How cholera kills you and how we kill it

This is an iHeart podcast. Guaranteed Human. Ready for a festival season you'll never forget. Shop Etsy for essential trending pieces like Y2K accessories and teas are your favourite artists or classic vintage denim jackets and jeans. Find bits for every kind of moment from singing your heart out at main stages to off the map events. Because with Etsy, there's a real person at the heart of every piece. Celebrate festival season with styles you can only get on Etsy. Celebrate being human. Shop Etsy.com to discover your finds today. Howdy, Extraordinaries. In a prior episode, we took a historic look at Cholera. And just like before, you should keep in mind that Cholera is a pretty awful disease. So we'll be discussing both disturbing symptoms and death. But today, we're taking a more modern approach. We'll talk about what we've learned about how Vibrio Cholera goes about inducing catastrophic diarrhea, where these bacteria can be found when they're not wreaking havoc upon our intestines, and the methods we use to treat Cholera. We'll also take a short foray through the colossally bad ideas we've had for treating Cholera because, wow, we've tried out some really bad ideas. Welcome to Daniel and Kelly's Extraordinary Universe. Hi, I'm Daniel. I'm a particle physicist, and I just installed bed days in every toilet in my house. Hello, I'm Kelly Weedersmith. I, uh... I'm... Oh, I didn't. I feel like I didn't need to know that. We're starting with the toilet information at the very top. I don't feel like I needed to know that about your house. Are we talking about diarrhea today? Sure, but that doesn't have to be connected to bed days. I encountered my first bed day when I lived in Davis, California, and I went to a sushi restaurant, and I was like, what is this? Why do toilets need buttons? And then I was like, I pushed a button, and I was like, whoa! Whoa! And I don't know that I need a bed day in my house. I see. Well, I just came back from two weeks in Japan and Korea, and so I experienced toilets with control panels, and I pressed that button, and I went, whoa! Ooh! Okay. I gotta say, this makes me wish we had... We were releasing videos so that people could see the face that you made, although maybe it's better we don't. No, yeah, exactly. Everybody makes that face in private in the bed day, you know? And it turns out it's actually quite easy to turn your toilet into a bed day. Wow! Is the water heated or is it cold? What is this? Yes, nice and warm, toasty water. Yes, exactly. Okay, so actually, it was your trip to Asia that made you come home and add bed days to all your... Okay. Yeah, I was like, wow, we are still using a very archaic form of this technology. It can be made much more pleasant. Why don't we do that? Oh my gosh, it's like $80. Let's do it. Man, you know, there are some people who are all like, man, it's a shame that cultures are homogenizing, and you're all like, no, this is great. We should be taking stuff from Asian cultures. We should be giving stuff to them. They've got McDonald's. Why don't we have bed days? Yeah, I mean, ask yourself this question. If you got peanut butter on a shag carpet, would you just wipe it up with a piece of paper? No, no, I wouldn't. Okay, well, there you go. There you go. I think we know the relevance of that example. Yes, we do. Thank you for choosing peanut butter and ruining peanut butter for me. I think it's time we move on. All right. And don't think about me next time you're having peanut butter. Thanks, Daniel. Thanks. All right, so in the last episode, we talked about the work that John Snow did to help us understand how cholera gets to people, the fecal oral route, passing through water into our mouths, unfortunately. And today we're going to talk a little bit about the science that has been done in the hundred plus years since to help us better understand what cholera is doing to our bodies and help us to treat people who have encountered the bacteria that causes cholera so that we can save their lives. Exactly. And so it's going to be a whole episode full of too much information. That is my specialty. Okay, so before we really dig in, I want to remind everybody that in the last cholera episode, I mentioned that we're actually in the middle of an ongoing cholera pandemic. And my sense is that most of us don't realize that because we're lucky enough to not have to hear about or deal with cholera on a daily basis. So I asked the extraordinary's, when did the most recent cholera pandemic, that is the seventh cholera pandemic, end? So let's go ahead and hear their answers. Cholera pandemic? I have no idea. Sorry, no answer. Kelly, I never heard of cholera pandemics. Please educate me on that. Hi, a bit of a guess here, but I would reckon the most recent cholera pandemic probably ended in the 1930s, sometime after the end of the First World War. I don't remember any cholera event, so I'm going to say before I was born, it ended 1968. If you ask like that, I would say it's ongoing, but I really don't have any idea. Just guessing here, the 1920s. Cholera pandemic? And there's been several. I have no idea when it ended, but I sure hope it was a while ago and that there are few possibilities of it coming back. But given the show, I'm a little bit concerned. Since there are still many parts in the world with questionable standardization, I would guess like last year, maybe? My wild guess here is that the most recent cholera pandemic is still happening. I have no idea. I don't even know when it started. Maybe it hasn't ended yet? When did the most recent cholera pandemic end? I don't know, but I think maybe it ended when they learned to treat the water that was causing the cholera. I don't know, but probably much more recently than one would guess. Maybe in the 1960s. Okay, so as we sort of suspected, not a lot of awareness that we're in the middle of a cholera pandemic because it's not really part of our lives if you happen to be living in a place like the United States, for example. Remind us, Kelly, cholera is a virus. It's a bacteria. It's a pathogen. What is it? It is a bacteria. It is a bacteria that gets into the water. And for you to get cholera, you need to ingest a lot of it. So if you just... How much? So something like a million or maybe a hundred million need to be ingested for you to get sick. What? And Daniel... A hundred million? A hundred million. And so you might think, how would you accidentally ingest a hundred million cholera bacteria? Is that like 10 liters of cholera-laced water? No, it turns out that in a regular cup of water, you could have something like 200 million cholera bacteria and you probably wouldn't detect them in there because they're pretty tiny. And the glass wouldn't look cloudy, so you probably wouldn't know. But if you put them under a microscope, you could probably see them? Yeah, yeah, yeah. But how often do you put your water under a microscope? Yeah, never. Never. From now on, always, but never until today. All right, so Daniel, a million to a hundred million before you get sick, how do you think we know that? Because people tried it on themselves? Not tried it on themselves, but tried it on prisoners. But the prisoners, they signed consent forms. And so this was the experiment that I read, was done on a prison population in Maryland and they signed consent forms and they were told that they could stop the experiment at any time and they were very carefully watched by physicians and as soon as they started to show symptoms, they were brought into an environment where they were treated very carefully and they were watched very carefully. This was done in the 70s. Wow, would that pass modern-day IRB standards? So we actually do continue to infect people with cholera today and we're going to talk about that later, yeah. Don't we know enough we're still doing this to people? We are still doing this to people. Hold your breath. Oh, hold your cheeks. We're still going to be talking about this later. I just hope those poor people have access to a bidet. Yeah, yeah. So they can feel clean and fresh afterwards. I guess in that, yeah. I'm behind bidets in that situation. All right, see, all right, I brought you around. You're getting me on the same page, I guess. So, but another thing that we learned from this prison population is that actually it turns out cholera is really susceptible to acid. So like if your stomach is particularly acidic at the moment, the cholera bacteria are much more likely to die. So even if you ingest something like 100 million bacteria and your stomach is having like a particularly acidic day, you might not get cholera. Wow, so cholera is a bacteria. You got to ingest zillions of them. A lot of them die in your stomach. Where do they end up setting up camp? The small intestine. And I'll note now that when we do experiments with people to try to study cholera, we give them something that makes their stomach a more basic environment. So maybe you'll take some like sodium bicarbonate along with your cholera bacteria. Wow. So you ingest a bunch of them and then they go through your stomach, some of them survive, and then they get to your small intestine. The cholera bacteria have a flagella. And so this is like a really long, whip-like appendage. And they use that flagella to try to get through the mucus that lines your small intestine. And so they like run into your mucus and they start shaking their butts. And they're trying to get through the mucus so that they can get to the cells that line your intestine. But I thought the flagellum is like a propeller. You have it at the back to push you somewhere, like you know, like the motor on a boat. But here they're sort of like backing in, they're using it like a drill. No, no, sorry, they run in head first. Oh, I see, okay. And then they're using it to try to corkscrew their way in. Got it, yeah. Okay, so they keep going until they hit the cells of your intestine. And once they hit those epithelial cells, they sort of cement themselves down and they start to replicate. And so now they've got these little batches that are replicating and they start producing a toxin. And so they somehow know where to go, like they are looking for this. They're not just swimming in all random directions and the ones that end up there set up camp, they're like all heading in that direction. They are all heading in that direction. Wow, that's a little creepy. It is creepy, yeah. Bacteria and viruses and things that we might think of as not being very smart can do pretty smart things. They seem more like aware of the environment than I imagined. Very cool. So then they start to replicate. Yeah, so then they start to replicate. And while they're replicating, they start producing a toxin. And this toxin is what is massively the problem for cholera. I see. So this toxin finds a way of binding with your intestinal cells and it gets taken up by your intestinal cells. And when it's inside your intestinal cells, it messes with your cells and it starts to mess with what we call osmotic balance. But essentially the way your body makes sure that you are extracting water from the small intestine to go into your body is by having different concentrations of ions on either side of the inside of your intestine and in your body. So without getting too much into the chemistry, essentially you want the water passing through the small intestines to be less salty than the water in your body so that it then comes into your body to balance the salinity. Right? Isn't that the way it works? Yep, that's exactly right. But then after this toxin gets taken up by your body, that changes and now your intestine is saltier and the water in your body starts getting dumped into your intestine. And you start losing massive amounts of water from your body like we talked about in the last episode. And is this good somehow for the cholera bacteria? Are they doing this in order to affect something which is positive for them? Or so that you'll have massive diarrhea which spreads them? Or is this just like a random accidental byproduct that they don't even care about? So once you start losing this massive amount of water, the bacteria that have been replicating like crazy release themselves from the outside of the cells and they get back into the environment. And so in this way, they manage to get back out so they can go off and infect someone else. I see. So it's definitely a part of their cycle. It's not just an incidental thing. It is easy to imagine how it could benefit the bacteria. So I do think it seems to be a beneficial thing. That makes me feel better somehow because if our suffering and death was just like, well, we don't even really care and we're accidentally doing this thing that kills you, that would feel more tragic somehow. Yeah, I guess so. I guess if no one's benefiting from it, but I guess, I don't know. Maybe. But okay, so here's something that kind of blew my mind. And maybe you already know this given who you're married to and maybe I've just given away the punch line by saying that. But these genes that produce the toxin, do you want to guess where they came from? Mars. Mars. Wait, wait, no, wait. There was a Katrina related clue here, so it's got to be a virus. Is it a virus? It's a bacteriophage. Oh, yes. I knew my wife. That's right. That's right. Well, and you probably read the outline. So it looks like there were two different bacteriophages that infected Vibrio cholera at some point. One of those bacteriophages, I believe, gave the bacteria the ability to cling to the outside of the intestinal cells so that they could form those mats and start replicating. And the other one gives them the ability to make these toxins. And so without this bacteriophage, Vibrio cholera would not be this human scourge that it, and did you catch that? I said scourge right. I didn't say it right in the smallpox episode, but I learned when the listeners write in lots of emails about how I'm not pronouncing things right. Gold star for Kelly. Thanks, everyone. But that's amazing that this is virus powered. It's like virus engineered. For those of you who don't remember, a lot of DNA, including human DNA, is affected by viruses. Viral infections in years past have altered our DNA, and some of our essential functions come from DNA that essentially was injected into the record by viruses, and that's true also for bacteria. It's incredible. It is incredible. But okay, so I feel like this begs the question, what was Vibrio cholera doing before these viruses came along? And it turns out that this question is really important for trying to figure out how you can control cholera around the world. And it's also important for trying to understand what cholera is doing when it's not in our body, right? And so the answer is that Vibrio cholera is a bacteria that you find in aquatic ecosystems all over the world. This is just an aquatic bacteria that you find living on zooplankton, like copepods. You find it living on aquatic plants. This is just an aquatic bacteria that is totally happy outside of our bodies living in aquatic ecosystems. You find it in the Gulf Coast. You can find it in Lake Erie. You can find it in the Ganges. It's just a happy bacteria out there that every once in a while ends up in a human body. So it looks like there's lots of different strains of this bacteria. Some strains don't have these toxin genes. So if you swallowed 100 million of them, nothing would happen. Other strains cause some like tummy issues, but nothing on the level of like cholera. But some of them cause pandemic cholera. And so like there's lots of different kinds of vibrio cholera that differ in how bad they are for us. But they're out in our waterways. So these were basically weaponized by these viruses. So the story isn't this cholera infects you and uses you to make more of it. It's this virus took over this bacteria and instructed this bacteria to infect you to make more of the bacteria, which in effect is making more of the original virus DNA. Yeah, I mean, that sounds a bit more directed than it probably actually was. I just wanted to make it sound like a conspiracy theory so we can climb up the podcast charts. Oh, yes. Okay, then I agree. That is exactly what happened, Daniel. This bacteria phase was out to get us and through vibrio cholera, it has achieved its goal. Probably was engineered by the CIA, wasn't it? Yeah, no, I know. Right, like, yeah, the exploding cigars for Castro didn't work. And so they were like, let's go after vibrio cholera. So... No, I don't think a CIA is pulling the strings. I think it probably is viruses. Viruses control the world. Yeah, yeah. Well, so I think we don't really understand what the bacteria phase was doing with this toxin before it got into the bacteria or, you know... So we don't really understand all of the steps and why they happened, but we're working on trying to understand that. But it does appear that, yes, this bacteria phase is what essentially gave cholera the ability to be this horrible scourge upon humanity, and here we are. All right, so I ingest a couple of fluid with 100 million cholera bacteria in it. Then they colonize my lower intestine to make lots more of themselves. How many come out the other end? Like, I'm a cholera factory now. How big a multiplier am I? You could produce a trillion cholera bacteria. A trillion with a T? With a T, yep. And you can release something like 20 liters of fluid with a bout of cholera. I know, just an incredible amount. Fluid. Yes, fluid. I mean, you're vomiting also, so the fluid covers it all. Mousy smelling rice-filled fluid, right? Yep, yep, it's pretty unpleasant. And so, you know, so you can see how this is a great route for cholera to reproduce itself and get back into the environment in large quantities. Wow, if I'm doing my math right, 100 million to a trillion, that's a factor of 10,000. So every individual can 10,000 X the cholera population. Yeah, but, you know, if you have good sanitation and all of those fluids from either end end up in a good sanitation facility and they get treated appropriately, then it's a dead end. And so, sanitation makes a huge difference here. So to me, like, you know, good sewer systems are one of the most amazing things that humanity has ever done. And you might understand now why I don't get invited to a lot of parties. But I'm very excited about sewers. And so, why do people die of cholera? The toxin itself does do more than just make you put out 20 liters or is it dumping 20 liters of fluid that kills you? It's dumping 20 liters of fluid that kills you. That's all it's got to do. At that point, your blood becomes super thick, your organs shut down because you just can't get oxygen and stuff to all the places it needs to go and you go into a coma and die usually. Yeah. Wow. All right, so now we know what the cholera bacteria are doing. Let's take a break and when we get back, let's start with the history of treatments and begin with some of the less good treatments we've tried throughout the history of time. All right, we're back and we are talking about cholera, a disease that makes people produce 20 liters of fluid out the north and the south ends of the body. On average-ish, yeah. And we've done a deep dive on the pandemics and now we understand the biochemistry of cholera, how it affects you. So let's talk about the good side of it, developing treatments. How did we start to make this better? Well, I'm going to start on the bad side of treatments first. So, while I was reading about the history of cholera, there was this book that kept coming up and it was a cholera, it's causes symptoms, pathology and treatment by Robert Barthelot. And Barthelot was a physician in the United States who was a physician through two cholera pandemics and people thought of him as an expert. And so I was like, okay, well, let's read what the expert was saying in 1893. And so when I got to the treatment section, I found myself saying out loud many times, oh no. Oh no. No. They didn't. Oh gosh. They wouldn't. So, okay, so here's bad idea number one. Okay. Okay, so quick background. They knew at this point, so this is 1893. So, Robert's totally believed the cholera was caused by vibrio cholera. He knows that it's a bacteria, that you're drinking it, it's in your gut. He's on board with that. We had the germ theory already. He had the germ theory already. Not everybody was on board with it at the time, but Barthelot was. Okay. So he's like, all right, so here's the idea. You've got these bacteria in your gut and they're going to give you cholera. If you are early in a case of cholera and you just got it, maybe the solution, and hear me out, is to give someone diarrhea. What? To wash out the bacteria. Oh, I see. And it's like, no, but if 20 liters of fluids washing through your intestines doesn't get rid of the bacteria. And so the idea was if you start the diarrhea early, you'll flush the bacteria out before the cholera can get worse. And so you'd give people castor oil to induce diarrhea. And then you'd try to stop the diarrhea later on. I see. And needless to say, this just started dehydrating people before the cholera had a chance to dehydrate them further. So this, not a good idea. Yeah, this is like there's a leak in the water tank, so let's blow a hole in the water tank. Yes, exactly right. And the word that they used for the diarrhea inducing medications were eliminants, which I had never heard before. And so that made me chuckle a little before I went back to feeling awful for the people who were being induced to have diarrhea before they were subsequently killed by diarrhea. And in the defense of these folks, there are some successful treatments which on the surface sound insane. Yeah, yep, yep. You know, like drilling holes in people's skulls can sometimes relieve headaches. Yeah, relieve the pressure. Yeah, yep, yep. Yeah, totally. So science is bizarre if you don't have a fully working model of how the body works. It's basically a Rube Goldberg machine and we were just mashing on the levers. You never really know what's going to work. That's right. And then in the past, we've given people malaria to cure late stage syphilis. Yeah, exactly. And it worked. And it worked in some cases. Yeah. Other cases, it killed them. But yes, we have done crazy things that have worked in the past. So, you know, you try stuff. In the defense of bad idea number one, make them poop more. That's right. I can't believe I ended up on that side of this conversation. You know, it's good that you're defending outside the box thinking or something. I just, I'm always fascinated on these historical journeys, trying to get in the minds of the people there because it's easy to judge them given our level of knowledge and our understanding and our mode of thinking. But it's another thing to try to get yourself in their heads and wonder, like, what did they know? What's this reasonable given what they understood? Would I really have done something different? Yeah. Yeah. So, you know what? Let's jump to what I had listed as bad idea number three because I feel like it kind of goes with the argument you're making right now. So, okay. So, bad idea number three was sort of built on this idea that if you made someone's stomach more acidic, you could fight the cholera. And I don't know that they actually understood at the time that stomach acidity did kill cholera, bacteria, but they were onto something. Right. And so. This sounds reasonable. Yes. And so, they would give people various acidic solutions and have them drink it. And, you know, it did turn out, we did discover later on through controlled experiments that acidic stomachs were good for killing bacteria. And so, that was a reasonable treatment. But then some prodigy decided what if we instead injected the acid under someone's skin. Oh, no. And I'm not sure what the thought was there because I get, you know, going after the bacteria in the intestine. But it turns out injecting sulfuric acid under the skin, quote, caused colossal gangrene. Wow, really? Yes. So, that's essentially when the tissues die. How many people did they inject this in before they decided maybe this isn't a go-to treatment? I don't think it was a lot. I hope it wasn't a lot, but it was some. So, that's not great. Yeah. Yeah. Because gangrene does not seem like a fun thing to have. On top of cholera. Right. Yeah. Yeah. Right. Yeah. So, okay. There's a bad idea. All right. So, the last bad idea before we get to the good ideas, the last bad idea is what was called enterolysis. Or no. Enterolysis. And the idea here is that maybe it would be helpful if you rinsed off the intestines from the inside with the chemical. And so, they took a long tube that was connected to a bag with a solution of tannins, which are like some chemicals that plants make. And they inserted the tube up the rear end as far as it would go. And then they squeezed the bag to try to rinse the inside of the intestines off with these chemicals to try to essentially dislodge the bacteria and sort of kill them. So, this is a tannin enema, basically. This is a tannin enema. I guess I'm going to admit now that I am not super familiar with how enemas are conducted. I am not aware of them being attached to like a hose. I thought it was more of, I won't go into too much detail. Anyway, this sounded- I don't think it's that complicated, Kelly. I think you're maintaining an ignorance intentionally. I thought it was just just stuck like pouch up there and then that's done. Isn't that the end? There's no like tube and you don't rinse the inside. Enemas aren't that complicated, are they? Have you- Have I? Never mind. Never mind. Never mind. Okay. Point is, they used to rinse out people's intestines while they were suffering from cholera. Why tannins though? Like, I understand the idea is to rinse it out, maybe do something to reduce the bacteria, but do they have a theory that tannins were going to impact the bacteria? So I have recently started keeping this amazing, to me, timeline of medical advances. And it wasn't until 1928 that Alexander Fleming discovers penicillin. And so this is around 1893. And so we didn't really have antibiotics at that point. And so I don't know, I'm guessing tannins were just, they were like, I don't know, those things like kill stuff. And they're just kind of, they seem like the kind of thing that might make an intestine inhospitable. So I'm not really sure what the thinking was for tannins. Yeah. I mean, because if they're just guessing, you think maybe they would try a few things. They're like, oh, let's put in some cayenne pepper or something. There was more than one thing that they were trying. Okay. Tannic acid is, those are tannins, right? Tannic acid? Daryl, neither one of us know. They were putting stuff in people's intestines, rinsing it out. So anyway, bad answer. Did that make things worse or have no effect? So Bartholow, the author of this book, seemed pretty convinced that this was a good method. But, but here's the thing. If you are dying from cholera, you probably don't want to sit through this procedure, especially when it turns out that what works is very simple. It is rehydration. And Bartholow notes that there's this guy named Lada, who in 1831 was saying, hey, y'all, if you just use this intravenous infusion of fluids that have some electrolytes in them, they seem to survive. And Bartholow is like, yeah, okay. So if you give them a bunch of fluids intravenously, or you just make them drink it if they're able to, they perk up and they seem like they're in such a good mood. But it's temporary because then they get diarrhea and they throw up and then they don't feel good again. And it just kind of feels like you have to keep doing this over and over again. And that's frustrating. And so they abandoned this technique until, until like 1915, when this new physician named Rogers is like, hey, y'all, actually this rehydration thing, like this is the thing that works. All of those fluids that they're losing, you just need to put them back and then everybody's okay. And Daniel, you have a story about this, right? Yeah, key to this rehydration technique is getting the like salt and sugar balance of the rehydration correct. So the things are actually absorbed and you don't end up like stealing more fluids. And what works best is a particular mix, not just like salty water, we're also having some sugar in there. And a guy I know here, Jonas Schultz, who's a particle physicist, his brother, Stanley Schultz, is the guy who figured out like exactly the right balance of salt and sugar and the chemistry for why that works. And so now we understand exactly like how to sweeten and salty that water so that when you rehydrate people, they absorb and keep as much of that water as possible. That's amazing. And so like whereas previously cholera was pretty darn fatal, these days, if you use the appropriate rehydration technique, we expect that you only lose about 1% of patients who come in with cholera. And the 1% that you lose, of course, ideally you lose no one, but the 1% that you lose tend to be people who had some other issues going on and the cholera just sort of was more than their body could take. But for most people, if you can get the fluids back, they survive. So that's why I asked earlier, like, what is it that kills you? And if it's just really the loss of fluids, then yeah, it seems very straightforward to say, well, let's just prevent you from losing those fluids or replace them as they exit. But then the other question, of course, is like, how long do you have to do this for? Does the body eventually kill the bacteria without any external assistance, without penicillin? If you can just sort of survive long enough for it to do that? Yes, that is the case. Every once in a while, they will give people antibiotics to try to speed the process up. But in a lot of cases, they don't even give people antibiotics and eventually your body clears it out and you will be fine. And that's fascinating because then everybody gets what they want, right? Like, the cholera still got to do their thing and make more cholera and exit your body in 20 liters of disgusting fluid and you survive. Yeah, I don't think the World Health Organization is like making their recommendations based on trying to make everyone happy, including the one trillion cholera that were produced by an infection. And I don't think the cholera are happy if they end up in like a modern sanitation system. But yeah, so I mean, the World Health Organization says you need water, sanitation, and hygiene. The acronym there is WASH with the water providing the W and the A. Loving it. And you know, if you have these things, you can usually keep cholera out of your population. And then with this oral rehydration solution, you can treat anyone who does happen to get cholera. And so these days, if you happen to get cholera, it's still the go-to treatment. It's basically just an infusion of fluids. Yeah, an infusion of fluids. Sometimes you'll get antibiotics, but yes, just trying to replace those fluids is what happens. But it has to be quick, right? Because cholera can kill you in like 12 hours. Yes, yeah, yeah. You want to get to a hospital immediately. Yeah. It's amazing when like minutes or hours matter for outcomes in these medical decisions. Yeah. Scary. It is. All right, let's take a break. And when we come back, we'll learn about how we're going to prevent people from getting cholera in the first place. All right. All right, we're back. And now we're going to talk about something which is unfortunately controversial these days. Vaccines. Yes, yes. Unfortunately, controversial. And also in this case, a little bit hard to study. So it turns out that cholera is one of those diseases that acts differently in humans than it does in a lot of animals. So it's been hard to have animal models because, for example, if you give cholera to an animal, like a rabbit, they don't produce the massive quantities of diarrhea that humans produce. And so if you are testing out a vaccine on a rabbit, for example, you don't necessarily get the information that you want from studying a rabbit that you would get from studying a human, for example, because it's just not doing the same thing to rabbits. Even proportionally. Even proportionally. That's right. And do we understand what's going on in the rabbit small intestine that makes it respond differently? We've done some research to like understand a bit about why it differs in rabbits versus why it differs in humans. To be honest, I didn't dig into that part too much. But at the end of the day, rabbits don't tell us everything we need. We've learned some great stuff from rodents that's been super helpful. But not everything we need will be able to come from rabbits. And another thing that's difficult. So we had talked about in the prior segment, the fact that vibrio cholera has a lot of different strains that act differently. The strains that cause pandemics, there is a lot of them. So you know how every season, you go and you get the flu vaccine because there's a different strain of the flu that's going around. Cholera isn't really that different. It doesn't have a different strain every year. But there are something like five or six different pandemic strains and you do need to keep an eye on it over time because every once in a while, a new pandemic strain will sort of pop up. And now you need to worry about trying to include that strain in the vaccines. And if you're vaccinated against one of the six strains, that might protect you against a subset of the other strains, but not all of them. And so when you're creating a vaccine, you need to have multiple strains in there. And this isn't totally foreign. Like when I went to go get the flu shot this year, I think there were three different flu strains in that flu shot to protect me against the most likely strains that I'll encounter this year. And so we do do a variety of different strains in the cholera vaccines. And interestingly, that we also try to include subunits of the toxin that cholera produces because our body also produces like antibodies to stop the toxin from binding to our intestines. Wow. Fascinating. And so how do we go about making this vaccine? Like do we inject it in humans and look at the antibodies and then use those antibodies somehow? Is it just those antibodies? How does this vaccine work? Yeah. So the way that we test these vaccines is different than the way we test a lot of other vaccines. So I think that the way that I most often think of how we test vaccines is that we give the vaccine to a large population of volunteers, and then we track those volunteers as they go about their lives. And then after like three or four months or maybe half a year or something, some amount of time, we ask them to report back and say, for example, you got the COVID vaccine. Six months later, can you let us know did you get COVID or not? And then we look and we say, okay, for the people who got the placebo, what percent of them got COVID and the people who got the actual COVID vaccine, what percent of them got COVID. And you hope the percent that got the actual vaccine is lower than the percent that got the placebo, which is, you know, maybe like a solution of saline and not actually the vaccine. What we do with something like cholera often is we know that cholera is the kind of thing where if you have somebody in a medical setting and they are healthy to begin with, if you treat them, you can make sure that they will survive. And so you can do a much faster trial if you essentially give people the vaccine, give some people a placebo, you know, like a solution of saline, and then you give everybody a hundred million cholera bacteria because then you can control how strong of a dose everybody's getting and what strains of cholera they're being exposed to. And so that tends to be what we do. And so what we'll do is we'll try to pick strains of cholera that we think are the most likely to be a problem in a particular region at a particular time. We will kill them. So usually what we're doing is like oral vaccines of killed cholera cells. And then we will set up a facility where people will volunteer. First, we'll do tests to make sure that everybody's healthy. And then they will either get the vaccine or a placebo and then they'll get exposed to the kind of cholera that we think they're going to encounter, you know, in the areas that we're worried about. Are these prisoners? No, I don't, I haven't seen, the prisoner experiment was from the 70s. I think these days they're probably, you know, college kids who are volunteering. We'd need a few hundred bucks and have a day to spend over the toilet. But I'm wondering, you're saying we do this for cholera because we're confident that anybody who gets it, they will recover. And so it's not really dangerous to give people the disease. And therefore it's a very useful way to directly study whether the vaccine saves them or prevents the disease. So is that only true for diseases where we're very confident that we can save people? That's why we don't do this for the flu. We don't give people the flu vaccine and then intentionally eject them with the flu because of the higher mortality rate. We're careful with things like respiratory illnesses. I do think we've done some challenge trials on influenza, but on very healthy volunteers. I'm sure that this was implied in what you said, but like, you know, we, for cholera, we only know we can save people because they are like already in a hospital. Like, you know, you wouldn't, yeah, yeah, you wouldn't test this out like in the field where somebody got cholera, you'd have to drive them two hours to a hospital or something. Call us if you feel anything, right, like already in the hospital. Yeah, right, right. These are under conditions that are very controlled and you know you could very quickly get them to safety. But is the mortality zero? There was one instance where somebody had a cardiac thing happen and this was over, I think, 30 years of experiments where these controlled studies, challenge studies have been done and I'm pulling this number from my head and that might have been from challenge studies. So these kinds of trials are called challenge trials and that might have been for all challenge trials, including studies that weren't just cholera because this has been done on other diseases too. So that this technique has very high success because folks are really cautious when they do it. But we have still had quite a bit of difficulty when we go to use cholera vaccines in the field. So just because you have tested a cholera vaccine, I don't know, for example, in London, doesn't necessarily mean that when you go to use the cholera vaccine in children in India, an area where cholera pops up quite a bit, it doesn't mean that immune systems are going to do the same thing. So, for example, maybe if you're, I don't know, a teenager in India, you have encountered the cholera bacteria before and so your immune system might respond differently, whereas like a college kid in London has probably never encountered the cholera bacteria before. Additionally, they have different microbiomes and I've seen papers indicate that that could matter. And kids in India probably have some different, I don't know, intestinal parasites than kids in London and that could impact how bodies respond to things like vaccines. And so we're finding that sometimes in challenge trials, what you see doesn't always match what you see in the field when you're giving it to communities. So challenge trials still seem useful, but we don't always see exactly what we expect. And who takes this vaccine? Is it only for people who are living in cholera endemic regions and people traveling there? Or is everybody getting it? Have I been vaccinated against cholera? Well, it depends. Have you traveled to an area where cholera is endemic? I don't think so. I've never been to India. Well, you know, it's also in South America and Africa. I've been to South America and I definitely got some vaccines for that. So maybe. Maybe. I've gotten the yellow fever vaccine before, but I think, but I don't think I've ever gotten the cholera vaccine. Most people have probably haven't gotten the cholera vaccine. If you travel to an area where cholera is endemic, you might have gotten the vaccine and challenge trials were used to develop the travelers version of the cholera vaccine. And if you live in an area where cholera is common, you and your kids may have had the cholera vaccine. And actually, if any of our listeners want to write in and let us know if they got the cholera vaccine, I'd be interested in hearing about that. But you need to get the cholera vaccine pretty often. So even if you get cholera in real life, the immunity that your body provides doesn't last for a lifetime. Like, if you get cholera and it's like a mild case, your immunity might last for like three years. I read one source that said a really bad case of cholera can give you immunity for 10 years. But after that, your immune system kind of forgets what cholera looks like, which seems like a bad plan. And so you need to get immunized regularly. And if your immune system only remembers an actual case of cholera for three to 10 years, probably that's the best we can do with the vaccine, which means you need to get vaccinated regularly, which is hard because a lot of areas where cholera is endemic are areas where you don't have good sanitation. And those are also areas where it's probably hard to get vaccines, especially if the vaccines need to be refrigerated. And so there are areas where it's hard to get vaccines to people regularly. And so we don't currently have vaccines that we feel like amazing about. Research on cholera vaccines continues because we would like to have even better cholera vaccines. And is there a campaign to eradicate cholera, like we did for smallpox? Or is that impossible because cholera is happy to live in the environment, even if we got it out of all of the people? I think that the goal is to reduce cholera. I don't think it would be reasonable to try to eradicate cholera entirely because it can live in the environment without us. Like, I just, I don't see how you would, how you would do that. And because it's out in the environment and there's viruses out there, there must be constantly new versions of it. And it's mutating. And there's gazillions, uncountable number of these things floating in every lake, one mutation away from being the next pandemic. Yes, right. Yeah. And you know, even if we had a perfect vaccine tomorrow, the week after that, you could have horizontal gene transfer. And you know, the genes for the toxin could be passed to a new strain of cholera. And that's the next pandemic. So you need constant surveillance to try to understand this stuff, which is why it's really important that we fund organizations like the World Health Organization, which the United States pulled out of. And so who does this research? I mean, it doesn't sound like there's a lot of money in cholera vaccines, since the places where cholera is endemic tend to be poorer countries. You don't have a whole lot of cholera happening to like U.S. senators, for example. And so who is funding this research, if anybody? Cholera research is funded by the World Health Organization wants there to be cholera vaccines. There's money from government organizations like the National Institute of Health. There's, I think there's U.S. companies that make cholera vaccines to sell to tourists in the U.S. who want to go. And there's lots of people living in areas where cholera is endemic. So if you could sell the vaccine, you can probably make some money, although you probably can't sell it for too much. There's philanthropic organizations and government organizations funding this kind of research. Yeah, not everything happens from a profit mode of y'all. Yes, that's right. This research is super important. The seventh cholera pandemic, as we said in the last episode, is still happening right now. The next cholera pandemic could start at any time. Cholera pandemics can overlap if a new strain pops up and starts spreading around the world. Seven to eight could be happening at the same time. And I'm grateful that there's continued funding for research into technological developments in advanced bedets. As I traveled around Japan, I discovered, ooh, some of these have music. Ooh, this one has a strong deodorizer button you can press. What does that do? Okay, all right. I'm grateful for good sanitation systems. And I am grateful to organizations that are trying to bring good sanitation systems to communities that don't have them yet. Because that's, you know, vaccines are great. But sanitation systems that keep people from getting poop in their water, yes, is probably a better long term solution. You're so much more wholesome than I am, Kelly. I'm glad that the bidet is bringing you so much joy. Hey, it's a small pleasure in life. That's right. Anyway, today it's been a great pleasure learning about cholera. Thank you, Kelly, for this deep dive into the experience of cholera, how we treated it, and how we continue to. Thanks for listening. Daniel and Kelly's Extraordinary Universe is produced by iHeart Radio. We would love to hear from you. We really would. We want to know what questions you have about this extraordinary universe. We want to know your thoughts on recent shows, suggestions for future shows. If you contact us, we will get back to you. We really mean it. We answer every message. Email us at questionsatdangelandkelly.org. Or you can find us on social media. 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