The Toxopocalypse: Jessica Brinkworth

Dave

00:00:43 It seems like you haven't been that zombified by it, then it seems like [probably] it should,

Athena

00:00:46 Yeah.

Dave

00:00:46 It should make you more pro cat. Right. [Laughter]

Athena

00:00:50 Welcome to the Zombified podcast. Your source for fresh brains. I'm your host Athena Aktipis psychology professor at ASU and chair of the Zombie Apocalypse Medicine Alliance.

Dave

00:01:01 And I'm your cohost, Dave Lundberg-Kenrick, media outreach program manager at ASU and [inhale] brain and I don't know. Maybe sometimes cat enthusiast. So

Athena

00:01:14 Yeah. You have mixed feelings about cats or just- [ Dave interupts "It depends on the cat"] -not a lot of feelings.

Dave

00:01:19 I think. You know. [Athena confirms] Its like some cats I really like. And then some, no, so.

Athena

00:01:23 Yeah.

Dave

00:01:25 Um. [Laughter]

Athena

00:01:26 Well we do love brains.

Dave

00:01:27 We do. Yes.

Athena

00:01:29 Whether they're infected with Toxoplasma gondii or not.

Dave

00:01:31 That's right. Toxo also really loves brains. Right?

Athena

00:01:34 Toxo loves brains.

Dave

00:01:35 It likes taking over brains.

Athena

00:01:38 Especially rodent brains.

Dave

00:01:40 Yeah. So this is really a wild episode because it really changes their behavior in a way that's not in their best interest at all.

Athena

00:01:48 Yeah. This is a, a real life zombification episode, like real biological zombies. Toxoplasma gondii gets into the brains of all sorts of organisms and fucks with them basically. [Dave agrees] And their muscles. Yeah.

Dave

00:02:07 Yeah and so, so we're talking to Jessica Brinkworth.

Athena

00:02:10 Yeah. Our guest is the amazing Jessica Brinkworth, who is a combination of an anthropologist, immunologist and infectious disease expert. So you really couldn't get a better person to talk about Toxoplasma gondii and we hear all about not just how toxo manipulates organisms, but how toxo actually also can manipulate cells.

Dave

00:02:34 Yeah. Um it's really wild.

Athena

00:02:36 It's like zombification all the way down.

Dave

00:02:38 Yeah, it is. It's just, this is another, is another scary episode. I think like this is one where it's kind of gross.

Athena

00:02:47 This is a little gross. Yeah. Cause it involves poop and pee [Laughter] and parasites, so

Dave

00:02:54 [Laughter] Yeah. But it's really interesting. I think so [agreement] hopefully it'll be right up everyone's alley.

Athena

00:03:00 Yeah. Great. Well, let's hear from this week's fresh brain Jessica Brinkworth

Intro

00:03:08 [Psychological by Lemi]

Athena

00:03:43 Jessica. Welcome to Zombified.

Jessica

00:03:45 Thank you.

Athena

00:03:47 Would you introduce yourself in your own words?

Jessica

00:03:50 I am Jessica Brinkworth. I am an assistant professor at the University of Illinois, Urbana-Champaign. And I study the evolution of immune systems.

Athena

00:03:57 Mhm evolution of immune systems. Is that been something you've been interested in for a really long time?

Jessica

00:04:02 Yeah. I think this for me goes back to like childhood.

Athena

00:04:08 Childhood wow.

Dave

00:04:08 Really?

Jessica

00:04:08 Long, intrigued by evolution. Long intrigued by things that make people really sick.

Athena

00:04:14 So we're you like a morbid child.

Jessica

00:04:15 I think a lot of people might've described me that way [Laughter] I like to think of myself as just a very serious child. Yeah. [Athena agrees]

Athena

00:04:23 So, so are there like formative experiences that got you into disease and the immune system and its manifestations?

Jessica

00:04:32 Yeah. There are a couple of things. Um, so first I had untreated asthma most of my very young childhood, [Athena reacts] which was a real pain in the butt, but I was one of maybe two kids at the time of my class that had like serious asthma that was going like largely untreated. So that made me think a lot about, so why no one else in my family has this problem. I had lots of smokers in my extended family. No one else seemed to have this condition. It was like me and a bunch of people who were over the age 80. And that's when I first started thinking a little bit about, okay, so why is this happening? Why do I have so much inflammation? That's how it was always described to me. Uh, and then later in life, when I was in my twenties, I started to lose a large number of relatives to sepsis, [Athena reacts] um, which is pretty common.

Dave

00:05:22 What is sepsis?

Jessica

00:05:22 So sepsis is a very big response to a very substantial infection that kills the host.

Dave

00:05:33 Oh sure, sure.

Jessica

00:05:33 The simplest way I can think of, of putting it, the current definition for it is sort of contextualizes the response as being pathological. But I think that that's debatable.

Athena

00:05:43 So the idea is like you get sick, there's some sort of infection and then your body, your immune system has this response to it. Is that the idea?

Jessica

00:05:53 Right? So, yeah. And that infection can be any number of things. Like you can get sepsis from malaria, you can develop it from the flu. You can develop it from E. coli doesn't [Mhm] it could be any number of things. But the issue is the severity of the infection is such that this enormous immune response is sparked.

Athena

00:06:14 And that's what kills you.

Jessica

00:06:15 Yeah. That's what kills you.

Athena

00:06:17 So it's like your body turning against itself unwittingly because it's like trying to fight something, but.

Jessica

00:06:23 Yeah, kind of, I mean, the way that I sort of like to think of it is that almost all the things that are engaged in sepsis are things that you need [Laughter] to survive an infection. It's just that the infection itself is so severe that the response becomes big and rolling out of control.

Dave

00:06:40 So when they talk about people going into septic shock. Is that?

Jessica

00:06:43 Yeah. So that's when you would have like profound loss of blood pressure and it just comes because things leak out.

Athena

00:06:51 So it's almost like you would die anyway from the infection. And so your body is like putting everything into it, but then, that, putting everything into trying to fight it actually can kill you. Right?

Jessica

00:07:03 Yeah, yeah. [Inaudible mumbles] Anyways, so that was another formmative experience [Laughter] Uh, yeah. And so I guess I was just always intrigued by infectious diseases specifically, and then I ended up in anthropology and that was kind of a bummer because [Laughter] I ended up, I ended up in a, in a program, it was very geared towards socio-cultural anthropology. So asking questions about cultures and, um, and very traditional one at that during my undergraduate. And so I decided to focus on, so anthro also has a human evolution side and I decided, okay, I'm going to do that. And then gradually over time, I realized I could ask these questions about hosts and pathogens and, you know, resolve a lot of my, [Laughter] my questions from childhood and, uh, and still be in anthropology. So that's,

Athena

00:08:00 So that's how you got [Jessica confirms, "how I got there"] to be an anthropologist who is essentially like a evolutionary biologist and an infectious disease expert.

Jessica

00:08:10 Yeah. That's, that's kind of how it happened. I mean, I'd like to say it was more deliberate than it ended up kind of being, because I ended up, started off studying fossils and I took years off to pay off student loans and I landed a government job regulating biologic drugs [Athena reacts] and that, so like vaccines and, uh, and I worked on really out-there, things. Well, out-there things at the time which were gene therapies and phage therapies. Like the use of bacterial viruses to kill severe infections [Dave reacts]. So I wrote policy on background stuff mainly on that. And then I started my PhD and that's when I sort of switched over and I started off in HIV, but then I ended up in a sepsis lab and that's

Dave

00:08:52 So, so now as a professor, [Jessica confirms with a "yes"] tell me what you research. And

Jessica

00:08:59 So right now, uh, most of my questions revolve around severe infection. So most of the questions I ask in one way or another are trying to explain why some species will be made severely ill by a particular pathogen and other species will not. So what are the host factors at play and what are the interactions between the pathogen and the host? And I have a couple of human population questions around that too. So for example, like why do certain people succumb to sepsis more frequently than, than others, but that's.

Dave

00:09:32 Sure.

Jessica

00:09:32 a little less exposed or less explored.

Dave

00:09:34 Okay.

Jessica

00:09:35 For me anyway.

Athena

00:09:36 And maybe this is a good time for us to start talking about Toxoplasma gondii.

Jessica

00:09:43 Yeah.[Laughter]

Athena

00:09:45 So, um, when did you start getting interested in toxo?

Dave

00:09:51 But actually before we get into that, [Jessica agrees] could we just quickly tell us what is [Jessica agrees] Toxoplasma gondii?

Jessica

00:09:58 So Toxoplasma gondii is a parasite, it's a single cellular organism kind of like an amoebae. It looks a little bit like a comma or a really demented piece of candy corn. [Laughter] I like to think about it as like, sort of like a candy corn squished at the, you know, at the bottom. Uh, and it can infect any nucleated cell. So any cell with a nucleus it's it can in fact, and it has very few cell boundaries and very few species boundaries. It tends to be carried by, uh, cats as the, as the definitive host. So it can sexually reproduce in cats, but it can live in any number of other organisms. It just doesn't sexually reproduce they're clonally reproduces in the sort of [mumbles].

Dave

00:10:45 It's the thing like where you're not supposed to, like, if you're pregnant, you're not supposed to scoop cat litter. [Jessica agrees] Cause you don't want to get that. [Jessica agrees] That's toxo.

Jessica

00:10:54 Yeah. It's the other reason why you want to make sure that you wash all your fruits and vegetables very well and that you cook all of your meat for 20 minutes at at least 180 degrees,

Athena

00:11:03 because toxo is in lots of it's mammals,

Jessica

00:11:06 Lots and lots. It's in every, it would be fair to say that it's probably in every warm blooded vertebrate, minimally, and there's lots of evidence now that it's eggs, oocysts, are in all kinds of uh marine life as well.

Athena

00:11:24 So that's kind of mind blowing, right? Like we thought toxo is like, you know, human, cat, rodent. So actually maybe can you give us the human cat rodent story of toxo and then maybe blow, you can blow it up. Blow up the whole world after [Laughter] that, but tell us, okay. Yeah.

Jessica

00:11:42 So Toxoplasma gondii. So the very origins of it are in South America about 2 million years ago. And then it gradually spreads probably over the, um, Siberian land bridge, right. Beringian land bridge, uh, over into the rest of the um world. So Asia, not the rest of world, but Asia, Europe, and Africa.

Athena

00:12:06 And it was in cats.

Jessica

00:12:07 it's in cats during this period. Very likely. And um, so it's.

Athena

00:12:13 and how do we know that? Like.

Jessica

00:12:15 How do we know it's in cats?

Athena

00:12:17 How do we know like that early history? Anything? So how do we know it's started 2 million years ago,

Jessica

00:12:23 There's technically four types of strains.

Athena

00:12:25 Okay.

Jessica

00:12:25 of toxoplasma. Um, and they're named type one, type two, type three, very conveniently. And the rest of them are atypical. These atypical strains appear to be very, very old. And so someone has sat down and collected as many atypical strains as possible and put together with, uh, basically filed geography. So literally the evolutionary relationships of these strains across the geography of the world, by doing various genomic analyses,

Athena

00:12:50 It's like 23 and me for toxoplasma [Jessica agrees] more or less.

Jessica

00:12:53 Okay. [Laughter] So that's its origin in this, but within cats, the relationship is, um, it's a transient infection, meaning it's temporary, a cat gets, it has a fecal oral route in, in cats. Uh, they eat it and they poop it out. It reproduces in the gut and it reproduces sexually. So this is the means by which it can create lots of diversity, right? Lots of genomic diversity, because it's able to mate inside the gut of the cat and the cat poops it out as oocysts. These little eggs are super hardy and live on in the environment for years and can't be bleached and are really okay with big shifts in temperature. So that's the cycle.

Athena

00:13:37 Rodents come in.

Jessica

00:13:38 And rodents come in as an intermediate host. Um, and because they're low to the ground and a frequent prey, animal of cats, there's lots of different means by which they can catch it. Um, and then, so they are able to carry it off. Also, the biggest problem with being in rodents is that they're able to carry it off in all kinds of other locations,

Athena

00:13:57 Are the rodents eating the poop?

Jessica

00:13:59 They can

Athena

00:13:59 or are they just eating the eggs because it's there like around,

Jessica

00:14:03 I mean, anything that, those eggs touch [Athena agrees] hypothetically then carries it. So if they want to go at a snail that has run through a bunch of oocysts, [Athena agrees] there it is like, so it's on the ground and they're able to get it there.

Dave

00:14:17 So, so the cats, so the cats poop out these eggs, right? [Jessica agrees] And then the eggs just go everywhere and then

Athena

00:14:26 Rats consume them somehow.

Dave

00:14:28 The rats eat the eggs. And then, and then when you said, you said that it reproduces sexually in cats. That's, it's not like the cats transmitted sexually by having sex with other cats. Right. It's like inside the cat, the bacteria.

Jessica

00:14:39 Except it can be transmitted sexually. And the only study I've seen that demonstrates that actually isn't in a rat.

Athena

00:14:46 Yeah. So, and it's not a bacterium, right? It's uh.

Jessica

00:14:49 no, it's a, it's like an amoeba.

Dave

00:14:52 Yeah. Okay. So what do you mean by, with like in the cats? It reproduces sexually,

Jessica

00:14:57 So there are sexes of the parasite and you can.

Athena

00:14:59 talk there's male toxo and female toxo.

Jessica

00:15:02 effectively. And so they can mate.

Dave

00:15:04 So does that, that, that allows it to increase its population a lot more

Jessica

00:15:07 Genomic diversity, right. So that, you know, it's the, the upside of that is that there's lots of different types of toxo then in case there's a post that comes up with an adaptation to take one out, there's plenty of other ones that are around. Um,

Athena

00:15:22 but there's also the toxo effects on the rodents right? On the prey?

Jessica

00:15:27 Yeah

Athena

00:15:27 They get into the muscles and the brain.

Jessica

00:15:29 And yeah, so that's true of all intermediate more, uh, all intermediate hosts that are warm blooded. So then, um, intermediate hosts, so anybody who's not a cat, who's a warm blooded, vertebrate eats an oocyst or more, or also a possibility, uh, is that they get it from the tissue in some other form of an animal that was infected. And so a lot of this transmission that I talked about at the beginning of 2 million years worth of moving around, uh, likely also is associated with like carnivorian practices of carnivorian among cats and other animals. Um,

Athena

00:16:07 so you've got prey,

Jessica

00:16:08 so you have prey.

Athena

00:16:09 and they're eating.

Jessica

00:16:12 these oocyst,

Athena

00:16:13 And they're going into the tissues of the prey,

Jessica

00:16:16 right? So same thing comes in, sits in the gut, but the difference between a cat and any one of these other organisms is that, uh, it will breach the gut barrier and an intermediate host. And then it goes off to more or less universally distributes itself across all the tissues of the body, including the central nervous system which it includes the brain.

Dave

00:16:38 Right. So you're saying it breaches the gut barrier in an intermediate hosts or are cats an intermediate hosts?

Jessica

00:16:43 No, there are a definitive host. So it doesn't seem to breach those barriers in a cat, [Dave agrees] but it definitely does it in an intermediate house. So anybody else it'll bust through the gut and come out and.

Athena

00:16:57 It actually does stuff right? It will replicate and express genes and stuff.

Jessica

00:17:02 Right? Yeah. So in the gut, it turns into a version to comes in maybe as an oocyst, or maybe it comes in as part of uh, as a version called rhizoid tha'ts sitting inside like infected tissue. So it comes in like that it converts uh eventually to a tachyzoite, which then it's a Trojan horse style infection. So [Athena agrees] it has to get into another cell. They can't stay outside of cells very long. Um, maybe a couple of minutes. So they, uh, have to get into another cell, which in most cases appears to be an immune cell of a particular origin. So.

Athena

00:17:41 Really?

Jessica

00:17:41 Yeah. And then that cell, as it tra, transfers around and transits around rather than moves around tissues will lodge somewhere. And then that,

Athena

00:17:53 well um,

Jessica

00:17:54 A parasite starts to become a cyst.

Dave

00:17:55 So, so the, the idea, so when you said a Trojan horse style? So that means it's like it hides in another.

Jessica

00:18:01 Yeah. It hides inside another cell. And so that immune cell that it's hiding inside will then take it to some other location. There, this tachyzoite stage converts to what's called a brachyzoid stage. And so that stage is this, um, I mean, it depends on what animal it's in, in a human or in a mouse or a rat, it becomes this very slowly reproducing stage that just sort of sits in a cell, hiding out and reproducing and that hiding out and reproducing very slowly thing, likely stems from host responses, because there are animals where it gets systemically distributed like this, and then it just goes crazy.

Athena

00:18:41 And even some humans will get acute infections with toxo, right?

Jessica

00:18:45 Yeah. So immunocompromised people and, uh, severely immunosuppressed people can develop these large systemic infections. [Athena agrees]

Athena

00:18:52 And now in rodents, when they have a Toxoplasma gondii infection and it's in their tissues and in their brain, and it actually has affects on their behavior. Right?

Jessica

00:19:02 Yeah. So this is really interesting. So in, so on the topic zombies, right,

Athena

00:19:09 Yeah [Athena laughs]

Jessica

00:19:10 it's really, it's really great at doing a couple of different types of zombifications. So the first is that it can zombify cells straight up. It can make whatever cell it's living in, not die.

Dave

00:19:19 Oh really?

Jessica

00:19:19 So dying is a really important anti-microbial mechanism. [Athena agrees] So programs let us, our programmed cell death is really important for controlling infections. And there are plenty of cells that you have whose main jam is if they eat something that's, you know, not supposed to be in your body, they die. And they take that thing that they ate down with them.

Dave

00:19:41 Oh wow

Jessica

00:19:41 So there's, there's lots of, that's a really important mechanism. Toxo is really good at manipulating cells to tell them not to do that.

Dave

00:19:48 Wow

Jessica

00:19:48 Yeah. So that's the first thing.

Athena

00:19:50 Wow

Jessica

00:19:50 And there's other things that they do too.Oh my God! So, I want to tell you about the cell stuff first.

Athena

00:19:53 Yeah. Yeah, go for it. [Jessica laughs]

Jessica

00:19:55 Okay. So there's other things that it'll do too. So when it enters um a cell, so in mice, this entry seems to be very deliberate. In humans, there seems to be a role for humans actually trying to take it out, like eating it. So meaning that the immune cells in humans will try to eat the toxo and then it manipulates the cell that way. So it wants to be detected

Athena

00:20:19 Oh wow.

Jessica

00:20:19 But, in mice, we know that it's very deliberate that the toxo docks on a cell, on a target cell, and then it just pushes its way in. And when it does this, it creates a sliver around itself. And something called a parasitophorous vacuole. That allows it to control what, like intracellular things come to it. And it allows it to sort of cloak itself too at the same time. So that immune factors that are inside the cell, can't see it and can't attack it. But very, very quickly it does get identified and shortly by the host immune system. And then shortly after that, it'll start grabbing like cellular organelles, like mitochondria and endoplastic reticulum and sort of pulling it around it's vacuole.

Athena

00:21:04 so inside the cell the toxo is just like grabbing everything,

Jessica

00:21:09 Yeah. It's recruit. The parasitophorous vacuole starts to recruit these other organelles, which is thought to maybe be a mechanism for cloaking. So on top [Laughter] of this really grabbing stuff from inside the cell and cloaking itself.

Athena

00:21:21 Wow.

Dave

00:21:21 It's like a little disguise

Jessica

00:21:25 Yeah a little disguise. A little groucho marx style thing with the endoplasmicreticulum. 00:21:28 Yeah. So that that's among many other things that it does in the cell. That's one of the things that it does, but within hosts, it does alter behavior. So there's been some question about how it does this, but, um, it's associated with hyperactivity, major alterations in dopamine, um, amounts. Like, so it seems to interfere with the process of recycling dopamine and therefore dopamine levels go way, way up. Uh, it's also associated with like a loss of fear.

Dave

00:22:05 This is at the creature level,

Athena

00:22:07 At the organism level,

Jessica

00:22:08 It's associated with the loss of fear. Um, and that's been measured in a whole bunch of really interesting ways. But, so for example, if you take, there's a, uh, a construct called an Elevated Plus Maze, which I'm sure you guys are in psych, right. So you know more about this than I do.

Athena

00:22:28 It's an experiment, yeah.

Dave

00:22:29 Yeah.

Jessica

00:22:30 So uh if you were to take two large yard sticks and sort of cross them over, so it was an equal cross, and then you elevated that off the ground by a couple of feet, um, and left one uh, yard stick there, and put walls up at the ends of the other yard stick. This would be this elevated maze. So there's a space in the middle. One run, so, one yard stick is totally open and the ends of the other two are closed. So what this does is it provides an environment where mice can run into one another in the center, and it has a totally open area for mice to run across. And then these closed areas where they are more sheltered. Mice and rats, generally, don't like to be out in the open. They like to run across walls, they're prey animals so they don't like to be out like this. In animals that are infected, they spent a lot more time on that open run. Um, and they'll also spend time cuddling cat fur. 'Cuddling' is probably not the best way to describe it, but they'll spend time sitting and hanging out on cat fur when they're infected when they won't otherwise. Uh, and then there's also things.

Athena

00:23:33 Don't they also like have sexual arousal if they smell urine.

Jessica

00:23:35 Yeah so there was a paper that suggested that they also get kind of excited [laughter] by the smell of cat urine. And there has been a ton of experiments on, not a ton, there have been a number of experiments around, like, certain types of cats and other types of carnviors. Like, are they more likely to stay away from say bobcat urine versus like urine from a mink which is another formidable mouse preditor. And, yeah they are more likely to just hang out in the feces of like, obviously there's cats. There's another paper that suggests that they are more into getting it on in the presence of cat urine

Dave

00:24:18 Interesting.

Athena

00:24:18 So it's almost like, you know, it, like the toxo is in there, like puppet mastering the rodent to get it eaten. [Jessica agrees] So that gets in the cat.

Jessica

00:24:28 It's got that feel to it. Right.

Athena

00:24:30 Yeah.

Jessica

00:24:30 That, I mean, and that's a really, really nice narrative and it could very well be true. Uh, but overall that behavior is also something that would not disagree with just enhanced hyperactivity. So that's one thing that's con that's reasonably consistent animals that have this infection and show signs of being super hyperactive.

Athena

00:24:54 Mhm and humans also there's some behavioral effects.

Jessica

00:24:57 Oh my goodness. Yeah. So the stuff that that's been associated with humans reaches from everything to like more likely to start your own business through, to more likely to commit self harm or be in car accidents, to have auditory disturbances, um, to be disengaged if you hear, uh, like strange sounds.

Athena

00:25:16 Huh so does it seem like there's a, there's good evidence that the fear response stuff is different in humans who are infected with toxo and the risk taking.

Jessica

00:25:25 So it's really kinda tough with humans, right?

Athena

00:25:27 Okay.

Jessica

00:25:27 Cause you can't just like infect them. You have to, you have to go sort of posthoc and they have to allow for maybe personality things and stuff too. But in mice, there's definitely evidence that there's alterations in anxiety. So, sometimes it's increased sometimes it's decreased, but there are like just stacks of studies that show alterations in like the level of anxiety that a mouse will show given, um, a degree of toxo infection.

Athena

00:25:54 And what's your view on like the work that has been done on humans? Are there parts of it that you take more seriously than others or things that you think we should be skeptical about?

Jessica

00:26:04 Yeah. So I take the schizophrenia stuff that's been done pretty seriously. So in around 2006, 2007, the first series of papers connecting, uh, toxoplasmosis during pregnancy to, um, diagnosis with schizophrenia in the offspring in adulthood [Dave shows interest] to come out. And I think that there's, I think there's a pretty strong connection there. Also because it's a preventable infection. So one of the reasons why like this should be really important is that no pregnant woman has to have this severe infection. And certainly no offspring has to suffer any downstream consequences from it. Right. It's a preventable condition. [Athena agrees] So, uh, that's such a severe condition to come like to have come from that infection. Right. So that's a few stuff that I think is pretty, I think there's strong evidence for it and I think it's pretty serious. [Athena agrees]

Athena

00:26:57 And then the other papers you were alluding to about,

Jessica

00:27:00 Yeah I don't know how I feel about the entrepreneurial spirit thing [Athena laughs], but I do think that, um, I do think that the, the other ones around major depression and anxiety,

Athena

00:27:11 and so what are those findings?

Jessica

00:27:12 So the findings overall, just as a lump or that there's a uh statistically significant relationship between testing positive for toxoplasma exposure and these conditions. And one of the things we know toxo does is that it messes around with neuroinflammation, so inflammation in, in the central nervous system. And also because it messes around with inflammation outside the central nervous system that appears to affect the central nervous system. And these same alterations are strongly associated with all of these conditions. So I think like to me, that strong.

Athena

00:27:54 Maybe a by-product just of the fact that toxo is messing with the nervous system. Is that kind of the idea?

Jessica

00:28:00 Yeah. Uh, that would, yeah, exactly. Or at least confounded by it.

Dave

00:28:07 So, okay. So essentially just to clarify one thing, so we can have toxo in us and then essentially it's not like a thing, like Ebola where we get it and then we die. Right. So people can live with toxo for years. It sounds.

Jessica

00:28:22 Yeah. I mean, most people have it and it's asymptomatic.

Dave

00:28:26 Okay.

Jessica

00:28:26 At least we think it is.

Athena

00:28:26 and what proportion of people have toxo, like in the U S or in the world, or?

Jessica

00:28:31 So it varies by region.

Athena

00:28:32 Okay.

Jessica

00:28:33 The range is like 30 to 90%, depending on where you are. It's about 30% of the U.S. and roughly 30% worldwide. So it's about 3 billion. People are estimated to have it, but in France, the, uh, the percentage is really high. It's like estimated 90% of the population.

Athena

00:28:52 Wow.

Jessica

00:28:53 That probably comes from dietary habits,

Athena

00:28:56 Eating all that raw meat,

Jessica

00:28:57 eating, yeah. Eating raw and under cooked meats. It's big on organic farms. So if you're not washing fruits and vegetables that are coming from these locations, it's there. It's definitely uh in. So it's been found in like plankton it's, the oocysts itself, themselves. Right. They get washed out to the ocean. So all roads lead to the ocean. And if you have somebody pooping oocystsand I mean specifically like a cat pooping oocysts out in the environment, they will eventually go out somewhere out into marine environments. And we've, it's definitely been found in marine snails. It's been found in all kinds of edible fish in the oocyst form.

Athena

00:29:42 So maybe we can now like go back to this bigger picture of like, you know, where toxo came from, and what it's, you know, prevalence now is across life.

Jessica

00:29:56 Yeah, so I mentioned those four strains, right?

Athena

00:29:59 Yeah.

Jessica

00:29:59 So atypical being this really large set of many different strains that are ancient ancient, and then strains, uh, types one, two and three. And so those types emerge about 10 to 20,000 years ago and likely out of Africa, but it's with the fever of the European favoring of domesticated cats around the 16 hundreds that we started, we think we start to see it spread out. And so, uh, that also coincides with colonization. And so these strains then come back in many, many larger numbers back to the Americas.

Athena

00:30:39 And is that happening sort of through ships and like cats and rodents on ships? What's the mechanism that we think?

Jessica

00:30:47 Yeah. That's exactly the, the mechanism it's coming with animals on ships. So cats and rodents.

Athena

00:30:53 So, um, do I remember correctly that rats and rodents in general, just like were a big problem on ships that are like transporting grain and other foods and that they put cats on there to keep the rodent count under control.

Jessica

00:31:07 Yeah. More or less the relationship, but I mean, so rats are great stowaways. The rats have been everywhere humans have been right. Very intentionally in space, but like, otherwise they've literally been everywhere a human has been, so they're uh they're uh, and house, house mice as well. So they're good human companions, well like not good human companions, but they were companions. So that's how they move around. And they're also, it's also likely moved around by birds as well. So there's all these other factors, right? How do things actually,

Athena

00:31:36 So it's not just mammals.

Jessica

00:31:39 No. Warm blooded vertebrates can move it. Um, but then invertebrates can too. Cause like I said, it shows up in plankton. So one of the ways that it gets into the oceans, some terri-, humans have awful habits [Laughter] and one of them is flushing kitty litter in down the toilet. So if you're flushing, if you have an indoor outdoor cat, so indoor/outdoor cats can pick up and move toxo around. Right. Um, whereas if you have a permanently indoor cat, it may never get a toxoplasma infection. Um, so if you have an indoor/outdoor cat and you're flushing your cat feces down the toilet, you're literally sending these oocyst out to the ocean. And so that's a big problem because there's a number of marine mammals that are highly susceptible to.

Athena

00:32:22 So what happens when marine mammals get toxo or what are the marine mammals that are most susceptible? I mean, I don't even know, like what's the, how big is this problem?

Jessica

00:32:32 It could be substantial. So, um, there's at least eight marine mammal families for it's been identified. It's a leading cause of death for the Californian Sea Otter, which is an endangered marine mammal. It's knocked off a number of Australian. Uh, well, it's knocking off a number of Australian mammals as well. Um, so which is not marine, but.

Athena

00:32:57 So it's causing extinctions..

Jessica

00:32:59 Yeah. It's a driving force behind extinctions. So the other thing is that it does in fact, so we know it infects dolphins and we find it in often in beached dolphins.

Dave

00:33:08 So let's just, I was going to ask, does it like when it's killing them off, cause like, we're saying with us, it tends to be something where we can have it, but we're asymptomatic, but then it can lead to these other things. With these like sea otters and dolphins. Are they more, it is-

Athena

00:33:24 More symptomatic?

Dave

00:33:24 Are they simply dying? Is it changing their behavior?

Jessica

00:33:27 Well, so anybody who has an evolutionary history with cats or the parasite, the way that it tends to manifest is asymp- largely asymptomatic unless you're immunosuppressed or immunocompromised. But, it does do other things. So it can reactivate if you have it and it's been asymptomatic your whole life and then you start to age, um, it can reactivate and cause you know, necrotizing infections, so infections where there's lots of tissue death, uh, and it's also a cause of miscarriage, and... The total impact of it in humans, I don't think it's really, truly appreciated terribly well. I think even in asymp, in like asymptomatic, like in closed infections, it's possibly contributing to other things. But in animals that don't have this evolutionary relationship, then we see necrotizing infections. That's really common.

Athena

00:34:15 And that means that the flesh is dying, basically.

Jessica

00:34:17 Lots and lots of tissue death. Yeah. And it's very speedy. So for example, in a number of South American primates in Malagasy primates or primates from Madagascar who have limited exposure to these strains of toxoplasma. Meaning the type one, two and three.Until very recently we see these speedy deaths where it's system like this parasite of system-wide and there's lots of inflammation and lots and lots of tissue death. Uh, and that's also what we kind of see in these marine mammals as well. But again like this, this is all stuff that's also happening technically below the surface. Right. It's really hard to get.

Athena

00:34:58 Literally below the surface.

Jessica

00:34:58 It's really hard to get a good grasp on what's happening in oceans. Right.

Athena

00:35:01 But you're seeing beached dolphins and other animals.

Jessica

00:35:05 Yeah. So it's implicated also in, in whales and then uh there's even.

Athena

00:35:10 So beached whales have toxo often?

Jessica

00:35:12 Yeah. It has been found in beach whales. So, and then there's also odd migration. So we were just talking about this like a couple of days ago, but there's odd migratory patterns for North American Deer, for example, that have been associated with toxo infection. So,

Athena

00:35:27 So, like what? What are they doing?

Jessica

00:35:29 They just don't go to where people expect them to be. They show like behavioral abnormalities. [Athena agrees]

Dave

00:35:35 Interesting. And the beach whales, do they think they're like beaching themselves because of, or is it just they're dying and they're getting washed up.

Jessica

00:35:42 It's sort of hard to tell, right? Because you can, it's not like anyone's going out and sampling [Laughter] whales that are just perfectly healthy and fine. If we find dead dolphins in the beach, we look at them and they have, you know, not me personally, but like very examined and it's reported when they do and they don't have toxo and it does come up. Um, so the implication is that that might be playing a role in why they're, they're beaching themselves, or beaching themselves in groups, which is something that, dolphins sometimes do when they get sick [Dave expresses amazement]. But they also hunt by throwing themselves up on the beach. So there's lots of like things that could be at play there, but the toxo is present, which suggests the possibility of abnormal behaviors, given all the other stuff that we see in all these other animals.

Dave

00:36:25 Interesting.

Athena

00:36:26 So, just how prevalent is toxo? Like how is it more or, is like toxo more successful than like cockroaches or like, is there a way to like kind of quantify like just how successful toxo is?

Jessica

00:36:38 I mean, I think it could I mean, I think it could be as successful as the cockroach or more so because it's literally everywhere. It has been found everywhere and it lives for a really long time in the environment in this sort of egg-like stage. And a cat can shed, like an infected cat can shed like a hundred million of these oocysts. [Dave reacts] So right. It's really difficult to get rid of. It's like bleach resistant. It is tough to get rid of this stuff. And it's in the entire food chain as far as we can tell, like it shows up in our food chain. So meaning like in our commercialized food chain, it shows up in animals with, you know, relative, you know, high frequency,

Athena

00:37:20 Mhm, but then you said it's also an algae.

Jessica

00:37:22 Oh my goodness. It's in plankton. And yes, this is really upsetting. We should all be deeply upset by this! In oocyst form... So since all things are washing out to the ocean, the long-held model has been that toxoplasma, uh, infects, warm blooded, veribrates and everything else that's just out in the environment, you guys don't worry about it. Not don't worry about it, but like that's where it is. Uh, but it is in plankton and it shows up in snails and it shows up in things where, you know, pinnipeds like seals and animals like that who have limited contact with this thing, otherwise. It's the of foods that they would say, like eat various little fish and things like that. So if it's in plankton, it's all, it's almost all the way up the marine food chain. And that should be really upsetting.

Athena

00:38:17 It's not just in our food supply. It's in food supply of,

Jessica

00:38:19 No, it's like everybody's food supply. Right. Which is where, like, which is where things diverge for cockroaches and toxo, I would say toxo is was way more successful than yeah, than cockroaches.

Dave

00:38:31 Interesting. So, okay. So then is it in, but is it in fish and things like that?

Jessica

00:38:37 In oocyst form. So if they eat it and then it hangs out and the interesting thing about it is that the last couple of papers I've read about this indicated that it hangs out kind of tissue wide, but in oocysts. So for whatever reason, it's not leaving, you know, fish body.

Dave

00:38:53 So when it's oocyst form, you said that's like, it's like a little egg [Jessica agrees] so then how does it know? Okay, now is the time to hatch. Like, you know what I mean? Like.

Jessica

00:39:02 Yeah, that I don't know [Jessica laughs] That I can fairly say, I don't know, I don't work with it in oocyst form. There's a limited number of labs that have been able to do that. I work with it in tachyzoite form where it needs to be inside of a cell.

Athena

00:39:17 So what are the, like, I'm just fascinated by these there's like three different forms or more ?

Jessica

00:39:24 Of uh, you mean like the-

Athena

00:39:26 The toxo, no

Dave

00:39:28 The oocyst form, the tachyzoite form,

Jessica

00:39:30 And the brachyzoid.

Athena

00:39:31 Yeah. Like if you had to like, you know, describe those forms like as like different kinds of monsters or something. [Laughter] like what kind of monsters would they be?

Jessica

00:39:41 Okay. Oh my goodness. So what kind of monster would they be? So, um, so oocysts, like in Gremlins. You know the movie Gremlins.

Dave

00:39:54 Yeah.

Athena

00:39:54 Yeah

Jessica

00:39:54 Gremlins great. So I can't remember the name of the friendly gremlin.

Dave

00:39:58 Uh Gizmo.

Jessica

00:39:59 Don't feed him after midnight. You know how they feed him after midnight, he becomes like the spiky gremlin for like three seconds and then he lays a bunch of eggs. So your oocysts are your eggs [Laughter] your tachyzoites are you gremlins. And hypothetically your bradyzoite is, I'm sorry, Gizmo?

Dave

00:40:17 Gizmo is the friendly.

Jessica

00:40:18 It's just a friendly looking guy who's not doing very much, but has all this potential, right? TBradyzoites aren't friendly per se, but they have potential to like, [phew], blow up

Dave

00:40:28 So wait, so to go back to the, [Laughter] to go back to the actual toxo. So [Laughter] it's in an egg, right. And then that's the oocyst form.

Jessica

00:40:37 Yeah.

Dave

00:40:37 Is that right? And then it's in the part where it's got to hide in the cell and that is which form?

Jessica

00:40:46 Tachyzoite

Athena

00:40:46 And that's the Gizmo?

Dave

00:40:46 that Gizmo where it's kind of cute and it's not,

Jessica

00:40:48 No,

Athena

00:40:48 No, that's not.

Jessica

00:40:49 I'm saying that that's your gremlin.

Athena

00:40:52 That's the Gremlin

Dave

00:40:52 That's the gremlin oh okay

Jessica

00:40:52 That's the, granted, you know, in Trojan- I said all the gremlins were in the Trojan horse.

Dave

00:40:57 Was so cute where you're sort of like, Oh, it looks cute. And it hasn't quite

Jessica

00:41:00 No, no, no. I was thinking more about like, cause I guess it depends on how strongly you feel about Gizmo as a cute character. To me [Athena laughs] as a child watching that movie, I was like, he's up to no good.

Dave

00:41:12 Sure

Jessica

00:41:12 Like he looks nice, [Laughter] but this idots gonna feed him. Cause otherwise there's not going to be a movie. [inaudible]. [Everyone laughs]

Dave

00:41:23 I mean, I do want to say, in Gizmos defense, I don't think they ever fed Gizmo after midnight. I think they got Gizmo wet

Jessica

00:41:30 Oh is that the other one? [Dave agrees] Awww. And that's when he made a whole bunch of little ones. Is that how it worked? Yeah. Okay.

Dave

00:41:36 So let's, let's not get too bad of a name. He was all right. [Jessica agrees]

Jessica

00:41:42 This might not be the best analogy.[Laughter]

Dave

00:41:45 There's another movie that I think is very similar. Alien, right? The creature from Alien starts in an egg, then it goes inside a person [Athena and Jessica consider] and then it bursts out of the person and it runs around sort of wild doing, whatever it likes. Is that?

Jessica

00:41:59 Except that, I guess it depends on where you are in the cycle cause in the bradyzoite stage in intermediate hosts with an evolutionary history with the parasite, it kind of sits still, not, really slowly replicating.

Dave

00:42:14 Inside a cell, right?

Jessica

00:42:17 Inside a cell. Now it's doing lots of stuff. Like it's able to.

Athena

00:42:20 Expressing genes, and changing the cell, and,

Jessica

00:42:22 it's able to alter any number of things. Yeah. And it's potentially interfering with neurotransmitters and there's lots of stuff that it's doing, but it's slowly reproducing. So I would say that like your alien stage is... So your oocyst is when it's in the body, your tachyzoite is when it's grown... Yeah, I guess if like, rather than taking on Sigourney Weaver, it kind of just [Laughter] sat down on a couch and like had a beer, that would be the sort of. So it's causing havoc by the mere fact that it's like, you know, threatening and it's flipping the television channels and it's changing the environment around it. Right. Drinking all the beer or whatever else. But that, that would be the bradyzoite stage.

Dave

00:43:07 So it's like Alf. Right.

Jessica

00:43:13 [Everyone laughs] That's not to say that it's not serious. Right? Cause it could reactivate if it wanted to get up off the couch and just like, I can't remember if alien lays eggs, do they lay eggs?

Dave

00:43:22 Oh the, in the movie Alien.

Jessica

00:43:24 Yeah they do right

Dave

00:43:24 They find them, their eggs. And then the thing comes out and goes on their face.

Jessica

00:43:28 Right

Dave

00:43:28 and then they think it's cool for awhile where they're like "Oh, that was weird when it was on your face". And then it bursts out.

Jessica

00:43:34 [Laughter] Poor John Hurt right? Like no one around him has any sense of urgency. Wasn't that not the strangest thing?

Dave

00:43:41 Let's not take care of that. Let's all go have dinner. And then is bursts out and then their like uh oh. [Laughter]

Jessica

00:43:46 Yeah. I forgot about that. But there's the, what, the second is the one where she has little kid friend. Right?

Dave

00:43:51 Yeah, yeah, exactly

Jessica

00:43:51 And she does the number one shot in that movie. She kind of cocks her head to the side before she, but there's a scene before she blows up the alien where they're literally among all these eggs. Right? That's the,

Dave

00:44:03 Oh, like when they're walking through and there's all the people like they've got all the people, [Jessica agrees] it's like sort of stuck to the walls.

Jessica

00:44:09 I have very vague memories of those first two movies.

Dave

00:44:13 Okay.

Jessica

00:44:14 Yeah. In any case, all that to say, [Dave laughs] uh, bradyzoite stage is still very threatening. Cause if you reactivate and that's the thing that's causing all these other disturbances. So it's

Dave

00:44:27 So take, take away movie references for a second. I'm still a little unclear on the, tachyzoites versus the bradyzoite forms, which is, which?

Jessica

00:44:36 So the tachyzoites is inside your Trojan horse cell. It's the hatched version [Dave confirms] of the oocysts. So the oocysts becomes the tachyzoite. And then the tachyzoite goes into one of a number of different immune cells after it crosses, you think this is how it works any way after it crosses the gut barrier. And then that immune cell drops it off in some other location. And the bradyzoite is this slow reproducing version that lives inside a cyst that it makes inside of the cell so,

Dave

00:45:11 Its inside of a different cell, now?

Jessica

00:45:13 It can be. Yeah. So the way that it works, say, in brain infection is that it comes in with this, through this Trojan Horse who drops it off, presumably, and or it ly, sorry lysis out of it. And the first set of cells that.

Dave

00:45:31 Like what do you mean by lysis out?

Jessica

00:45:31 Meaning it breaks, open, it, breaks the cell, sorry. It breaks the cell open and busts out. And then it's got a,

Athena

00:45:36 That's the alien moment.

Jessica

00:45:37 That's your alien John Hurt. [Laughter] And then it's got a couple of minutes to find another cell. What it tends to do at that point is it it'll affect one of two types. So astrocytes, which are the main brain cell you've got. And that could be just like, because there's lots of them. And then the other kind is an immune cell. That's in the brain called the microglia. And so it'll stay in those for a couple of days. And then a few days out from there, it starts to show up in neurons. And the reason why that's important is that neurons are missing a whole bunch of the anti-microbial tactics that just about every other cell has.

Athena

00:46:13 Oh really?

Jessica

00:46:13 Yeah. So for example,

Athena

00:46:16 Sorry but, what the fuck? [Laughter] Like why don't neurons have the same, anti-microbial,

Jessica

00:46:21 Yeah, there's a whole bunch of stuff up there that's really different. Um, so.

Athena

00:46:25 cause they're just like, you know, Oh, the rest of the body's got me covered with this blood brain barrier thing, [Jessica: Right] I don't have to invest in antimicrobials.

Jessica

00:46:33 The cheap answer is that, uh, any out of control immune response would be really, really bad if it happened in the neurons.

Athena

00:46:45 Oh so the costs are high?

Jessica

00:46:46 So there are certain things that other cells will employ where like, it's fine if there's bystander damage. In the brain bystander damage, I think the notion is that like the, the [Athena agrees] hypothesis is that it needs to be limited. So certain things. So for example, cells will make nitric oxide and nitric oxide, super reactive, just busts up pathogens and neurons can't do that. And so, once inside of toxo just kind of lives happily in a neuron.

Athena

00:47:14 Hmm because the brain is like, we don't want to deal with the collateral damage of trying to get rid of something dangerous. So we're just gonna.

Jessica

00:47:22 Right. So there's, they can't, there's a couple of things about neurons that are really different from other cells. The first this, that, um, so other cells that are up there that the microglia, which are an immune cells can do something called antigen prescence. So they can, if they're infected or they chop something, they eat something, they can chop it up and they can throw a piece of it up on their cell membrane and send out signals to nearby immune cells. Come and take a look at this. Do you recognize it? Let's kill it. So that's something that they can do. [Athena agrees] Uh, astrocytes have some other capabilities that are really important anti-microbially too, but neurons don't do any of that stuff. So they can't present. So once something is in there, they can't send out signals to say, guys, there's a problem.

Dave

00:48:07 Oh wow.

Jessica

00:48:07 they ask. And they don't and they can't kill it. Well, they can't send up that kind of a signal. And generally speaking, they kind of just sit there. And one of the things that toxo does really well in neurons is it tells them don't die. [Athena agrees] So then they just live on zombied, like,

Athena

00:48:22 Wow. So they're literally, zombifying [Jessica: neurons] not just the brain, but actually the cells that are [Jessica agrees] transmitting the neural signals in the brain.

Jessica

00:48:31 Yeah. And that might be more important than the presence of cysts overall. So like in, in the brain specifically, because there's no real strong correlation between cysts in the brain and any, one of the things that we just talked about in terms of behavioral issues.

Athena

00:48:48 Oh really?

Jessica

00:48:48 Yeah. In fact, when they have, when they infect mice with strains that can't make cysts, they still get these same behavioral changes. So what they're doing out here outside of the brain seems to matter just as much,

Athena

00:49:02 Maybe those cysts are just like little nests for the, you know, what is it at that point, the brachyzoid?.

Jessica

00:49:08 Oh the bradyzoite?

Athena

00:49:08 Yeah. [Laughter] And then they like send them out and they get in the neurons.

Jessica

00:49:14 I mean, they, yeah, they could, once they're in the neuron, they're kind of happy campers compared to all other cell types that are kind of kicking around. Um,

Athena

00:49:23 They got this nest and they're like, I really hope that my, you know, brachyzoite offspring go off and find a good neuron and have a good life. [Jessica laughs]

Jessica

00:49:31 Let's get them out. Yeah, exactly. But what's more likely is that they're causing low-level inflammation out and there's this like out here and that that's altering stuff.

Athena

00:49:39 Out here?

Jessica

00:49:40 Out here. Here in the rest of the body, sorry, versus up here, which I'm clearly gesticulating. [Athena laughs] To where no one can see, [laughter] sorry uh, in the, in the brain. So, um, so there was an interesting, uh, paper that came out in, I want to say, end of April/May out of Bill Sullivan, Jr's lab, the author on it's a young doctoral student, Jennifer Martynowiczit. Um, and this really I'm emphasizing that because this is really exceptional work for, for a doctoral student. So this is really, really cool. So they took two different strains of mice, uh, one which tends to have this sort of like low level inflammatory response to infections. It responds to infections by let's heal all the wounds. You guys, it's kind of sort of response that it has. It's called Balb-c mouse and then.

Athena

00:50:31 A bob? Bob-z?

Jessica

00:50:31 Bulb, B-A-L-B-C [Athena: Okay] little white mice, a little pink eyes. So a very common lab strain. So if you see pictures of white rice, odds are, that's what it is. And then another one, which is also a very common lab strain called B6 mouse, whose approach is just to blaze everything with a super proinflammatory response. If they get infected, they mount these massive inflammatory responses to them.

Athena

00:50:58 Okay

Jessica

00:50:58 To the pathogen. And so you're a little itty-bittyblack mice, black eyes kind of aggressive. Um, at least in my experience, cause I've been bitten by them before and in any case. [Laughter] So what they did was they infected them with toxo. And then so many weeks they gave them this drug that's typically used to help with hypertension called Klonopins. And in these bald mice these little white mice, they saw an 80% reduction in cysts. So that's.

Athena

00:51:33 Okay

Jessica

00:51:33 first time that that's been demonstrated to work typically.

Athena

00:51:40 Why the hypertension meds?

Jessica

00:51:40 So there's a relationship between that drug and the altering of, um, a couple of important steps in cell signaling between the phos, [Athena: So, its not] the phosphorylation but it, it messes around with some.

Athena

00:51:56 hypertension. It's just that, that mechanism, that particular action interferes with toxo.

Jessica

00:52:02 Exactly. Right. So, uh anyway, so they thought, well, let's give this a shot. [Athena agrees] And so they saw an 80% reduction in tissue cysts in these little white mice and,

Athena

00:52:12 That, that don't have a crazy immune response.

Jessica

00:52:14 They don't have this outsized immune response. And so, and they saw a loss of hyperactivity and they saw a drop in neuro inflammation and they thought this is awesome! So then Jennifer took, uh, these B6 mice,

Athena

00:52:28 The little black ones. [Jessica agrees] Yeah.

Jessica

00:52:31 Now infected at so many weeks gave them the drug. And what happened in these high, in these like pro-inflammatory mice was that the cysts number went up.

Athena

00:52:42 What??

Jessica

00:52:43 Yeah it significantly, went up. So they had way more cysts afterwards, but loss of hyperactivity, loss of neuroinflammation.

Athena

00:52:51 Oh.

Jessica

00:52:52 Yeah. Weird. Right?

Athena

00:52:55 Yeah.

Jessica

00:52:55 So the take home [Athena agrees] is that, uh, A) it's possibly a drug that could be used to clear chronic infection maybe, which currently there's no drug that can do that. [Athena agrees] Uh, but it's going to depend on host factors like whether, what kind of, yeah.

Athena

00:53:16 Well, I don't know, to me, it really seems like, you know, the cyst might just be a source for the agents that are then like going out and doing the action and those agents that go out and do the action. They might be a little more vulnerable to [Jessica agrees] your host immune system or, you know, other antimicrobial things, but maybe the nests are like fortresses and like.

Jessica

00:53:41 Yeah, yeah, yeah, exactly. What I thought was sort of strange about it was that in this B6 mouse, right. Where they still have huge number of cysts, we see the loss of all this behaviors.

Athena

00:53:50 Right So maybe.

Jessica

00:53:51 the connection between like the number of cysts that you have is maybe like, maybe that's not relevant. Maybe we need a couple because yeah. Maybe it's an issue of like who's out and whether things are being reactivated at this little level, I'm not sure that anybody's looked at that.

Athena

00:54:03 I wonder if maybe they even are like, is it possible for them to like reaggregate, like for them to be out there and then like come together to like protect?

Jessica

00:54:14 Oh gosh, wouldn't it be? I mean, I guess possibly, but the way that I understand, just based on my own cellular infections, the way I understand it is that they find something, they go in, they go, [Athena agrees] they can't be out for very long. It's a couple of minutes. So, um,

Athena

00:54:29 well, either way, it's interesting.

Jessica

00:54:30 Right? It's kind of neat. So possible treatment option and it kind of does away with this notion that like cysts as a structure are hyper important for the cysts.

Athena

00:54:40 they might just be another intermediary.

Jessica

00:54:42 Right? Exactly. And there's another paper that came out, I want to say, last year or the year before that looked at strains, uh, and this new phobia. So the loss of, this fear loss in mice and all the other things that we were talking about [Athena agrees] productivity and that kind of thing, and they found these changes to be permanent. So if you clear them and you gave them an acute infection. So you can clear infections in the first couple of days by giving any number of drugs, if you cleared them, if that infection didn't matter, the behavioral changes stayed.

Athena

00:55:18 Really.

Jessica

00:55:18 Yeah. So it's, uh, in that paper, it suggests, and I think the other paper suggest this too, that there's just some sort of fundamental disturbance in inflammatory milu, like the inflammatory milu [Athena agrees] you that then is potentially permanently altered and so perpetuating,

Athena

00:55:33 So they like hijack something and then recalibrate it and then we're just stuck with it.

Jessica

00:55:37 and that's it. Yeah. And that can be strain specific too, but yeah.

Dave

00:55:41 Sort of a question going to sort of the behavior change and things like that. Right. Cause we've talked about how with mice, it sort of makes them less afraid of cats. These are things that seem like they would help toxo get passed along. Does it, does it seem like they're deliberately changing the behavior of the host?

Athena

00:56:03 When you say deliberately don't actually mean like consciously or intentionally just that they made it [Jessica: evolved] have evolved.

Dave

00:56:09 Yeah. Like [Jessica: that its been official], are they programmed to specifically seek out certain cells or they programmed, you know what I mean? Like to, to somehow, or is it just,

Jessica

00:56:18 They don't favor, Yeah. They don't favor any particular cell type and there's no area in brain that they typically aggregate. It's completely random as far as anyone can tell. So they don't just like, hang out in the hippocampus. They don't hang out, like in the cerebellum specifically, they hang out anywhere. Um, but that said, like I said, it doesn't seem to matter whether the cysts are in the brain or not, it can still lead to these behavioral changes. So in so far that it's an adaptation that like benefits the sexual reproduction or reproduction and ensures like continual, um, diversity in the genome. Yeah. I mean that, I think that that's a circle that probably really does exist. I think it is beneficial, but I think it's also beneficial generally. Like if you're a mouse, not just cats are gonna eat you. Right. [Dave agrees] And so, you know, if you're hanging out in bradyzoite form somewhere in the tissue of that mouse, you're still going to, as a toxo, be able to enter an intermediate host gut and move on into their tissues.

Athena

00:57:23 Yeah. So, I mean, I think that brings up just as much bigger picture question, which is so my sense from like my surface reading of the toxo literature is that the kind of conventional wisdom about it or thinking is, you know, the, the cat rodent, um, you know, life cycle is like the one that is like, you know, how like toxo evolved to have the brain manipulating effects that it does and everything else, all the other effects on warm blooded vertebrates, including us, those are all just byproducts of the fact that toxo evolved this thing with, you know, rodents and yeah. [Jessica agrees] Do you buy that or do you think that there's more?

Jessica

00:58:13 That more, I think that it might be more complicated than that. I think that's definitely a side of it. I think it might be more complicated, but one of the reasons why that's pointed to repeatedly as the relationship is because mice have a ton of adaptations that no one else has to it. [Athena agrees] And they're clearly like a frequent target of this infection. So, I mean, so for example, um, there's a type of enzyme that we, uh, that mammals have called an immune related gene. I'm not going to give you the whole name cause it's enormous, but, uh, immune related GPT are GTPA, uh, dang it GTPase. So this is an enzyme that breaks up guanosine triphosphate. So that's a nucleotide. Um, there's a bunch of reasons why this is important, but specifically in immune function, it, uh, is engaged in targeting a number of pathogens. Toxo, one of them. And it can in a mouse anyway, squeeze toxo out of it's vacuole and shove it out into the cytoplasm of a cell where then the cytoplasm vectors kill it. So, and then the cell will undergo this sort of programmed cell death, and it's free to die and no longer be zombified, but the uh [Laughter] and so mice, and it varies by lab strain.

And it's becoming very obvious that wild mice vary in the number of these genes that they have to have at least 21 in some cases like the B6, mice, they have like 23 of these things and humans only have one. And so they only have one gene for this and it's largely expressed in the testes. So there's this, and they do other things, but this is something that's specifically targets toxo. So is there stuff that heres with it that looks an awful lot like that, like, but the way that.

Athena

01:00:01 Yeah that there's been a history of selection on the counter adaptation.

Jessica

01:00:05 Right that this cycle of cat, literally cat and mouse [Laughter]

Athena

01:00:11 The whole cat and mouse game

Jessica

01:00:11 Exactly, its very real and exists, I guess from my perspective, is that I think that it might also be additionally more complex than that because it's always had these other intermediate hosts potentially as well.

Athena

01:00:21 Yeah.

Jessica

01:00:21 So yeah, but mice being a target of cats and mice being low to the ground and mice liking to forage and get into a dark little spaces, um, cats do things like they like to poop in the shade and stuff. Like I don't even like cats, so it's just weird that I know this, but yeah, they like to do things like they'll poop in the shade and they'll bury their poop. And these are like dark little corners where rodents like to be. Right. So there's this closeness between the environmental connection and then also the fact that their cat prey. So there's yeah.

Athena

01:00:51 Interesting. Well, so when we kind of get towards the end of the episode, we like to ask this question about, um, well, in this case, the toxapocalypse. [Everyone laughs] So, so, you know, if we like look at what toxo can do and this sort of like multilevel zombification that it can do to like cells and to organisms and different organisms. Um, if we kind of follow this to its logical conclusion, either like you enhance toxo's capabilities a little bit, or you just say, okay, well, given what we know about what toxo can do now, like where's this going?

Jessica

01:01:34 Oh my God, It's like the perfect parasite you keep, like, why would you mess with it? [Laughter] It knows no cell boundaries. It apparently knows very few species boundaries. So, uh, where is it going? So we're in the middle of it right now. I mean, we do so many bad things, humans and one of [Athena laughs] environmentally speaking, one of the terrible things that we've done is like domesticated cats and worse we've domesticated cats. And we brought them up to other places. And even worse than that, we have outdoor cats and we have tons of ferral cats. Right.

Athena

01:02:05 So I just have to ask like, do you hate cats? [Laughter] Are you a cat hater?

Jessica

01:02:12 So like, I can objectively look at a cat and say like, Oh, that's a pretty animal. Or, you know, like kittens look cute and everything.

Athena

01:02:20 Do you like to pet them.

Jessica

01:02:21 No. I don't like to touch them [Athena laughs], they make me sneeze! [inaudible]

Dave

01:02:26 Do you think if you had toxo you'd be more likely to want to pet them,

Jessica

01:02:28 Oh, I mean,

Athena

01:02:29 Do you have toxo? Do you know?

Jessica

01:02:30 I've never tested myself for it, but,

Athena

01:02:32 Are you afraid to find out?

Jessica

01:02:33 I really don't want to find out [Laughter] Yeah, it's true. It's like, don't ask questions. You don't want the answers to. [Laughter] Um, yeah but I don't and this stems from a formative childhood experience of having [Laughter], a sandbox that the cat next door used to come over and poop in [Dave: Ew]and that's it. So this one big litter box,

Athena

01:02:54 This really is the full explanation for why you are, where you are today. [Laughter]

Jessica

01:02:59 Kind of in a moment of realizing there is cat poop in my, my sandbox, for sure. Yeah I mean so I appreciate,

Athena

01:03:05 And so now you have like a career where there's always cat poop in your sandbox. Like you're always studying.

Jessica

01:03:11 I will always do, I'll always be thinking about the cat poop, that's true. Yeah. So, no, I appreciate that other people like them. And I have dear friends that I love dearly that love them.

Athena

01:03:22 Some of your best friends, love cats.

Jessica

01:03:23 Some of my best friends love cats, thats true. I have friends, uh, uh, you give a shout out to Missy Johnson in NYC who goes out and like in the dark of the night. So her spare time activity is going out to like junk yards and stuff in New York and pulling feral cats out and treating them and sterilizing them and sending them back out to be feral cats, uh, which involves lots of cat wrestling and lots of getting up into other people's cars and like, [Everyone laughs] right. She's she, and she loves cats. I just, you know, I appreciate, and I, I love Missy, so this is fine, but I just can't get into it. That's it? [Dave and Athena laugh] That work is very admirable and I'm very happy for anyone to go and do that. [Laughter] So,

Athena

01:04:06 yeah. All right. So the Toxopocalypse, so where like, you know, if, if you just like give toxo a little like superhero bump, so like the things that it can do, you just like, let it, like you give it a little more power, so it can do that a little more, a little bit more. Where, where are we?

Jessica

01:04:24 So, um, so there is one study. Actually, I should have mentioned this earlier. There's one study that suggests that it might lead to cognitive improvement in humans. [Laughter]

Dave

01:04:35 Really?!

Jessica

01:04:37 Now I'm just thinking of other bad movies. I've never seen that dude from that movie with lady Gaga, but in reality, it's like, right.

Dave

01:04:46 Oh sure sure

Jessica

01:04:46 Okay. What's his name? Brett,

Dave

01:04:49 Yeah brad, Bradley Cooper.

Jessica

01:04:49 So he's in that movie where he was like, my mind is so amazing movie,

Dave

01:04:51 Limitless, maybe, I think?

Jessica

01:04:51 That's it? Okay. So, I mean, if you were going to boost it, then I guess,

Athena

01:04:58 Wait so the toxopocalypse is actually us getting smarter. I thought it was like ecological destruction.

Jessica

01:05:03 Yeah. No, the toxopocolypse is definitely ecologically destructive but I was just saying if there was a benefit, if we're going to deduce it, [Laughter] so I was trying to get it positive spin. Total world annihilation [Laughter]

Dave

01:05:13 Ecological destruction and we're smart and we're starting our own businesses. Right? So,

Jessica

01:05:18 Yeah we're starting our own businesses. Exactly. Lot's of entrepreneurial-ship

Athena

01:05:19 Lots of great cat videos on the internet

Jessica

01:05:21 That's true. Yeah. True. Right. Yeah. There you go. Late fees, capitalism, [Laughter]

Dave

01:05:29 So, like, what can we do to prevent this very bizarre toxopocalypse if we want to? [Laughter]

Jessica

01:05:36 If we want to, if there's an incentive to do something about it, stop fricking flushing your cat feces down the toilet. [Laughter] So if I, if I were going to sit back and do things, okay. So the very first thing I would say is that, all right. So for human infections, wash fruit and vegetables, you want to make sure you have access to clean water and make sure that everybody has access to clean water.

Athena

01:05:55 And when you say wash, what do you mean?

Jessica

01:05:57 Like thoroughly wash,

Athena

01:06:01 With a cleaner that has detergent? or just with water?

Jessica

01:06:03 Yeah. I don't. So [Athena laughs] at the Duke Lemur Center where they used to have these outbreaks, um, not infrequently in the early 1990s, they started bleaching the food. So they would put it through the light bleach wash and then they stopped. So I'm not suggesting you bleach your food. There's lots of downsides to bleaching your food [Dave agrees] , but, uh, but a thorough. So like this is gonna, I'm going to reveal myself as being kind of eccentric now. [Athena laughs] I, I wash,

Athena

01:06:38 Don't worry I think that we're already established this [Laughter].

Jessica

01:06:38 That I'm eccentric.

Dave

01:06:38 I can't wait to hear about this formative childhood experience.

Jessica

01:06:45 [Laughter] I know! All these people dying and this cat pooped in my sandbox. [Laugher] Um, right. So, uh, okay. What was I [Laughter] I forgot what,

Dave

01:06:57 You're washing food.

Athena

01:06:57 How do you wash your food?

Jessica

01:06:57 Yes. Okay. So I like I'll wash my fruits and vegetables with dish soap and things. It's a little bit harder to do this with leafy greens, but I'll do that. Yeah.

Dave

01:07:05 That doesn't taste kind of gross.

Jessica

01:07:07 Well, dish soap is designed to be rinsed off. Right? It's the flavor is not there. You might smell rosey lemons or whatever [Laughter] the smell it, but like when you rinse the plate, it's not there anymore.

Dave

01:07:18 Really?

Jessica

01:07:18 It's really easy. So I'll do that. I'm not sure how effective it is, but it makes me feel better, which is a reason why I do it. I don't do that with leafy greens. I kind of just give them a good, thorough repeated washing, [Dave agrees] but most people are probably also picking it up in meat. Right. So, um, so I don't, so don't eat under cooked meat, 180 degrees for 20 minutes.

Athena

01:07:38 Is pork, really a particularly bad one for toxo or -- ?

Jessica

01:07:43 So my understanding, you said organic farms really struggle with this and most of the research has been done in sheep. And one of the reasons for that is that it causes it's taste. It really nails the sheep industry because it causes a lot of spontaneous abortion. So it has this big economic effect. So in that you don't have as many sheep because you have toxo on these farms. So I'm unclear about pork, but I would say generally speaking, you don't want it to be pink. And I know that that's a bummer, [Athena agrees] but that's the state of affairs. And then that would also apply to sushi. So I actually don't eat fish sushi anymore for over fishing reasons. But, um, but a really good reason not to is that it very likely also has this and also sushi scams, man, lots of counterfeit sushi out there.

Athena

01:08:34 Is there?

Jessica

01:08:34 Yeah. So, uh, [Laughter], as a side I note for a your show notes. Uh, yes. So, um, there are different, so there's cheaper fish in some cases, fish that actually aren't great to eat at all. They get swapped in and out for common types because who knows its actually, kind of hard to find.

Dave

01:08:49 Really?

Jessica

01:08:50 So there's whelming too many, shortages and things at times. Um, and so these other questionable fish get into the mix,

Athena

01:08:58 You know, chopped up in your spicy tuna roll might not be tuna,

Jessica

01:09:02 Yeah especially if you're eating it like that. Right. Where you get, don't get visual ID on it. Um, so yeah. Um, yellow tail and, uh, red snapper often get like switched out for a fish. I can't remember the name of it, but it gives you the runs. There's uh, [Athena: Ew] yes. It makes people really ill. Uh, there's a study that came out of the University Toronto last year where the, it was a class assignment. The teacher just told everyone to go out to a different sushi restaurant, bring home one piece of sushi and then they would do like genetic testing [Athena laughs] to see if it lines up. None of the fish were identified as the fish that they were served as being. [Athena: What!] Yeah. So all that aside from a toxo perspective, they can carry oocysts. So that's another reason that.

Athena

01:09:43 Yeah turns out in that genetic study, they actually discovered all those fish were toxo. Right.

Jessica

01:09:47 Right just one big toxo. Those are things that could be done. And then, I mean, honestly, indoor/outdoor cats are the, are the primary nuisance. So feral cats and indoor/outdoor cats, keep. If you're going to have a cat. You insist on having a cat, keep it indoors.

Dave

01:10:04 Okay. And then, but then don't flush. It's,

Athena

01:10:07 Don't teach it to poop in the toilet, even though it might impress your friend,

Jessica

01:10:10 Like who else knows what else they've got [Laughter] Find new ways, get better friends [Laughter] and hand washing is super. Like to all of this hand, washing is super, super key. So yeah, if they're not outdoors, um, if you've adopted a cat, then yeah. Don't have them pooping down the toilet. If they, if you're getting like a kitten that's from the long running indoor family has never been out and then odds are, they're not going to acquire it unless you're feeding them raw meat.

Dave

01:10:37 Okay.

Athena

01:10:38 Did we already like completely fuck up our ecosystem with the toxo thing.

Jessica

01:10:42 Oh yeah no is done. So, uh [Everyone laughs] So for now its an issue

Dave

01:10:50 Light it up folks!

Jessica

01:10:50 It's totally, it's totally done. So now it's an issue of trying to figure out what it's actually doing. Right? We have this, so it's a neglected tropical disease. There are lots of people that are studying it, but it's not prioritized the way that a lot of other uh pathogens have been. So there's real reasons to go out and try to get a sense of like, where is this? You know, let's do some more environmental surveys, you know, if its happening in dolphins, who, if there's lots of dolphins out in the world that people track. Let's look and see, like what can, what information can we get off of animals that we actually have possible biological samples from? And things like that. You know, if it's out in deer, like somebody gets to be the wild deer population on the whole, the wild deer population. [Dave agrees] But there's, there's lots of other things that could be done. Like let's figure out what's, what's the overall effect of this. And I think the other thing that's kind of worth considering is that given that these oocysts have, so the climate change, lots of things are changing. Migratory patterns of animals are changing anyway.

So you should expect that there's going to be changed in the pathogens that they carry and where they're going to go. Uh, and then on top of that, these oocysts are super environmentally hardy. So with the melting of, of ice caps and things like that, they can, you know, toxo can more substantial, can potentially substantially live longer in regions where it would have died because of severe cold. So there's things like that to think about, like, if it's in plankton then like that's the world's blue whale population really there's things that we don't have eyes on that would be important to get, you know, a sense of what's going on.

Dave

01:12:27 Okay. I see one last question. So this is like rats and cats, you know, they're sort of.

Athena

01:12:32 co-evolved with toxo

Dave

01:12:34 All so that they don't die off. Is that likely going to happen or is it like, I guess maybe, maybe for, of them now for others, like, are we going to get to the point where deer like, or are they going to eventually.

Athena

01:12:47 Other organisms are coevolving?

Jessica

01:12:47 I mean, I mean, hypothetically sure. Uh, but I, you're going to see extinctions. We already know that they're animals that are being driven to extinction by this parasite. Right? So there's certain animals that maybe. So I guess it depends. It could be like the Dutch Elm disease thing, right. Where like now we have all these elms that can resist it, but everyone thought that all of these elms were going to die off and certainly plenty of elms are gone. So it's a major change in the landscape, no matter what. So it'd be better to try to limit the effects of it.

Athena

01:13:21 So it sounds like it can both just have selective effects on like a particular species in terms of selecting for individuals that maybe can tolerate it better or better at clearing it? [Jessica agrees] But then it also has these potential implications for actually just causing extinction. So really important to know more about it for conservation of [Jessica agrees] Lots of different species.

Jessica

01:13:47 And it should be approached as a one health issue, right. If we are looking for drugs. So for example, one of the things.

Athena

01:13:55 Can you say what a one health issue is?

Jessica

01:13:55 So one health issue would be an issue where animal and human health intersects. So, um, so for example, I mean there's a lot of them, but HIV, hypothetically immunodeficiency viruses or hypothetically could be, it's not a great example. Staphylococcus aureus is a great example. Staphylococcus aureus has been with humans since the neolithic period during the dawn of agriculture. And we gave it to cows who now suffer from staff related myositis. And can, you know, so that's a one health issue resolving myositis infections in cows and, you know, keeping staff from killing humans.

Athena

01:14:34 and any zoonotic diseases [Jessica agrees] those are one health issues.

Jessica

01:14:37 No, exactly. Yeah. So, um, so toxo is a one health issue. And if we look at who's being most affected by this, it's the most vulnerable people in our society, right? It's, it's new needs like itty-bitty babies and often itty-bitty babies that are also additionally immunocompromised. So HIV itty-bitty babies, pregnant women, the elderly, uh, and it's, it's a disease also that we can, you know, you can see in like poverty, severe poverty has an effect on immunosuppression. There's lots of reasons to think that it's affecting lots of people that we don't know all that much about or, not all that much about what they. Affecting lots of people and we don't know all that much about it. So, uh, so there's that, and we know that we have these animals that succumb to it quickly. So wouldn't it be great if we could find chronic and acute treatments that are more effective in humans that also work in these other animals or study these other animals and also help humans. So that's kind of the perspective that I think about it from.

Athena

01:15:47 Great. Well, Jessica, thank you so much for sharing your brains with us. [Laughter] It's really amazing.

Jessica

01:15:58 Yeah, no problem

Dave

01:16:00 Yeah, this was fun

Jessica

01:16:00 This was a lot of fun.

Outro

01:17:09 [Psychological by Lemi]

Athena

01:17:18 Zombified is a production of Arizona State University and the Zombie Apocalypse Medicine Alliance.

Dave

01:17:23 And we would like to thank everyone who helped make this episode possible, including the Psychology Department at ASU,

Athena

01:17:32 The Interdisciplinary Cooperation Initiative and the President's Office at ASU,

Dave

01:17:37 The Lincoln Center for Applied Ethics of Zombies.

Athena

01:17:41 and the zombie apocalypse.

Dave

01:17:42 That's right. [Dave laughs]

Athena

01:17:46 We made that last part up.

Dave

01:17:46 That's true. We did.

Athena

01:17:48 As we always do.

Dave

01:17:48 Yes. [Laughter] Hopefully that's ethical. Um, and uh, also the Z-Team.

Athena

01:17:55 Yes. We have an amazing group of undergraduates and other researchers who help us with so many aspects of making this podcast happen, including the transcripts and social media.

Dave

01:18:10 That's right. And then of course our illustrator, Neil Smith,

Athena

01:18:14 Neil Smith, who does all of our podcasts illustrations, including the terrifically scary toxopocalypse, uh, that, that you're seeing on this episode's illustration.

Dave

01:18:28 Yup. Uh, and our audio mixer Tal Rom.

Athena

01:18:31 Yeah. And Lemi, who is the creator of our song, Psychological.

Dave

01:18:36 Right. So, um, anyone else?

Athena

01:18:40 Those are all of the brains that helped make this podcast. So now if you want to help make this podcast, you can follow us and support us on, uh, on Patreon. You can buy our merch. We have awesome t-shirts and amazing stickers with the Zombified floating heads.

Dave

01:18:57 That's right. So [Dave laughs] , and if you want more of us and more of our friends and many of our guests who we've had on the show.

Athena

01:19:08 and their brains.

Dave

01:19:09 and their brains, you should totally check out Channel Zed.

Athena

01:19:12 Yes. We have an amazing meeting coming up. Also the Zombie Apocalypse Medicine Meeting, which is going to be live cast on Channel Zed, which is our newest concept television in the apocalypse. And, um, you can find us and many of our awesome colleagues and their brains, all on Channel Zed. So, uh, so yeah, if you are interested in attending the whole meeting too, you can register it's happening August 15th through 18th.

Dave

01:19:43 August? No wait.

Athena

01:19:43 No! October. Obviously, because that has already passed. So [Laughter] October, October 15th through 18th, um, all online and, um, you can find more information about it at www.zombiemed.org.

Dave

01:20:03 That's right. And if people are listening after October, they. Can still check out Channel Zed,

Athena

01:20:10 That's right.

Dave

01:20:10 Which has a lot of great content.

Athena

01:20:12 Yeah.

Dave

01:20:13 That's it. Channelzed.org.

Athena

01:20:15 Yeah.

Dave

01:20:16 Um,

Athena

01:20:17 Yeah. Great. Well, thank you everybody for listening to Zombified your source for fresh brains.

Outro

01:20:27 [Psychological by Lemi]