This Podcast Will Kill You - Ep 81 Chagas disease: The Reverse Triple Discovery

Episode Date: September 7, 2021

A nighttime “kiss” from a bug that casts a curse on its recipient in the form of a lifelong, and possibly fatal, illness. No, this isn’t some half-remembered fairy tale. It’s the true story of Chagas disease, caused by the parasite Trypanosoma cruzi and transmitted by many species of triatomines (aka kissing bugs). In this episode, we take you through the utterly complicated biology of Chagas disease in its acute and chronic forms, the surprising evolutionary and historical background of this parasite and the scientist for whom it’s named, and finally the grim reality that is the global status of Chagas disease today. The dizzying ecological complexity and pathophysiological mystery of this disease makes it a challenge to study, and the lack of funding only compounds the issue; Chagas disease bears the dubious distinction of the most neglected of all the neglected tropical diseases. In spite of this, many people are dedicated to easing the global burden of Chagas disease, and we were delighted to interview two of these Chagas champions for this episode. Daisy Hernandez, Associate Professor at Miami University, joins us to discuss the inspiration for her recent book The Kissing Bug: A True Story of a Family, an Insect, and a Nation’s Neglect of a Deadly Disease, and Dr. Sarah Hamer, Associate Professor at Texas A&M University, delves into the ecological aspects of this disease and shares the incredible community science program that raises awareness about T. cruzi and the bugs that transmit it.To learn more, check out the links below:Daisy Hernandez: website, Twitter (@daisyhernandez), Instagram (@iamdazeher), Facebook Dr. Sarah Hamer: lab website, lab Twitter (@hamer_lab), Community Science Program See omnystudio.com/listener for privacy information.

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a true story of an insect, a family, and a nation's neglect of a deadly disease. I first learned about Shaga's disease when I was about five years old. My auntie was diagnosed with Shagas in New York City, actually, and she was from Colombia, where around the time that she was 29, she started to get really seriously sick. And the doctors in Columbia were able to do some exploratory surgery, which is how they found out that her large intestine was under some kind of attack. They actually did not diagnose her with Shaga's disease. It was in New York City that that happened.

And my auntie was very lucky that she was diagnosed and she was able to receive some interventionist kind of treatment at that point. But, you know, she had chronic Shaga's disease for the next almost three decades of her life. And so she, well, I was growing up, she was in and out of hospitals over the years. And sometimes she was in the hospital for one night or two nights. And some years she was in the hospital for a month or two. The parasite ended up not only affecting her large intestine, but also her esophagus. She had multiple surgeries during these years. And I grew up thinking that Shaga's disease was a very rare or unusual illness.

I thought my auntie had just been extremely unlucky. And it was not until 2010 when she became very, very ill and actually died from this disease. That was the point at which I started asking questions about Shaga's disease. I think because I had grown up without knowing anyone else who had this disease except my auntie, I thought it was rare and I was really surprised to find out that there were, that there are an estimated 300,000 people in the United States who have Shaga's disease. And they're like my aunties, they're immigrants from South America, Central America, Central America, Mexico.

And that number was very shocking to me. And it made me wonder who these families were. And that's how I ended up starting my book, actually, was that I wanted to meet other Latinx families in the United States to find out what their experiences with Shaga's disease were like and what obstacles they were facing and just how they were navigating the medical system in this country, given that as far as I knew is a very neglected disease. And something that I discovered while working on the book that I did not know about. about when I was a child was the issue of congenital shagas disease. I met an incredible woman in the DC Maryland area named Janet, who is from South America and her second son was born here in the United States with congenital shagas. She herself knew about the disease similar to me.

She thought that it was an affliction of actually in her case, she thought it was the elderly because she knew her father had shagas. She knew her older sister had Shaga's disease. She comes from a part of South America where the disease is pretty common, but she, even though it's common, she did not know about congenital Shaga's disease. And her son was born already having cardiac complications due to the disease. I'm happy to share that the baby is now, gosh, now five or six years old and is very much is doing well.

But he was a very unusual case. he ended up being only the second documented case of congenital Shaga's disease in the United States. And he was unusual just in that he showed symptoms. Her situation, though, also really touched me because she herself did not have health insurance. She was not working. She had a toddler and a new baby and she was home. And her husband worked in construction. And she did qualify for the Affordable Care Act or for Obama Care.

but she had not signed up for it, and it's an additional expense that the family would have to bear. And so she really struggled to actually find a medical provider who could diagnose her, who could work with her. It was a series of obstacles that I kept hearing over the years that I worked on this book while I was talking to both families and medical providers is this constellation of obstacles, not having health insurance, not being fluent in ingress. sometimes being fluent in English, but really struggling to advocate for yourself with a medical provider who doesn't know about the disease and doesn't understand or isn't being proactive.

And also something else, which came up often, which is that, you know, if patients aren't experiencing symptoms, they have so many other things that feel more urgent and are more urgent in some ways in their lives. Like in Janet's case, she was, you know, very concerned about her child's welfare before her own. She was concerned, obviously, about her family's financial life. She herself has legal residency, but is trying to learn English to work towards citizenship. Other families that I interviewed, you know, what felt more urgent in their lives were the immigration status of different family members. and job security always comes up.

And so it's easy, it becomes easy to actually ignore Shaga's disease in a way because they're not having symptoms and it's not the most pressing concern in their lives. Although I knew about this disease from a very young age, there was a kind of stigma in my family around it. My auntie never wanted anyone to know about this disease that she had it. She was really afraid, I think, as an immigrant to be rejected in some way by her coworkers, by this country, by, you know, just she wanted so much, I think, to be the perfect immigrant turned citizen. And in so many ways she was. She got her teaching degree.

She taught Spanish in a public school system in New Jersey. She got her master's degree as well. She traveled. She married an incredible man. She had such a wonderful life in so many ways. And she didn't want to have this disease and felt like it tarnished. I think when I was growing up, I thought it was very normal that we did not talk about Shaga's disease. We did not tell anyone that my auntie had it.

We did not mention it. It definitely felt like something that we were supposed to have shame around. And now I look back on that with so much sadness because it was just, just a lack of information for my own family. It was a lack of information, of course, in the healthcare community in the United States. The one sadness that I have is that I do wish my auntie had lived so that I could tell her a lot of what I learned about the disease. You know, even the difficult parts of this, you know, even the learning about congenital shagas, like I wish I could have told her that. I wish that I could have told her more about

just all these, you know, species of the, of this insect, of the triotomine insect. I wish I could have told her about that, even though she hated insects. She would not have wanted to probably hear that much detail. But I do wish, and I do have sadness that I could have told her because I think that ultimately she died knowing very little about her disease. And so for me, part of working on the book was also a desire that people who have Shagas and their families have a chance to know what they're really facing, you know. and so that, you know, no one else should have to die without knowing about their own disease and what's happening to their bodies. Thank you so much, Daisy, for taking the time to come on the podcast and chat with us.

We really appreciate it. Yeah, thank you. Hi, I'm Erin Welsh. And I'm Aaron Alman Updike. And this is, this podcast will kill you. And today we're talking about Shogas disease. Shagas disease. I, okay, listen, Erin.

How do you feel right now? I feel, I'm feeling a lot of different feelings. Like, I'm just, I'm full of feelings. Okay, okay. Listeners, you probably don't know this, but I technically did my PhD research on Shagas disease. Technically. Technically.

Yeah. So it feels like, I feel like I'm just going to. feel like I didn't do a good job on this no matter what. Like, I just don't know enough. I mean, well, first of all you do. You literally have a PhD in different aspects of Shagas disease. Yeah. And secondly, you know, we are, it's like we say every episode, we are not experts. No, we're not. And this is a really big one to cover, like massive. It is. It's so, it's so big. I'm excited about it, but it's going to be big. Yeah. But also, Erin, you're going to do a great job. I know it. You always do.

Oh, Aaron, you're so nice. I'm serious. I think before we really get into it, though, it's definitely quarantini time. It is. It is. What are we drinking this week? We're drinking the kiss goodnight. And it's called this because Shagas disease is transmitted by what are commonly called or one of the names for them is kissing bugs. And what they do is they feed on you and animals mostly while you're sleeping and they suck your blood.

And that's how you get chagas disease. It sure is. So, Aaron, what's in a kiss good night? In the kiss good night is tequila. Of course. Canelope. Uh-huh. agave syrup, lime and orange liqueur.

Yum. Yeah. That sounds fantastic. We'll post the full recipe for that quarantini as well as our non-alcoholic placebo Rita on our website, this podcast will kill you.com and all of our social media channels. Yeah. Other business. Let's see.

You can check out our website. This podcast will kill you. com. It's got lots of great stuff like transcripts, like the sources for all. all of our past episodes. It's got links to music, to merch, to our Patreon, to our bookshop.org affiliate account, to Goodreads list, and so on. Definitely check out our website. And also, remember that you can listen to this episode and all of our past and future episodes on Amazon Music, Apple, Stitcher, or wherever you get your podcasts. Before we get into this episode, speaking of

the fact that we are not experts. I have a correction to make. Bartonella was an episode that came out a few episodes ago now. I want to hugely thank multiple listeners that have reached out to help us solve the mystery of cat scratch disease that we were postulating about during that episode. In that episode, we were trying to figure out how Bartonella makes it from a cat's blood onto their claws or their teeth and then into our bloodstream after a bite or a scratch. Okay, multiple people have written in, it turns out unsurprisingly, when you really think about it, it is largely flea feces that are to

blame. So infected flea feces, or in some cases just infected cat's blood itself, can contaminate a cat's claws during grooming, which then can introduce the bacteria via a scratch into our skin or a bite wound flee feces can contaminate a bite wound, etc. So mystery solved, Aaron. Flea feces, say that three times fast. I can't. I couldn't even say it once. I also learned with the people who sent in those corrections, which was very helpful, thank you, that it's called flea dirt, too. Flea dirt.

Flea dirt. I like it. It's easier to say than flee feces. Yeah, but it's also... I know. Either way, it's gross. But thank you. you so much honestly like we are not experts we never get everything a thousand percent right so thank

you i appreciate getting to learn from you yeah okay okay with that should we get started i'm so nervous okay let's take a break and then get into it dinner shows up every night whether you're prepared for it or not and with blue apron you won't need to panic order takeout again blue apron meals are designed by chefs and arrive with pre-portioned ingredients so there's no planning and no extra grocery trip. Their assemble and bake meals take about five minutes of hands-on prep. Just spread the pre-chopped ingredients on a sheet pan, put it in the oven, and that's it. And if there's truly no time to cook, dish by Blue Apron meals are fully prepared. Just heat them in the oven or microwave, and dinner is ready. And here's the exciting news. Blue Apron no longer requires a subscription.

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designed to be your new wardrobe essential. And each piece is made with premium materials in ethical trusted factories and priced far below what other luxury brands charge. I recently got a pair of Quince's Bella stretch wide-leg jeans, and they are now in constant rotation. They are so comfortable. The fit is amazing, and they come in a bunch of different washes, so I'm about to go order some more. Refresh your wardrobe with Quince. Go to quince.com slash this podcast to get free shipping on your order and 365-day returns, now available in Canada, too. That's Q-U-I-N-C-E.com slash this podcast to get free shipping and 365-day returns, quince.com slash this podcast. So Shagas disease. Shagas is a severely neglected tropical disease. Historically, very much considered a disease of poverty,

like many, if not all, neglected tropical diseases. And like you mentioned, up top, Aaron, it's a vector-borne disease, for the most part. It's caused by a protozoan parasite called tripanosoma cruzzi or cruzai. Take your pick. Tripanasoma cruzai, T-Cruzai, it's a very cute little parasite. It has a little, like, looks kind of like a comma with like wavy flagella. Okay, okay. Picture it. It's cute. So T-Cruzai has a, shall we say, relatively complex life cycle. So we're going to go through the life cycle and then from there we can understand the different ways that we as humans can get infected. So we'll start the life cycle in the bug, the insect vector that transmits it.

So T-Cruzai gets picked up during blood feeding by bugs, like you mentioned Aaron, called kissing bugs, aka triatomines. They have a lot of different names in different countries. Kissing bugs are a type of what's called true bug. in the order. Hemiptera. Okay. Already I'm on tangents. These are blood-feeding insects. I think a lot of people might not know what they look like. So let me paint you a visual. They're pretty large bugs. The adults are like between three and four centimeters, so a good inch, inch and a half long. And they look like they have like a flat oval body with a pointy head and a long curved proboscis. That's the straw that they use to drink blood.

So these are big honkin bugs. They're big. Right? Like way bigger than ticks, way bigger than mosquitoes, way bigger than most things that bite you. I would say like, well, I mean, cockroaches are a whole different, a whole bunch of different sizes. But like, you know, about the size of your average cockroach. Yeah, like your house, your U.S. house cockroach. Yeah.

Definitely. If not bigger. Now, both males and females drink blood, as do all of the nymphal states. So these are bugs that have multiple in-star stages, and they all blood feed. They often have, like, a nest that they stay near, but then the adults can fly so they can fly farther from home base to look for bloodmails. They have a nest family nest or individual nest? Like little families or even like multi-generation little families. Just like a lot of bugs will often hang out together in like a palm tree or whatever.

Ooh, that's interesting. Yeah, so like a bunch of nymphs. a bunch of adults, you might find a lot kind of living together. Okay. Depending on the species. We'll get into that later. Okay. So this bug takes a blood meal from someone, picks up a whole bunch of parasites.

These parasites travel through the bug's guts. They differentiate. They replicate. And then when that bug gets hungry again and goes to take another blood meal, that bug will poop. And in that poop or frass are a whole bunch of parasites. Not unlike the fleas in Bartonella. Hey. Yeah.

And then these parasites that are now pooped onto your skin have to find their way either into that bite wound that the bug just made or some other mucus membrane like your eye or your mouth, etc. And from there, they make it into our bloodstream. You look like you have a question, Aaron. I do have a question. Okay. So they're pooping while they're eating. Or shortly thereafter. Or shortly after. And so the poop that they have, that they're pooping out is from the fresh meal or from the previous meal? Great question. It's from the previous meal. Yeah. And how often do they have to feed? Great question. It totally varies by species and by life stage. So at least once per nymphal stage. And then as adults, like the females have to feed every time that they're going to make a clutch of eggs. So it kind of just

depends. Okay. Gotcha. Yeah. Good questions, Aaron. Okay. So now this parasite is inside of us that made it into our bloodstream. Inside of us, these parasites penetrate our cells. They actually can penetrate a pretty wide variety of cells and what cells or what tissue type they infect can then lead to different symptoms of disease. They replicate, they, they, they, they differentiate again inside our cells, they replicate a whole bunch, and then they burst out from our cells to travel through our bloodstream and either infect another cell and start a new replication cycle to just keep going, or in the bloodstream, they can be picked up by another kissing bug, thus completing their life cycle. So that's just like the life cycle of T-cruise.

Yeah. It's a complicated one. Yeah. It's part one of complicated. Yeah. But what I'm in my very biased opinion, what's also very important and interesting about the Shagas disease story is how complex the ecology of this disease is. I'm biased, but I think listeners will agree once I get into it. So this is one parasite, right? Tripanosoma cruzi. But it has like six different clades within the, this species. And these different clades vary in terms of virulence, so how sick they make you, and disease manifestations, what tissues there may be more likely to infect or how likely they are to cause more chronic disease. And these different clades can vary in geography. They can vary by vector. There's a lot of variation in these different clades of T. Cruzey. Then there's the vector. And I hinted at the, this already. So I said that it's a triatomine, a kissing bug. But Erin, is it just one bug?

No, Erin. It's many bugs. It is many bugs. It's a lot. Yeah. It is. So there's like 138, I think, maybe more species of triatomine. Everyone could potentially transmit tripanosomacruzy. There's at least three species that are often cited as being the most important. One in particular, triatoma infestins is a species that's most closely associated with human dwellings. It has adapted to live its entire life cycle within human dwellings. So in walls, in roofs, inside of our homes. So historically, that's been the one considered kind of the biggest deal. But there's a lot of other species in a whole bunch of different genera of triatomine that are capable of and potentially important vectors of Shagas disease.

Spoiler. That was like my whole dissertation. So like I could go on and on. But I think I can pause there. Okay. Each of these species has differences in terms of their ecology. So like where they like to live. Do they live in palm trees? or do they live under rocks, et cetera? They have differences in terms of who they like to feed on. And like you asked Aaron, how often they feed. They have differences in how long they feed for, how soon after feeding they take a poop

and where they take a poop after feeding. It's really, really complicated. Yeah. I mean, all of this just kind of serves to like underline how difficult this is to control or prevent or to like reduce. the numbers of. It's sort of like you have to hit it from so many different angles. Right. Yeah. Yeah. And to throw one last angle on there, Aaron, this isn't a human-specific

disease. This is a parasite that infects over 150 species of mammal. All right. So that's a lot. That's really complicated. So we know that. In general, this is a group of insects and therefore parasite and disease that was typically considered endemic to the new world, so North, Central, and South America, and mostly just the southern part of North America because it's really restricted to more tropical-type latitudes. But as we'll see when we talk about the clinical picture of disease, which I promise I'm about to get to, because of the way that Shagas disease manifests clinically, it is a global disease today. It is not limited to South America or even just the Americas. So let's talk symptoms. In humans, Shagas disease has two forms, the acute disease,

like you get sick shortly after getting infected, and then a chronic disease. This parasite can lay dormant in our bodies for decades, 10, 20, 30 years, and then pop up and cause disease very long down the road. So we'll go through those one by one. In the acute phase, honestly, is mostly asymptomatic. And by mostly, I mean 90, 95% of the time, completely asymptomatic. So you get bit, you scratch this parasite into your bloodstream, and you don't know about it at all. If people do have symptoms, so that 5 to 10% of people that do have symptoms, they're often quite mild and consist of something like maybe some fever, maybe inflammation wherever the parasites entered. And because it's common for the parasites to enter via something like your eye, there's a

classic sign that's called Romagna sign, which is when one eye, whichever eye the parasites went in from, gets really swelling, unilateral swelling of your like eye and eyelid. But it could be anywhere. So let's say it happened on your arm, then maybe your arm swells up. Occasionally, you might also get some hepatospinomegaly, one of our favorite. TPPQAWI words, yeah. So that's swelling of your liver and spleen from the parasite and inflammation and immune response associated with it or swelling of any various lymph nodes. Potentially it can cause things like anemia if it gets more severe.

And in very rare instances, like I think usually only one to five percent of the time, although one paper I read said five to ten percent, it can be a little bit more severe. and the specific symptoms depend on which organ is infected severely. So if it's the heart, we can see things like myocarditis or pericarditis inflammation of the heart muscle or lining. Very rarely, if it infects the brain, you can get meninjo encephalitis. And these kind of severe manifestations can be fatal, but that's very rare. It can be fatal in the acute phase.

In the acute phase, exactly. Yeah. Okay. So, like, why is it the enlargement? Why is there such inflammation? Like, what cells are they attacking? Yeah, good question. They enter into our cells. And from what I can tell, it's not very specific. So they can enter white blood cells, which is probably why we see a lot of hepatospinomagally and lymphadenopathy. This is where our white blood cells are congregating. But they can also enter the lining of your heart. They can enter. a whole bunch of different tissue types. What makes them either decide or just happen to end up somewhere probably depends on how much parasite you have, like how far they make it before our immune system kicks in. Probably depends on how great of an immune response you have to it. Probably depends on what specific genotype you were infected with. There's probably a lot of variables

that I don't know the full answer to. Okay. Okay. And then of the, so you said 95% are asymptomatic. Are there any patterns as to why, like who the 5% are that become symptomatic? It's a good question. I don't know. Okay. Yeah. Yeah. Good question. And another question real quick. While I have you. Yeah. Immunity. Like with re-exposure, so you said that your immune system can kind of recognize, take care of it. If they, if someone gets reexper, are they immune or can they get reinfected? Okay, let's keep going. Okay.

I had a feeling I was jumping the gun. Yeah. Okay, so let's then talk about the chronic phase. Yeah, yep. So the chronic phase is the phase of disease that's more severe. Here's the thing about it. Most people. And when I say most, I don't have an exact number,

But some of the papers I read made it sound like almost all people, if untreated during the acute phase, will in fact have some level of chronic infection. But only about 30 to 40 percent of those people will actually go on to have any chronic disease as a result of this infection. Okay. Okay. Okay. Okay. So for those unlucky 30 to 40% of people, anywhere from 10 to 30 years after the initial infection, which again, most of the time is asymptomatic, so you never know that you had it. The two most common organs that end up getting infected are the heart and the gastrointestinal tract.

And the parasite ends up doing similar things, but with very different outcomes since it's heart versus GI tract. Okay. So in the heart, often what happens is this parasite and this infection causes an enlargement of the heart. It causes what's called a dilated cardiomyopathy, an enlargement of the heart. This causes the heart to not be able to conduct electrical impulses properly. That's your heart's like one job, right? It's to have electrical impulses that all go simultaneously so that your heart contracts in one beautiful, thump-thump with enough force to pump blood to the rest of your body. When it gets dilated and those electrical impulses can't transmit, the heart can't contract in sync or it can't contract with enough force or the right timing and synchronization to be able to push your blood forward. So there's a lot of different ways that this can manifest, anything from things like heart block to heart failure to different arrhythmias, just depending on like what parts of the heart are the most affected and when. But overall, the most common cause of death in these individuals is sudden cardiac

death because your heart is just all of a sudden not able to pump properly and then you die from sudden cardiac death. The other organ that's most commonly affected is the GI tract. And same as with the heart, Shogas disease tends to cause enlargement of either the esophagus or the colon, either or usually. In the esophagus, this leads to dismotility, and specifically leads to something called acalasia, which anyone in med school will be like, oh yeah, shagas disease, achalasia. Basically means your esophageal sphincter, the one that lets your food into your stomach, doesn't relax properly and your esophagus gets expanded and then it looks like a bird's beak. So there's a really tight hole where it enters the stomach and then the rest of

it is really dilated. Does that make sense? Instead of being a nice little tube. And so this leads to like not being able to swallow properly, etc. Oh, that sounds really difficult. It's really problematic. It can lead to reflux. It can lead to weight loss because if you're not able to swallow your food, then you're not eating essentially. And a similar thing can happen in the colon. can lead to what's called megacolon, where the entire colon becomes dilated and then isn't able to contract properly to move your digested food along. So that leads to constipation, which is problematic, but what's even more worrisome is it can lead, this dilation can lead to twisting of your bowels, which is called volvulus. And that can lead to eczemia,

because that twisting can then cut off blood flow to the organ. Okay. Okay. Yeah. So it's, It's a problematic disease and it's a cause of really, really chronic disease problems, right? These are like megacholine, esophageal dismotility, heart failure, dilated cardiomyopathy. These are things that happen from a lot of other sources. But now this is happening from an infectious disease. So what's going on? Okay. Yeah.

Off the bat, Aaron, this is a very understudied disease from like every possible angle. that's still true for the pathophysiology. So especially in the chronic phase, we still don't know the exact details of this pathogenesis. So we don't know exactly what's going on. But we know a few things. So we know that in the acute phase, the organ damage, when it happens, is due to direct action of the parasite. So it's parasites causing damage to the tissue from bursting out of our cells, that stimulates an inflammatory response, et cetera, et cetera. Okay, that's the acute phase. So you think probably similar things are happening in the chronic phase.

We know that you asked about who gets chronic disease versus who doesn't. The balance of who gets chronic disease versus just who has infection without ever having disease from it seems to depend a lot on individual balances between, our chronic inflammatory response and the parasite infection itself. So, like, how much is our immune system trying really hard to kill off this parasite versus just tolerating this parasite and, like, coexisting with it? Right. But, okay, it gets really complicated because in some areas where transmission has been reduced significantly, So where control efforts have reduced incidents of disease, but of course people are still infected, right?

Because it's chronic infection. The development of things like cardiomyopathy have actually decreased. There's been a reduction in the development of things like heart disease. So it's thought that maybe there's also some interaction between recurrent exposure to the parasite and increased inflammation. Yeah. So it's like every time, like let's say you, get infected and then your body never sees this again and it's just like okay well this is just this thing here right then if you get continually re-exposed and your immune system keeps waking up and

keeps getting like inflammation right exactly yeah okay but it is it does seem to be the case that a lot of the damage is parasite persistence like and that's important because it's not purely an inflammatory or purely an immune response. Like the parasite is a really big part of it. Does that make sense? Yeah, yeah. It's important when we talk about things like therapeutic vaccines, like this interplay between parasite and immune response. So it's really complicated. We don't know the full answer. Huh. I'm going to throw a little bit more complication in there before I hand it off to you, Aaron. Okay. Okay. Because it's important to mention that while this is largely a very vector-borne disease.

Vector-borne transmission is the primary root. It is certainly not the only root. Right. So because this is essentially a blood-borne pathogen, this is something that can also be transmitted via blood transfusion or organ transplant. But of course, that's quite rare, and in many places, blood is screened for Shagas disease. It can also be a congenital infection. So during pregnancy, it can cross the placenta and infect a fetus, which can result

from anything from spontaneous pregnancy loss to premature birth to a number of different problems in the newborn, or in many cases asymptomatic infection, but then lifelong infection of the baby. Yeah, it's really bad. Yeah. And increasingly, people are realizing that it's a much bigger problem than had ever been thought before, probably just because nobody had thought to study it. Can I read you a disheartening statistic? Oh, gosh, yeah.

So there was a survey in 2008 by the CDC and the American College of Obstetricians and Gynaecologists. And there was the question, can a pregnant person pass T. Cruzee onto their baby? And so, again, these are obstetricians and gynecologists in the U.S. And 84% of them answered, I don't know, to that question. I'm not surprised about that. I can tell you that this absolutely never came up in medical school. Yeah. That's a huge problem.

I mean, Shagas came up, but not congenital transmission of Shagas. Right, but that's like such a big problem. It's a huge problem. Yeah. Oh, my gosh. That's frustrating. Yeah. I know. That's not the end.

Yeah. Shagas has also, though rarely, been associated with oral transmission. Mm-hmm. Because this parasite is found in the feces of bugs and a lot of species of bugs and a lot of species of triatomy make their little nests in the tops of palm trees, there have been a handful of outbreaks of Shagas disease associated with consumption of things like palm fruit juice or other fruits and vegetables that were contaminated with the feces of kissing bugs. I always see assayi being called out.

Yeah, assayi is like, I think, the most well documented. Mm-hmm. Yeah. Oh, that's a lot, Erin. And there's not any good news in this section because there is treatment, but in general, it's really effective only during the acute phase of the disease. It's much less effective during the chronic phase, and you can imagine it's pretty difficult to catch during the acute phase. Yeah. Why is it only effective in the acute phase? It's a good question, Erin.

Okay. I think if we knew that, we might have better drugs. Okay, yeah, fair. So Aaron? Yes. Do you think you could tell me a little bit about this little parasite here? And I mean, it's got a lot going on. It's got a lot going on.

Yeah, I'll tell you all about its history. Let's take a quick break first. Anyone who works long hours knows the routine. Wash, sanitize, repeat. By the end of the day, your hands feel like they've been through something. That's why O'Keefe's working hands hand cream is such a relief. It's a concentrated hand cream that is specifically designed to relieve extremely dry, cracked hands caused by constant hand washing and harsh conditions.

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We're offering our listeners 15% off their first order of O'Keef's. Just visit o'Keef's company.com slash this podcast and code this podcast at checkout. Hello, hello, I'm Malcolm Gladwell, host of the podcast Smart Talks with IBM. I recently sat down with IBM's chairman and CEO, Arvin Krishna. And I asked him, how can companies use AI to its fullest potential to create smarter business? My one advice to them, pick areas you can scale. Don't pick the shiny little toys on the side. For example.

If anybody has more than 10,000. 10% of what they had for customer service 10 years ago, they're already five years behind. If anybody is not using AI to make their developers who write software 30% more productive today, with the goal of being 70% more productive. Yeah. So we are not asking our clients to be the first experiment on it. We say, you can leverage what we did. We're happy to bring out all our learnings, including what needs to change.

in the process, because the biggest change is not technology, is getting people to accept that there's a different way to do things. To listen to the full conversation, visit IBM.com slash smart talks. Truck Month is going on now at your local RAM dealer. Hurry in for great deals and exceptional offers on a powerful selection of RAM trucks. And right now purchase and get 0% financing for 60 months on 2026 RAM-500 Big Horn and Laramie models. Don't miss this great offer. See your local RAM dealer.

Not compatible with any other offers. 0% APR financing for 60 months equals 1667 per month per 1,000 financed for well-qualified buyers through Stalantus financial services regardless of down payment. Not all customers will qualify. Contact dealer for details. Offer ends 3-2. I am so excited to talk about the history of Shagas disease because at each step of the way, from its evolutionary origins and prehistory to the research leading to its discovery

and then a better understanding of disease progression, I was surprised at all of these steps by what I learned. Ooh, fun. I really was. I mean, granted, I didn't know much about the history of Shagas going into the episode, but I think it does stand out for me as a parasite and a disease where things didn't really happen in quite the way you might expect, which is definitely something that can be said for its biology as well.

It's complicated. You're like, I don't know what you're like. I don't know what's going on. You can't really predict things sometimes. Yeah, definitely. So like always, let's start at the beginning, which is easier said than done. Until fairly recently, like maybe within the last 10, 15 years or so, the origins of tripanosoma cruzies seemed like fairly cut and dry, or at least like as cut and dry as evolutionary origins can be in terms of like, you know, stuff. Yeah. It's always.

being rewritten. That's fine. That's how science works. But there was a general consensus that the tripanosome cruzic clade originated on the southern supercontinent made up of South America, Antarctica, and Australia, where they evolved in isolation in early terrestrial mammals. And then when that supercontinent broke up around 40 million years ago, the T. Cruzee-Claid further diversified in South America. And so if this were the sequence of events, that actually happened, we would expect to see a great deal of diversity within T. Cruzee in South America, as well as maybe some evidence of co-evolution between mammalian host and parasite with some maybe species-specific strains. However. However, however, there's actually

fairly low diversity of the T-Cruzzy clade in South American mammals, like lower than you would expect if it had been there for 40 million years. And in addition to this, members of the T. Cruzy clade also have been found in African and Australian land mammals. So what's going on here? Yeah. Well, it seems most likely that T. Cruzee originated elsewhere, likely in Africa, where the other major human tripanosome is most prevalent, which is T. Broussi, which is the causative agent of African sleeping sickness. We should figure how to pronounce that before we do an episode on that, which we will. Definitely will. Yeah. Yeah, so then it originated in Africa and then was brought to South America. And this is where I introduced to you the bat seeding hypothesis. Bat seeding?

Bat, yeah. Okay, okay. This idea basically holds that T. Cruzee was brought over to South America from the old world, likely the African continent, by bats between 7 to 10 million years ago in several different independent colonization events. And this bat seeding hypothesis has gotten a good deal of support more recently, with molecular studies showing that the closest relative to T. Cruze is a South American bat tripanosome that diverged like 6.5 to 8.5 million years ago. and two other tripanosome species recently described that are related to T. Cruzee are found in bats from Mozambique. Huh.

Yeah. And in addition, one genotype of T. Cruzee called T.C. Bat is only found in, yeah, like, bats in South America. I knew about that one. Yeah. And that one is closely related to T. Cruze TC1, which, like, I'm not going to get into all the different genotypes. stuff, but this is, I think, a really interesting part of the story. So TC1 is mostly associated with opossums and arboreal triatomines. Right. So once these tripanosome infected bats, infected with T. Cruzee or some, you know, ancestor of

T. Cruzee, made it to South America. They were fed on by blood-feeding insects, triatomines, that also took meals from other mammals also living in trees or up high, right? Right, right, right. Yeah, makes sense. Like opossums. Yeah. And so then those opossums were probably some of the first to get infected with T. Cruzee. Okay. Yeah, yeah, yeah. Okay. And the ancientness of this relationship might be reflected in the way that the parasite infects those animals. Ooh. Yeah. I read a paper. Actually, I think it was mentioned in two that I read because I was like, for real, this is wild.

And these papers reported finding amastogotes, which is like the, I know. I know. I didn't even get into it, Aaron. I know. It's a part of the life stage of T. Cruzee. It's an intracellular part of the life stage. Right. Thank you. And so they found a mass. Mastigotes in the tissues of opossums, which is totally what you would expect of mammals susceptible to the parasite. That's where you find them. Uh-huh. And then they found epimastigotes, which are found usually only in the insects.

Yeah. They found them multiplying and differentiating in the opossum's anal glands. What? Yeah. Okay. That, I think, is fascinating. I don't even know how to interpret, Aaron. Okay, so they were able to take those epimastigotes and then, like, complete the infection cycle.

Stop it. Yeah. So opossums might be able to transmit tripanosomacruzy in their poop. That was my interpretation of this, and I think that's what it means. What? Yeah. And so... I can't even handle this.

I know, I know. And so this paper, which was written before the bat's... seeding hypothesis gained, you know, momentum. It suggested that this might have been the earliest route of transmission before the triatomines got involved, but it might also have evolved after. In any case, this mode of transmission, where, you know, opossums might be able to transmit through their poop or through like the anal gland secretions, this might play a role currently in semi-urban environments or places where the vectors aren't quite as present. Prevalent. Yeah. What?

Yeah. My mind was blown. I just feel really glad that I finished my PhD. Before you found that paper. Yeah. Yeah. It's really interesting. I will definitely, I'll definitely put the paper in this. I feel like I would have had my hands on a lot more possum poop or something to be thankful.

Yeah, it's super interesting. So, okay, so, but once Tripanasoma Cruzi landed in South America and found its way into opossums, and it, you know, of course, other host mammals followed, and the parasite diversified into its current lineages around one to three million years ago, which seems. seems to be around the same time that the triatomine vectors diversified. Okay. And then over the past, you know, few million years, it just continued to spread across South America, up through Central America, North America, through primarily animal movement.

Eggs and nymphs, for instance, have been found to be carried in bird feathers, which I think is interesting. And then later, of course, human movement would have helped to spread things along, too. All right. By the time that humans arrived in South America, which was at least 15,000 years ago, Tripanosoma Cruzee was present in animals across the continent, although to what extent is not quite known, since not all habitats might be conducive for the insect vector and whatever susceptible mammal species. But here comes the next. First we thought it was this, then we realized it was that moment. It was originally thought that humans first became exposed to the parasite after the

domestication of like guinea pigs around 2000 BCE, along with other animals that would have like attracted the bugs and thus the parasite to, you know, human dwellings. Or it was thought that human dwellings built later on and particularly after European invasion would have provided, you know, excellent homes for the triatomine vectors. And that's, I mean, those things are probably true in that they did increase contact with the bugs. But paleo-parasotology came along to change the story. The Atta Kama Desert in southern Peru and northern Chile is, you know, it's a desert. So as you would expect, it's extremely arid.

There's virtually no rainfall. And so when a body is buried, It rapidly dehydrates rather than decays or disintegrates, and that has left many, many mummified remains in the area. And genetic analysis of these mummies has shown not only the presence of T. Cruzee, but there are actually enough samples to get prevalence estimates. What? Yeah. So one study from 2003 screened 283 mummies. for T-Cruzy, with the mummies dating as old as 9,000 years and as young as the 1800s. Wow.

Yeah. Overall, the prevalence of T-Cruzy was 40.6%. Yeah. Yeah. Yeah. And that prevalence is actually fairly steady over time. I mean, there are a few like dips and a few surges, but like, and the sample sizes in some of these groups are low and, and whatever, but that was, that's a pretty like shockingly high number, I think, nearly 50% of

people. Yeah. And the oldest of these mummies infected was this 9,000-year-old mummy. And that indicated that humans in South America were exposed to the parasite long before domestication of guinea pigs and construction of European-style housing or whatever, and that they probably first became infected from the sylvatic cycle of the parasite. So between like the wild animals and the bugs. And that was well established by the first human occupation of the area.

And it's not just in South America, but also in Central and North America that we have evidence of prehistoric infection. The oldest known case in North America, for instance, is a mummy in South Texas from around 1,150 years ago with a megacholon full. of feces. Oh, wow. And analysis of these coprolites, because we love our copperlights, shows that this person, I think this is so fascinating, like you get to see what people ate. We're eating. Oh, my gosh. Yeah. This person had ingested fish, snakes, bats, white-footed mouse, pocket gopher, and grasshoppers. And so this led the researchers to suggest that the oral route of transmission might have played like a stronger role. maybe in that area, especially if triatomine bugs were directly ingested.

Yeah. Yeah. And so evidence of chronic infection in these prehistoric humans, like with this megacolon in Texas, has also been found in Peru and in Brazil in the forms of megacolon or cardiac lesions. So it seems pretty clear that humans became infected with T. Cruzee basically as soon as they arrived in an area where it was circulating in mammals. And since that time, the geographic distribution of the parasite, the dominant genotype, the transmission root, the vector species responsible, all these things likely shifted as human settlement patterns changed, as housing construction changed and like materials, and as cultural practices changed as well.

But what didn't change and what remains true today is that there continued to be opportunities for infection. So the prevalence estimate that I mentioned in the mummies from the Atacama Desert is like pretty dang high at 40.6%. And in the more recent mummies tested, like in the last 600 years or so, it was even higher at over 50%. Wow. So people had to know about this disease, right?

Wrong. Wrong. Wrong. Wrong. Yeah. I mean, Shagas disease has been called the most neglected of the neglected tropical diseases. Yeah. And that is due possibly in part to its relative clinical invisibility.

Right. Just like you talked about, like the acute stage when it is there, it doesn't necessarily have super distinctive signs or symptoms. And it's not often severe. And so you just kind of get over it and then you forget about it, right? And the chronic stage can go unnoticed for a very long time, and it can then be attributed to other things or just like, oh, heart failure. Right. Oh, you have all these other risk factors for heart failure. You have heart failure.

It's a normal kind of heart failure. Right, right. It's not like Leshmaniasis with its visible lesions or river blindness with the itching and blindness or draconculiasis with like the actual worm coming out of your foot. Right. And because of this relative invisibility, there don't really seem to be many historical descriptions of Shagas disease prior to its discovery. I'm not surprised about that. Yeah. The triatoming bugs, on the other hand, do get some early mentions.

Ooh. I've talked a lot on this podcast about what we can tell from the name of a disease or in this case, like the vector, the name of the vector. The name itself can tell us what it meant to the people using it. how it was perceived, the number and geographic spread of the names can tell us how widespread the disease was, and it can help trace the history. When did the name first appear? How often was it used? Did it increase in use? Etcetera. In the case of Shagas disease, we don't have historical descriptions of the disease, but we do have a long history and a long current list of names for the insect vector. Oh yeah. We have Vinchuka, Akhetwa word.

meaning bug that lets itself fall, chinché, and many other nicknames that mean things like barber or sucking blood, bloodstealer, kissing bug, bug that dislikes the cold, big piercing bug, and so on. I like bug that dislikes the cold. Yeah. In one of the chapters I read, there's like a giant table showing these different nicknames and where they are used. It's really, really cool table, actually. The most famous description of these bugs, though, or at least the one that I saw referenced over and over, comes from none other than Charles Darwin. What?

Yeah, in 1835. Okay. Quote. The night I experienced an attack, for it deserves no less a name of the Vinchuka, a species of Reguvius, the great black bug of the pompous. It is most disgusting to feel soft. wingless insects about an inch long crawling over one's body. Before sucking, they are quite thin, but afterwards become round and bloated with blood, and in this state, they're easily crushed. That's really good, but Darwin, the adults have wings. Yeah. I mean, he wasn't like a famous naturalist

or anything, right? No, just like, you know, a minor naturalist. Just a minor, yeah. It was a side gig. You know, isn't it thought he might have died from complications of Shagas disease? Oh, well, well, look who's jumping the gun now. Oh, oh. Look at me go. Yeah, so many people have retrospectively diagnosed Darwin with Shagas disease, thinking that he was maybe exposed while on the HMS Beagle in like 1834, 1835. And it is true that he did become quite sick while in Chile and ended up being bedridden for seven weeks. And at the time, it was thought to be typhoid, but no one else on the crew got sick. He eventually recovered, but later in his life, he complained of palpitations, extreme fatigue, trembling, flagealance, and vomiting.

And he was diagnosed first with hypocondriasis. Are you serious? Yeah, and like a nervous condition or whatever that called it back then. And then later with heart failure after experiencing anginal attacks, accompanied by extreme exhaustion and digestive disturbances that forced him to abandon his work. But it also might not have been Shagas's disease since at least some of these like health problems that he complained about he had before he ever went to South America. So, I mean, it's possible. Who knows? And other descriptions of the blood-feeding nature of the bug comes from Augustine Liza Raga,

a Peruvian farmer who discovered Machu Picchu in the early 1900s before Hiram Bingham stole all the credit. I just really wanted to throw that in there because I didn't know that it, like Hiram Bingham had stolen all the credit from somebody else, but I should have guessed. And then there are some earlier descriptions of the bugs and even some that might hint at the disease by conquistadors, although these descriptions I didn't even put in because they're pretty hand-wavy. Like one of them is like, or it could be hemorrhoids. And I'm like, okay, well, this is like, kind of different. They are pretty different. Yeah. All right, but I jumped around a bit in time back in here. So let's, let's get reoriented with things. Basically, by the very early 1900s,

although Shagas disease was probably quite prevalent across parts of Central and South America and into North America, it seemed to be unknown entirely as a medical condition. Wow. But by 1921, all of that would change. Mm-hmm. Mm-hmm. Not only would it become well-known across the world to infectious disease researchers, but its discoverer became famous in his own right, earning both acclaim.

He was nominated for a Nobel Prize twice, as well as criticism. Oh, okay. Oh, this is funny. I didn't know this. Yeah, this is a very, I think this is a very interesting story. Okay. And I'll get to why. And I hope that your mind will be blown.

I'm sure. I'm sure. Okay. Carlos Shagas was born on July 9th, 1879, on a coffee farm in Minas Gerais, Brazil. His father and two brothers died while Carlos was still young. leaving him to become head of the family. When he was old enough for college, his mother urged him to become an engineer, but he didn't pass the entrance exams and became very depressed

until one of his uncles, who was a physician, was like, hey, you know, why don't you try for med school? And so that's what he did. And in his time at med school, he focused his work on malaria. Okay. And after graduating in 1903, he received an invitation from the man who would become his friend and mentor, Oswaldo Cruz. Oh. Yeah.

To work at the hygiene and public health office monitoring malaria. And Shagas readily took him up on this since he needed a steady income in order to support his new family. Like he had just gotten married, just had a kid. And when Shagas began working there, he was not only. starting his medical career at a unique time, but also at a unique place. So around this time, in the early 1900s, germ theory had been fully embraced, and many pathogens and parasites had been described and were continuing to be discovered. Tropical medicine as a field was really starting to grow, as imperialist countries struggle to develop the countries that they had laid claim to,

with many people dying of tropical infectious diseases. And for all its imperialist and colonialist beginnings, tropical medicine did mean looking at the whole picture of public health, from the life cycle and habitat preferences of a vector to the epidemiological characteristics of a disease, to the economic and productivity costs of these infectious diseases. It involved combining a plighteous diseases. and basic research with an aim of prevention and control, not just descriptive knowledge building.

Right. And Oswaldo Cruz and the institute he founded, which was later to bear his name, the Oswaldo Cruz Institute, encapsulated this and then some. This institute placed the highest importance on the combination of research, education, and assistance. Like other tropical medicine organizations, it integrated, applied in basic research to solve problems. But unlike the others, Cruz wanted his institute to focus not just on the economic benefits of urban development for like the colonialist

countries or like the big companies, but also on the improvement of the lives of Brazilians of everyone by preventing infectious disease. And Carlos Shagas picked up this attitude from his mentor and it greatly influenced his career and the way that he viewed medicine. In the words of his son, quote, for Shagas, science was valid only if it was directed toward the welfare of humanity. I feel like those are pretty good words. Yeah, they are. His first project under Cruz was to implement a malaria control strategy, which was pretty

successful in reducing the cases of malaria and also showing that a lot of transmission actually occurred within a home rather than outside, as was previously thought. His clinical background as a physician and his research background on vector-borne disease, it perfectly qualified him for this type of work, and soon he was assigned to a new, bigger project. A cross-country railroad to transport agricultural products, the Brazil Central Railroad, linking Bello Horizonte to Rio de Janeiro. It was under construction, but it kept getting delayed when workers fell ill during malaria outbreaks, like big, bad outbreaks. In 1907, Shagas was called in to stop the outbreaks using the method that was most commonly

employed at the time. Combat the vector, combat the disease. Essentially, he was tasked with setting up research stations at the towns along the railroad ahead of the construction to identify potential malaria hotspots and then get rid of the mosquitoes. Okay, cool. And it was at one of these towns, LaSance, I hope that's how you say it, a small town on the South Francisco River where Shagas heard a chief railroad engineer describe a blood-sucking insect that was infesting the huts in the region and feeding on people while they slept. He called the bug the barber bug, since barbers were kind of like surgeons at the time.

They did a lot of like cutting and whatever. They did. And from this tidbit of information, Chagas pulled off the reverse triple discovery. What? Reverse triple discovery? Yeah. So we've been doing this podcast a while, which means we've gone through a heck of a lot of disease discoveries. Yeah.

And it usually goes a little something like this. First, a bunch of people get sick and their symptoms. are described and classified into one illness. Second, researchers began digging around for the causative agent after the rise of germ theory and begin using that as part of like diagnosis. And then third is usually when the root of transmission is determined, whether that means like arthropod vector or fecal oral or whatever. But what rarely, if ever happens, is that sequence in reverse.

I love this. That's fantastic. And that is exactly what Shagas did, the reverse triple discovery. Wow. All right. I'm going to read you a quote. Okay. From Shagas. Once we heard of the blood-sucking habits of this insect and of its proliferation in human

dwelling places, we became very interested in knowing its exact biology and above all in ascertaining if by any chance it were, as I immediately supposed, a transmitter of any parasite of man or of another vertebrate. Oh, my gracious. So he found these bugs, was shown these bugs, and then was like, I'm pretty sure these probably because they feed on humans, they must transmit a disease. Super logical, honestly. Like, he'd been working with malaria mosquitoes forever.

He's like, bro, everything that bites you is going to get you sick somehow. Let's be honest. Exactly. It's like this discovery was the product of. his training, you know, his like bright mind, but also like the type of job that he was doing too and like the way tropical medicine was being practiced. It's definitely like a, of course it happened this way, but also, oh my gosh, it happened this way. I know. Yeah. Wow. That's cool. Amazing. So he tested his suspicion of this barber bug as a disease vector by dissecting its hindgut

and examining it under the scope where he found tripanosomes. So he gathered up a bunch more bugs, shipped them off to Oswaldo Cruz, and asked him to feed them on monkeys. And he did. They got sick. And Shagas then later named his parasite Tripanosoma Cruzee after his mentor and friend Osvaldo Cruz. You know what's so interesting, Aaron, is like it could have gone so differently. Uh-huh.

Right? Like he could have found, I don't know, just like, he could have found something that transmitted a virus that he never could have figured out or something that only infected humans. So he tried to feed it on monkeys and it didn't work. Or like there are so many ways that this could have not gone the way that it went. But it was like, here's an obvious parasite that looks like not so dissimilar to malaria, which I'm familiar with. Let's feed it on a monkey. Does the monkey get sick? sure it does because any mammal will like what i i know i love it i think it's such a like fantastic

fascinating story in the history of medicine i love it it's it's just so like it's so unbelievable but also totally believable she's like yeah exactly what it's a good way to describe it unbelievable but totally believable yeah uh And so at this point, yeah, Shagas had identified a vector and a parasite that was at least somewhat pathogenic to, you know, animals or some animals, but he still didn't know whether it was a disease of humans. And for a couple years after first discovering the tripanosome, he looked for it in animals and humans all over. And it took him a while, but in 1909, he found it in both. First in a cat, and shortly after, on April 14th,

which was declared in 2020 by the WHO as International Shagas Disease Day. Oh. So on this date, he found this parasite in a two-year-old girl named Berenice, the first described case of what would later be known as Shagas disease. And Shagas disease was named, in fact, by Oswaldo Cruz. Of course it was. Isn't that just like really cute? I just think that's really nice.

He's like, I'll name the parasite after you. Oh, cool. I'll name the disease after you. Yeah. I think it's nice. So Shagas wrote in his famous 1909 publication that Berenice had a swollen liver and spleen, hepatosplenomegamy, oh my God, I can't say it, had a spleen omegaly, and swollen lymph nodes. She was febrile. She was anemic. She had edema. And also he found circulating tripanosoma cruzzi. In this publication of the acute form of the disease, he also described the morphology of the tripanosome as well as its life cycle and its intermediate and definitive hosts.

He described his attempts to culture the tripanosome, he described the course of infection, and so on. And over the next couple of years, he continued to work on the disease looking for it and more people in autopsies and better characterizing the acute stage of the disease as well as looking at chronic infection and long-term consequences. He just, like, decided to do that, or just, like, because of doing autopsies was, like... I think probably doing the autopsies kind of, like, led him along. And then he got a researcher involved named Gaspar Viana, who was especially crucial in

investigating some of the cardiac impact specifically. But it is, to me, it's really impressive that Shagas was, like, I found that, acute stage and then was like, there's something about, I wonder if there's a chronic stage to this. Yeah. Yeah. Like, I don't want to keep going on this. Yeah. And after this, this publication was released in 1911, you know, which was more thorough about the parasite itself and the disease progression. It was like immediate success and attention for Carlos Shagas. Other researchers throughout South and Central America began looking for and sometimes finding the tripanosome in their area. and Shagas himself was awarded the Shawden Prize, which was given out only every four years

for the best work in parasitology and tropical medicine in the world. Wow. But all the success and acclaim came with an ample supply of haters, as it usually does. German microbiologist Rudolf Krauss took great issue with Shagas' claim that the disease was prevalent all across South America. Krauss, who was working in Argentina, had looked but had been unable to find any tripanosomes in any of the areas that he looked. And attacks also came from members of the Brazilian National Academy of Medicine who undermined his research and tried to discredit him. It's disappointing, I know.

Why? Why? And so I was thinking about, like, he got in some ways so lucky, right? like you were saying. Yeah. There is always like with new discoveries, there is always resistance. Like there does have to be the sort of like ping ponging of like, well, wait a second, we need to introduce some healthy skepticism into this.

And so maybe their attacks were way more personal than they needed to be. But I do think at the time, you know, part of their skepticism or hesitance might have been reasonable, considering also the fact that Shagas didn't get it all right in his first first go, but I mean, whoever does. Yeah. But, you know, he first thought it was the bite of the bug that transmitted the parasite, you know. Sorry, pretty reasonable.

That's very reasonable. And then the French parasitologist Alexander Brumpt soon realized it was through the feces of tritomines. And, but the other big thing, the big mistake or false association that Shagas made was that he incorrectly associated the disease with goyters, which were really prevalent all across Brazil, goyters being caused by an iodine deficiency. And so other researchers were finding people with goyters, but without tropanosomyasis. It couldn't find the tripanosomes. Yeah. And so they were like, we're not, like, you're seeing something that we're not seeing. Yeah. And I feel like the reverse

story where those detractors, those haters, like, have been right in other, you know, histories of disease where they're like, you're not seeing what you're seeing. It must be something else. So anyway, it's just, it's the way history is written now. Yeah. And so some of these haters might have simply been jealous of his quick rise to fame and his ample success, but some may not have wanted to recognize that someone not from North America or Europe had made such a monumental discovery. That was going to be my guess. Yeah.

So like I said earlier, Shagas was nominated twice two times for the Nobel Prize. And in the second time he was nominated, it was 1921. The Nobel Prize wasn't awarded to any scientist that year. And there was no evaluation. There's no record of evaluation of his nomination. or like his research or whatever by the committee. What? So it's a little fishy.

Yeah, apparently there's like some drama in those early years about who got the awards and whatever, which is unsurprising. Yeah. But as a result of all this negative press, Shagas disease was like all but forgotten about for a short period of time, like a few years until physician Salvador Mata from Argentina began researching the disease. His studies across Argentina, which were conducted in the late 1920s, found hundreds of cases of Shagas disease where Kraus had found none. Okay.

Yeah. I think in one of the publications, Shagas, like, kind of hinted about like, oh, well, you might not really have the right technique for scope, you know, microscopy or whatever. And Mata was the first to suggest that the tripanosome could be transmitted through. blood transfusions, which were slowly improving and becoming more accessible in like, you know, 30s and 40s. Mazza's work showing widespread prevalence again kicked things off for Shagas disease research as more and more researchers became aware that it was this tip of the iceberg type of situation.

Increasing development, deforestation, and urbanization throughout the mid-20th century led to both this increase in disease prevalence, as well as the construction of hospitals where the chronic manifestations of the disease and congenital transmission could be more easily studied, especially as technology improved to actually see what was going on inside like with your heart and with megacolon and so on. Shagas's son, Evandro, followed somewhat in his father's footsteps and played a big role in uncovering the widespread and hidden nature of the disease. And the little girl, Bernice, Shagas' first Shagas' first shawes.

Chagas patient was found again at the age of 53 still with circulating tripanosomes, but no sign of disease. Oh, good. Yeah, yeah. She died, I think, at the age of 73 or 78 maybe with, I think 78 with no relation to Chagas disease. That's pretty good for being born in the early 1900s. Mm-hmm.

Mm-hmm. Yeah, 1907. Shagas himself became a huge figure in the history of Brazilian public health as the director of the Oswaldo Cruz Institute for 17 years and the head of pandemic influenza campaigns, the head of the Department of Health in Brazil, he discovered numasista's pneumonia and created a nursing school. He did a ton of work in his relatively short life. I think he died in his 50s. Oh my gosh. Mm-hmm. Oswaldo Cruz died at 44 of kidney disease. I know. Oh, my gracious. Yeah. There's also a journal named after the Institute. Oh, yeah, I got a lot of paper. I've read a lot of papers from that journal. I was like, I know you as an institute and a journal, not as a human being. Yeah. It's fun to learn about you. Nice to meet you. But not all Shagas disease researchers were like Shagas. Not all of them cared about. the well-being of the people that they studied. For example, in an instance of medicalized torture in Texas, a researcher named Ardzruni Pachanian

crushed some kissing bugs and smeared them into the eye of a black man in his 20s, who was likely a patient at Austin State Hospital, formerly known as the Texas State Lunatic Asylum, just to study the progression of disease and how long this person would remain with like circulating parasites. Yeah, so the symptoms of the person did show symptoms of disease and eventually they recovered and were declared tripanosome free, but yeah, the study continues to be cited. What? I know.

So Carlos Chagas recognized all the way back in 1909 the public health relevance of American tripanasomiasis. But it wasn't until the 1980. that countrywide surveys were conducted using standardized protocols and a reliable estimate of the number of people infected and at risk could be even estimated. And those numbers were often shocking. I'm not going to go through all of them, but, you know, I'll throw a few out there. So from like 20% in Bolivia to 20% of rural Chile and up to 50% in parts of rural Venezuela, Shagas was a much bigger problem than I think. anyone had any idea about. I feel like that's still true. Yeah, definitely. And around the same time, the HIV-AIDS pandemic revealed that tripanasoma cruzzi could be reactivated in immunocompromise people and proved to be a huge complication there. And this growing awareness of the enormous problem that

Shagas disease poses did help lower the incidence of disease in some places, such as through like the Southern Cone Initiative and other pushes for eradication and control. And the existence of the somewhat effective drug that's used, I think it's Benzni-Dazoli. Sounds close to right. Yeah. Which was introduced in 1966. These things also helped. But we're still a long way off.

Yeah. But exactly how far off are we, Erin? Oh, what a good question. Let's get into it right after this break. It's interesting, Erin, because despite just how, when you think about it, just how inefficient the transmission cycle really is in terms of trying to get the poop of this bug somewhere near a bite wound. The overall ecology of this disease is so complex. with so many different wildlife and domestic mammal species involved.

And in humans, the infection can persist for so long that this is not only a very difficult disease to control, but estimates of incidents and prevalence are also very difficult. Right. But we'll do our best here. Yeah. Estimates of incidents, the number of new infections, annually range from 0.1% to 4% of the population in endemic regions, so largely in Central and South America. Wow. Yeah, which is pretty high in and of itself. Right. I mean, if every year

4% of people are getting infected. Yeah, yeah. But in a lot of places, Chagas isn't even like a reportable disease everywhere that it's endemic. And it's often, it's often. often only diagnosed in the chronic phase, and a lot of places don't have, like, registries. So all of these are really just estimates. When we look globally, it's estimated that between 6 and 7 million people worldwide are living with Chagas disease currently. And what I don't know, because I see your face thinking, is does that mean 6 to 7 people living with some amount of illness from Shagas disease or 6 to 7 million people living with

tripanosoma cruzzi in their bloodstream. Right. And I imagine, because that number is from the World Health Organization, that that means people with some amount of disease. Okay. Okay. But what's worse than that number, 6 to 7 million people, which is probably an underestimate, that's pretty bad already.

Mm-hmm. But it's estimated that only one to two percent of those people living with Shagas disease have access to treatment. I was going to ask, A, what is the treatment for chronic disease? And B, how much does it cost? So once you get to chronic disease, what you're dealing with is whatever your disease manifestation is. So if you have heart failure from Shagas disease, you're treating someone for heart failure. You're not treating them for Shagas disease. Right. Right.

If you have somebody with mega esophagus, you're treating them for megastasis. esophagus. That's a huge part of the problem, right? Right. So you have to be able to find people before they have heart failure from shockus. And like we've touched on, though historically this is a disease of poverty and of Central and South America and the southern part of the United States, we live in a globalized world. And because of global migration, this is a global disease. And like you touched on Aaron in non-endemic areas like Europe and much of North America, physician knowledge of the disease is seriously lacking. And it's thought that cases are underdiagnosed by like 95% is one of the estimates that I saw. That's horrifying, but not surprising. Right. I mean, because it's, again,

if somebody comes in with heart failure, it's not going to be the top thing that you think of as someone living in Europe or a lot of North America, like, is this the underlying cause of your heart failure? Right. Yeah. If we look at economics, and you know, I don't really love talking about the economic part of it, but I think it's important from a public policy perspective. Shagas disease is estimated to have a global economic burden of over $7 billion annually. That's more than rhodovirus. That's more than cervical cancer. That's more than Lyme disease. And results in an estimated over 800,000 disability-adjusted life years annually.

Okay? Yeah. It's a big deal. It's a huge one. Yeah. Huge. So when it comes to research needs, there's a lot of them, right? Like I said, there's a lot of parts of this from the ecology to the pathophysiology, to treatments.

to vaccines that we just don't have enough information on. We also just don't have a great handle on prevalence. So there's a lot of room for investigation. And luckily, there's a lot of incredible people who are researching Shagas disease from every single angle. At this point, as far as I could tell in my research, there aren't any novel therapeutics that have made, made it very far in the research chain.

There are a couple of different avenues for promising vaccine research, both in preventative vaccines, so vaccines to help prevent the disease as well as therapeutic vaccines, which would be something to help prevent the development of chronic disease. But as far as I could tell, these are all in pretty early stages of development, and one of the biggest issues is funding. Mm-hmm. And then, of course, people are really starting to realize the impact of not. non-vector-borne transmission roots such as congenital infection and how little we know about that.

So suffice to say there's a lot of different research needs. Oh, yeah. For that reason, we wanted to talk to somebody who has done research on a lot of different aspects of Shagas disease, from trying to better understand the dynamics of Shagas here in the U.S. and involve citizen science, which is so cool, to really nitty-gritty molecular biology to better understand the vectors and the pathogen itself, and so much more. So we wanted to talk to someone about all of these lingering questions that we have regarding Shagas. And for that we turned to one of our faves, Dr. Sarah Hamer. All-time faves.

I'm Sarah Hamer. I'm an associate professor in the College of Veterinary Medicine and Biomedical Sciences at Texas A&M University. I'm a veterinarian, and I lead a research lab on the ecology and epidemiology of infectious diseases. Awesome. Thank you so much for taking the time to chat today. I'm super excited to hear more about Shagas disease. So in this episode, we have so far largely focused on the health impacts of Shagas disease on humans, but many different animal species can also be infected with tripanasoma cruzi, including both domestic and wild animals. So what can infection with the tripanosome look like in these different animal species? And do some animals tend to be

more negatively affected than others? That's a great question. So I think the first issue is, you know, this is a generalist parasite that can infect virtually any mammal. And it's a generalist vector that will happily feed on lots of different animals, you know, domestic, wild. So I think it, yeah, it makes sense to try to think about right. How does disease differ, you know, depending on the host that's infected? Sadly, we don't really know about the impact on a lot of different wildlife species that are infected because it's hard to come up, you know, to find them. It's hard to get money to study the, you know, clinical outcome or to follow them forward over time. It's hard to do that in nature. The nice thing is, you know, from what we can understand, what we know,

disease seems to look similar to what it does in humans. We know the most about the disease outcome in dogs, in non-human primates, and in humans, just because that's where the most amount of clinical attention has been paid. So just as we see in infected humans, what we see in these infected animals is that there can be a subpopulation of infected animals that might not ever develop signs of disease. They might remain asymptomatic for life. So that's a very good thing. But there is, you know, some percentage, some unknown percentage of infected animals that will develop disease, usually heart disease. And depending on where the parasite affects the heart, we might see different, you know, outward manifestation of the infection. So, you know, just like humans, we can see inflammation, fibrosis of the heart, depending on, you know, exactly where the parasite localizes in the heart. This can lead to, you know, acute problems. This can lead to chronic problems in the animal.

especially with fibrosis of heart failure. We see sudden death. Often young dogs can die suddenly from this infection. We're working now to try to figure out, you know, if there's an infected animal, what are some ways that we can predict the outcome of infection? Is this something we need to be worried about versus is this something that the animal will be able to live with this infection for life? And we don't need to be as worried about it. Awesome. Yeah. That was really interesting that you might be able to try to figure out who is going to be able to live with this long-term those that might not be. And so since some animals can act as reservoirs for a tripanasoma cruzzi,

they can, of course, have a big impact on the transmission cycle of Shagas disease and then the risk of exposure to humans. So let's start with the domestic side of things. Which domestic animals play a role in the infectious cycle, and what does that role look like? And are there some domestic animals that contribute more than others to the risk of exposure for humans? Yeah. So when we think about domestic animals and Chagas disease, the main, you know, domestic animals that come to mind would be our dogs and cats, you know, the most

commonly owned pets here in the United States and elsewhere. And both those species can play roles in sort of the ecology and epidemiology of Chagas disease. We know most about dogs. K-9 Chagas disease has received far more veterinary attention than feline chagas disease. But what I, what I'd like to start by saying is that there's no evidence that, you know, that infected dogs or infected cats pose a direct transmission risk to people. So even if you knowingly or unknowingly own a dog that's infected, for example, that sort of direct risk dog to human transmission hasn't been shown. Instead, the role that infected dogs might play is that they could potentially infect kissing bugs

that feed on them. And then those kissing bugs that are around the home could be a source of infection to other animals or to people. So when we think about, you know, domestic animals and their role as a reservoir, by reservoir here we mean that it's an animal that not only gets infected, but it gets infected and can kind of sustain that parasite in its body and then serve as a source of infection to another animal or to, in this case, to a vector that's feeding on it.

And dogs can certainly play that role. It's actually really hard to figure that out, though. It's not as simple as just figuring out if an animal is a reservoir by taking a blood sample, and doing a molecular test, and yep, the parasites there, it's a reservoir. Instead, the approach that we've used, you know, in our research settings at least, to define the role of dogs as reservoirs, is that we can sample their blood and then bring that blood to our kissing bug insect colony that we have on campus. And then we can feed the blood from the dogs to clean insects in a very controlled environment. We can monitor those kissing

bugs for infection to see if they become infected and will shed the infection in their feces. We can do that days, weeks, or even months after they've been fed, this potentially infectious blood meal. So it's through, you know, some really neat techniques like that that we can begin to define who are the important reservoirs in domestic environments or in wild environments. And that, you know, helps us understand the ecology of this disease better. That is fascinating. Oh, my gosh. A little. colony of clean kissing bugs and then feeding them blood. I can't. That's really cool. Yeah, it's a unique resource that we have for sure. People have mosquito colonies and tick

colonies, but this kissing bug colony is pretty unique and is definitely open the doors for research. Yeah. Wow. Amazing. Wow. So, you know, I want to ask you a little bit more about some of the research that you do, in particular your incredible citizen science or community science projects and what they have told us so far or what they can tell us about the landscape of Shagas disease risk in Texas. Yeah. So back in 2013, we started a big community science program where we intended to provide a lot of good material for the public about kissing bugs and about Shagas disease. And in return, if members of the public happen to see or find kissing bugs in their home, you know, on their property and their dog kennels, they could safely collect these insects and then submit them to our

lab for part of our research. So this really started, you know, out of desperation because we were out doing fieldwork and these insects are really hard to trap using standardized traps. You know, manual fieldwork to find them can be pretty labor intensive. But we were trapping on these Texas ranches and other areas. And the landowners would tell us, oh, yeah, I've seen those insects before. And, oh, I've, you know, I captured a couple of those. I saved them. You know, and they might have them in an old pill jar in the freezer. And so it was really through that. That was the start of our community science program.

And it's definitely a two-way street. You know, we want to provide a lot of good info. We do that through our website, through a smartphone app, through printed brochures and outreach seminars that we give. And then in return, since 2013, we've received over 8,000 kissing bugs from people in 27 different states. Then they've submitted these insects to our program. and we can learn a lot. And basically at the state level, this community science program has replicated, you know,

what's known of the historic distribution of kissing bugs in the United States and has provided just a wealth of great material for our research program. So from the community science program, we've learned that on average, it's just over 50% infection prevalence of these insects. So of all the insects that we've received from community members that have submitted them, to our program, we will dissect them, take their gut material out, do DNA extractions, and then try to figure out if they're infected with the parasite or not. And we found over 50% of the adult insects are infected with tropanosoma cruzzi. So pretty high infection prevalence.

And then furthermore, we've learned that there's two major genetic variants of the parasite that we find in kissing bugs of the United States. And we're kind of mapping out those genetic variants and trying now to figure out if there's different health consequences when people or animals are infected with one type or another. But the most exciting thing I think that we've been able to do with these community science submitted kissing bugs is what's called a blood meal analysis where we can take an individual insect and figure out what has it fed upon, what type of blood meal did it get from what species? And this is really important for not just understanding the ecology of the disease, but trying to open the doors for management, because if we can

figure out what types of animals are important for feeding kissing bugs and maintaining their populations, then maybe we can try to manage those species so they have less contact with the vector. So just a glimpse of some of our data from blood meal analysis of these community science kissing bugs, we find overall about half of them have evidence of feeding on a dog. And that makes sense because we know that a lot of these bugs submitted by the public are actually found in dog kennels or in areas where their dogs sleep. A lot of people submitting bugs will report that they own multiple dogs. So that makes sense. We also find that kissing bugs have fed on cats, chickens, tortoises.

A lot of it is, you know, just depending on the habitat where they're found, whatever the most abundant host is there, that's what they're going to feed on. Like, you know, kissing bugs collected from a chicken coop, they're going to feed on chickens. But we also get some exciting observations like tigers, and that was found from some bugs that were submitted from the local zoo. So it makes sense that that host is available and the bugs will happily feed on it. And two of my favorite observations was an elf owl. We found evidence of a kissing bug feeding on the elf owl, which is the world's tiniest owl. And this was a bug that was collected by a community member from Big Bend National Park, where these elf owls will nest. So that was pretty neat.

And then a more recent one was our results from blood meal analysis was a peach face love bird. And we thought love bird, like this isn't a wild species, you know, where this insect was submitted from. So we wrote back to the submitter and we said, we're trying to make sense of this, you know, DNA sequence that we got. And she wrote back immediately and said, that's my pet love bird that I have in a cage in the house. And so this, you know, this technique can really open our eyes for just how flexible these kissing bugs can. be in what they feed on. And this was all enabled by our community science program. That is incredible. 8,000, first of all, and also feeding on a tiger. Like, that's so cool. I never would have thought I was like, okay, what is the coolest animal I could think of?

Like the most surprising animal I could think of in terms of kissing bugs. And a tiger definitely is shocking and very cool. Yeah. And over time, it's data like this that will help researchers piece together, not just the feeding patterns of the insect, but if we can couple that with what animals are infected and what insects are infected, we can just piece together these transmission networks. And I think that's going to be really exciting for, again, opening the doors for management. Yes, absolutely. And so, you know, on the note of the fact that these kissing bugs feed on so many different species of animal, I kind of want to shift to now talk about the wildlife and, like, the sylvatic cycle of these bugs. And so, you know, humans might not have as much

contact with wildlife as they do with domestic animals, but many wild animals can still increase the risk of shagas disease or the prevalence of the tripanosome in certain areas, which then might impact the risk to humans. So which wildlife species are considered the most important reservoirs? I know this changes a lot geographically as well, but are there some, you know, more than others that seem to be, you know, play the largest role? And, you know, I also wanted to kind of ask you about how things like deforestation and land use change is impacting shagas disease in wildlife and then thus exposure to humans. So across the southern United States where kissing bugs are endemic, there have been a lot of different infected wild animals that have been identified.

But in terms of the key species that are most likely playing that role as reservoirs, infecting other kissing bugs and kind of perpetuating this transmission cycle, in nature. Some of the key species that have emerged include raccoons, possums, armadillos, woodrots, coyotes, to a lesser extent other rodents or bats. But very little research has been done to really rank their importance to figure out what is the exact wild species that's the most important reservoir in this area or another area. In terms of your question about land use change and, you know, deforestation or other types of land use change that's occurring, Of course, we know there's some pretty cool and compelling stories from different vector-borne diseases that would say that certain types of deforestation might really increase transmission.

For example, the Lyme disease system. I think it's a little premature to understand exactly how deforestation or other land use change is likely to impact the ecology of Chagas disease. These triadamines, you know, they're not just found in silvatic or natural environments or more rural environments. we also regularly find them in urban areas. For example, lots of collections from San Antonio, Dallas, Fort Worth, some of these major urban cores here in the South. So they're flexible in where these different kissing bug species can thrive.

But certainly, you know, if we have changes to the landscape like deforestation, that might make that area more or less attractive to the raccoons or the possums, who really can thrive in small forest fragments adjacent to human, dwellings. And so maybe if we're changing the landscape in a way that makes it more attractive to some of these medium-sized mammals, then we could have even more, you know, more of these reservoirs across the landscape that could increase transmission risk. But we can imagine scenarios where the opposite could be true as well. Yeah, it's such a complex system. It's something, it's a theme that we've hit on so many times during this episode is that there are just so many

moving parts at play. And so it makes sense that, you know, there's not a clear path forward or a clear prediction as to things like climate change, things like deforestation, land use change, and what impact they'll have. Yeah. Yeah. So what do you see as the biggest challenges in the control of this disease? Yes. There are two big grand challenges that come to mind when I think about the control of Chagas disease. The first is just simply that this is a sylvatic disease. And by that we mean it's associated with these vectors that are out in nature interacting with a lot of different.

members of the wildlife community. We talked about how the insects will happily feed on all different sorts of critters. The parasite can infect virtually any mammal species. So it's sylvatic and it involves a lot of players in the transmission cycle. So it's not as simple, not that it's simple, but you know, when we think of a different vector-borne disease, you know, human malaria, for example, main reservoir would be humans, you know, certain mosquito species. In comparison, here we've got just dozens of species that need to be considered in the management of this disease in nature. So it's silvatic. The second big challenge that comes to mind is just this relative lack of awareness,

lack of medical awareness, lack of veterinary awareness for Chagas disease. Tripana's a McCruzi, this is neglected from medical attention. It's neglected from research communities. And so it's typically, especially when we're thinking about Chagas disease in the United States, it's quick to conclude, oh, this is a, you know, this is a problem elsewhere. This is a problem across Latin America. But we've got these endemic kissing bugs and we've got endemic infected wildlife. And we have spillover transmission to humans and to our domestic animals that are causing big problems.

But because there's not more attention, we're not testing more. So we don't have a good understanding of really, especially from the veterinary perspective, how many animals are impacted, what species, you know, what are the impacts for their health? And without those numbers to show just how many animals are impacted, then, you know, it's hard to convince big granting agencies to put more money towards this problem. And so I think the overall lack of awareness is one of the biggest challenges for this disease. Yeah, absolutely. So on that note, could you mention the name of your, the app and the community science project that you're talking about in case listeners want to get involved or want to find out more about? the work that you're doing? Sure. Our community science website is kissingbug. Tamu-T-A-M-U.

And from that website, you can learn all about kissing bugs, Chagas disease, wildlife reservoirs, dog infection, and so forth. But importantly, this is also the portal from which you can contribute your observations and insect specimens to our program. So there's instructions there on how to safely collect these insects and submit them to our program. And the same would be true. Our app is available for Apple and Android from the iTunes store and Google Play. And you can download that there and has the same capability as the website. Thank you so much, Dr. Sarah Hamer, for talking with us.

It was absolutely thrilling and enlightening and wonderful. And you remain a hero to us. A true hero. Should we do sources? We should do sources. Okay. So I'm going to shout out, I think I have more sources for this than any other episode. Wow.

Yeah. I just couldn't stop. I'm going to shout out a few. So the first one is the kissing bug, a true story of a family, an insect and a nation's neglect of a deadly disease by none other than Daisy Hernandez. Go check it out. And a couple articles I found super helpful were by Althurhide at all from 2004, a 9,000-year-old record of Shagas disease by Clement et al-N-Ale, 200020, out of Africa, the origins of the protozoan blood parasites of the tripanosoma cruziclade found in bats from Africa, and by Stiever Ding from 2014, the history of Shagas disease. and a whole bunch more that I'll post. I also had probably not as many as you, Erin,

but there's a number of really great kind of comprehensive reviews. A couple in the Lancet, one in the New England Journal of Medicine. There's actually a whole bunch of really nice reviews. We'll post a list of all of our sources from this episode and every single one of our episodes on our website, this podcast will kill you.com. Thank you again so much, Daisy, for taking the time to chat with us. We truly appreciate it. Yeah, thank you. Thanks to Bloodmobile for providing the music for this

episode and all of our episodes. Thank you to the exactly right network of whom we're very proud to be a part. And thank you to you listeners. We appreciate you so much to like keep tuning in episode after episode and listening to us talk on and on about pathogens and parasites and metals and genetic diseases and all of the things. And a special shout out to our patrons. We love you guys. Okay, well, until next time, wash your hands. You filthy animals.

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