This Podcast Will Kill You - Special Episode: Snake Venom Evolution

Episode Date: May 31, 2022

Our snake venom episode last week took us down some fascinating roads, from the pathophysiological effects of these compounds to the snake detection hypothesis and from the development of antivenom to the incidence of snakebite around the world today. But how did we make it through that whole episode without discussing how and why these venoms evolved in the first place? It’s because we were saving it for this one, where we enlisted the expert help of Professor Nick Casewell, Professor of Tropical Disease Biology at the Liverpool School of Tropical Medicine and Director of the Centre for Snakebite Research & Interventions. In this bonus episode, the last in our series for now, Professor Casewell takes us through the remarkable world of snake venom evolution, covering such topics as the genetic basis for venom evolution, how snake venom is related to prey type, why spitting cobras spit, and so much more. Tune in wherever you get your podcasts to gain an even greater appreciation for these venom-producing snakes as well as the brilliant people who research them! See omnystudio.com/listener for privacy information.

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This is a job for Indeed Sponsored Jobs. Hi, I'm Aaron Welsh, and this is This Podcast Will Kill you. You are listening to the latest and last for now bonus episode in our mini series of bonus episodes that have been coming out over the last several months. I've had such a great time putting these episodes together and I've learned so very much along the way. I'd love to pick up this series again in the future, so let's just consider this a break for now. If this is your first time tuning into one of these bonus episodes, I'll give a brief explanation of what they're all about, and if this is not your first time, then I'm sorry that you've had to hear this intro over

and over again. In these bonus episodes, I'm taking some aspect of the topic we discussed in our previous week's regular season episode and bringing on an expert guest to help me investigate this subject in more depth. For instance, my guest and I have gone further down the rabbit hole of mixomatosis by following up with an episode on rabbit hemorrhagic disease virus. We've explored in more detail how electricity actually works, and we've re-examined the origins of epidemiology. I'm also rounding out many of these discussions by asking my expert guest about their own journey into science, what they like about it and what they don't, and any advice they may have for people interested in pursuing a career in this field. And this week, I'm especially excited to learn more

about the absolutely fascinating world of snake venom's. In our regular season, an episode last week, Aaron and I covered the different groups of venoms that some snakes produce and what happens to your body if you are unfortunate enough to be at the receiving end of a bite from a venomous snake. If you haven't listened to that episode yet, I recommend that you go back and listen to it before continuing on here, since that will provide some good background information on what's actually in these venoms and how they work, which turns out to be a pretty complicated subject. Too complicated even for me to begin to scratch the surface of the different types of venoms in a recap here. But in addition to talking about the action of these different venoms,

as well as the significance of snake bites as a neglected tropical disease, we also spent some time talking about how snakes may have played a role in primate evolution, specifically in the evolution of our visual systems. What we didn't discuss, however, was the big question of venom evolution. So many snakes and other animals have evolved the ability to use venom, and the resulting diversity of venom is simply astounding, which is why for this bonus episode, I really wanted to take the time to dig into how these venoms evolved in the first place, why there is such diversity across venom type and function, and what happens when venoms evolve as a defense mechanism rather than as an aid in predation. And I'm absolutely thrilled to have

one of the world's leading experts on Venom Evolution as my guide, Professor Nick Casewell. And with that, I think we'll just take a quick break here before diving in. 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 derived with pre-portioned ingredients so there's no meal planning and no extra grocery trip. There, assemble and bake meals take about five minutes of hands-on prep. Just spread the pre-chopped ingredients on a sheet pan, put it in the oven, and that's it. And if there's truly no time to cook, dish by Blue Apron meals are fully prepared. Just heat them in the oven or microwave, and dinner is

ready. And here's the exciting news. Blue Apron no longer requires a subscription. You can order meals when you want them and skip when you don't without adding another recurring charge. Order now at blue apron.com. Get 50% off your first two orders plus free shipping with code this podcast 50. Terms and conditions apply. Visit blue apron.com slash terms for more information. Anyone who works long hours knows the routine. Wash, sanitize, repeat. By the end of the day, your hands feel like they've been through something. That's why O'Keefe's working hands hand cream is such a relief. It's a concentrated hand cream that is specifically designed to relieve extremely dry, cracked hands caused by constant hand washing and harsh conditions. Working hands creates a protective

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I recently got a pair of Quince's Bella Stretch Wide-Legg jeans, and they are now in constant rotation. They are so comfortable, the fit is amazing, and they come in a bunch of different washes, so I'm about to go order some more. Refresh your wardrobe with Quince. Go to quince.com slash this podcast to get free shipping on your order and 365-day returns. now available in Canada too. That's Q-U-I-N-C-E.com slash this podcast to get free shipping and 365-day returns. Quince.com slash this podcast. So my name's Nick Kayswell. I'm a professor of Tropical Disease Biology at the Liverpool School of Tropical Medicine.

And I'm the director for the Center for Snakebite Research and Interventions. This is a research group at LSTM where we essentially study snakebite and try and develop new interventions to improve the lives and livelihoods of snakebite victims. Awesome. Thank you so very much for joining me today. It's a real pleasure. Thanks for the invitation to talk snake venom and snakebite with you. Of course.

I am so excited to learn more about these fascinating compounds. And so can you start us off by talking about exactly that? What do we know about the earliest emergence of venomous snakes? And what is thought about why this trait emerged when it did? So we start on a really tricky subject really in terms of we know lots about what's in the venom of snakes today. Actually, we don't know all that much about the wise and the wares venom evolved in snakes and in fact in many venomous animals. So what we do know is that venom evolved in snakes on one occasion. So all these venomous snakes we find today are all related to one another.

And their venom systems are related to one another as well. This probably happened, well, it certainly happened at least 40 to 50 million years ago. So it's a relatively old trait, and it may go back even further than that. But we don't know for sure. And we don't know why only this group of snakes have evolved the venom system compared to others. But what we do know today, looking at snakes, is that although those venom systems are effectively the same or they evolve from the same common ancestor, they're actually incredibly different. The toxins that you find in the venoms of these different snakes are very

different and the effects that these venom have on a prey item they're trying to kill or immobilize or on someone who's bitten by one of these snakes can be really, really different depending on which snake you're bitten by. What are some of the drivers for this diversity? What is thought about that? So we think the primary reason that snakes ultimately evolve venom and the primary driver that's kind of honing the competitions of venom we see today is for predation. So snakes are primarily using their venom systems to catch prey, to help them to catch prey. And if you think about a snake, it's pretty obvious why that might be, right? These are limbless animals.

They don't have claws or arms or legs to help them to catch their prey. All snakes are predators. They're all eating other animals. And what's interesting is that while some snakes use things like constrictions, so they wrap body coils around prey to immobilize them. Many snakes have taken a different strategy, which is the use of venom, a chemical weapon, which is injected into the prey and ultimately has the same effect.

It immobilizes that animal or it kills the animal or in some way just enables the snake to actually feed on it relatively unharmed. So we know that the venom is really crucial for these snakes to catch their prey. Snakes can use their venom defensively too, but this is not the primary purpose. And the reason we think that is because there's been a number of scientific studies done over many years that show that there are associations between, for example, the potency of venom and the diet of that particular snake species.

So you can start to see associations whereby certain snakes that feed predominantly on one type of animal have venom toxins that are honed towards that particular prey type, or even specific to that particular prey type. We also see evidence in some species where venom is no longer being used, that that venom system has started to degrade or disappear. So in sea snakes, for example, that feed on fish eggs, they don't need venom to catch their fish egg prey anymore. And we actually see that the toxins in their venom have begun to degenerate,

so they're not functionally intact anymore. they're not functioning active. And also the venom glands in the snakes themselves have started to reduce in size too. So they've been trophied. So there's this clear association between diet and venom itself. It may not be the only factor. There may be other things that come into play

that may hone that final composition of venom. But without that, we think that the prey is the key thing that has driven venom evolution in snakes. In terms of the types of venomous that we see, you know, we have these nerve, neurotoxic or cytotoxic venoms, is there any association between the type of prey, you know, whether it's fast-moving rodents or something else, you know, and the actual type of composition of the venoms among different snakes? Or is that just sort of like an accident of evolution?

Yeah, more the latter than the former. So there are lots of different kind of classes of venom toxins and what they do. And there are different groups of venomous snakes as well. So the most famous ones we think of from a human context of vipers and elapids, these are the two most medically important group of snakes to people. They're the types of snakes that can put us in hospital and killers. And broadly speaking, they have quite different venoms with elapid snakes. So these are things like cobras or coral snakes or mambors. They typically have a neurotoxic venom that causes your nerves to be paralyzed.

And this causes particular issues when your breathing muscles ultimately stop work. their venom is quite different to viper venom. So with vipers, we're talking about things like rattlesnakes, puff faders, Russell's vipers. These venoms broadly are hematoxic venoms. They have toxins in there that are causing damage to blood vessels. They're causing people to bleed internally or prey to bleed, cause strokes. And these two did very different groups of snakes ultimately are feeding on similar prey. So, you know, some might be mammal specialists. within the lopids, some might be mammal specialists within vipers, some might have broad diets within lopards, some might have broad diets within the vipers. That kind of hemotoxicity versus

neurotoxicity, both those strategies are really great at killing prey quickly. Either you paralyze the prey or you cause it to have a stroke. Both strategies work equally well. And so although we do see some examples where certain snakes have very prey-specific venom, it's not that this group of snakes only feed on mammals, they must have a neurotoxin. This group of snakes only feed on reptiles. They must have a blood-acting venom. It's not quite as simple as that. So we see a lot of variation within those different groups. And I suppose there are a number of ways that a snake can rapidly kill its prey no matter what that prey is. And ultimately, those snake families diversified many millions of years ago when one snake family, the elapids, has evolved neurotoxins and really

increase the abundance of neurotoxins in its venom, whereas the vipers have gone down a hematoxin route, and they've really increased the abundance of those hematoxins. And that's what's dictated those different kind of venom pathologies. So earlier you talked about sea snakes having slowly lost or losing their ability to produce venom or deliver venom because they don't use it as much, meaning that venom is probably a fairly costly thing to produce and maintain as a trait. And there's this thing I want to mention that's sort of in line with that, the economy of venom and the overkill hypothesis, where it seems like the deadliness or the toxicity of venom is much, much greater than would actually be needed to kill a particular prey. Can you talk about why this may not

fully capture the relationship between venomous snakes and their prey? Yeah, absolutely. So this overkill hypothesis proposes that because snake venom's are so toxic, And because snakes, well, certain snakes species are able to inject a lot of venom when they bite, when you kind of extrapolate that, you know, certain toxicity at a certain amount scale to how much they actually inject. It seems that for many snakes, they just have way more venom than they would actually need. And therefore, this idea that venom's a hone towards certain prey doesn't really hold because no matter what the prey is, their venom is going to be sufficiently toxic to kill it. But this is quite a simplified view, really, because the toxicity of snake venom is often modeled just basically in terms

of their toxicity to laboratory animals. Usually, this will have historically been lab mice. And these snakes aren't feeding on lab mice in the wild. And we know that from lots of different species, there's quite compelling evidence that prey items and also predators have evolved at least some degree of resistance to many snake venoms. So to simply say that because a lot of venom's injected, you know, these snakes are all kind of wasting their venom is simply not true. There's a lot of different prey out of there that have mechanisms that have enabled them to evolve resistance to snake venom.

And we suspect probably that snake venoms are also responding and evolving further in response to that resistance. So you have this kind of armed, race between prey and predator in terms of the potency of the venom. And we also know that from a few studies at least, that there seems to be some evidence that snakes can meter the amount of venom they might inject. And so certainly snakes will not use all of the venom they have in one bites. They may bite multiple times, but also lots of feeding attempts from snakes are unsuccessful. And so they need to retain enough venom to then go on and try and feed on the next prey item too. So we know

snake venoms are toxic, but ultimately, a lot of that extrapolation has been based on an artificial scenario. These snakes are not feeding on lab mice in the wild, and there are studies that have shown that certain snake venoms, it may take, for example, half an hour to kill a scorpion, which might be a natural prey. And clearly, if these venoms were super toxic and overloading prey with a huge amount of venom, it would take much less time than that. So you mentioned arms races. So can we now kind of shift to talking about, venom as a defense mechanism and sort of some of the ideas about spitting cobras. Why is venom spitting so unique and what are some of the drivers for its evolution?

Yeah, venom spitting is a really interesting one because, you know, we talked already about why venom's have evolved in snakes and it's for predatory purposes. And there doesn't seem to be much evidence really that venom composition is evolving secondarily for defense, although snakes will use their venom defensively, right? Every human snake bite that happens many millions every year. These are defensive snake bites. The snakes aren't trying to eat us. But there's actually very little evidence that the composition of venom is evolving in response to the use of that venom defensively, except with the spitting cobras. So the spitting cobras to this one group of pretty closely related elapid snakes. So these are very highly venomous

snakes. And within this group, on three independent occasions, we see the evolution of venom spitting. So this is the ability of these snakes to eject their venom in a stream of liquid from their mouth directly targeting the eyes of a predator or aggressor over a couple of meters. So it's a really effective way. And what that venom does when it hits the eye or the area around the eyes is it causes extreme pain. And so this is a really nice strategy to deter a potential aggressor or predator from eating you is by causing pain and to be left alone. But what's interesting here is that we find that there is some evidence that the venom composition has also changed in response to the evolution of this venom spitting trait. And so this goes against everything I've said.

This is the exception. There's always in biology. They're exceptions. This is a perfect example. And each of these three groups of spitting cobras, so the African spitting cobras, the Asian spitting cobras, and also in a closely related cobra species called the wrinkles, they've all evolved to increase the abundance of a particular toxin, which works together with another toxin to cause this pain, enhance pain causing effect. And so it's likely, we think, that only spitting cobras have evolved the ability to spit because of a variety of these, what we would call pre-adapt. if you like. There are a few things that these snakes had to have before spitting could evolve. So one of them is this toxin that can kind of cause a bit of pain and then could be enhanced upon later on. And the other thing is this defensive behavioral posture that cobras have in that they can kind of raise the first third of their body up in the air, which gives them a very nice kind of position from which they can spit. If you imagine most snakes are lying flat on the ground

and if they open their mouth to spit their venom, it's just going to go straight into the ground. So they have to be able to raise their body up. And so this is kind of a defensive behavior that cobras would already have done prior to the evolution of spitting. So probably those two things have enabled this particular group of snakes to evolve this special defensive adaptation that we don't see in any other venomous snakes.

And so we think, we think possibly that the driver for having a specialized defensive use of the venom in cobras, it may have been stimulated by our ancestors, so ancestral hominins, which in Africa came out onto the plains. They were bipedal. And we know that certainly many primate species will defend themselves from snakes. They'll actively identify them and mob them, throw stones at them, try and kill them. And we suspect that for cobras, it may well have been an advantage for them to have a long-distance defensive weapon that could protect themselves from. from our ancestors. And indeed, we know that the timing of the origin of venom spitting in Africa,

in African cobras about 15 million years ago correlates quite nicely from when our ancestors diverge from chimpanzees. So this remains a speculative hypothesis, but it may well be that human ancestors may have shaped snake ancestors many million years ago. In terms of trade-offs, are there trade-offs that we've observed in terms of, you know, where a more prey-specific venom could mean a less effective defense venom? Yeah, I would really like to know the answer to that question. I think it's a great question. So if I go back to the example of the spitting cobras, here there's clearly potential for a trade-off, right?

Because you have a venom that's working to dual purpose. the snakes are still using that venom to catch their prey. But we know that they've also evolved certain venom components that are increased in their abundance to help them defend themselves. And so, you know, in theory, there should be a trade-off there with a reduction in terms of the content of other toxins. And I think ultimately we don't understand this yet. We don't understand to what extent in a natural prey capturing scenario. the evolution of a toxin that's helping that snake to defend itself might have upon capturing a prey item. And what's quite interesting with many of these venom toxins is that they can be multifunctional.

There are toxins that have evolved to enhance the pain-causing ability of the venom if it hits the eye of you or me. Actually, when that toxin's injected into the prey item, it's almost certainly still going to be helping the snake catch the prey. and whether that's just by destroying cell membranes and lending the snake permeate further into the prey or whether it's by having a much more specific effect, it's likely not to have any detrimental effect on the ability of that snake to catch the prey item. Ultimately, there are still destructive venoms. But we do know there has been a change, again using this example. If you look at all non-spitting cobras and most alapid snakes, we've talked about what their venoms usually do and it's to cause neurotoxicity.

So if you're bitten in Africa by a non-spitting cobra, like an Egyptian cobra or a Cape cobra, you will suffer from neurotoxic effects. If you're bitten by a spitting cobra, chances are you won't suffer any neurotoxicity at all. And in fact, what's likely to happen is you're likely to have local tissue damage around the bite sites. You're likely to have swelling, pain, maybe some blistering, and maybe some destruction of your flesh. you're unlikely to die, whereas from a neurotoxy bite, the risk is much higher. So the evolution of defence has had a knock-on effect in terms of venom composition and in terms of venom functionality for humans.

But to what extent that applies to natural prey is a far more difficult question to answer because there's very little research that's been performed upon how these venoms actually are incapacitating or killing prey items in the wild. So we're talking about some very complex things, right? Complex behaviors, complex, venom's themselves are incredibly complex. Can you walk us through how venom evolution happened in a genetic sense or may have happened in a genetic sense? A non-venomous snake didn't turn venomous overnight. So what might that process have looked like? Yeah, absolutely right. So we're talking here about timescales of 40 to 50 million years from

at least from the earliest inception of venom, if you like, in a snake ancestor to modern day snakes today. But in principle, we do understand at least some of the bases for how this may have happened. So venom glands are essentially modified salivavery glands, the same as you or I have in our mouths. And these saliva glands produce proteins that are used for different purposes for us. that are used to help digest our food, for example.

And we believe that on many occasions, snakes may have repurposed some of the proteins that were being expressed in these salivary glands to turn them into kind of incipient or primitive venom toxins. And that doesn't mean that these proteins were only present in the saliva glands. There's quite good evidence that the kinds of toxins that are present today have evolved from proteins that are they expressed at low levels in lots of our, different internal tissues, so whether that's the heart or the pancreas, lungs, wherever it might be. But there are certain examples. So there's a protein in our saliva called calicrene.

This is a serene protease. And this protein, amongst many of its roles, one of the things that it does is it drops your blood pressure. So it helps to reduce blood pressure. And we know that that calicrine protein is related to calicrines that are found in snakes, that are, are toxins now found in snake venom. And so what we think happened was that in early venomous snakes, there were a handful at least of these kind of incipient proteins that are probably doing a role that might be somewhat helpful to enable a snake to catch its prey.

And then gradually over a period of time, there's probably an increase in the abundance or the expression of these particular proteins to reinforce their use for capturing prey. And so in the case of calicoan, you can imagine a scenario whereby if you are using your saliva at that time, soon to be venom, to catch a prey item, having more of it might help because it might just reduce the blood pressure of an animal, which might just enable you to catch it slightly better than if it didn't. And so what we then see is that over those big time scales, 50 million years, we see lots of changes to these kinds of toxins. So as snakes diversified and split from one another, certain groups of snakes evolve new toxins or new protein types that became toxins. And other snakes evolve different types of toxins.

So the example there is those elapid snakes having neurotoxins that we don't see in the vipers and vipers having more hematoxins that we don't see in the alapids. And one of the key things, parts to this process that's ultimately generated the, the, diversity we see in snake venom's today. So snake venom's can have anywhere from 20 to 100 to 200 different proteins in them. Now that's gone from a small number to a much larger number over those kind of 40 to 50 million years. And one of the key processes that's underpin that is gene duplication. So we know that the genes that are ultimately producing these proteins like this calicrine protein I mentioned, we know that in many venomous snakes, those, genes have been duplicated.

And so instead of there being just one of those calicoine genes in the genome, there might be two, or there might be three, or they might be four, or there might be ten, or there might be 20, or actually some modern day snakes we see more than 25 isoforms, related genes that produce related toxins within certain gene families. And that duplication process that certain toxins have been subjected to has seemingly been really important because it frees those genes up to evolve new functions ultimately. Usually then snake venom have evolved from these normal housekeeping proteins that are doing normal physiological roles and they probably still are doing these normal physiological roles today.

But following gene duplication, there are copies of those genes that are now free to do anything that enables that snake to better catch its prey. And so we see, for example, with serene proteases related to calicrines, we know there are toxins that still cause hypotension. They're injected now. They're venom toxins. Producing the venom gland, they cause hypotension much the same way as calicines do. But there's other searing proteins that have evolved that chop up bits of your blood clotting proteins, for example, or that interact with platelets or do other functions that ultimately help those snake catch their prey. And so, again, over those long evolutionary timescale, snakes have evolved a suite of toxins.

They have multiple toxin families. And within those multiple toxin families, they have multiple toxins. Lots of them doing different things and collectively having this really rapid and potent effect on their prey. It's easy to kind of group these things, group snakes into, oh, well, these produce this type of toxin and this type of toxin. But there's so much diversity within that. within a species, even within populations, where different populations of snakes can have different levels of certain toxins or different compositions of venom. And we also see this, I think, in individuals within those populations. Why do these differences exist? And what are some of the

implications? You're absolutely right that the differences we see between venomous snakes can be really quite stark in terms of their toxin composition. And it's those processes, particularly that June duplication process that give rise to that kind of substrate that then can be tinkered upon or varied between different snake species. But you make a really good point. This isn't just a variation from one species to the next. So although a cobra might have 10 neurotoxins and two hematoxins and a rattle snake might have 12 hematoxins and three cytotoxins and no neurotoxins, and that's the process that's generated that variation, but ultimately we see huge examples. where there can be really extensive variation within species

at the population level, onto genetically, so as an animal develops from being a juvenile to being an adult, we can see major shifts in venom composition in certain species. And also sexual differences between males and females have been reported too. So this variation in venom composition is ubiquitous across every level between snake families, you know, a lapis, vipers, between species within those families, but also within a particular species. And the implications to that can be quite substantial.

There are examples in the southwest U.S., for example, where there is a rattle snake species where, you know, from one place, if you're bitten by that snake, you'll have swelling and bleeding disturbances, 200 miles or 200 kilometers, whichever you prefer up the road, you know, you would have a neurotoxic syndrome. You wouldn't have that local swelling or hematoxicity at all. So there's clear medical implications to this venom variation and how we go about actually preventing the pathology that those different snake venom's caused too.

So understanding venom variation, I think, is one of the critical roles that the scientific community has to serve relating to snake bite, because without that understanding, we can't make effective treatments for the populations who need it ultimately. Of course, all snakes should be respected, but what factors determine which venomous snakes pose more of a risk than others? You know, are there things like urban versus rural, propensity to strike,

how much venom is typically delivered, potency of the venom, etc.? Yeah, it's a really good question there. I like teaching students about this as well. Because, you know, one of the things that we focus on around snakes or, you know, if you watch any kind of nature documentary, is which snake is the most deadly, which has got the most toxic venom? and there's always this list where I think like nine out of the top town, maybe eight out of the top ten snakes are based in Australia that have the most toxic venom.

But the reality is very, very rarely do people die of snakebite in Australia, of course. And so there are lots of factors that come into play here in the context of snake bite that makes a snake dangerous to a person or not. So one of the key things that you alluded to is the potential for an interaction. So the inland Taipan in Australia, in theory, has the most toxic venom to a lab mouse in the world based on previous studies. It lives in the middle of the outback. Almost no one interacts with that snake because there's no one in the outback. And so bites, thankfully, are extremely rare.

And compare that to a small snake called the Sawscale Vipar in West Africa. There's a snake about well up to a metre long. It's living in an environment where lots of people are working. So agricultural farmers, they're kind of work in the earth with their hands or herdsmen. They're walking around better footed. These environments in Savannah areas of West Africa are heavily populated by sawscale vipers. So the potential for bites are really, really high. Snake behavior is another factor.

These source scale vipers are sitting weight predators. They use camouflage to kind of protect themselves, if you like. And so they won't move if they hear you coming. They'll just sit there. the inland hypan in Australia is a really active snake. It's using its senses to hunt its prey. It will detect you coming long before you will detect it. And so it will, chances are disappear before you have the opportunity to see it.

And then we've got the kind of the venom toxicity, if you like. Venom toxicity is another factor that comes into this. Of course it does. But by and large, most venomous snakes have the most medically important venomous snakes have the potential to cause you harm. Some may do it more rapidly than others. But I think the key thing here is the ability for the health infrastructure to protect you from the consequences of that bite.

So in Australia, even if you're bitten in the outback, there is the flying doctor service that can get you to a health center that may be thousands of miles away. And there is very specific antivenom that is very effective available in those hospitals to treat that bite. The same is not true. in Africa. So you can be bitter by a sore scale viper that's venom is much less toxic. And you might, you know, have much longer to live, if you like, the venom's acting less quickly than that of a type. And but if it takes you a day to get to a health center and there's no anti-venom then at

that health center and you have to go on to the next place or the next place after that, then there is clearly going to be more possibility for a poor outcome for that patient. So the socioeconomic of the situation, most snakebite deaths are occurring in lower middle-income countries, the health infrastructure and the availability of effective treatment is at least, if not much more important than the biology surrounding the snake. We are going to take a quick break here. And when we get back, I want to hear all about you and your journey into snake venom research. 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.

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We have been having such a fascinating conversation about the world of snake venom's and snake venom evolution. But now I want to turn towards what it's like to actually study these snakes and how you got started in the first place. So what did you think about snakes? growing up, how did you become involved with snake venom research? Yeah, so I mean, I always had a fascination with animals, I would say, when I was growing up. And I, yeah, I was always interested in animals. I didn't necessarily have a specific fascination with snakes, I would say, but, you know, I can remember, you know, being on holiday in France and seeing snakes in the wild, you know, just walking around and, you know, being really intrigued by them. I mean,

It doesn't take much to look at a snake and to realize it's quite an unusual animal when you think of other vertebrates, right? They have these long, elongated bodies and no limbs. And I think there's something certainly about them that can fascinate. Of course, often snakes can do the opposite and people can be very fearful of them. But I think usually they provoke a response in a person. They certainly did with me. But really, I kind of, in a way, I fell into snake bite. I studied zoology at the University of Liverpool, and at that time I became quite interested in the interplay between animals and humans, but mostly from studying parasite interactions at that time.

And that's what really then took me to the Liverpool School of Tropical Medicine, which is where I work now, because they were teaching courses relating to tropical diseases and particularly how parasites cause tropical diseases. and it was there that I was really exposed to kind of the detail of snake bite as a global kind of neglected tropical disease. And there again, I really just got sucked into the interesting biology. In particular, I was really fascinated by this idea that we've talked about, that there are different venoms in different snakes and this variation between the different toxins you find in different species can have such implications for people who are bit and, by them and that was really interesting to me because I guess it lent on two things I was passionate about. One was the kind of zoological side of understanding animals and the biology of animals

and the other hand, the global health aspect in terms of ultimately wanting to try and do research that can have an impact on people and people's lives. So snakebite really pulled both of those strings for me and it continues to fascinate. me today, to be honest. One of the ways that people study snake venoms is, of course, by milking snakes. So, first of all, how on earth do you milk a snake? And second, what was your first time milking a snake like? Were you terrified?

Were you completely confident? Yeah, good questions. So you're right. So at LSTM, we have a collection of about 200 venomous snakes in the facility. And we have now, thankfully, a team of people who look after. to these snakes and do the really dangerous stuff of venom extractions. And I suppose in many ways it's relatively straightforward. And I hope they won't, you know, judge me for saying that.

It takes a certain degree of nerves for sure. It takes a lot of skill and kind of calmness. And one of the key things is obviously safely restraining the animal. And so we use specialized tools and we use soft matting to make sure we don't hurt the animals when we do this. And we're able to then restrain the animals so that ultimately we can pick it up behind the head, so kind of on the neck area, so that it can't turn around and bite us. We always do this in a pair in our facility, so there's always two people working together. And then what we will simply do is we'll just gently move that head towards a glass dish,

often covered in a material, to kind of simulate the fangs biting through a prey eye. item. Not always. If the snake is small and has delicate fangs, we won't do that. And then as the snake's head goes towards that dish, it will instinctively bite. So it will put its mouth around the glass dish, and then it will expel venom into the container. And then we kind of reverse the process. So we have to then safely restrain the animal again, let it go, put it back in its enclosure. And we're left with this venom, this substance, obviously, that we want to use for our research. And we freeze that overnight,

and then the next day we'll use a special instrument called a liophilizer, which extracts the water out of this sample. It turns the venom into a powder. And we do this because it keeps the venom extremely stable for a long period of time, so we can use it for lots of different purposes over a period of many different years.

So that's kind of the analytical side of it, if you like. The difficulty is that every venom extraction is different, because the snakes are wild. They're animals and they have behaviors. And irrespective of how well you know a snake or how many years you've worked with it, they can be unpredictable. And so you really do have to have high levels of concentration at all times

and make sure that you know what you're doing. And when you're working in a pair, it's really important that you kind of build up that relationship so that you know what the other person is doing as well. And that's really been one of the keys to working safely. So we have two people at LSTM who do our venom extractions now, and they're both excellent, one of whom trained me when I started working on venom many years ago now. And yes, I was nervous for sure, but he was doing the hard work.

He was doing the really dangerous work and I was helping. And that definitely made a big difference. He was also someone with a lot of experience. So I think kind of the key to this is being trained by someone. who kind of instills that calm and confidence in you. And yeah, that certainly helped me kind of get over those jitters around what we were going to do. Yeah, I bet. Have you ever had any close calls with venomous snakes either, you know, in the field or ones you're working on

or just throughout the research that you've been doing with other animals while doing snake research? Yes. Yeah, I mean, it does happen. Of course it does. You know, it is a risk of the job. I can, yeah, so there's a few times we work in our facility where, you know, there are things that that you reflect back on. I think, well, okay, you know, we could have done that better or, you know, we could have given ourselves more space or more time to do something. But I think,

not really any near misses as such. I think field work is, is tougher for obvious reasons. You're far more isolated. You're out of your comfort zone. You're more at risk of something. If something does go wrong, the consequences of it being serious. I guess for me, I can remember we were, we filmed a documentary with the BBC around snakebite a few years ago. And at the time we were there, I was working with a colleague, sorry, this was in Kenya, I was working with a colleague there. And he received a call that one of the local villages had a red spitting cobra that was

up a tree and in the middle of this, village and could he come and come and rescue it because there was, you know, there's a risk, obviously, to the villagers there. And so we went to, um, to, to find this snake. And the snake was quite high up this tree. And so between the two of us, we had to try and, um, catch the snake, obviously safely with a big crowd of villagers watching us. Um, and when you're balancing halfway up a tree, using snake tongues with a hand and clinging on with another hand and it's obviously not, an ideal situation and it's not it's not perfect when you have a crowd um kind of judging your capability at the same time so that was an interesting experience um and it's it's yeah it's not an

experience i would like to have every day shall we say but all was well in the end so yeah the snake um we we we safely caught it it it was quite tired by that time because i think it had been spitting the villagers for so long um and so in the end we were able to get it and bag it up safely and we took that and then released it into the wild well away from the villages the next day. And so, I mean, it's satisfying doing something like that, even though it's quite challenging at the time. You do feel that, you know, you are helping in your own small way to try and avert something from happening.

Do you have a favorite venom, particular venom, or a favorite snake or a favorite story in venom evolution? Well, we talked through my favorite story at the moment on Venom Evolution, and that's the spitting cobra story, which it was such a fascinating project to be involved in to try and understand how, you know, a defensive trait within the context of venomous snakes had evolved and also perhaps why it had evolved

and what the consequences of that were. And it was really satisfying because it was a large project that took many, many years and also involved a lot of people from a lot of different places all over the world with lots of different expertise coming together and bridging that kind of laboratory research and ecological natural history research divide. That was really satisfying as a scientist to be part of.

In terms of my favorite venoms, my favorite venoms, I think, will always be the sore-scale viper venoms. This is a group of snakes found throughout kind of northern Africa, Middle East and into India and Sri Lanka. and they're probably the most medically important group of snakes in the world. Most people haven't heard of them. They're quite small and innocuous, but they kill tens of thousands of people every single year. And they're my favorite because they're what I dedicated four years of my life studying as part of my PhD. And so I was keen to understand what was in the venoms of these snakes, what do they do, how are they different from one species to the next?

And what does that mean for treatment of snake bites? So if species X is different from species Y, does it matter if you're bitten by those snakes and there's one antivenom available? Or actually, is that a real problem because we haven't got an effective treatment? And so that was my training as a scientist. So that was really an exciting period of my kind of scientific life. And I got to do some field work and collect sore scale vipers and worked with them and still work with them today. You know, they are a really important group of snakes. We've been developing new treatments against them in recent years.

And yeah, I think it's pretty hard for me to think that and I think it will replace them in the future. Many, many people are afraid of snakes. Fear of snakes is one of the most common, if not the most common phobia. But knowledge is power, as we kept saying in our previous episode. Can you talk about why you feel outreach and science communication about venomous snakes is so important. Yeah, absolutely. I mean, I think one of the key things here is what you've said already.

Snakes, you know, they provoke a reaction. They provoke fear in many people. And it's interesting, you know, when we tour people around our facility, talk to them about what we do and show them the snakes, lots of people do have an inherent reaction to them. Lots of people already are frightened of them. But lots of people are also just fascinated by them. I think it's important.

that we don't demonize snakes ultimately. Yes, they are a problem in that they, you know, they kill 138,000 people a year. So snake bite is a real public health challenge, particularly in the parts of the tropics. But in these same areas of the world, the snakes are really doing an important ecological role. They are killing the pests that would otherwise destroy

the agricultural crops that these people are growing to survive. And so simply culling snakes, even if it was feasible, is not a very sensible strategy in that economically these people would suffer too. I think the other argument as well is that these venomous snakes are of intrinsic value to study. Their venoms are interesting. Their venoms are a source of potential new drugs and treatments for lots of different diseases. We already have medications that have been developed from snake venomes that treat high blood pressure or bleeding disturbances. And lots of people are looking at toxins in venomous potential cancer treatments as well.

And so there is a pharmaceutical value to these animals too. But ultimately, I think every group of animals in the world has an intrinsic value, an intrinsic right to be protected. So snakes are fascinating to many, interesting from a pharmaceutical point of view, and fundamentally crucial for the economic livelihoods of many people living in. in low middle income countries. And I think those arguments are really important to convey the other side of the coin to snake bite. So we've spent most of this interview so far, or at least a significant part of it,

talking about the research that you do on snake venom's and snake venom evolution. But I want to round out our conversation by hearing more about the work that is being done at the Center for Snakebite Research and interventions. So what are some of the missions of the center and what is some of the work? and what is some of the work being done there? So the mission of the center is really to, it's scientific research that focuses on developing, testing, and implementing strategies to try and mitigate the burden of tropical snakebite.

So ultimately, we're performing a variety of different research from laboratory research all the way through to hospital research and public health research to try and improve outcomes for snake bite victims with a predominant focus on the tropics and the subtropics. So the kind of research that we do is quite diverse on a very fundamental level, things that we've touched on already. We want to understand what toxins are in the venom of snake X and what do those toxins do? How do those toxins cause damage in a person who's bitten by them?

We want to understand how well or not existing treatments might work at preventing that damage if someone is bitten. We're also doing quite a lot of research to try and just make much better treatments, much broader treatments than those that exist today. So current anti-venoms are quite limited in many ways. You need different anti-venoms for different parts of the world. That's because, again, we have venom variation between different snake species. But also, lots of people have adverse reactions to treatment.

they're quite expensive in the context of low middle income countries. And also they have to be given to a snake bite victim in a hospital environment. You have to manage the adverse reactions that might happen to the drug. And you also have to give the antivenoms intravenously. So you need a certain amount of clinical capability to do that. So because antivombs have to be given in a hospital, there's often this big time lag between someone being bitten and treated. treatment starting. And that's a real problem because it leads to poor patient outcomes. So a lot of

our research is trying to circumvent those limitations. We want to make more effective, more broadly effective anti-enoms that are more affordable, that are safer, and that might be able to be given to a patient much sooner after a bite. So for example, as an oral tablet in the community rather than in a health clinic. But we also do work in snake bite affected countries too. So we're active at the moment in Kenya and in Nigeria and in Eswetini and in India, working with partners in those countries to better understand the burden of snakebite, the cost of illness to the hospitals and to the governments, and also trialing how different interventions might work or might be effective

to reduce the kind of the burden of snake bite on those populations. So this could be community education or it could be, for example, using a motorcycle to try and more rapidly transport someone at a hospital as an ambulance. And ultimately, the kind of the last key pillar of the work that we do is to strengthen the capacity of people in those countries to undertake snakebite research. So we've been fortunate enough to receive funding to help develop snakebite research centers in Kenya. where they've established their own herpetarium to collect snakes and venoms, develop capacity for them to perform medical research on snake bite victims,

so they can understand what to expect when someone is bitten by a species of snake or a different species of snake. And ultimately we believe that's really important that those countries where snake bite is a real problem, that individuals in those countries have the capacity to perform the research to enable policy changes and to have a real impact in terms of mitigating this disease in the long run.

Are there any projects that are currently being done? I know you discussed a broad variety of all the different work that's being done at the center. Are there any particular projects maybe in anti-venom therapy or access to anti-venoms that you are most excited about that is being worked on at the center? Yeah, I think there's a couple, if I'm honest with you. So in terms of therapy, we have three main strategies at the moment. One is to try and improve existing treatments. And so we're looking at ways that we can quite quickly improve the potency of existing products, kind of as a short-term solution to tackling snakebite.

And then there's the more longer-term approach where we're completely changing the strategy, if you like, from how current treatments are made to a new format, almost like a next-generation approach. And one of these is looking at drugs that have been used for other diseases and seeing whether they can be repurposed for snakebite. So, for example, there are toxins in the venom of snakes that are also related to proteins found in URI. So I mentioned the Syrian proteases earlier on with the calicrines. And there's other proteins called metalloproteases and phospholipases. These are proteins that are in URI, and they're actually the targets for medication.

related to other diseases. So metapropoteneases were an important target for cancer and phospholipases for coronary heart diseases. So drug companies develop molecules that would block these proteins, trying to develop new treatments for those conditions. And what we're doing at the moment is we're trying to understand whether any of these drugs that ultimately didn't make it or got close to making it as medications for those diseases

might be useful for snake bite. And so one of those drugs is actually a medication that was used for treating heavy metal poisoning. And this is a metal chelator that's a licensed medication. It's used in Europe already. And we've been able to show that it has some ability to block sore scale viper venom. And so we're now moving into clinical trials with that medication for snakebite to see whether it's able to actually prevent some of the toxicity or the life-threatening. effects of sore-scale viper venom as an oral drug, so as a drug that could be taken quite quickly after a snake bite, still with a patient going to hospital and still potentially

getting anti-venom too, but whether that early oral medication ultimately might be able to have a lasting benefit and give that patient a much better chance of surviving or reducing the severity of a bite. I think it's a really exciting time for snake bite treatment. So collectively as a snake bite research community, we've been very fortunate that the Welcome Trust about four years ago invested 80 million pounds into research for snake bite and predominantly around that translational biomedical therapy diagnostic space. And they funded a number of projects to ourselves,

but also to lots of other groups all over the world, looking at innovative strategies to combat snakebite. So to try and bring treatments, into the modern day. We don't know which are going to be the best strategies, ultimately, as treatments. And there are lots of different ways of doing this. And we might need certain strategies for certain toxins and different ones for other toxins. So I think it's really exciting at the moment that there are different groups with different

ideas and that collectively as a community, I hope in the next five years, we're going to be much clearer as to which strategies are going to give us those broad, effective and safe therapies in the long run. It does take many years, of course, to develop new medications. So this is not a short-term thing. But I am very hopeful that in the next five to ten years, we will have at least a couple new treatments for snakebite that hopefully will deliver real impact over above current strategies we have for mitigating

the Cs. But it's not all about treatment, sadly. It would be lovely if we could just have these magic bullets that solve everything. But, you know, the World Health Organization stresses as well, the importance of getting those treatments to the right places and getting the people to the right places too. So there really is still a lot of work that needs to be done around the kind of the health seeking behavior and the health infrastructure relating to snakebite. And of course, many other tropical conditions too. It's only with that kind of collective push that I think

will have a real impact on reducing the burden of snake bite across the world. Thank you so, so much, Professor Casewell. What an absolutely fun and fascinating conversation. I feel like I could have just asked endless questions about snakes and snake venoms and anti-venoms. It's so cool. And if you would also like to learn more about venom evolution or the incredible work that the Center for Snakebite Research and Interventions is doing, check out the post for this episode on our website, This Podcast Will Kill You.com. Where I'll link to a few people, papers and videos as well as the website for the center. Also on our website are the sources for all of our episodes, transcripts, quarantini and placebo-rida recipes, our bookshop.org affiliate account, Goodreads list, links to music by Bloodmobile, links to merch and Patreon, and so much more. Listen, follow, and leave us a review on Amazon Music, Apple Podcasts, or wherever you get your podcasts. And don't forget, you can listen to new episodes one week early on Amazon Music, or early and ad-free by subscribing to Wondry Plus in the Wondry app.

I want to give a big thank you to all of my guests for these bonus episodes over the past few months. I have absolutely loved chatting with you, and I appreciate so much the time that you've taken to share some of your knowledge. It's been fantastic. Thanks again also to Bloodmobile for providing the music for this episode and all of our episodes. And thank you to you, listeners. Did you love hearing about Venom Evolution as much as I did? I bet you did. And a special thank you, as always, to our wonderful, generous patrons.

We appreciate you so very much. We've got a brand new episode on a brand new topic coming out next week. So until then, keep washing those hands. Success starts with your drive. An 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.appus.edu. This is Matt Rogers from Los Culture Eastas with Matt Rogers and Bowen-Yang. This is Bowen-Yang from Los Culture Rees with Matt Rogers and Bowen-Yang. Hey, so what if you could boost the Wi-Fi to one of your devices when you need it most? Because Xfinity Wi-Fi can.

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