessed that this population that gained this ability to defend itself would be where natural selection is. But it wasn’t it was the other population is population that goes tapeworm. Okay? Go for it, unless the tapeworms grow. And the selection actually involves a deletion in the gene. So basically, the gene has been damaged in a way that we think changes when it’s turned on or turned off. And that seems to be modifying the fibrosis in a way that is beneficial to not have fibrosis. So we have evidence based on the history of selection at this gene, which is how we go about saying that there’s actually been an evolutionary loss of immunity, they’ve said, immunity against parasites, yeah, not worth it. And they abandoned it, which is a shock. It’s not intuitive.

Tan Deleon
But it seems to work for them, which is…

Daniel Bolnick
Seems to work for them.

Tan Deleon
Which is always telling…

Daniel Bolnick
Although they’re swimming around with like, you know, 5 to 10 tapeworms in them on average, you know, these are really sick fish, but they don’t have fibrosis, and they lay big clutches with lots of eggs. And ultimately, that’s what matters. The population with low with high fibrosis, no tapeworms at all. Small fish, small clutches, they don’t play very many eggs. They’re paying the cost.

Tan Deleon
So really, the opportunity is you want to pass your genes on. So in order to do so, you have to have enough energy to lay enough eggs so that those eggs can survive to live another generation basically. Is that is that the crux or am I off base here?

Jesse Weber
No, that’s pretty accurate. And I think the question is, there are just lots of ways to do that. And one thing that my students have been now setting here at Wisconsin is that the like, what are the other things that come out of turning off this, this immune response, those fish that actually do this, it really looks like they grow and a lot faster than the fish that are resistant to the tapeworm. So that’s a pretty neat way to grow faster, eat more, have more eggs have more babies pass on your genes. And so it looks like they can get away with that and the lakes in which they live, while maybe that strategy wouldn’t work so well, in a different lake where maybe you had fewer resources available to you that you tried to grow really fast, but now you just don’t have food all the time. And you’re always in a bad condition. And now your tapeworm infection is going to be more severe for you. We don’t really know the exact details of this interaction yet. But I think it’s really exciting also that even though we started with maybe just one lake that looked like it was resistant to tapeworms and had this fibrosis, and one lake of fish that I shouldn’t say it’s not the lake that has the fibrosis – the fish in the lake – and another lake that had fish that had lots and lots of tapeworms. But because of Dan’s work, and now, because of going out to other lakes on these islands and other parts of the world, we find that the same genes that we are that are giving rise to tapeworm tolerance has actually arisen multiple times, and different lakes over and over again. So this is the really neat aspect of the Stickleback study system is that it’s not a one-off, if we want to go in and ask questions about the repeatability of natural selection, and just whether there are particular optima that are arrived at again, and again, we can do these questions because we have hundreds and hundreds of natural experiments that go on in every watershed that we go to, to ask, are they coming to the same outcomes at the end of tapeworm resistance or tapeworm tolerance? And if they come to similar outcomes, why? We can do the same genetics to get at it. It’s one of those big questions in evolutionary biology is how repeatable is evolution? Can we predict it? And so I think in this system, we’re getting to a case that we can predict both from the top down and maybe even from measuring the genes first going from the bottom up to say, well, if you have this genetic variant of this one gene associated with fibrosis, maybe we can predict an awful lot about the environment in which we’re going to find you.

Tan Deleon
I mean, I’ve had a really, really fun time learning about the Stickleback and your research. And I think there’s a lot more to be had. And, you know, we should invite you back in and have and continue this conversation even more because I feel like there’s so much more that we can discuss and learn about this wonderful creature. For in the time that we have left, I just want to ask both of you, for someone that’s trying to, or considering a career or even getting into STEMM-related fields, and potentially has never had kind of the background or the upbringing, you know, that that would foster them getting into this field. Do you guys have any advice for a young person that that’s interested in, potentially evolutionary biology or something similar?

Daniel Bolnick
Yeah. You know, evolutionary biology today is an incredibly exciting field that isn’t just about fish on lakes. And it’s not just about Darwin’s finches in the Galapagos, or peppered moths and things that are taught in high school classrooms. When students learn about evolution and adaptation. Cancers evolve a tumor inside a single patient is an evolving population of cells. The reason why COVID is a recurring problem is because it evolves and mutates certain mutations have an advantage in transmission or avoiding detection and spread more readily. Evolutionary Biology is pervasive in medicine, whether it be infectious diseases, or cancers, understanding the origin of human genetic diversity and why everybody’s different from everybody else, and what that means for medicine. And so there’s an incredible wealth of directions, you can get engaged in evolutionary biology, whether you are a naturalist who loves being outdoors or whether you’re interested in health professions, or agriculture. I was meeting just the other day with somebody in the animal sciences department at UConn, who’s using evolutionary genetics tools to understand cattle breeding. So it’s really a way of thinking about the world. And so your best bet, if you find this kind of thing interesting, is to read about it – they’re wonderful books written for the public about this. Books like The Rebel Cell about the evolution of cancer is a wonderful example. And, and then in terms of preparation, Evolutionary Biology draws a lot on computer science today. It draws a lot on mathematics. It draws very heavily on genetics and really any discipline in biology. And so if people find this interesting, it’s absolutely a discipline that’s welcoming to a wide variety of people. You don’t have to grow up as a world traveler in order to get into this. I know plenty of people who did not at all. And it’s really a discipline that is just thinking about genetic diversity and biological diversity, whether it be among people among viruses, and so any field in biology can be approached with an evolutionary frame of mind.

Tan Deleon
Okay, thank thank you for that. So, in the interest of time, I just would like to thank our guests, Professor Dan Bolnick and Jesse Weber. For those living in Connecticut, and others tuning in from outside our state, we enjoyed learning a lot about this research. And as I said, we should bring you guys back and continue this discussion, because to me, it’s fascinating, and I’m sure there’s a lot of folks that will be listening that will be very interested in carrying this discussion on further. Thank you.

Jesse Weber
Yeah, it was a pleasure.

Tan Deleon
So with that, I encourage you to subscribe to this podcast on Apple Podcasts, Google Podcasts, or Spotify. And visit the Academy’s website at ctcase.org. That’s C-T-C-A-S-E dot O-R-G to learn more about the guests, read the episode transcript, and access additional resources as well as to sign up for the case bulletin. Again, professors Dan Bolnick and Jesse Webber, I can’t thank you enough for entertaining me today and teaching me all about the Stickleback. And I look forward to hopefully having you on a future podcast.

Daniel Bolnick
That’d be great. It’s been a pleasure.