This Podcast Will Kill You - Ep 97 Snake Venom: Collateral Damage

Episode Date: May 24, 2022

How do you feel about snakes? Intrigued or terrified? In awe or creeped out? Of course, those aren’t the only options; the sight or thought of a snake can evoke many different emotions, but chances are indifference isn’t one of them. And is it any wonder? Some snakes can produce incredibly potent venoms that can seriously harm or even kill you, a characteristic that likely helped earn them their prominent role in many cultures and religions as a creature or god to be respected, if not feared. In this episode, we take a closer look at the diverse compounds that make up these venoms by exploring how they impact our bodies in the myriad ways they do and the current tools we have to combat their effects. Then we turn to evolution, not of snakes themselves but rather the role snakes may have played in primate evolution (snake detection hypothesis, anyone?) before discussing the historical development of antivenoms. We round out the episode by reviewing the current status of snakebite as a neglected tropical disease and mentioning some very exciting therapies on the horizon. Don’t missssss out on this enlightening envenoming episode today! See omnystudio.com/listener for privacy information.

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Terms and conditions apply. Need to hire? This is a job for Indeed sponsored jobs. Hi, my name is Gwen, and this is my story. It was the last day of our 10-day field trip. We were working and camping at our most remote field site in western Colorado, conducting botany surveys for a research project. My field assistant Chloe and I decided that we would spend the evening swimming and relaxing by the Dolores River.

As the sunset, I started to get ready for bed. I was tired and ready to snuggle up in my sleeping bag. I walked over to the truck to refill my water bottle and grab my toothbrush. As I reached for the driver's side door handle, I heard a noise and looked down just in time to see a rattlesnake's fangs penetrate the skin on my right ankle. The snake coiled up and started rattling its tail and I backed away quickly. Chloe and I decided to leave all of our camping gear and head straight to the hospital in Grand Junction, which was about a three-hour drive. We left at about 9.30 at night and the only road home was a two-lane highway over the Uncompaw-Gray Plateau. Because we

didn't have cell service, I used our satellite messenger to text my husband with the news and to call ahead to the hospital. I was in a lot of pain, really the most pain that I can remember. We were 30 minutes into the drive when I started throwing up. We didn't pull over because I didn't want to lose any time. I was heaving for about 30 minutes, but eventually I stopped, sweaty and exhausted. At this point, I had to poop. I instructed Chloe to pull over now, and I pooped right there on the side of the road. Once I had nothing left in me, we continued on. Soon as, I began to experience muscle spasms. It began in the tips of my fingers and toes.

All of my muscles tightened as the spasms worked their way up my extremities so that my hands turned into fists and my arms and legs tightened. This was the only time during this experience that I thought I might not be okay. Chloe told me to focus on breathing and I did. My body felt like a tight ball and was not in my control. Eventually the spasms subsided. The emergency room staff was expecting me. I was admitted quickly and given a large dose of antivenin and a tetanish shot.

While there, I believe I met every doctor and nurse in the emergency room. It turned out they didn't see snake bites very often and wanted to take this opportunity to look at my 10-day unwashed foot. I happily told everyone my story. A lot of the pain had subsided, and I was just so relieved to be safe. While there, I asked a lot of questions about the recovery and didn't get clear answers. It seemed like the recovery time could be quite variable. I was discharged from the hospital in 24 hours. My husband picked me up.

We picked up our gear from the campsite and then headed home. My foot was a gray and blue swollen lump for about a week, and people stared everywhere that I went. Luckily, the recovery was quick for me, and I was just about back to normal in four weeks. Whenever I do fieldwork now, I always have snakes on my mind. I don't really prefer doing fieldwork in places where rattlesnakes are common or we might run into them. I always wear shoes and sometimes I wear gaiters. I prefer when I'm hiking for fun to go to higher elevation areas where there's really no chance we'll run into any kind of rattlesnake. And I worry about my dogs a lot.

but in the end like I still do a lot of field work it's just more present on my mind and I tell everybody that I work with what happened to me and um hope that they're more cautious as well wow I mean that is absolutely terrifying absolutely terrifying I can't imagine what a long and just I don't know awful car ride yeah wow yeah thank you so so much Gwen, for taking the time to chat with me and for telling your story. I'm, yeah, it's just, we're really glad that you're better now. Yeah. Hi, I'm Aaron Welsh. And I'm Aaron Alman Updike. And this is, this podcast will kill you. And today we're taking a few steps outside of our comfort zone. And we're talking about snake bites. We are specifically venomous snake bites.

Yes. Yeah. And there's a lot out there. And there's a lot to this story. And just in advance, I want to say that, you know, we're probably not going to cover everything that you would want us to cover about snakes and what's going on with snakes in the world and snake bites and stuff like that. But don't worry because we are going to cover some very interesting things. Number one, number two, I think this also leaves us open to revisiting snakes. in the future, like, I really want to cover that snake fungus someday. Ooh. I don't even know about snake fungus, Aaron. Yeah. It's called snake fungal disease. And I don't, to be honest, know all that much more about it. But I remember seeing presentations about it and like different conferences. And I was intrigued. So we're not talking about that today. We're just focusing on the venom that a lot of snakes produce and how it affects humans if we get bitten. That's correct.

Yeah. And speaking of snake bites and what happens when you get bitten, should we talk about our quarantini for this episode? What a great transitioner, and I really loved it. It was not at all forced. It was super smooth. But our quarantini for this week is the snake bite. It's the snake bite. It's a real drink, which makes our job, you know, easier.

in that regard. It's a very simple drink as well. It consists of two ingredients, cider, and then either logger or stout. Up to you. And we'll post the full recipe for the snake bite, as well as the non-alcoholic placebo-rita. I'm very curious to see what I come up with. Same. On our website, this podcast will kill you.com, as well as on all of our social media channels. Our website, this podcast will kill you.com, has some pretty incredible things that you can find on it. If you haven't checked it out yet, we have our bookshop.org affiliate account. We have a goodreads list. We have all of the sources from all of our episodes. We have transcripts from them all. We have a link to Bloodmobile who provides the music. We have our Patreon. We have

merch. I might have missed a few things, but that was all that one breath could handle. I think you did a great job. My post-it is not currently with me. So I can't I can't. I can't I can't add what I forgot. Exactly. But that's okay. I don't think we have any more podcast business, so can we please get started? I am really, really curious about snake venom's. I can't wait to talk about them right after this break. Dinner shows up every night, whether you're prepared for it or not. And with Blue Apron, you won't need to panic order takeout again. Blue Apron meals are designed by chefs and arrive with pre-portioned ingredients so there's no meal planning and no extra grocery trip. There,

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slash this podcast to get free shipping on your order and 365-day returns, now available in Canada, too. That's Q-U-I-N-C-E.com slash this podcast to get free shipping and 365-day returns. Quince.com slash this podcast. So here's the thing. I am not. We are not herpetologists. Oh, no. And like you said at the top, we're not going to pretend like we are for this episode.

So I'm not going to be getting into a lot of detail about the snakes themselves. And I'm going to try to avoid getting anything wrong when it comes to the biolns. of snakes by mostly ignoring the snakes themselves. Yeah, I know. Herpetologists who follow us, I'm sorry. But what I am going to focus on instead is the venom and the effect that various types of venom have on our human body. And so what I hope that listeners will take away from this is the very broad strokes of

the different varieties of venom and how they work and why it is that some snake bites are so dangerous to humans. Shall we begin? Let's do it. Snakes are an incredibly diverse group of reptiles. I learned there are over 3,500 species of snakes. But today we're going to focus on just a few of the families of snakes in the clade clobroides. Oh, yeah.

That is how you say it. Which contains the families and the sub-families of snakes that are of, quote, human medical importance. Okay. And these snakes, there's three major groups of them. the elapids and the family elapid, which are the cobras, the mambas, the sea snakes, which I still to this day am terrified of the idea of sea snakes. Even though they're the ones you're probably least likely to encounter. I know, but something about them, it is the most, like I'm not afraid of snakes. I think snakes are very cool, but sea snakes terrify me. Something you learned about me

today. Yeah. Yeah. Also the group the Vipyriids in the family Vipyriidae, which include the vipers and pit vipers, which are like rattlesnakes and other things, as well as adders. And then the subfamily, and I might not pronounce this right, attract a spittinae. This is mole vipers and stiletto snakes. It's a smaller group, not super common.

Stiletto snakes. That's like a very cool band name. I wonder if it is a band. I wonder. It should be. Someone may get. And so these are the three major groups, the elapids, the vipyrians, and the attracta spittany snakes that are considered of medical importance because their bites are extra dangerous to humans. All of these types of snakes have venom glands on either side of their cute little faces, and these glands are connected to ducks that transfer the venom to the base of their fangs. And in many cases, these fangs are very cool.

They have canals in their hollow fangs through which the venom travels and can then be rapidly injected into the victim with a bite. It's so cool. It is. Snake fangs are very cool. They vary a lot evolutionarily between groups. Like some of them fold back. Some of them fit into grooves. Some, like, spitting vipers can actually spit their venom out.

It is very cool. Someone else can get into that. But let's talk about venoms. So venoms are specialized types of toxins that have to be injected into their victim in order to have an effect, as opposed to a poison, which can exert its effect after ingestion or even just by diffusing across the skin, right? So venoms, including snake venoms, have a lot of large molecules as part of their composition that actually have to then be injected through the skin to any. enter the bloodstream and then exert an effect. And venom, I know you know this, Aaron, but a lot of listeners might not. Venom is inherently an ecological phenomenon. So the composition and the activity of any given animals, but especially any given snakes, venom, inherently co-evolved over time with the specific physiology and ecology of primarily the prey animals that this venom is being used to, you know, assist in eating, right? And probably

to some extent as well, the predators that these snakes are in threat from. So some snakes, their venom is primarily used to immobilize their prey. Other snakes, their venom is actually beginning the process of digestion for them. And other snakes, they're using their venom primarily to ward off other predators. So there is an incredible amount of variation in snake venom. It's unbelievable. It's so beautiful. Yeah, it really is.

It's amazing. I just, I, it's also, of course, a lot more diverse than I realized. As always. As always. So humans, as it turns out, are probably not super important in. the evolution of snakes or snake venom. And so I want to quote from a paper that I liked here, quote, human envenomings are best viewed as collateral damage of the chemical arms race taking place between various snakes and their prey. I love that. It's definitely an arms race.

Yeah. And we're just collateral damage. So that's how I want us to view all of these symptoms that you'll see when we talk about the different types of venoms. Because as it turns out, snake venoms are some of the most, if not the actual most complex venoms of the entire animal kingdom. Lots of other animals, scorpions, bees, ants, lots of different animals make venom. Snake venom is incredibly complex. Each individual like venom that a specific, snake is going to inject into you is composed of anywhere from 50 to 200 different components, some of which are toxins, are harmful, and some of which are not but serve some other purpose, right? Like just helping facilitate the entry or something like that. So venoms are comprised

of proteins, carbohydrates, lipids, and the snake venoms that are of human medical importance, despite their incredible complexity can generally be broken down into three major categories based on how they exert their effects. These are the neurotoxic venoms, which affect our nervous system, the hemotoxic venoms, which affect a lot of times our ability to coagulate blood, and we'll get into it, and then cytotoxic venoms, which cause tissue death and tissue damage. And the complexity of all these different toxins tends to fall into a few major, like, molecular biology or biochemistry groupings. Like there are certain proteins that are very common across snake venom's. But they don't necessarily neatly fall into these categories of neurotoxic, cytotoxic, hematoxic, because there's a lot of variation in their potential sites of action where specific

toxins that might look similar actually have a very different clinical effect in different snake species, which is mind-blowing. Yeah. And it's also often a generalization that's made that the venom from elapid snakes, so those cobras, mambas, coral snakes, is primarily neurotoxic in nature. And venom from viperid snakes, vipers, pit vipers, rattlesnakes, is primarily cytotoxic and hematoxic. And these generalizations are true to some extent, but there is so much individual variation, and there are so many exceptions to those rules, like spitting cobras, which cobras are

generally neurotoxic, but spitting cobras often have a lot of cytotoxicity, hemotoxicity. Rattlesnakes generally have very hemotoxic venom, but some species also have neurotoxic properties. And a lot of of Australian snakes, just do the most wild and crazy things. Well, and isn't there also a lot of variation among populations or even individual to individual? Exactly. Exactly. So even between, for example, Mojave rattlesnakes, some groups, some populations of that species of rattlesnake have more neurotoxic venom and others have more hematoxic venom. So interesting. I can't even express how fascinating and mind-blowing it is. But it's incredibly complicated.

And so to just be able to understand the basics of like the different ways that various snake venom's could affect our bodies, we're going to focus on those three broad categories of venoms, cytotoxic, hemotoxic and neurotoxic. And how each of those would present if you got bitten by snakes with these various venom properties, shall we? Let's do it. So the first big distinction between bite types, if you get bitten. by a snake. Besides, I should mention, is it a dry bite or is it an envenomation? Because it's also important to note that while many snakes are venomous, not every venomous snake bite results in invenomation because some bites are what we call dry. So they don't actually spit any of their venom out. But other than that, we'll just focus on the venomous bites.

The first big distinction is whether or not there are going to be any local effects of that bite. Cytotoxic venom causes a significant amount of local effects. Cytoc, meaning cell, toxic, meaning toxic. So cytotoxic and venoming symptoms often look like incredibly painful and sometimes very severe swelling at the sight of the bite, which can sometimes lead to very large, like, blue, blood-filled blisters or extensive deep tissue bruising. There can be tissue damage and necrosis or death of tissue of your arm or your leg or wherever the bite occurred. And it can be so severe that if it isn't surgically debreeded or cared for, the limb can end up needing amputation because of how

severe tissue death can be. I have, in my research, I came across some pictures of it by accident and it's terrifying. Terrifying. Yeah. Yeah. There's also in some snake venoms a type of tissue damage that occurs that ends up causing blood clots in small vessels that actually then contains the venom toxins to the site of the bite wound so that they don't travel more extensively so that those toxins can exert

their effect very locally, which I think is fascinating. Yeah. So if you have a snake bite that is very painful, very swollen, very obvious, then there's a component of cytotoxicity that's going on there. Okay. Okay. Another place that cytotoxicity can come into play is actually in a more systemic way. So that was all kind of the local cytotoxic effects. But as snake venom travels through the lymphatics and reaches kind of the rest of the body, some snake venom toxins have specific effects on our muscle sex.

cells, which is known as myotoxicity. These end up actually damaging or killing primarily our skeletal muscle cells, so muscles in your arms, your legs. And this process of muscle cell breakdown leads to the release of a lot of enzymes from our muscle cells and proteins that actually are very damaging to our organs, especially our kidneys. So this process can actually lead to kidney failure. This is called rhabdomyelysis. It's not specific to snake bites, but it's a really important complication of the skeletal muscle breakdown that snake venom toxins can induce that can then cause kidney failure and death. Your face has questions. I have a question. How is this so targeted? Like, are we going to talk about the structure of these different

venom's and like how they do the things that they do? Yeah. So that's a good question, Aaron. I'm not. And it's not because it's not necessarily known, but it's because it is so incredibly complicated. So there are kind of a few dominant categories of proteins and enzymes that are involved in snake venom. Some are called phospholipases. Some are called SVMP's snake venom metalloproteases or snake venom, searing proteases, SVs, and then there are three finger peptides. Those are the four kind of major groups of proteins that cause a lot of damage. And there's a lot of overlap. For example, the PLA2s, the phospholipases, they have a lot of the myotoxic and inflammatory cytotoxic effects, but they also are very neurotoxic as well. Different ones. So it's, it's, okay, so yeah.

Yeah, so it gets really, really complicated. But in general, it is these phospholipases that have a lot of that specific myotoxic activity. Okay. It's, I just, I know. I know. I know, Aaron. And it's so like the, there are so many different ways, even in under the grouping of, say, cytotoxic, there are so many different specific ways that these enzymes and these proteins and these toxins can end. up killing cells. It's not just like one mechanism of action. I see. Okay. Yeah. But that's kind of the first category of big effects that you might see is tissue death either locally or more systemically with muscle breakdown. Okay. That's cytotoxic venoms and cytotoxic components. The next thing that you might notice or you might look for when it comes to a bite wound, is is that bite wound oozing? Ousing what?

Ousing what? Ousing what? Ousing what? I don't know if it was like pus or like clear liquid or something. No, oozing blood. Snake bites can cause both local and systemic hemorrhage. And the way that they do this can vary a lot, but there's two main mechanisms. And they both fall under the umbrella of a hematoxic venom.

The hematoxic venom. have two different presentations that, as we'll see, kind of go hand in hand to create a very bad potential outcome. So some toxins, some hematoxic toxins in venom, can cause vascular permeability, which we've talked about in other episodes in various ways. But basically, these toxins attack and break down the basement membrane, the bottom layer of our blood vessels, especially in our small blood vessels are capillaries. And this leads to leaky vessels, which leads to loss of fluid and what we call extravization of the blood out of your blood vessels and just into your general spaces in your body. And that means that there's less fluid in our blood vessels, which can then

lead to hypotension, low blood pressure, because you don't have enough fluid to have enough pressure in your blood vessels. And that can lead to shock, which is when you're not able to perfuse, your tissues because of how low your blood pressure is. Okay. That can lead to death. And so that is indicated by an oozing, a bloody oozing wound. Potentially. That's one possible sign. Yeah. Okay. Okay. A number of other toxins might cause vasodilation, basically opening up our blood vessels

in diameter, which has the same effect of reducing our blood pressure. Right. It's actually, incidentally, how a lot of our blood pressure lowering medications work, and I think you'll probably talk, Erin, about how at least one anti-hypertensive class of medicines was actually developed from snake venom. Yeah, I'll mention it very briefly, but it is one of the coolest things. And I, yeah, I just, I love it so much because it's such a beautiful little example of how we're like, let's take this thing that can be very harmful. And wait a second, how is it useful? Exactly. Yeah. And it is. It's a very useful class of medicines. But basically, in an envenomation sense where you're getting a large load of this all at once, that can also

lead to hypotension and shock. It's a different mechanism. It's the same end result. But the other part of hemotoxicity that I think is even more absolutely fascinating is that various different snake venom toxins have specific effects on our coagulation cascade. Which isn't it great that we did hemophilia. So if you've listened to it, you're familiar with the clotting cascade. Exactly. If you haven't, I'll refresh you. Basically, in short, the process of blood clot formation in our bodies, which begins when endothelial or our blood vessels are damaged in some way, the process that we use to form a blood clot to fix and heal off that damage so that we don't just keep bleeding freely. It's a series of

a very complex steps where there are like 13 or more different factors or proteins that have to be activated in series to then go on to activate other factors so that the end result is formation first of what we call a hemistatic plug and that happens mostly with platelets which are like our first line defense and then eventually a fibrin enhanced really strong. clot, and then eventually our body's able to repair that area. So this system, this coagulation cascade, is very tightly regulated in our body. It requires all 13 plus of these factors to be activated in series to make that clot and then break that clot down to repair the area. Well, one of the hallmark effects of a lot of snake venom toxins is what's known as a consumption coagulopathy, which means that what they do is they activate various factors in this coagulation cascade.

And in so doing, they use them all up. So then we have no factors left and we can't make a blood clot so we bleed and bleed and bleed. Oh, that's so interesting. So it causes both like clotting but also massive hemorrhage. Exactly, Aaron. Weird. Yeah. So what it tends to do is it causes clotting that's because it's being activated by the snake venom toxins and not the normal coagulation cascade. It doesn't go through all of the steps. So the clots that tend to form get broken up very easily. And this process uses up all of our coagulation factors.

So then we have none left to actually make a clot. That's amazing. And if you combine that with the fact that other toxins in this venom are also causing leaky blood vessels, now you have leaky blood vessels and the inability to clot, you get massive hemorrhage, which especially if it happens in somewhere like your brain is life-threatening. Right. It's fascinating, Aaron. And what's even more fascinating is how many different specific toxins, specific forms of those various proteins that I mentioned, affect different parts of this coagulation cascade.

Almost every single step can be affected by different snake venom toxins. Evolution is an amazing thing. It really is. It is, it blows my mind. If it wasn't so terrifying, even though it is so terrifying, it is still. kind of a beautiful, beautiful thing. It is. I mean, and I think that snakes are, fear of snakes is the most common or one of the most common

phobias. And I get it. Yeah. And snakes have a really, they hold really important meaning in human history. I read somewhere that up to 50% of people report dreaming about snakes at some point. And so. I dreamt about them last night. And it's amazing. And so what I really don't want people to think after listening to this episode is that we don't like snakes or that snakes are bad or anything like that because they're not. They're amazing, beautiful creatures. And they just happen to sometimes bite people with these venoms that are very, very bad.

Yes, I know. I feel the same. I was really worried after all of this where I'm like, this sounds so terrifying. And I know. so many people are terrified of snakes and it's not the snake's fault. Right. And it's, I feel like it's definitely one of those cases where, hopefully, knowledge is power. And the more you know about something, the less sort of mysterious and scary it might be just if you have that understanding. But also, it's, it's reasonable to be afraid of snakes because it's evolutionarily adaptive. Exactly. Exactly. As I'll talk a lot more about. I can't wait. Okay. We have one more class of toxins to talk about, though. The neurotoxins. Neurotoxic-invenoming symptoms often start with a descending paralysis. That is, paralysis of the muscles starting in our face, the small muscles

of the face that are innervated by our cranial nerves. And it progresses downward through all the nerves in our body until it eventually affects our respiratory muscles and can cause death from respiratory failure. Does that sound familiar? It sounds like botulism. It sure does. I'm actually just going to do a lot of callbacks to old episodes in this episode. Okay. It's a lot like botulism. But the way in which snake venom toxins end up doing this paralysis is amazingly variable. There are dozens of different specific targets that they have, and it almost all ends up in this same descending flaccid paralysis. So let's kind of go over it a little bit more detail. In our botulism and our tetanus episodes, and I also think in a lot of our crossover episodes with Matt from In defense of plants,

because we end up talking about neurotransmitters a lot. But I've talked in detail about our nerves, our neuromuscular junction, which is the junction between where our nerves actually exert their effect on our muscles to cause them to contract. And I've talked about all of the various neurotransmitters that are involved in sending those signals and converting an electrical signal to a chemical signal to have the effect on the muscle. It turns out that snake venom toxins can affect almost any part of either the presynaptic that is the nerve end or the post-synaptic that is the muscle receptor end of this neuromuscular junction.

So some toxins that are pre-synaptic that act on the nerve itself like botulism does inhibit the release of certain neurotransmitters. others cause the release of all of our neurotransmitters at once and use them all up. And both of those different mechanisms have the same effect of depleting the ability of our nerve to transmit a signal to our muscle. Some other toxins on the postsynaptic or the muscle side block the breakdown of neurotransmitters after they've been sent so that they can't unbind their receptor. so that new or repeated signals can't go through. Some of them just block receptors directly or even interfere with the neurotransmitters while they're in that synapse crossing the space between the nerve and the muscle. It is incredible and incredibly complex how many different specific mechanisms of this have evolved.

And what is even more amazing is that the symptoms, regardless of those specific mechanisms, mechanisms are an acute, flaccid, so floppy paralysis that starts with the muscles of the face and travels downward regardless of where the bite wound was or what that specific receptor is involved. That is, it is, it is, you're right, it is amazing, it is incredible, it is fascinating, and it just leaves me to wonder, are there any spots along that sequence that haven't been targeted by or like can't be targeted by venoms. You know what I mean? Because it seems like, yeah, it's a great question. There are so many different types of ways for this to happen. And they've all been check, check, check, done. Yep. And if not by snakes, then by scorpions or somewhere else. Right. Oh, it's amazing. I know. I will say there are some exceptions, like there are some South American rattlesnake venoms that cause more of espastic paralysis like Tetanus does. But in general, almost across the board. It's a,

a more flaccid paralysis. Interesting. I know. And so that's kind of all of the different types of venom. And I know that for a lot of people that probably wasn't enough detail and you want to know a lot more, I have tons of good papers for you. And for some people, that was probably like way too much. But hopefully, you know, we get at least the broad stroke pictures where different components

of different types of venom can have a huge variety of effects on our. human bodies. And when we look at it back evolutionarily, it's because of all the different ways that these specific snakes were interacting with their prey or their predators to try and immobilize them or make sure that they die quickly or etc. There is treatment a lot of times. Is it like I saw in Hey Dude growing up sucking out the venom of the bite? It absolutely is not. Please never suck the venom out of someone's bite or your own. That is a falsity.

There's probably a lot of myths we can dispel right here. Don't suck out the venom. That's one. Please don't cut open the wound to try and let the venom drain. Don't do that either. I heard that is another one that can make things so much worse. So much worse. And just invite more infection.

Don't tourniquet off the limb because that can cause a lot more tissue damage. immobilizing the limb and potentially doing a pressure dressing, which is like, think of like an ace wrap, like you would put on a sprained ankle, like that level of compression. But even that, only if you're not having a lot of swelling. If you have a lot of cytotoxic local effects and your ankle, for example, gets really, really swollen. You wouldn't want a wrap to be so tight that you're cutting off blood supply, especially if you, like Gwen, have a three-hour drive to wherever you're going. But immobilizing your limb can help reduce the spread of toxin through your lymphatics. I also read something. And I want you to tell me if this is true or not that you should, that sometimes

it is advised to not wash the wound very carefully, because especially if you don't know what kind of snake bit you, then it's important to be able to get the venom if there's any like around the wound. So from what I read, it's only in Australia and New Guinea that they have. ability to swab a wound and be able to test for a specific type of venom. Okay. And so as far as I know, those are the only places where they have that type of detection available to be able to say what a specific venom is by swabbing a wound to try and find venom. Gotcha. So anywhere else if you have, and especially if it's going to be a very long time until you can get medical care, cleaning a wound is always going to be a good idea. Just gently. That makes sense. Yeah. Good question,

though. And then what about if you don't know what snake bit you, because like that's, that's one of the biggest challenges, right? Is if you get bit by a snake, how do you get the proper treatment? Because that can vary a lot depending on a snake species. You are so correct, Aaron. And it's also a problem because how do you identify a snake that you just got bitten by? That's very difficult to do. You might not have even seen it. It might have happened while you were sleeping. It might have happened in the dark. It might be that you don't know snakes very well. I don't know snakes. I would have, I would know rattlesnake because of rattles, otherwise generic snake. And that's it. That's literally all I've got. It's a great question. It is very difficult to know exactly what snake bit someone. And one of the

things they say sometimes is if you bring the snake with you to the hospital, then that can facilitate identification. But there's a huge but to that. It's very dangerous to try and kill and then bring a snake in. So don't do it. I wouldn't recommend it. And even if you brought it to a hospital, there's no guarantee that there's going to be an expert herpetologist around who's going to be able to say exactly what that snake was. Right. The same holds true for trying to get a photograph of the snake to use that for identification.

It can be very difficult. So to some extent, yes, being able to describe a snake might help in certain regions to be able to identify. Is it an elapid snake or is it a viperid snake? So is it more likely to be neurotoxic or is it more likely to be hemotoxic or cytotoxic? But really, what it comes down to is actually having to just evaluate it clinically, and you might never know exactly which snake it was. Oh, I see. Okay. Yeah.

And you're right. It's important to know or to try and know what type of snake it was to be able to give the right anti-venom. Anti-venom, by the way, is produced by hyper-immunizing or exposing horses or sheep, usually, to venoms from snakes and then purifying the antibodies that they make and using that as a therapeutic. So it's horse or sheep antibodies against snake venom that we use as therapy. Do you know when anti-venin and anti-venom? because I've seen it written both ways, Erin. I never saw anti-venin except for Pfizer's specific, like, trade name as anti-venin. Okay.

So I don't know. It might be an old-timey name. Yeah, maybe that's the case because I did see it in some older papers, but I didn't. Yeah, I don't know. I didn't know if there was a difference. I don't think there is. I think it's the same thing. Okay.

There is a difference between toxinology and toxicology, as I learned. I had to learn that too. I was like, are they doing typos right now? Yeah. No. Well, because even Word or Google or something was like, did you mean toxicology? And I was like, I don't think so. No. I Googled it multiple times, more than twice, to make sure I understood. But yeah. So knowing the snake can be very helpful in. trying to get the right anti-venom. It's not always possible. It's also the case that a lot of anti-venoms are not specific to one snake anyway. They're polyclonal. They're made from

hyper-immunizing horses against multiple different snakes that are present in a given region to try and provide immunity against a wider variety of snakes, which can be great, especially when you can't identify what type of snake you got bitten by. But the problem is that then it tends to be much lower tithers, so like a smaller amount of an antivenom that's going to help any one specific snake, if that makes sense. Or one specific snake bite, rather. But really, when somebody comes to a hospital with a snake bite, it's all about looking at what are the symptoms that they're having and doing a lot of blood work to see, are you having problems with coagulation? Are you having problems with tissue swelling. Are you having evidence of that rabdomiolysis? Are you having any

evidence of, you know, your eyelid is droopy, you're having paralysis, etc. And then you treat those based on. And this is the other thing that I think is so incredibly interesting and difficult about snake bites is how hyper-local this knowledge all has to be. Right. Right. Because in Western Colorado, the profile of the types of venomous snakes you could possibly be bitten by is very different than in the eastern United States or in Australia or in Sri Lanka, right? It's incredibly different. And so it's all going to be specific to where you are and what your symptoms are to know what's the most likely type of antivenom to use to treat this. Yeah. So I understand that the venomous.

are very variable and the composition and among the different types of venom's and so on. But are there certain types of venoms like hematoxic versus neurotoxic where you need to get the anti-venom delivered sooner? Very good question, Aaron. In general, there's a lot of studies that have shown that the sooner that anyone gets anti-venom, the better. Right, of course. When it comes to especially neurotoxins. Just like we saw with botulinum toxin and tetanus toxin, if we are talking about a presynaptic toxin, so something that affects the nerve end of a cell, once those toxins bind, there is nothing that you can do. Antivenom doesn't do anything. So in those cases especially, the sooner that you can get an effective antivenom on board, the more likely it is you can prevent

further toxins from binding. In the case of post-synaptic and in the case of hematoxic, you have a lot more ability to reverse the damage with antivenoms. Okay. And in terms of these neurotoxins, what we learned in tetanus was that basically how long the tetanus toxins exist, how long they are functional. How long are these pre-synaptic neurotoxins functional? It's a good question. I think It very much depends on the snake species. So I don't think there's like an easy half-life I can give you. Got it. Okay.

Yeah. But people do tend to recover with supportive treatment. It's definitely treatable. What is supportive treatment besides anti-venom therapy? Great question. Of course, depends on the type of toxin. If it's something where it's cytotoxic and things need debreedment or they need cleaning, that sort of a thing is going to be more supportive care. If it's a rabdomyelysis, the most important thing is actually hydration.

So it's a lot of IV fluid administration to keep the kidneys from becoming damaged from that muscle breakdown. And then in the case of neurotoxins, it's more about making sure that people have airway support. So mechanical ventilation and the same kinds of things we saw with tetanist toxin. Okay. Yeah. And that's a lot. It's a lot. I mean, it's fascinating. As we said a thousand times so far. But it's still so true. So, Erin, listen, I don't even know where to begin to ask you. Like, what's up with this? This snake venom thing.

Yeah. And how have humans interacted with snake venom and the idea of snake venom through time? Such good questions. I'll do my best right after this break. Anyone who works long hours knows the routine. Wash, sanitize, repeat. By the end of the day, your hands feel like they've been through something. That's why O'Keeffe's Working Hands hand cream is such a relief. It's a concentrated hand cream that is specifically designed to relieve extremely dry, cracked hands caused by constant handwashing and harsh conditions. Working hands creates a protective layer on the skin that locks in moisture. It's non-greasy, unscented, and absorbs quickly. A little goes along way. Moisturization that lasts up to 48 hours. It's made for people whose hands take a beating at work, from health care and food service to salon, lab, and caregiving environments. It's been relied on for

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wire stuff. Nibbles would have loved you like a brother. Connecting homeowners with skilled pros for over 30 years. Angie, the one you trust to find the ones you trust. Find pros for all your home projects at Angie.com. Success starts with your drive and American Public University is here to fuel it. With affordable tuition and over 200 flexible online programs, APU helps you gain the skills and confidence to move forward. Whether you're changing careers, starting fresh, or pursuing a lifelong passion. Our programs are designed for people who never stop. You bring the fire, APU will fuel the journey. Learn more at APU. APU. APUS.edu. This was definitely a tricky one to research because there is absolutely so very much that you could cover when it comes to the history of snakes. Or even how snakes have

featured in human history. And before I started reading for this episode, I didn't really know where the research was going to take me or what story I wanted to tell, and it was kind of daunting. But I thought to myself, okay, in this episode, we're talking about venomous snakes and what happens when you get bitten by a venomous snake. So why don't I look into how humans have responded to these snakes and the bites from these snakes over time? And that led me down some very surprising, but also very interesting roads. And I decided to structure the history section in two parts. The first part deals with evolution, how the encounters that our primate ancestors had with snakes over millions of years may have shaped how we look at the world literally.

What? And the second part covers how more recently we have learned to deal with those encounters through the development of anti-venom therapy. Ooh. I am very excited. So let's dive in. Okay. First, the snake detection hypothesis. Oh, okay. Also, sometimes called the snake detection theory, but I really don't like that it's

called a theory, since it isn't a theory, strictly speaking, it's a hypothesis. Right. Have you come across this before? Nope, but I can't wait. I am so excited. Okay, I'm so excited. At its core, the snake detection hypothesis proposes that humans and other primates have such excellent vision because of snakes, which were among the earliest and most important predators

of early primates. Individuals that couldn't see the venomous snake in the grass or distinguish a snake from a vine were more likely to get eaten and less likely to pass along their genes. This is a lot. Yeah. So let's break it down. Okay. Why vision, first of all?

Primates are actually unique in that they have some of the best vision among males. animals. Forward-facing eyes gives them excellent depth perception. They have high visual acuity, and many species have trichromatic color vision, which allows us to distinguish among like greens and reds and stuff. The parts of our brain that are devoted to visual processing, both the non-conscious and conscious parts, are expanded. And these parts are the parts that provide like an automatic predator or threat detection and then allow us to process. that information to decide what we want to do. It's our visual system and our reliance on vision as our primary sense in large part that distinguishes us primates from other mammals. Throughout the years,

researchers have put forth different hypotheses to explain why primates have such good vision. For instance, resource acquisition, like grabbing insects or grabbing fruits, being able to do that visually directed movement and grasping. And like I've I've also read a lot of like recognizing, especially with color vision, being able to see red fruits in green trees, etc. Yes, exactly. Yeah. And then also there's the arboreal movement. So like moving through trees, being able to use that depth perception to reach and grasp branches so you can move better through trees. Those are some of the hypotheses. Most recently, there is the snake detaintinger. hypothesis, which was put forth by UC Davis professor Lynn Isbell in 2006. She proposes that primates

evolved this excellent vision to better detect snakes, specifically venomous snakes. To see how this might have happened, let's travel back to around 60 million years ago, a few million years after the massive extinction event that wiped out so many of the non-avian dinosaurs and other life on earth. With the Non-avian dinosaurs gone, small mammals began to flourish, which opened up a new food source for snakes, which had been around for tens of millions of years already. But with the dinosaurs gone, they had even more opportunities to expand and diversify. And so they did. After the huge Cretaceous paleogene mass extinction event, venomous snakes began to appear,

possibly in response to the emergence of faster-moving mammals. So you could, as a snake, you could hide, strike, and then wait for the venom to do its work, rather than having to get close enough to constrict, which is what most snakes used as their like prey kill method before this. And it's thought that snakes also evolved large gapes, as in they can open their mouths really wide so that they could take advantage of these diversifying mammals. I'm loving this so much already, Aaron. I'm glad. I'm glad. I feel like I'm back at like a natural history museum and I'm walking through the like, you know, evolution display at field museum. Just like, oh my goodness. That's how I feel right now. I love this. Oh, I love it so much. I love it. Yeah. I find this absolutely thought provoking. I'm, I'm, it's very interesting. And so yeah, of course, venomous snakes and the earliest primates would have been well acquainted with each other. In fact, the earliest primates would have faced the continuous. threat of venomous snakes as predators well before the other important predators like wild cats or birds of prey emerged, which was later on. If snakes are one of the biggest reasons why certain individuals aren't surviving long enough to reproduce, that's going to strongly select for traits

that will help individuals avoid getting eaten. And in this case, that's proposed to be vision. being able to distinguish that well-camiflaged, unmoving snake from a pile of leaves could save you. And detecting snakes close up is more important than detecting them at a distance, unlike other predators, where you'd presumably want to have as much lead time as possible to run away or hide. So can we agree here that the logic seems to be there for the snake detection hypothesis? Yeah, I like it. It's logical. Okay, cool. what evidence is there to support it?

Is there? Is there? Tell me. So up to this point, I've basically been talking about primates as one large homogenous group, which, of course, they are not. And it's actually some of these differences among groups of primates that provide some very compelling bits of support for the snake detection hypothesis. So when I say that primates have excellent vision, that's true in comparison with most

other mammals. But within primates, there's a good deal of variation within visual ability. For instance, lemurs from Madagascar have some of the worst eyesight of all primates, and they only have dichromatic color vision, meaning they can see or distinguish among fewer colors. Okay. Interesting thing about Madagascar, no venomous snakes. Okay. Uh-huh.

And if we look at the places where venomous snakes are the most numerous or have, have the most potent venom, places like parts of Africa and Asia, the monkeys there have the most advanced vision, the best color vision, and some of the largest visual processing regions in their brains. And so this would suggest that lemurs, which did not evolve in the presence of venomous snakes, didn't experience as strong of drivers in terms of vision compared to these other monkeys. It's cool, but it's also possible, of course, that this pattern emerged for other reasons besides venomous snakes. Yeah, something else.

Yeah. So let's get a little more specific by looking at some neuroscience, but without getting too much in the weeds. Okay. Because I don't know anything about neuroscience. Earlier, I mentioned that the visual processing areas of the brains of primates are expanded

compared to most other mammals. One of these areas deals with non-conscious automatic predator detection and then an immediate motor reaction. So imagine you're seeing, a snake slither in front of you while you're out for a run. You may react by freezing or leaping backwards, even without realizing you're doing it. You just do it completely unthinkingly. Yeah. That region is called the Pulvinar region. And in 2013, a group of researchers set out to

test whether the snake detection hypothesis could be backed by neuroscience. They showed macaque monkeys who had never seen snakes before a series of images. Snakes, other macaque faces, macaque hands, and geometric shapes. And then they measured how strongly the neurons in the pulvenar region of these monkeys responded. Images with snakes led to the strongest and fastest responses compared to other categories. What? And there's more. The position of the snake also made a difference.

Snakes that were in a threatening pose led to a stronger response. And these are monkeys who were raised, like, in a lab and so they had never seen snakes. Born and raised in captivity. Okay. Yep. So this is a really nice piece of neuroscience support for the snake detection hypothesis. And I'll include this paper on our website. It's by Van Lee et al from 2013, if you're curious. What about humans, though? Yeah. Another study from 2017, measure. responses to images of snake skin, like close-up images of snake skin versus bird feathers, so not images of like the complete animal, but just the patterns. And the images of snake skin got the earliest and strongest response again.

And yet another study compared fear responses in humans when presented with images of venomous snakes, non-venomous snakes, and leaves, and found the strongest fear response with venomous snakes, which I think is interesting because I don't necessarily. know if I know all the time whether a snake is venomous or not. I know that like head shape matters, but it's not just head shape. No, because even that, like the elapids have very different head shapes than the vipyrians and the alapids are incredibly venomous. So that is really interesting. Yeah. Yeah. And these studies aren't alone. These are just like a couple that I, that I'm mentioning. There have been quite a handful, a surprising handful, of neuroscience or physiological studies that

have tested this hypothesis and have generally found support for it. And I think that is so cool, but what I also find cool is the behavioral responses that primates show towards snakes. I have a question real quick before we get into the behavior. In any of these like neurologic response studies, did they test other predators in addition to snakes? It's a good question. I don't know. It's possible that there are. There were a lot of studies out there. and I didn't read through them all. In the ones that I mentioned, they did not, but they may have. And so I think that, yeah, that is one criticism that this hypothesis often faces is like, well,

could it just be more generally be called the predator detection hypothesis? It seems a little bit much to pin all of our visual evolution, or not all, but most, on one single predator. Right. That being said, I think that it's also interesting in that the predators of primates that we see today, like you think about lions or jaguars or birds of prey, a lot of those things would look very different 60 million years ago compared to how they look today, whereas snakes largely look kind of the same. Yeah. So that is interesting. That is interesting.

Right. That they were our evolutionary pressures millions of years ago when this visual acuity was evolving. Right. And so the general shape of them, we may have evolved specific recognition of snakes as specific cues and the shapes of snakes. Yeah. Whereas like, you know, larger cats we may not have. Yeah. But I don't know.

It's definitely a really good point. Yeah. And I don't know. I wonder if you compared it to other things like, say, alligators, crocodiles. Right. That also existed millions of years ago. Even sharks, right? Although I guess we can't ever see sharks, so maybe not those.

Maybe not sharks. But also, like, how numerous in the landscape were crocodiles. That's true. That's true. Good point. There's, like, so much more that you could dig so much more deeply on this. Yeah. And I will definitely link to the book that Lynn Isbell wrote this book about the snake

detection hypothesis that has so much more information in it. Cool. But yeah, so behavioral stuff. Yeah. I just find behavioral studies so interesting. Oh yeah. We love it. Oh, yeah. So while being afraid of snakes does seem to have a learned component to it among primates. So for instance, a snake naive monkey, as in it hasn't ever encountered snakes before, may show a fear response after watching a video of other monkeys responding fearfully to a snake. Okay. Yeah. It also seems. to be this fear of snakes seems to be innate to some degree. Macacques that were born and raised in captivity responded fearfully when seeing a snake in a different study. And there are some studies showing that human infants startle in response to snakes and that their attention is grabbed

by snakes. Although those infant studies do seem to have somewhat mixed results, like it's unclear whether it's just startle or fear. Is there actual fear to it? Yeah. And going back to our among primate group comparison, behavioral studies of lemurs from Madagascar show that they don't seem to react to snakes, at least visually, in like a fearful way. Smell might be a different thing, because there are constricting snakes on Madagascar. Some primate species have a completely distinct alert call that they only use in the presence of snakes. And often, a group of primates will do something called mobbing. They'll approach, stare, and vocalize at the snake, sometimes the mob turns violent, throwing sticks at the snake or even

beating the snake with a stick. Oh my God, poor snake! I feel so bad. So up to this point, I've talked a lot about evolution, but mostly in terms of primate vision evolving in response to venomous snakes. Yeah. But what about the snakes? Yeah, Aaron. Did they ever feel pressure from primates? Especially once we learn to mob the snakes or use tools to hurt or kill them? They may have. Research from the past few years suggests that spitting cobras may have evolved the ability to spit venom, which is a defensive behavior, which I find so cool in response to threats from primates.

Oh. And even cooler is that this venom spitting has evolved three times independently. Amazing. It's very cool. Yeah, the venom spitting, there's so much more there, and I would love to dive deeper into why Cobra's spit. Right. And also the evolution of venom in general.

Right. Why did snakes evolve venom? Why are there so many different types of venom? Where do we find the most venomous snakes? And why? How do you milk a snake for venom? There is so much that I want to ask, but I'm going to have to wait for next week, as well, all you listeners, for when I interview.

Professor Nicholas Casewell, who is the director of the Center for Snakebite Research and Interventions at the Liverpool School of Tropical Medicine. I am so excited. Aaron, I can't wait for you to ask about how different snake species that feed on different types of prey have different venom. And like, oh my gosh, I'm so excited about it. I am very excited too. And all of you out there, mark your calendars. Yeah. It's going to be good. Okay, but back to the snake detection hypothesis. Yeah, okay. It's a very cool hypothesis, and it does have some support from research.

Yeah. But I do want to say that it is still just a hypothesis, a proposed explanation for why things are the way they are. And while it's possible that snakes did play a role in the evolution of primates, most researchers, including Isbell, don't claim that snakes have been the sole driver of vision evolution in primates. they may have like kickstarted a little bit of it, but enhanced vision was obviously useful for many other things. Right. And there are some problems with this hypothesis. For instance, the suggestion that trichromatic color vision evolved to better recognize camouflage snakes, studies have actually shown that primates with dichromatic color vision, like those lemurs from Madagascar, detect camouflaged objects better than their trichromatic counterparts. Oh, interesting.

Yeah. And so like you said, Aaron, the trichomatic color vision might be better explained by needing to distinguish ripe red fruits among green foliage. Right. As with everything, more work needs to be done. Oh, but I love it. It's so fun to hypothesize, you know? It is. It is. There's something about it that just I love, it's so fun to think about why. Why things are the way they are. I think that's why we ended up in academia for so long, Erin is because that's how our brains just like to like ask those questions of why and think about possible explanations and then also find a way to like pick apart those explanations and find potential issues with them and then ask more questions because of it. Where are the limitations? Yeah.

Yeah. Yeah. Yeah. We're like we're perpetual toddlers. We are. But why? That's honestly, so true. Okay.

Enhancement of vision may be one way that primates have dealt with the threat of venomous snakes throughout history, but what about other ways? A recent study from 2021 showed that primates in Africa and Asia have increased levels of resistance to alpha neurotoxins, which are carried in the venom of some of the vipers in these regions. What? Notably, no resistance is seen in Madagascar lemurs. But I want to move past these discussions of evolutionary defenses to talk about the history of antivenom therapy. Snakes feature prominently throughout human history and culture. One of the oldest, if not the oldest, religious artifacts is a stone python in a cave in Botswana. Archaeologists estimate that 70,000 years ago, people engaged in a ritual where they sacrificed colorful spearheads to this python.

Hmm. Snakes hold a prominent position in many religions as creator or destroyer, as a symbol of fertility or one of evil, as a god or a demon, as representing wisdom or cunning. And this duality, I think, is really interesting when we think about how snake venoms can kill, but also how they can be used as highly effective medications. It's beautiful. And it's way beyond the scope of this episode to talk about the meaning that snakes have held and continue to hold for different cultures throughout human history. But I think it goes almost without saying that snakes have held a great fascination for humans throughout all of time. Likely because, or at least in part, because of the threat they could pose.

The famous physician Galen from ancient Rome wrote, quote, it seems that there is nothing more dangerous in life than poisons and the bites of noxious animals. Humans have always sought ways to protect from snake venom or find antidotes against it. Drinking small amounts of venom, for instance, or using a venomous snake's flesh as an ingredient in an antidote recipe like Theriac, which was a cure-all created in ancient Greece. And the variety of, quote, cures shows us just how feared snake bites were and how helpless physicians were in treating them. And part of their helplessness probably stemmed from the fact that no one really knew what was in the bite of some snakes that caused such horrible injury or death. For a long time, many people just believed it was bad spirits in the snakes. At one point, the Archbishop of Madrid reportedly exercised the venom from all snakes of Spain.

Oh, it's just like... It's gone now. It leaves you. It's gone. Nice job. It seems that the Italian physician Francesco Reddy was the first to suggest that rather than bad spirits, it was actually the substance coming from a snake's fangs, the venom that was responsible for all of the symptoms experienced after a bite. And side note, the word venom is derived from the Latin word veninum, meaning a magical charm, as well as poison. Oh, that's kind of fun. I didn't know that.

Yeah. And his conclusions were not widely accepted. Several physicians insisted that it was bad spirits. But Reddy refused to budge. And about 100 years after his work, his ideas found support in research done by Felice Fontana on the mechanism of envenation. and some characteristics of venoms in the European viper. Fontana, who is often referred to as the founder of modern toxinology, also determined that the European viper was immune to its own venom, which raised the question, if snakes are immune to their own venom, does this mean that other animals can become immune as well?

I don't know why my mind is so blown by that. Because it's amazing. Yeah. It's amazing, yeah. And so Fontana published his book in 1781. So that was a little bit, I think a little bit ahead of its time, right? And about 100 years after this publication, let's take stock of things, right? Germ theory was well underway.

And immunology had also gotten its start. So the study of how immune systems respond to foreign substances, pathogens, pathogens, whatever. And if humans and other animals could become immune to pathogens, pathogens, did that mean that they could also become immune to toxins? Henry Sewell, who was a researcher at the University of Michigan, decided to test this question in the context of snake venoms. Using the venom from the eastern Massasauga, which is a type of rattlesnake found in the U.S., Sewell injected small amounts of diluted venom into pigeons. And he repeated

these injections over the course of weeks and found that after about a month, the tolerance of the pigeons had increased. Whereas previously, less than a single drop of venom could kill the bird, at the end of the experiment, it took closer to four whole drops. Wow. Which to me, I was like four whole drops. That's still not a ton of venom. But what's really cool, I think, about this is that it demonstrated that animals could gain some immunity to toxins. Right. And suggested also that the serum from those animals could be used to counteract the effects of the toxins. Soxins, you know, sins in others. That is the part that I really truly love, that it was so early that people came up with this. Yes, I do too. And this is what's really, what's really amazing is that this was before the

work of Kitasado Shibasa Burro and Emo von Bering in 1890 on Tetanus, which, as I said in our Tetanus episode, you know, people consider these two scientists the fathers of modern serum therapy, and which, of course, they had huge significance in the history of diphtheria antitoxin and tetanus antitoxin. But Sewell may have gotten there first with these snake venom. Yeah. And so he's generally overlooked and not just overlooked in the history of serum therapy, but also overlooked in the history of antivenom therapy, which generally starts with the French physician Albert Kelmei, who's the C in the BCG tuberculosis vaccine. That's why that name's familiar. Uh-huh.

In 1891, Kalmay started as director of the Vaccine Institute in what was then known as Saigon, now Ho Chi Menc City. He had been picked for the job by none other than Louis Pasteur. While at the Institute, very exciting, while at the Institute, Kalmay became interested in the venom of the Indian cobra, scientific name Naya Naya. For several years, he tried to induce immunity to this venom. in animals, but it wasn't until he used the methods described by Sewell that he got anti-cobra serum, which he could use as an actual therapy for a cobra bite. I mean, this was monumental to be able to actually counteract the effects of a cobra bite, which previously would have been at least severe injury, if not death. Yeah. Other researchers had been doing

similar work around the same time as Cal May, but their work focused more on how the venom worked and how snakes were immune to their own venom, rather than focusing on applications for their research. Whereas Kalmey's anti-cobra serum, which he began production on in 1895, was revolutionary because it laid the groundwork for other people to create their own anti-venom for venomous snakes in their particular region. Right. Although Kalmei wasn't convinced that snake-specific venoms were needed. Oh, okay. He thought that his anti-cobra serum would save you from any snake bite.

Ah, I see. Yeah. But this misconception was eventually set straight by Brazilian physician Vital Brazil. He noticed that in Sao Paulo, where snake bites were a huge problem, an estimated 5,000 people died each year from venomous snake bites in the state. Whoa. At that time, yeah. So he noticed that snake venom seemed to produce different reactions in terms. people, right? Sometimes there was this paralysis. Sometimes there was this like blood. Sometimes there was

a cytotoxic effect. And this suggested to him that there were different venoms causing these different reactions. And this idea made sense, especially in light of the fact that when he had used Kalme's anti-cobra serum, it was not very effective. Yeah. So Vital Brazil set to making his own anti-venoms and also made mixtures for when the identity of the snake was not known. I love it. Isn't that amazing? It's amazing. And so by the early 1900s, the building blocks for making antivenom for most any venomous snake or even any other creature were pretty well established. The rest was really just tweaking things, such as the quality of serum. One person who received anti-venom for a tiger snake bite in 1930 said, quote, the discomfort of the serum sickness, which followed a large intravenous injection of crude, venom was worse than anything the snake venom could have done. Oh, dear. Yeah, that's a problem. Yeah, yeah. And also, of course, people developed more specific antivenoms as well as general ones that would be effective against a wide range of toxins. And improvements were made not just in the

quality and availability of antivenom. There have also been some amazing strides made in terms of vaccines against venom. For instance, the rattlesnake vaccine that is available for some pets, I believe. Because anti-venom is great, but you need to get it to the person or the animal very quickly. And so preventing the reaction in the first place is really the golden ticket. And finally, what I feel like is one of the most beautiful developments in the history of how humans have dealt with snake venoms came in 1981 with the approval of the first animal toxin-based drug, Capdipril, which is a hypertension and congestive heart failure medication derived from a

compound in Bothrop's Jarrahaka snake venom. Specifically, if you're interested, it's the Brady-Kinin potentiating factor. It's thrilling. It is amazing. It's an entire class of anti-hypertensive medications that are like literally our first line anti-hypertensive, anti-high blood pressure medicines are the ace inhibitors of which captopril was like the first one. It is so cool.

Yeah. There's more too now. There's so many. There's so many. There's no. There's noelaisin inhibitors. Yeah. Oh my goodness.

I counted. So there's a paper that I read. I think it was from 2020 maybe. And I counted at least eight other medications based on snake venom alone that have been approved. And there are many, many more in clinical trials. Yep. Yeah. But even with all of this amazing work and the huge strides that have been made in anti-venom therapies, we still have a long way to go, especially in terms of making those therapies available to those who need them when they need them. So I'll stop here and let you tell

me, Erin, more about where we currently stand with the neglected tropical disease of snake bites today. I can't wait. That was a beautiful segue. Thank you. We'll take a quick break and then get into it. So I'm glad that you said it already, Erin. The World Health Organization has listed snake bite envenoming as a neglected tropical disease. And in fact, a neglected tropical disease of, like, incredible importance. Yeah.

The World Health Organization estimates that between four and a half and about five and a half million people, human people, get bitten by snakes every year, and that this results in between 1.8 and 2.7 million inventations. Wow. 1.8 and 2.7 million invenomations and clinical illnesses every year worldwide, and an estimated anywhere from 81,000 to 138,000 deaths. And potentially three to five times that number of like long-term morbidity from these envenomations. It's it's a lot and it's a lot more than I thought. So much more than I had any idea. I I can't overstate how much I would have underestimated that number. Yeah. Yeah. And like in I think probably every TPWKY episode, those numbers are definitely estimates because of how much underreporting.

there is that happens. Right. If we wanted to break things down by region, which I think is important because those snakes are found worldwide and venomous snakes are found on every continent, except I think Antarctica. I don't think there's snakes there. These snake bite in venomations are not evenly distributed across the globe. They are primarily affecting rural and impoverished areas that lack a lot of public health and medical infrastructure. But if we break some of those numbers down by region, at least one paper had estimates of different regions of the world. So in sub-Saharan Africa, it's estimated there are 90 to 420,000 invenomings, resulting

in 3,000 to 32,000 deaths, huge range of estimate there. Yeah. Yeah. In North Africa and the Middle East, it's estimated there are between 3,000. to 8,000 bites that lead to 4,000 to 8,000 deaths. I feel like that's a pretty important distinction there, where the death rate is essentially the bite rate. Right.

In Latin America and the Caribbean Islands, it's estimated there are between 80 and 129,000 in venomings, leading to 540 to 2,300 deaths, so like smaller numbers, but again, huge range. In the U.S. and Canada, check these numbers, 6,500 bytes a year. That's a lot. Yeah. Five to six deaths. Oh, wow. Yeah. And then in Southeast and South Asia, I couldn't find exact numbers, but the overall mortality rate of snake bites is between 1.05 and 5.42 deaths per 100,000 people. So like significant mortality. Yeah. And then a lot of the rest of Asia, including, including China, Japan, Korea, and then Central and North Asia, like Russia, there's just not a lot of data on snake bites. One study estimated a significantly lower mortality rate in a lot of China that's like much less than 1 per 100,000, less than 0.5 per 100,000. Australia, likely between 500 and 3,000 bytes, but only 2.2 deaths annually.

Oh, wow. And in Europe, there is an estimated bite rate of 1.06 bytes per 100,000 people and four deaths annually. Okay. So you can see that the vast majority of deaths are happening in sub-Saharan and North Africa, the Middle East, some in Latin America as well, and then Southeast Asia. And this also follows the distribution of venomous snakes as well, where you're having a lot of high contact, but also a large proportion of the population. that are living in areas and in conditions that put them in close contact with these snakes and without access to the infrastructure to provide them with antivenom. Right.

I feel like you could do some sort of risk of death per bite calculation based on these different regions or something. Totally. And it's not all to do with, of course, these are different snakes. And so different toxicities of different venom's, but that's not what's driving this. Yeah. It's access. And one of the problems with the fact that. that, and we've talked about this before, but I think it's especially poignant in talking about

snake bites, is that underestimation of the cases of snake bites and snake envenomation leads to difficulty in estimating the need for antivenom, and what types of antivenom are needed and how much of it you need. Because while antivenom can be very effective, if there isn't a, quote, perceived demand for it, then producers who are in it to make money stop making it. And then there isn't enough of it. So then the price increases. Then it becomes unaffordable for the people and the populations who actually need it. And that is exactly what has happened with a lot of snake anti-venom manufacturers because capitalism. I mean, unsurprising, but frustrating. It's incredibly frustrating. Yeah. And I think that process over the last few decades has been part of why the

World Health Organization has such a push to reduce snake bite mortality. Right now, they have a big series of initiatives that were started in 2019, 2020. But I haven't actually been able to figure out exactly where they stand in that progression. And I would guess that like everything else, it's been massively disrupted by COVID. Uh-huh. Yep. Yeah. There has been because of this recognition of how important snake bites, snake invenoming

is in terms of a public health issue and the difficulties in anti-venom, not just because of capitalism and manufacturers not wanting to produce specific types of venom if they don't perceive a need, but also in that, like we talked about in the biology section, it's often very difficult to know what snake you got bitten by and what the best anti-venom might be or how much of it you might need, especially when we're talking about a polyclonal antibody that comes from a lot of different snakes, right? Right. So there has been so much incredible research being done all in pretty early stages, but on

things like recombinant anti-venoms. So being able to make in the lab anti-venoms that don't have to rely on horses and and that whole process, or even using small molecule inhibitors to affect entire classes of toxins so that anti-venom treatments wouldn't have to be so specific. Mm-hmm. Mm-hmm. And also looking at mixtures of modalities that might have multiple effects on the various toxins present in a wide variety of snake venom.

So it's, I think, really interesting, especially because while snake bites are, are a global issue, they are also an incredibly local one, right? Where every region is going to have different specific issues of different types of snakes that they're coming into contact with. And that can make anti-venom manufacturing and administration really difficult. And so I think that this type of research is so compelling and interesting because it can help really even the playing field in a lot of ways. Yeah.

Yeah. That's very cool. Yeah. And then like you said and kind of mentioned, there's also a ton of really interesting research on the utilization of the properties of these toxins in these venoms to actually use them as therapeutics. So there's a lot of really cool interesting research being done, both in terms of the treatment of snake bites and also in the utilization of snake venom, which I really love. It's amazing. Yeah. It's amazing. And there's still so much to be learned.

there's still so much out there in terms of questions like snake ecology, for instance. Exactly. How much does land use change and climate change? How are those things impacting our encounter rate with snakes? Right. It's very interesting. I also really do want to emphasize for all of our listeners, especially those of you who might be afraid of snakes or terrified of snakes even. And now even more so because of this episode, there historically has been a lot of

of like push of like kill all the snakes because they hurt us. Right. Rattlesnake round up and blah, blah, blah, blah. Snakes are an incredibly important part of ecosystems. And killing them is not the answer. I don't know. I just don't want people to leave this only terrified of snakes with nothing else. I think that they are an incredibly fascinating group of creatures. And while the venoms can be very scary, it's just collateral damage. It is. And for me, what always helps is learning more about them. Learning the local snakes in your area and being able to identify which are the venomous ones, which are not, and how you can avoid them so that you don't have an encounter with a snake.

Snakes are very cool and beautiful. Don't hate them. Yeah. Anyways, should we do sources? Let's do sources. I have a ridiculous amount of. sources actually for this episode. And so I am going to shout out two alone that were very helpful for the two different sections of the history section. The first one, of course, is the book by Lynn Isbell titled The Fruit, the Tree, and the Serpent, Why We See So Well. And the other one is a paper by Squyella Baptisto et al from 2018 called The History of Antivenoms, Development Beyond Calmei and Vital Brazil.

Those were both great. I had a few papers for this episode, a couple that I want to shout out, especially if you're interested in more detail on the biochemistry of these toxins. There was a paper called multifunctional toxins in snake venom and therapeutic implications from pain to hemorrhage and necrosis. I think that was my favorite, just like broad picture one. And another one that had a lot of diagnostic algorithms on like how you can in different regions of the world know what types of snake your bit.

by, etc. It was called snakebite-invenoming diagnosis and diagnostics. I liked that one too, but we will post all of our sources from this episode and all of our episodes on our website, this podcast would kill you.com. We will. Thanks again so much to Gwen for taking the time to chat. It was really terrifying and awesome to hear your story and we're really glad that you were willing to share it. Yeah. Thank you for sharing it with us and all of our listeners. Thank you also to Bloodmobile for providing the music for this episode and all of our episodes. Listen, subscribe, leave us a review on Amazon Music, Apple Podcasts, or wherever you get your podcasts. And don't forget, you can hear every episode one week early and ad free by subscribing to Wondry Plus in the Wondry app.

And thank you also to Exactly Right Network, of whom we are proud to be a part. And thank you to you, listeners. We hope you liked this one. Yeah. And hope it made you want to be able to. read more about snakes and learn more about snakes if you aren't already a herpetologist. I know. And if you are, I hope we didn't get things too incorrect. Yeah. Yeah. And a special shout out to our patrons. Thank you so much for supporting us. We love you. Yes, thank you. Well, until next time, wash your hands. You filthy animals.

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