How do parasites evade our immune system? (featuring Dr. John Hawdon)

Daniel and Kelly chat with Dr. John Hawdon about how parasites like hookworm, malaria, and schistosomes hide from our immune system. See omnystudio.com/listener https://omnystudio.com/listener for privacy information.

Speaker names marked ? are inferred from speaking time and the show’s known hosts — they are not voice-verified.

• 0:00Daniel Whiteson?

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• 0:04Speaker 01

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• 1:34Kelly Weinersmith?

  Howdy, friends. Just a heads up that we're talking about parasites again. And as you're probably aware of by now, that can get pretty gross. Also, it's kind of upsetting to hear about parasite life cycles and the effects of parasites on our health. I get that. Today, we're going to be talking about malaria, schistosomiasis, and hookworm. So decide if those are topics you are prepared to hear about. All right, here we go.

• 2:03Kelly Weinersmith?

  According to the World Health Organization, in 2023, about 263 million people were infected by malaria, of which 597,000 passed away from this disease. Most of these deaths happened in Africa, and 76% of the deaths were children under five. You might remember from a past episode that we were able to create a vaccine for smallpox and that that vaccine was used to wipe smallpox off the face of the planet, saving humanity from this ancient scourge. And yes, thanks to all who wrote in, I pronounce the word correctly now. We also have vaccines for other bacterial and viral infections like polio, chickenpox, human papillomavirus, COVID-19, measles, mumps, et cetera.

• 2:47Kelly Weinersmith?

  With the exception of some tricky viruses like HIV, which hide in our immune cells, we've had a lot of success making vaccines for viral and bacterial infections. And we know that our immune systems attack big stuff, as well as the little stuff like bacteria and viruses. In a past episode, we talked about how our immune systems will attack entire organs following a transplant. So why do our immune systems seem to do such a crummy job of attacking parasites in our bodies, things like nematodes? And why is it so hard to make vaccines to give our immune system a leg up on these invaders? We've been working on malaria vaccines for a really long time, but only recently have two malaria vaccines become widely available

• 3:30Kelly Weinersmith?

  in areas in Africa where malaria is prevalent. That's good news, but why did it take so long? And why don't we have a vaccine for hookworms yet? Remember hookworms? Those dirt worms we talked about a few months back? Yeah, those guys. There are many parasitic diseases that have proven stubbornly difficult to control with vaccines. And so today, we're going to talk to Dr. John Hawdon, a molecular biologist and parasitologist who's going to help us understand why it's so darn hard to make vaccines against parasites. Welcome to Daniel and Kelly's Extraordinary Universe.

• 4:17Daniel Whiteson?

  Hi, I'm Daniel. I'm a particle physicist and I'm excited to be talking about all sorts of icky invaders today.

• 4:23Kelly Weinersmith?

  Hello, I'm Kelly Wiener-Smith and I always love talking about icky invaders, although with all the required sensitivity for the pain and suffering that these parasites cause. But anyway, I study parasites and space. And today, we're talking about my first love, parasitology.

• 4:37Daniel Whiteson?

  Your first love. Something I love about science is how excited people get about their funny little tiny little niche. You know, you're gonna meet somebody who's like amazed at the hairs on spiders' legs, or somebody else who like can't stop thinking about how, you know, the mantle flows and how rocks form. And like, these nerds get so excited about their little niche. It's wonderful, right? That's why we know so much about the universe and spider legs and rocks and parasites, because people get weirdly excited about stuff.

• 5:10Kelly Weinersmith?

  My friend Ashley Smythe refers to this as a limitless human curiosity.

• 5:14Daniel Whiteson?

  Yes.

• 5:15Kelly Weinersmith?

  Because I was asking her about like, oh, why do parasitologists sometimes infect themselves with the parasites that they study? Isn't it weird that we do that? And she was like, Kelly, that's our limitless human curiosity. And I was like, okay.

• 5:28Daniel Whiteson?

  I totally love that about humanity. I mean, curiosity is something deep about being human. Actually, I wonder if it is just about being human, or if, you know, aliens are curious about the universe also, if that's something that really is universal. But today, unfortunately, we're not talking about aliens. We're talking about critters so gross that invade you that it almost feels like they are alien.

• 5:49Kelly Weinersmith?

  And today, we invited on the show my friend John. He's going to be talking about three different kinds of parasites. And specifically, we invited John on the show because we had two listener questions that felt somewhat out of my expertise, even though I'm a parasite person. And so I knew the guy to invite on the show. So let's go ahead and listen to the two questions from listeners before we bring John on.

• 6:11Speaker 06

  Hi, Daniel and Kelly. This is David from the San Francisco Bay area. And this question is for Kelly. What makes developing a vaccine for parasitic infections so difficult? It seems like progress has been only recent and incremental with some experimental vaccines for hookworm, and the one-approved malaria vaccine is not very efficacious. So what gives? And this topic is at least tangentially related to what I do for a living, which is working on a new platform to produce RNA-8 therapeutics, so I'm especially interested in what you have to say. Anyway, keep up the great work, both of you, and Daniel, I forgive you for your chemistryphobia. Cheers.

• 6:44Speaker 07

  I got my master's degree in the late 70s. At that time, there are three theories on how systems evade the immune system. My advisor's theory was called molecular mimicry. Although it was over 40 years ago, I remember it well because for the final exam, we had eight hours to answer two questions, one of which was to name the three current theories of how the treatment hosts evade the immune system, and which one do you agree with and why? Of course, I chose my advisor's theory, but after receiving my master's degree, I lost track of the issue since I got my doctorate in different but related subjects. My question is, what advances have been made and have any conclusions been made pertaining to their evasion of the host immune system? And if so, will lead to a practical subject such as tissue transplantation?

• 7:29Daniel Whiteson?

  All right, these are awesome questions, and thank you to everybody who writes to us with your questions. We really do love to hear from you. If you have questions about comets, or about malaria, or about parasites, or about whatever you have limitless curiosity about, please do send them to us. We'd love to hear from you, [email protected].

• 7:49Kelly Weinersmith?

  All right, and without any further ado, let's bring my friend John on the show to answer these listener questions. Dr. John Hawdon is a parasitologist and molecular biologist at the George Washington School of Medicine and Health Sciences. He was previously the president of both the American Society of Parasitologists and the Helminthological Society of Washington. He's done some really fantastic work on hookworms, which you'll remember are one of the dirtworms or geohelminths that we talked about in a prior episode, and we're very lucky to have him come on the show to talk to us about parasites and vaccines. Welcome to the show, John.

• 8:22Speaker 08

  Thank you. My pleasure.

• 8:23Kelly Weinersmith?

  We're excited you're here.

• 8:24Speaker 08

  I'm excited to be here.

• 8:26Kelly Weinersmith?

  You sound really excited, John.

• 8:29Kelly Weinersmith?

  Okay, so let's start with hookworms. So we did have a whole episode on the soil geohelmets, which we call dirt worms. But just to remind everybody, can you talk about the life cycle of hookworms?

• 8:41Speaker 08

  Sure. So hookworms live as male and female worms in the intestinal tract of various mammalian hosts. And they get together and have their little party and the female will lay eggs that are been fertilized and they pass out into feces. They spend a period in the ground where they hatch and they develop through two molts to a third stage larva or L3 that's infective for the next host. And then the next host gets infected by either coming into skin contact with the infective larvae, or in some cases, like in dog hookworms, for instance, by ingestion of the larvae.

• 9:20Daniel Whiteson?

  We're talking about eating poop?

• 9:22Speaker 08

  Well, yeah. As I tell my students, you know, when you get one of these fecal oral diseases, it means you ate a tiny little bit of poop.

• 9:30Kelly Weinersmith?

  Yeah, poop to mouth.

• 9:31Speaker 08

  So, once they get into this, into your host body, if they go through the skin, they undergo a migration that takes them into the circulatory system to the lungs where they break out in the bronchioles and they crawl up your bronchial tree to the trachea, to your mouth where they're swallowed and then are carried to the small intestine where they will resume the development and molt to the adult stage. If they enter orally, they don't need to leave the intestine and they can develop directly to the adult stage.

• 10:05Daniel Whiteson?

  And they're called hookworms because they bite onto the wall of your intestine and hook in?

• 10:10Speaker 08

  That's a common misconception.

• 10:12Daniel Whiteson?

  All right.

• 10:13Speaker 08

  It's actually, it's actually because of the way the worms appear, they can't see me, I'm doing this for the camera, but do a little bend, but, uh, yeah, so there's a little bend in them that makes it look like a hook.

• 10:27Kelly Weinersmith?

  Okay.

• 10:28Speaker 08

  Like if you have gotten some from, from inside an animal and you put them in a dish, or even if you're looking at the surface of an infected small intestine, they will be appear to be bent.

• 10:39Daniel Whiteson?

  You said if you're looking at a dish of them, like you mean you're at a restaurant and somebody serves you like a, you know, hookworm salad or something?

• 10:47Kelly Weinersmith?

  Allo mode?

• 10:47Speaker 08

  Allo commode?

• 10:51Kelly Weinersmith?

  Sorry. We love potty humor, us parasitologists. All right, I don't want to get us too far off track, but I have to ask, when the worms crawl up your trachea and into your mouth, do people feel that? I think I asked our mutual friend Jimmy, who got infected with hookworms as part of an experiment, and he said he did not at any point feel the hookworms crawling in his mouth. What's the deal there, John?

• 11:12Speaker 08

  Well, he's the expert on that. I have never been infected, but my understanding is you don't notice it.

• 11:17Kelly Weinersmith?

  Okay.

• 11:18Speaker 08

  Right? So you'll swallow them with food or with saliva or whatever.

• 11:22Kelly Weinersmith?

  Gross and amazing.

• 11:23Speaker 08

  Oh, my God.

• 11:25Speaker 08

  Well, they're clean by the time they run through your body, so.

• 11:29Kelly Weinersmith?

  Sure. All right, so with a lot of infections like chicken pox, you get it once and then you have lifelong immunity. So why doesn't that happen with hookworms? Like, why can't you give everybody one hookworm and then for the rest of their life, they never have to worry about getting hookworm?

• 11:45Speaker 08

  Boy, life would be a lot easier if you could do that.

• 11:47Kelly Weinersmith?

  Yeah.

• 11:47Speaker 08

  Hookworms are, like most parasites, are very good at evading the immune system, and they can do this actively or passively, primarily actively. They release molecules, most of which are unknown, that alter the immune response to be a favorable environment for them to survive. The human hookworms, notably, you never really get a sterile immunity to them. You can be reinfected and over your entire lifetime. Dog hookworm, for instance, the second infection never takes as well as the first, and the older the dog gets, the less likely it is to get a heavy infection of worms.

• 12:25Kelly Weinersmith?

  So, okay, so wait, dogs mount an immune response better than humans? What, do we understand why that's different?

• 12:30Speaker 08

  No.

• 12:31Kelly Weinersmith?

  Okay.

• 12:32Speaker 08

  But there's a, independently, there's an age-associated resistance in dog hookworms, so that the older the dog gets, the less likely it is to get a heavy infection. This, you don't see this in any of the human species, to our knowledge. I mean, you can get infected as a kid and you can infect it as an elderly person with Nicater americanus, for instance, and you're gonna, you'll still be infected.

• 12:56Kelly Weinersmith?

  Got it. And just a quick reminder for folks that Nicater americanus is a species of hookworm.

• 13:01Daniel Whiteson?

  But microscopically, like, what's the issue? The hookworm has got to be a foreign body. Doesn't the immune system identify it as foreign and attack it the way it does if you like, get a splinter or get an organ donation? What's the obstacle for the immune system? Have these hookworms evolved to like, look like human flesh?

• 13:18Speaker 08

  There's a couple of problems. First of all, there's no good way to get rid of a large organism like a hookworm. It's also in the gut, which is a little bit harder to deal with, too. So you get what's called a weep and sweep reaction, where you get a lot of secretion of liquid, of water and things into the gut that cause it to be flushed out. And you don't see that in hookworm, then it's probably due to them suppressing that and turning the immune reaction into one that they can tolerate. And it basically, it becomes a trade off, because if the host puts enough evolutionary

• 14:00Speaker 08

  effort into getting rid of worms, they could do it, but it would be costly for them to do it. So in general, you come to this equilibrium where the number of worms is not really a big, has, has a large effect on the host. Now, there's exceptions to that. Some people get really high level infections that are dangerous. But for the most part, the, the host and the worm seem to come to an agreement where they kind of limit the damage, right? And it's this negotiation down on a molecular level, really, between the immune system and the molecules that the worm produces.

• 14:37Kelly Weinersmith?

  If the hookworms in our immune system have essentially like, come to a standstill, a standoff, why do we need a vaccine for hookworms if our immune system has decided this isn't worth fighting off?

• 14:49Speaker 08

  Did I say we needed one?

• 14:51Kelly Weinersmith?

  Okay. All right. So put yourself in the shoes of one of the people who are working on a vaccine for hookworms. What would they say for why we need a hookworm vaccine?

• 15:01Daniel Whiteson?

  I mean, I want a vaccine. I don't want to get hookworm. This sounds gross. Please give me a vaccine.

• 15:07Speaker 08

  You know, there used to be hookworm in the United States. And the reason you don't get hookworm here is because toilets, right? Once you've separated people from their waste, you break the life cycle and you don't have transmission anymore. In places where it's too poor to have sewers and sanitation like this, there's some need or desire to vaccinate, especially kids, so that they can minimize the effects of the infection. So it's thought that if you periodically deworm, or if you vaccinated, you would improve growth and development, you would improve school performance, and all these other economic indicators later

• 15:51Speaker 08

  in life, that people would make more money and this sort of thing. And there are some evidence for that, but there's also contradictory evidence that that would really happen. Again, in the most cases, even children aren't infected with dangerous levels of hookworm, right? But there is a small population, a group of the population that is highly susceptible to worms, called wormy people, basically. And for it's either genetics, or sometimes it's exposure, you know, behavioral things like that, that increase exposure.

• 16:24Daniel Whiteson?

  I can't tell because of your deadpan delivery if you're joking, or if scientists really called them wormy people.

• 16:29Speaker 08

  Oh, no, they do. They do. There's an article about this, a famous article by a man named Stoll, I believe, it said, this wormy world. So, and if people are called wormy, because they tend to get more worms. And it's that small, that group there that's going to have the pathology and everything. And I guess the question of skeptics of vaccines is, is it worth the investment to get to this small population with a vaccine, to target that small population with a vaccine? Or would the money be better spent either targeted treatment of this group of people, identifying them and then treating them, which is also expensive, but probably not as expensive as a vaccine? Or just improving sanitation in general in these places.

• 17:14Speaker 08

  And essentially, the only places that ever really controlled these dirt worms were places that economically grew out of it. For instance, Japan, South Korea, the United States, Europe, all these places basically built toilets and economically developed their way out of these parasites, these infections.

• 17:34Daniel Whiteson?

  Can I ask a question about that? I have a toilet-related question.

• 17:37Speaker 08

  Sure.

• 17:38Kelly Weinersmith?

  We get this a lot.

• 17:39Daniel Whiteson?

  You're saying that the presence of toilets basically separates people from their waste, and that breaks the cycle. And that makes sense to me, except that I live with a microbiologist, and she refers to toilets as fecal tornadoes, because when you flush, there's like a spray of microscopic poop, basically. And she does all these studies that show that if you live with people long enough, your microbiomes all sink, because you're basically breathing and eating each other's poop particles in the air. It's very romantic, let me tell you, to be married to a microbiologist. And so, how do I understand that at the same time as understanding that we've broken the hookworm life cycle? Are these hookworm larvae too small to like, take a ride in the fecal tornadoes? Is that the issue?

• 18:19Speaker 08

  Um, I don't know, but your fecal tornado is only gonna have the eggs, which are not infectious, right? It takes three or four days in a tropical temperature in order to develop to that infective stage. So unless you're leaving your poo sitting in the toilet for a few days, and then, I'm not even sure they would develop then. And then you did your fecal tornado.

• 18:42Daniel Whiteson?

  I see.

• 18:43Speaker 08

  But you know, I mean, why do we have an immune system? For things like fecal tornadoes, right? It's probably good for you to stimulate your immune system.

• 18:50Kelly Weinersmith?

  Yeah.

• 18:50Daniel Whiteson?

  A lot of life lessons here today on the podcast.

• 18:53Speaker 08

  I try to help the humans.

• 18:55Daniel Whiteson?

  Wormy or not.

• 18:56Kelly Weinersmith?

  Yeah. All right, so you said that hookworms release chemicals that sort of trick the immune system into not responding to it. So how do we have any hope of creating a vaccine against it? What have people tried so far?

• 19:08Speaker 08

  Well, the- I don't know how much of this I should say, but there is some promising results with vaccines now, and they seem to target antigens that aren't normally seen by the body and are involved in feeding, for instance, like gut proteins in the worm that will block feeding. Whether these pan out eventually to be vaccines is not clear, but in some early studies, they seem to be promising.

• 19:36Daniel Whiteson?

  Is an antigen something your immune system produces? No, that's an antibody. So then what's an antigen?

• 19:43Speaker 08

  Well, it's what your immune system recognizes to react to, produce an antibody or to.

• 19:49Daniel Whiteson?

  It's a thing that triggers the immune response.

• 19:51Speaker 08

  Exactly.

• 19:52Daniel Whiteson?

  Okay.

• 19:53Speaker 08

  To be honest, I thought, man, this isn't going to work. And sometimes I think it even surprised the people who do the experiments that it worked because, you know, these are hard organisms to kill. They're big and they have all these chemical defenses. The more we learn about them, the more there are, there are multiple overlying mechanisms to subvert the immune system. So, um, yeah, it is a daunting prospect. And one argument I've always had is that we jumped into making vaccines before we knew enough about the worm, that a lot of the money that went into early investment into the vaccines would have been much better learning some basic biology about the worms. And we're starting to know more about what they release, but we still don't know how

• 20:38Speaker 08

  they affect the immune system. So maybe had we waited a little longer, we would have had better antigens to use for the vaccine. But again, that money could also have been spent to build sustainable toilets in developing countries, which is something I had advocated for in earlier in my career.

• 20:57Daniel Whiteson?

  Well, it sounds like you have fundamental criticisms of this whole program, and yet you're the president of the American Society of Parasitologists. Why don't you have more influence? Why aren't they listening to you, John?

• 21:10Speaker 08

  Former president. Because, well, there are people with bigger voices than me involved in this. The WHO and various people there, there's a lot of money in trying to develop this. I don't want to be a cynic and say, well, this is how they make their money or whatever. This is what they truly believe and they're advocates for it, right? And they have a larger voice than I do in this. I don't think it's, you know, the money spent on the vaccine, you know, we did learn some things from that. So it's not money wasted in that case. And if they get a vaccine, I think it may be useful in certain situations. But then you get into the question of, do you want to kill all the worms? Right?

• 21:54Speaker 08

  I mean, there's a whole group of people in this, in this country and around the world who think having a few worms is actually beneficial for your immune system. And there's a lot of, there's an absence, let's say, or a dearth of information about how parasites and their hosts have co-evolved. And, you know, does this affect on the immune system that allows the hookworm to live? How does that affect other parasites and other diseases? And if you take that component away, what are you going to do to these other diseases? Some people think that that's why the West has this large number of autoimmune diseases like, you know, lupus and MS and all kinds of things.

• 22:38Speaker 08

  Because they've taken away some of the regulatory, we're getting now into the hygiene hypothesis. But, you know, they've taken away the early exposure to things, our old friends like parasites that have trained our immune system to not react to the little things and to only react to the big things that are dangerous. And you take that away and now you've got an entire arm of your immune system, which is designed to fight worms, is now looking for something to do. And it picks on, you know, it starts going after cell antigens and things like that. So these are all questions that we don't really know enough about. So jumping into deworming and vaccinating the entire world may lead us to places we don't necessarily want to go.

• 23:22Daniel Whiteson?

  We could end up nostalgic for the time when we had worms.

• 23:25Speaker 08

  We could. Some of us are.

• 23:29Kelly Weinersmith?

  All right. Well, in a future episode, I think we'll do a whole hour on the hygiene hypothesis because I find this topic absolutely fascinating. So wait for that in the future, folks. And in the meantime, let's take a break. And when we get back, we'll talk about parasite number two, the schistosomes.

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• 26:11Kelly Weinersmith?

  All right, and we're back. And now we are talking about the schistosomes. They cause a disease called schistosomiasis and they're quite nasty parasites. And Daniel's laughing at me. Why are you laughing?

• 26:22Daniel Whiteson?

  I'm laughing because we just went from the ones you get if you eat poop to ones called shisto, which you know, has some sort of resonance with other words we shouldn't say on the podcast. So tell me, is this another poop related parasite?

• 26:36Kelly Weinersmith?

  John?

• 26:37Speaker 08

  Indirectly. Indirectly. Its life cycle is a little bit different for a couple of reasons. The adults live in the bloodstream and the eggs come out in the feces. But let's just start with the feces and the eggs come out, they have to get into water. And when they get into water, they hatch and they get a small larval stage that now is on the hunt for a snail. And in the case of schistosomes, the snail is very particular. It has to be a particular species. They find it, they penetrate into it, and then they do several generations of asexual reproduction. And what this does is it builds up the number of the next stage, which is called a cercaria.

• 27:22Speaker 08

  And this is the stage is going to infect people. So in order to get schistosome, you have to have contact with water that has had both feces and the right species of snail. And if you do, the schistosome will swim and it will penetrate into your skin and then it will undergo a migration that goes, pretty much hits all the highlights in the body. It goes to the liver, it goes to the lungs. And eventually they come back to the liver and they pair up as a male and a female and they move up into the vessels. And depending on the species, it's either the vessels of the large intestine, small intestine, or the bladder. And here, the male and the female live in what's called Incopulo forever.

• 28:06Speaker 08

  The male has a body that's split, hence the name Shisto, soma, split body. And the female nestles in there and is mating essentially all the time with the male. And then they release their eggs into the bloodstream. That then undergo a remarkable journey to get out of the bloodstream.

• 28:27Daniel Whiteson?

  This is ridiculous. I mean, it just seems so implausible, like step after step after step. And then you got a snail and it's got to do this and you got to go swimming. But my specific question is, when you're swimming and the thing crawls through your skin, how big is this thing? Is this something you notice or just like you went swimming, you have no idea? And now it's inside you?

• 28:47Speaker 08

  Yeah, I don't think you notice it. It's pretty tiny.

• 28:50Daniel Whiteson?

  And why do they have to be snail sexuals? Like, why do they have to do this thing inside the snail? Why can't they just do it themselves in the water?

• 28:56Speaker 08

  Well, they, first of all, will need something to feed on. They basically will feed on the snail. Then it absorbs nutrients from the snail and makes all these new stages, these circaria. The purpose of this is that this allows them to go from a single myerosidium, it's called, that infects the snail into thousands of these circaria that's going to infect the next host. And what that does is it increases the odds of infection by putting more of these infective stages in the environment. If the myerosidium just tried to infect this host directly, even if it developed to the infective stage, the odds of that happening are pretty low. But the more of these infective stages you can put into the environment,

• 29:40Speaker 08

  the higher the odds are that one or more of them is going to get into the next host. And in the case of Shisto, sometimes you need a male and a female circaria to get in.

• 29:49Daniel Whiteson?

  So the snail is like a Shisto amplifier or something? It's just like?

• 29:52Speaker 08

  Exactly. That's exactly what it is.

• 29:54Daniel Whiteson?

  Crazy.

• 29:55Kelly Weinersmith?

  It's kind of ingenious. You know, the snail goes around grazing and collecting more food and that energy goes towards making more parasites. And so the parasites are getting like a buffet for doing nothing once they establish in the snail.

• 30:07Speaker 08

  This is a pretty gruesome parasite in the host, though. It causes a lot of problems. And it's not because of the worm, which is relatively tiny and living in the blood vessels. It's because of the eggs. So this mechanism that gets the eggs out is really elegant, but it's very inefficient. So a vast majority of the eggs don't get out. They end up in the liver and they form what are called granulomas when the host reacts to them. And that's where the damage comes from are these granulomas in the liver and other organs as well.

• 30:37Daniel Whiteson?

  Well, that was going to be my question. The hookworm we were talking about was mostly in the gut and there was some sort of negotiation. You can hang out there because it's difficult for us to attack you anyway. But these guys are all over. I hear them being in the blood, they're in the bladder, they're in the liver. So the immune system does respond to them. It forms these glastulomas.

• 30:56Speaker 08

  Granulomas?

• 30:57Daniel Whiteson?

  Granulomas, yes, thank you.

• 30:58Speaker 08

  Yes.

• 30:59Daniel Whiteson?

  Why doesn't it get rid of them?

• 31:01Speaker 08

  Well, the worms in the blood are pretty much untouched and they have a bunch of immunovasive mechanisms as well. Sort of similar to the hookworm, but different mechanisms. The eggs, on the other hand, they alter the immune system to make what's called a TH2 response, which is when you get a whole bunch of cells will come in and they'll surround the egg and form this granuloma. And then it will slowly move it through the tissue, right? And eventually they'll come to the bladder wall or the intestinal wall. And they will just basically dump the egg out, but they often get stuck. So you'll have these eggs stuck in the bladder wall. All this depends on the species, where it is, is it in the bladder? Is it in the large or small intestine?

• 31:44Speaker 08

  But in any case, you'll get them stuck in those, in the wall of those organs as well as in the liver. And then they're constantly releasing antigens that are pulling more cells in. And these granulomas can get very big and then start impacting the function of the tissue that they're in. And you get fibrosis in the liver and schistosomiasis can be really nasty disease. It's probably the most pathogenic of the worms that infect humans.

• 32:12Kelly Weinersmith?

  I thought I heard, and remind me if I'm wrong, I thought there were some areas where the kind of schistosome that they have is near the bladder and the granulomas build up in the bladder. And every once in a while, like the males will get it so much that they will start to bleed along with the, you know, with the females of the, a certain age. And it's almost like a rite of passage. So many kids get this, that blood in your urine is just something you expect for both sexes. Is that, is that still the case, John?

• 32:39Speaker 08

  Yeah, that's, that's called schistosome hematobium. It's found exclusively in Africa. And yeah, it will cause, because these granulomas move into the bladder wall, they cause it to erode and then you will get blood in the urine. And there's some evidence that I think they're pretty convinced now that schistosome, as well as some of these other trematoses, can cause cancer as well, including bladder cancer in that case.

• 33:07Kelly Weinersmith?

  Man.

• 33:07Speaker 08

  Because of over years and years of this erosion occurring and the body responding to it and the eggs releasing these, these antigens that it could result in cancer.

• 33:18Daniel Whiteson?

  Well, that sounds like something we should vaccinate against.

• 33:21Speaker 08

  Yes. I would be in favor of that. I think, I think schistosomiasis is one that we can do without. It's going to be just as hard though, to make a vaccine. Again, they have some promising candidates, but we're still a long way away from the actually using a vaccine. Again, it's a sanitation thing, right? In this case, if you keep your feces away from water, you're not going to have a problem. Snail control is, is possible, but it's difficult. It's expensive. We see some promise with introducing predators that actually eat the snails in some areas, West Africa that have done this. And they've seen,

• 34:02Speaker 08

  you know, you could combine it with chemotherapy as, and snail control, and you could see a huge decrease in the prevalence in the schistosome infections. So.

• 34:11Daniel Whiteson?

  But step one you said was keep your feces away from water. But in the previous segment, we were talking about toilets and that's like the basic operating principles, like turn your poop into sewage, right?

• 34:21Speaker 08

  Right.

• 34:22Daniel Whiteson?

  How do you do both at once?

• 34:23Speaker 08

  Well, as long as you don't have snails in your sewage, you're going to be okay. And plus, people generally, I mean, if you're talking about Western sewage systems, you've kept away from the sewage the entire time. The water, you know, goes through sewage treatment plant and gets treated and converted back into usable water. So, you know, you're still breaking the transmission in that case, right? Remember, you need water and snails.

• 34:49Kelly Weinersmith?

  This sounds like a particularly tricky problem because you've got like the adults that hide from the immune system. And then you've got the eggs that as they pass through the body, definitely do not seem to be good at hiding from the immune system. And the immune system responds and that's what causes the problem for people. So it seems to me that if you made a vaccine, you'd need to be careful to not make the problem with the eggs worse because now your immune system is over responding.

• 35:14Speaker 08

  Yeah, I think you would have to stop it before they got to the egg producing adults. And you would have to make your vaccine against the stages that are penetrating into the host.

• 35:24Kelly Weinersmith?

  Do we understand how the adults are hiding from the immune system?

• 35:27Speaker 08

  Right, so they do several things. First of all, they will actually take host molecules and bind them to their cuticle so that then the host immune system doesn't see it as foreign.

• 35:40Kelly Weinersmith?

  I mean, that's amazing.

• 35:41Speaker 08

  Yeah.

• 35:41Kelly Weinersmith?

  Like, can we, can we just sit on that for a second? That's like taking, like, you know, taking the skin off of a human and putting it on themselves or something like that's amazing. They hide with our own material.

• 35:52Daniel Whiteson?

  It's a wolf in sheep's clothing.

• 35:53Kelly Weinersmith?

  Yeah.

• 35:54Speaker 08

  But that's not all.

• 35:55Kelly Weinersmith?

  Go on.

• 35:56Speaker 08

  They also make what's molecular mimicry. They will make molecules that are very similar to molecules in the host, like a hormone, for instance, that'll then get processed by the host enzymes and act as a suppressor of the immune response.

• 36:11Daniel Whiteson?

  Do we know how all of this elaborate machinery evolved? Do we have any idea of the history here? Is it like, do you need all these pieces together to survive? Can you like do it one step at a time and refine it? How does it work? How does it evolve?

• 36:23Speaker 08

  Incrementally and ones that add more and more mechanisms probably are better at survival. So you made, you might have one of these things initially and that lets more of them survive and then you will get the mutations for the other things that occur. And they get just pile up to have a whole suite of things that is really efficient at inhibiting the immune system.

• 36:44Daniel Whiteson?

  So each of these tricks is helpful. None of them are absolutely necessary. And so as you evolve, you develop more and more tricks to sort of optimize survival in the host.

• 36:53Speaker 08

  Right.

• 36:53Daniel Whiteson?

  Wow. Impressive.

• 36:55Kelly Weinersmith?

  I know this episode isn't about the history of Kelly, but when I read about this in Carl Zimmer's book Parasite Rex, this was like literally a turning point in my life. I had gone from being like parasites. Oh, they're just kind of gross to being like, holy cow. It's like amazing the way they've managed to hide inside of our bodies and like, it totally changed the way I looked at parasites and like, literally altered the course of my life. So anyway,

• 37:18Daniel Whiteson?

  It infected your mind.

• 37:19Kelly Weinersmith?

  It infected my mind and now we got to share it with, with everybody. And so I'm very excited.

• 37:24Daniel Whiteson?

  Wait, no, this is the like intellectual version of the snail amplification. It goes into Kelly's brain, gestates for a while. She gets a podcast and then she spreads it to the whole community.

• 37:35Kelly Weinersmith?

  Through John. John is my snail and I am the parasite. This has gone, this has gone too far. Okay, so let's, oh, can I, can I play on the word shisto? Like, take a break. Can we split for a second? Nope. Not clever enough. All right. Daniel, do you have something?

• 37:54Daniel Whiteson?

  In case anybody needs to take a break and have a shist, go ahead and we'll be back in a minute to talk about another parasite.

• 38:01Kelly Weinersmith?

  Uh, poop related jokes. Love it.

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• 40:14Kelly Weinersmith?

  And we're back, and we are going to start with John's snail-related joke that he queued up during the break for us. Oh wait, did you just say that this might not be appropriate for the show?

• 40:23Speaker 08

  No, this one's fine.

• 40:24Kelly Weinersmith?

  Okay.

• 40:24Speaker 08

  This one's fine. So I tell this in my class, so it's, so this guy goes to a Halloween party, a costume party, and he's got this girl draped over his shoulders. And he goes in and the host says, hey, how you doing? Great and everything, says, are you a costume? He goes, yeah, this is my costume. I said, well, what's with the girl? And the guy says, well, that's Michelle.

• 40:50Kelly Weinersmith?

  Oh, Michelle, he's a snail? Is it? Okay.

• 40:54Speaker 08

  I think I left out the snail part.

• 40:59Kelly Weinersmith?

  We got there, though, as a team. As a team, we got to the end.

• 41:05Speaker 08

  Yeah, sorry, I blew the joke.

• 41:08Kelly Weinersmith?

  So malaria has some tricky ways of evading the immune system, but we're gonna start with the malaria life cycle and get to the immune system stuff in a second. And I've always found the malaria life cycle to be super confusing. It has a bunch of stages, all the stages have similar and kind of hard to remember names. So I'm gonna give a super simplified version of the life cycle that I think will be sufficient for the discussion we're about to have. All right, so when a mosquito bites a person who's already infected by malaria, the parasite goes to the mosquito's gut and it starts to replicate. So after that, it moves to the mosquito's salivary glands. And that's right, mosquitoes have salivary glands. I don't know why that's surprising to me. But anyway, when a mosquito bites a person,

• 41:53Kelly Weinersmith?

  the parasites are injected by the mosquito into the human body. The stage of the parasite that gets released into a person is called a sporozoite. This is the only stage we're gonna name, so just remember the sporozoite is the early stage in humans. From there, the parasite moves on to the liver and does some replicating. After that, it moves on to our red blood cells. When a parasite gets into the red blood cell, it's able to sneak proteins through the surface of the red blood cell, and those proteins stick onto the surface of the red blood cell. This helps the parasite hide from the immune system, and I'm sure John's gonna tell us more about this later. All right, so the parasite is living in the red blood cell,

• 42:37Kelly Weinersmith?

  and it's eating the hemoglobin in the cell. And as you might remember from our past conversation about synthetic blood, hemoglobin is the protein in your red blood cell that helps your cells carry oxygen to different parts of the body. So the parasite is hiding in the red blood cell and chowing down on the hemoglobin. It's replicating while it's in the red blood cell, and every like 24 to 48 hours, the red blood cell will burst open, and these newly released stages will go off to search for new red blood cells to infect. So that like red blood cell cycle will start again. Over time, a lot of the red blood cells get infected this way. So you're regularly losing your red blood cells, which can result in anemia.

• 43:20Kelly Weinersmith?

  And your body gets poisoned when these red blood cells burst open. And all of the stuff that used to be in the red blood cells is now like in circulation. And, and that's not good. Plus, when the red blood cells burst, there's suddenly loads of new parasites in the circulation and the immune system goes nuts. You get chills, you get fevers, et cetera. And the parasite is bad for a lot of other reasons, some of which I'm sure John is going to tell us about in a few moments here. And all of this, I'll note, is particularly dangerous for children or for adults who have never been exposed to malaria before, like travelers, for example.

• 43:55Daniel Whiteson?

  And does it use the mosquito just as a way to get from one body to another? Or is it something that happens inside the mosquito, like snail amplification?

• 44:02Speaker 08

  Oh, yeah. Very important part of the life cycle happens in the snail. So there is an amplification in number, plus there's also sex or recombination occurring in the mosquito.

• 44:12Daniel Whiteson?

  So we could definitely blame the mosquito for part of this.

• 44:14Speaker 08

  Absolutely, absolutely.

• 44:16Daniel Whiteson?

  Good.

• 44:16Speaker 08

  And you know, you blame the female mosquitoes because they're the only ones that take a blood meal.

• 44:21Kelly Weinersmith?

  Hmm. I don't like where this is going.

• 44:27Daniel Whiteson?

  I'm broadly anti-mosquito, female, male, I don't care. I'm not sexist about it.

• 44:31Speaker 08

  You know, it doesn't work without the male, so they're partially involved, but they're not the ones that are biting you.

• 44:36Daniel Whiteson?

  Yeah, exactly. Blame them all.

• 44:38Kelly Weinersmith?

  I'm broadly anti-dipterin. So dipterins are flies and mosquitoes. I'm not a big fan of any of them. But anyway, so inside the body of us, we get these cycles where they live in our red blood cells, they replicate and then they burst out of our red blood cells and then they go back into red blood cells. So it seems like when they're in red blood cells, I can imagine it would be harder for our immune system to find them because they're like hiding in our cells.

• 45:03Speaker 08

  They have evolved ways to transport things across their membrane, across the vacuole membrane, to be displayed on the red cell membrane. And one of the things that they display is a molecule called, in the case of Plasmonium felcyprum, which is the most dangerous one, erythrocytic membrane protein one, or as we, I call it PFEMP one. And PFEMP one then is expressed on the surface of this, of the cell. So there is an immune reaction that develops against this PFEMP one molecule. And the PFEMP is interesting because it is able to bind to receptors in the blood vessels,

• 45:47Speaker 08

  the veins of the host. And it basically takes those out of circulation, right? So they're bound to the inner vessels, right, of your larger veins and your, and everything. And they just sit there. So they're not being circulated through the spleen, which would recognize the red cells as being deformed and would take them out of circulation. So that's one way they avoid the physical destruction associated with the spleen. And they'll sit there and they'll do their, you know, their replication bound to these vessels. That's also a major cause of the pathology because when they bind to the small vessels like in the brain or in the placenta, in the kidney, this is where you get this micro

• 46:30Speaker 08

  occlusion of the capillaries and you get decreased oxygenation and then you get the metabolic acidosis. And these are the kind of things that cause the big problems with malaria.

• 46:42Kelly Weinersmith?

  I'm not a hundred percent sure I understand. Let me see if I can explain it back and if it, if I'm right. So I, I think what you're saying is that the red blood cells, they end up with this stuff that sticks out of the cell. It connects them to like the, the veins or arteries so that they don't go to the spleen whose job is to remove infected or disfigured cells and get rid of them. So they essentially keep themselves from going to the police station by hanging on in one spot. And, and if that happens like in your brain or in a placenta, it causes clogs that are bad.

• 47:13Speaker 08

  Right. And it seems to be particular bad. Like that's one of the major causes of the cerebral malaria, which is the big killer.

• 47:20Daniel Whiteson?

  So then what are the possibilities here for vaccines? Since this sounds pretty bad and we all hate mosquitoes and nobody wants this stuff in your brain?

• 47:29Speaker 08

  Yeah, that's a good question. So I think most of the success with, for the vaccines has been against the sporezoa. If you have an immune response to sporzoid when it gets into the skin, that can stop the infection right there. And I, there are some promising vaccines, some that have actually been used or in use, that maybe give you 60% protection or so. I'll take it.

• 47:55Kelly Weinersmith?

  Mm hmm.

• 47:56Speaker 08

  Yeah, it's, you know, it's kind of what a flu vaccine does too, you know? Yeah, so there are some promising ones in there, maybe more in the future because it put a lot of, a lot of effort into this vaccine development for malaria. And definitely would be a good thing. You just need to prevent people from dying because as they live there, they're going to build up this natural immunity that occurs over time. And it won't be an issue anymore, but it'd be important for kids. And also for travelers, like if you're going into Africa and you've never had malaria, then that would be very useful to have a vaccine or for the military or something like that. So there's definitely a need for vaccine here. We're getting closer, I think.

• 48:40Speaker 08

  There are, like I said, several have been deployed. So it's promising, I think, more so, I think, than with the worms at this point.

• 48:48Kelly Weinersmith?

  Oh yeah, we never said what kind of an organism malaria is. So the first example we talked about was a nematode. The second one was a trematode and malaria is a protozoan.

• 48:56Speaker 08

  Protist.

• 48:56Kelly Weinersmith?

  Protist, yeah. Why is it so much harder to make vaccines for parasites than for bacteria and viruses? And so my, my first question is, is that actually true? I, I feel like the answer is yes. And then is there a big picture reason for why?

• 49:12Speaker 08

  Uh, well, okay, it's generally it's true, but think about HIV. I haven't had a vaccine against that yet, right?

• 49:19Kelly Weinersmith?

  Yeah.

• 49:20Speaker 08

  So it's not always easy to do. Mm hmm. But I think it's because the immune system seems to be much better able to handle small things. Right? You can make an antibody response. It'll bind to the bacterium or to the viral particle. And then you can get your complement system involved to destroy it. But you know, the pathogens have ways to get around the immune system as well. Right? So your bacteria and your viruses could subvert the immune system too.

• 49:51Daniel Whiteson?

  Wait, I didn't understand the first thing you said, and it reminds me of a big puzzle in physics. You know, you said essentially the immune system is better at attacking small things, but big things are all made out of small things. So why can't it just attack all the small things that a big thing is made out of? It's like the puzzle of like every classical object is made of quantum particles. Why can't we understand it? I'm less suggesting there's quantum mechanical magic happening here, but what keeps the immune system from attacking each individual cell inside one of these bigger objects?

• 50:20Speaker 08

  In case of the worms, they all have a cuticle that protects the inner cells from damage. Right? In the case of like the hookworms, the immune system is able to go after the small part of the worm, which is the gut, right? That is exposed. It also takes a lot of cells to kill, you know, a bigger worm. It's just harder to do, I think. And like I said, a lot of the mechanisms where worms involve things like, well, we're just going to flush them out. Right? We're not going to try to kill them. We're just going to try to flush them out. Whereas we have cells that will actually ingest viruses and opsonize viruses at least and bacteria. Right? They recognize the antibody and then they bind to it and then ingest it and destroy it.

• 51:06Speaker 08

  Right? So it's a lot easier to do that than it is to try to kill a big worm that's got this protective armor around it and is living in the gut, for instance.

• 51:16Kelly Weinersmith?

  Yeah. So as a biologist, one of the things I think is super interesting about this conversation is not just how do the parasites evade the immune system, but it's also just that they have such complicated life cycles. There's so many different places where you could choose to try to protect against parasites. So you know, for mosquitoes, you can pay for bed nets because the mosquitoes are most active at night. And maybe you just keep the mosquitoes from biting and maybe that's even, you know, better than some of the medicines. Just, you know, if you don't encounter them in the first place, that's hopeful. But you know, all of these systems are evolving. So if you, for example, go after the mosquitoes with Pesticides, they evolve resistance. And anyway, it's a very complicated problem. And all of those complications is sort of what got me interested in parasitology in the first place. Anyway, back to Kelly's origin story. But this has been a fascinating,

• 52:01Kelly Weinersmith?

  fascinating chat. Thanks so much, John, for coming on the show to tell us all about the parasites you study.

• 52:07Speaker 08

  You're welcome.

• 52:08Kelly Weinersmith?

  And the parasites you don't study that I put you on the spot to talk about anyway.

• 52:12Speaker 08

  Well, you know, all these years of teaching, I've learned something, so.

• 52:15Kelly Weinersmith?

  That's excellent.

• 52:16Daniel Whiteson?

  You've learned how to nail a snail joke, or snail it, I guess.

• 52:20Speaker 08

  Yeah.

• 52:20Kelly Weinersmith?

  Well, John, let's save those for another episode. We don't want to overwhelm the audience.

• 52:24Speaker 08

  Thank you. It was fun.

• 52:33Kelly Weinersmith?

  Daniel and Kelly's Extraordinary Universe is produced by iHeartRadio. We would love to hear from you.

• 52:38Daniel Whiteson?

  We really would. We want to know what questions you have about this extraordinary universe.

• 52:44Kelly Weinersmith?

  We want to know your thoughts on recent shows, suggestions for future shows. If you contact us, we will get back to you.

• 52:51Daniel Whiteson?

  We really mean it. We answer every message. Email us at [email protected].

• 52:57Kelly Weinersmith?

  Or you can find us on social media. We have accounts on X, Instagram, Blue Sky, and on all of those platforms, you can find us at D and K Universe.

• 53:07Daniel Whiteson?

  Don't be shy. Write to us.

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