Snakes vs Octopi (featuring Dr. Matt Giorgianni)

This is an iHeart Podcast, guaranteed human. How does an animal end up with something like venom? I mean, I can see how it would be great to have something like venom to kill your prey, but could the evolutionary process through which venom is developed be dangerous to you as well? Like, I'm notoriously clumsy, but I can't be the only one out there who's bitten their cheeks or their lips while they're eating. What if a snake accidentally bit itself? How do you keep from hurting yourself with your own venom, or did something like personal anti-venom to your own venom evolve at the same time? And what evolves first? The venom, or the fangs needed to deliver the venom. The evolution of snake venom is endlessly fascinating and is associated with all sorts of misconceptions, and we got super excited about this question after a listener asked us a particularly fun inquiry, which was this, if a rattlesnake bit an octopus, would its venom have any effect? So, on today's show, we bring on venom expert Dr. Matt Giorgiani, who exhibits the patience of a saint as Daniel and I pepper him with loads of weird questions about snake venom and his culinary work with hot dogs and marshmallows. Welcome to Daniel and Kelly's Venomous Universe. Hi, I'm Daniel, I'm a particle physicist, and I've never been bitten by a snake. Hello, I'm Kelly Wienersmith, I study parasites and space, and for a while there actually, I thought it was going to be a herpetologist. I've been bitten by snakes a bunch of times, and I love them. You love being bitten by snakes, or you love snakes despite being bitten? I love snakes despite being bitten. I've never been bitten by anything dangerous that I worried about, but man, I love snakes. Tell us a story about how you got bitten by snakes. Were you going for a hike and when jumped out in front of you? Were you wrestling a python in the Amazon? What happened? I was working in a snake lab, actually it was more of like a herpetology lab. We had all kinds of cool stuff in there, and I was feeding the animals over Christmas break, and it was my fault. I was not really paying attention, because I was showing the snakes to some of my friends, and I had put my hand in some rat water, because I'm just really a disgusting human being. Wait, rat water is what exactly? That's rat flavored water? That's water for the rats? What is it? Well, you know, you got to thaw out rats before you feed them to the giant boas, and so I had just finished thawing out a rat. It's rat juice. It's rat juice, and I had put my hand quickly into the container with the boa, and I really should have very slowly done it, but I was talking to someone not really paying attention. The boa went for the rat and got my hand, because all my fault. It let go right away, and then it backed off and was like, oh my gosh, it was apologizing in its own way. Anyway, I went to the doctor just to be like, do I have to worry about an bacteria or whatever? My mom insisted I go to the doctor, and the doctor was like, no, you're probably fine. We'll give you some antibiotics just in case, but you are officially the weirdest case I've gotten. I think it was this year. It might have been today, but I think it was this year. Anyway, so I was proud of myself. How big a snake are we talking here? If it can eat a whole rat, then it could probably eat your hand, right? This is a big snake. I mean, so boas can't chew off your hand and separate it from the rest of your body. That's not how they roll. They swallow things whole. But it could ingest your hand and then adjust your arm and just gradually, you could end up with a boa arm, right? It didn't have that kind of personality. We didn't have hyper-aggressive snakes. They were all very docile snakes in this lab. But this is a big snake we're talking anyway. Yes, yeah, it was a big snake. Wow. Wow, Kelly got bitten by a big snake. I did not know that. That's incredible. It was a very nice snake, and it was 100% my fault. I was not being careful. But anyway, yes, I've been bitten by snakes big and small, and I love them all. When the rat snake gets into our coop, we very gently move it to another location. Yeah, snakes are the best. Yeah, I'm a fan of snakes the way I'm a fan of spiders. Spiders eat mosquitoes, snakes eat rats. It's all part of the evolutionary war that's going on outside all the time. Yeah, after we removed the rat snake from our coop, rats became a problem in the coop. That was way worse than the rat snake. I should have left the rat snake there, but I relocated it, and then I was like, I should have left the rat snake there. The rent that it was eating an egg every few days or something, and I should have let it do that in return for its rat control services. It's a pretty good deal. It was a pretty good deal, and I didn't realize it. Yeah. All right, well, today is a very sneaky episode of Daniel and Kelly's Extraordinary Universe, all inspired by a question we got from a listener. And this is an amazing question. This is a real head scratcher. We got lucky because Daniel has a friend who could answer it. But before we get to that, let's go ahead and listen to the question. Here it is. For rattlesnake but an octopus, would it's venom have any effect? Some toxins, like fly spray, are very specific as to what animals they harm. And rattlesnakes probably only care about what they can do to vertebrates. Are venomous snakes immune to their own venom? Does this give them resistance to the venom of other snake species? Do snakes ever try to invent them other snakes? So many great questions. And one of the things I love about science is knowing people who study so many different weird things. So if you send me a super weird question, I might just go, oh, I actually know a person who's dedicated their lives to understanding this particular question about the universe or snakes. I mean, I feel like that's one of the amazing things about grad school is you get thrown in with so many different kinds of people. And then 20 years later, you could be like, I know someone who studies snake venom. It could answer a question about whether a rattlesnake could kill an octopus if it bit it. I know the guy. Exactly. But before we heard from the guy who might know the answer, we thought, what do the extraordinaries think about this extraordinary question? So Kelly sent this question to the list and here's what people had to say. I would say that there has to be some effect, but maybe not the one we are expecting. But wait, how would these two creatures find themselves in such a situation? I don't think the bite of a rattlesnake would have any effect on an octopus. Octopuses have their own ink and venom. So I think a rattlesnake's bite might hurt or sting an octopus, but I don't think it would have any deleterious effect. Rattlesnake venom is not species specific. I would guess that octopus biology is not so divergently farmed from typical prey that there is no effect. It seems plausible that rattlesnake venom can kill an octopus because venoms can be effective across very different animal types. A blue ring octopus can kill a human, for example. I suspect it may depend on the species of rattlesnake and the species of octopus. I would think that the octopus, don't they have some sort of neurological isolation between tentacles? Maybe that would allow it to kind of minimize or neutralize the neurolitic effects of a toxin? They are species that evolved in very different environments, and the octopus is not an usual prey to the rattlesnake. I don't know. It may not work. Poison would not work on octopus because snake poison is formulated by nature to only work on land mammals. Possibly would kill an octopus, but how they're getting together, I'm not sure. It's a hell of a blind date. What? I didn't know octopuses had any venom at all, so that's spectacular. Now, to answer in honesty, I actually have no clue. If a rattlesnake been an octopus, its venom would be devastating to the octopus. Also, I don't know how the rattlesnake would get its scuba regulator back in its mouth with no hands. It probably would not enjoy it at all, but I don't know if it would kill it. Can a rattlesnake transfer its venom to the octopus? I don't think so, but who knows. The octopus could then transfer his or her back into him, but octopus, like the blue ring octopus, for example. So, for example, a venomous snake might be more venomous to one type of mammal than another, but I would have no idea about an octopus. Yes, but we need a bigger collider. Oh wait, the other one. It depends. Now, I don't want to be too negative, but there were a lot of people who were like, well, this premise is unrealistic. And I have to wonder, are you all not fun to watch science fiction movies with? Because we asked you to suspend your disbelief for this one. That's true. And we probably are not making our audience better watching science fiction movies by teaching them all this science, right? We're probably making them into the well-actually people watching those movies. On the other hand, I did laugh out loud at a lot of these answers. Yeah, these are great. These are great. So thank you, everybody, for speculating. If you would like to be part of this segment for a future episode, don't be shy. We would love to add your voice to the chorus. Questions at Daniel and Kelly.org will get you on the list. All right. So without further ado, let's bring the guy on the show to answer this amazing question. So then it's my great pleasure to introduce the podcast. My friend, my colleague, Matt Georgiani. He is an evolutionary biologist and a research scientist at the University of Maryland. He's also a long-standing adjunct faculty member at the Whiteson Research Institute, where he's best known for his pioneering work regarding hot dogs and marshmallows. True story. What? Is that what you all are colleagues on? Is work at the Whiteson Research Institute? Yeah, that's the work I'm most proud of. It's your enduring legacy. Whenever we mention you, Hazel goes, wait, is that the marshmallow hot dog guy? And we go, yes, that's exactly that guy. Because they have burned into their memory. One time when we were all on vacation together, I think was it in North Carolina? I think so. And we had hot dogs and Matt was like, hmm, I'm going to put marshmallows on my hot dog. And it blew their little minds. Yeah. Well, the key was the giant marshmallow and then tunneling a hole for the hot dog. So it was a marshmallow bun to a hot dog. Right. Yes. Incredible. Was this a bonfire? No bonfires required for this amount of creasing. This is a normal day thing for you. Oh, wow. Whoa. Now you see the kind of out of the box thinking that Matt is capable of, which is why we thought it would be great for him to come to the podcast and answer all of our out of the box questions. Well, I'm kind of amazed that a teenager would focus on the hot dogs and marshmallows thing when you had someone at the house who studies snake venom, which seems way more epic than marshmallows and weenies. But let's dig into a little bit more. We've got a bit of a picture now of what kind of a person Matt is. He's innovative in the kitchen. But Matt, as someone who studies snake venom, are you also the kind of person who owns a snake hook and is like regularly picking up venomous snakes? What kind of a snake person are you? So this is where I get to disappoint all your audience members right away. Oh, amazing. I am not a snake person by nature. I did not grow up handling lots of snakes. I don't like I didn't have some love for them, but I came to them through sort of as an evolutionary question. And I have since then become quite enamored by them. Have you ever eaten a snake inside a marshmallow? No, but essentially a snake and a hot dog are the same thing. Neither one has legs. They're both just tubes of meat. So I see why you two get along now. How did you two meet? In graduate school. So he was in Chicago and I was I was a graduate school in the University of Chicago. And Daniel and his physics crew would like come and hang out like the cool kids with their leather jackets. I don't believe any of this now. No, no, I feel like you're lying to me. Let's fact check that story. So that was in grad school with Katrina. They were both at the University of Chicago in biology and I was a physics interloper. I was not at University of Chicago. But since Katrina and I were living near campus, the physics department gave me an office. So I got to hang out and I mostly hung out with the biologists to be honest because they were more fun. But I would also bring a bunch of physicists to the biology parties. Oh, okay, great. Which always improves the party, right? I mean, until we start talking about poop, but you know, I mean, I think that's fun too. Okay, so you weren't snake wrangling when you were younger. Are you someone who handles the venomous snakes now? Or am I am I pushing this? No, I'm still quite a coward. I've only so we've gone down to extract venom and extract tissues and things like that. So the only snakes I've handled, while I have handled some dangerous snakes, it's only really after they're dead. And so I've dissected out venom glands and I've done these sort of things and it's they're great and they're exciting. But I went into a room that was full of rattlesnakes and I walk in the room and they instantly all pop up and start rattling and I bad had a heart attack right there. Some people go forward into that room and other people are like, yeah, this is not safe. So you came with this question you were saying from an evolutionary point of view, you got excited by the scientific question of them. So let's dig into that and let's ask them first basic questions like how common is it for snakes to produce venom? How many different species produce venom? Do you know how many times this evolved in the history of snakes? And why don't hot dogs make venom? Well, that you know of. If you let them sit out too long, they kind of do. So there is something like, you know, we have there's something like 4,000 species of snakes. And within venom is primarily in two groups of these snakes. And so I'll say three names now just to get like these are names I'll probably keep saying a lot. So within the sort of advanced snakes, which is is going to be most of the snakes that you're aware of, but does not include a few little guys and some big fat like pythons and boas. But all the rest of them fall into three groups, which are the alapids, which are like your cobras and crates. There's vipers, which include rattlesnakes, and then colubrids, which is most of your garden snakes and rat snakes, king snakes, all your little friendly guys. And so those three groups are many of the species, probably more than half of the species of snakes and colubrids being the biggest group of them. But alapids and vipers are your two big branches that are venomous. And those are each about three to 400 snakes each of our species. So there's hundreds of kinds of venomous snakes. There are, yes. Wow. Yeah, quite a few. And did venom evolve once and then branch into both groups or did it evolve multiple times? Right. So this is the great question that we get at. And one of the reasons that like that we were so excited to study it. So venom is cool because it's secreted, you know, it's secreted from these venom glands and it's in this like hyper pouch and they have like syringe like teeth and they can excrete it. But because it's in this kind of specialized pouch, it seems like evolution can run a little wild in there. So one of the things about most evolutionary novelties and things that happen in evolution is that you're trying to modify proteins or processes that exist elsewhere in the body. So if you mutate those things, you can have problems everywhere. You can have problems in your development or in other processes or other physiological things. But if you can just sort of sequester these venom genes to just the venom gland, you can, it's like laboratory and you can start to just mess with these things. And it seems that that's what snakes have done. Colin, let's back up and unpack that because not all of us are evolutionologists. Yeah, sure. You're saying that evolution works best when it's adapting existing genes. That's because it takes like fewer mutations to like turn my spit into acid than to like develop entirely new fluid inside the body, right? Right. And I mean, new genes like whole scale, new proteins are very, very rare. Like truly new things are very hard to develop or to evolve because you have to come from something usually. And so most things in evolution are sort of piecing together bits from other, you know, maybe merging things together or mutating things that exist already. But it could be difficult if the thing you're trying to mutate already has a really important function. And so if you want it for a new role, that's difficult. I see. So you're mutating one thing, but you also have to not mess up the system that already works. Yes, that's really critical. But if you were to be evolving a fluid into an acid, you wouldn't want that acid all over your body. So if you could just get acid in a little spot, that would be helpful. But then how do you evolve that little sack? Where does the sack come from? Right. So this is where, and this gets into that question of where does that come from? When did it first evolve? And then, so we'll start with just with those two groups of alabids and vipers. So they are sort of separated by this middle group that colubrids. So we have like this, there's an original ancestor of all three of those groups. And then there's the vipers branch off into their group. And then the next a little after that, some several million years later, colubrids and alabids branch apart from each other. So because colubrids are largely not venomous, we kind of have this, all right, so where did did venom come from in each one separately? But when we start to look, when scientists have looked back at ancestors of these snakes, they can see commonalities of like common proteins that are expressed in both of those venoms. And sometimes they see it in some of the oral glands or tissues of those middle group that colubrids. So that tells us that the ancestor of all three of them had some stuff that we know is in venom today. And so it's very likely that some kind of venom capacity or some dangerous spit, let's say, was probably present in that ancestor. Hold on, you're saying that because there's commonalities in their venom, then it's likely that it evolved before the split. Right. But isn't there another hypothesis there that like, maybe they discovered the same combination was useful independently? Like maybe you're not the only person to put marshmallows and hot dogs together, right? Other people can discover these delicious combinations. I'll definitely argue that point. So this there is, yeah, that's a really good point that we can get these things, what we call convergently when two different groups evolve the same thing. However, in this situation, what we're talking about often is a particular gene, a venom gene that gets recruited, we say recruited, because we mean that its expression, while maybe normally that's expression was in the liver to help digest enzymes. And now, suddenly, it's gained a new expression in this oral gland or in this, what will be the venom gland. And we consider that event to be a somewhat rare, exceedingly rare process, because developing the new like, you know, because you're just changing nucleotides at the DNA level in the genome, and you're saying, here's a new instruction set, I'd like you to now be expressed, let's say, in the venom gland. And that thing we think, we think that step is rare enough that when we see it in two animals, we don't generally think that that's a convergent event, but rather that it might indicate a shared ancestry. And when we see it out multiple genes, then that sort of reinforces that idea. And sometimes, and although people haven't done this part yet, if we could know what that instruction kit was, you could say, here's the specific instruction set, and we can see that it's the shared between the two groups. And that would tell us really that like this event is so rare that it must have happened further back. So that is often the deal when we're talking about, because many times when we talk about convergent events, it is convergent strategies to approach something. But rarely do we think it's the same mutations that have led to that. I see the way that like, for example, bats and insects both evolved flight independently, but the mechanisms underneath are quite different. And that's how we know that they're independent. That's right. If they had exactly the same internal structures, you would suspect that they really had a common origin. That's right. But it's not a definitive argument, right? It's just more likely. I mean, these things are always statistical and you're making arguments, but it's not a smoking gun. That's right. No, absolutely true. So you could imagine if there was something very special about these particular proteins that we would see that, that maybe there's enough pressure that we could see a multiple conversion of events happening at once. Would it also be fair to say that like, so if you're looking at individuals who are very closely related to each other and are splitting off from one another over time, in order for them to have independently evolved very similar ways of doing things, wouldn't they have had to have like lost traits and then gained them again since they were like, so, you know, if you split from a common ancestor, you probably have the same set of instructions for doing something. And so I feel like what Daniel is implying is that they would have had to have lost the ability to do something and then independently gained it at another point because given that they were common ancestors, they probably both had the ability to do it. Or is that not the right way to think about it? No, I mean, it's so lost, we think it's really important in evolution as well. So we think of oftentimes that evolution can be like gaining things, but like snakes, right away, you should just remember like they lost their legs. Yeah. Right. And so that's a really important step for them. It wasn't just like they fell off. They just, it was a really important. We all lost our gills, right? I can't breathe underwater to my great frustration. Right. And so these things were really important events. And so, so it could have been that there was a, the ancestor to all these snakes was venomous and that in the colubrid line, they lost that those gene, the instruction to say this is venomous. Oh, I see. But really what I think what ends up happening is we look at this complement of venom genes. So in venom, maybe I didn't really establish this, but venom is a cocktail of proteins. So it is, it is somewhere in the, you know, seven to 10 proteins or and these are, you know, proteins that are parts of large protein families, proteins that are conserved across all animals that are used in various physiological purposes. So they're important genes. We don't know what they all do natively in different animals necessarily, but they are large, they are largely conserved proteins that are, that are important in all kinds of things. And a lot of these proteins have multiple, there are families of proteins because there are many versions of these proteins. And this might be like a protease. So proteases are digesting proteins, and there are many types of proteases, but they're all related evolutionarily. And that relatedness goes all the way back into history to the base of animals, in many cases, if not further back. And so in the same way that like species are radiating across the planet, like you can imagine that these proteins families are radiating because it's a, once you have a protease, it's really useful. If you can make it and change it and slightly modify it, maybe it does something really important for you. So then we think that venom evolved once in an early ancestor to snakes or for the split into different categories. So one of the theories out there is that that's the case. And there are other theories that even say that it goes further back into the, their ancestors in the lizard world, which would be something like the iguanas or the Komodo dragon. Now this gets a little more suspect, but there is some idea that there's a whole clade of animals called toxicophora as a name that's often used for this. And the way to think of it might just be that they have a spit that's kind of cool, that has a lot of cool enzymes in it. But if we just want to focus on the advanced snakes and where our big powerful venom guys come from, it seems reasonable that they had some kind of spit or gland cocktail that was doing something. And maybe it just helped to digest maybe it's like, you know, you bite a, eat a mouse and you just need help digesting it. So you have a lot of enzymes and proteases. Wait, I have two questions before you get any further. Are there lizards that have venom like spit? Is that a thing? This is a little bit unclear. I'm, this gets a little bad where I know, but like for the most part, they don't have like venom, the ability to inject a venom. Komodo dragons are associated with certain bad outcomes for their prey, but that might be more to do with other parts of their spit. And so it's not clear that that's a venom in this case, but it could be that the, these families, these genes that I'm talking about have started to be used in that oral structure. I see. I thought Hila monsters had the grooves in their teeth and like a venom thing that dripped down the grooves. Right, right. Yeah. So it's exactly that sort of thing. And how these things are, you know, whether we call them venom or not becomes a little tricky at times. Okay. And does this give us any insight into the question of like venom and fangs? Like, does venom precede fangs? Cause like, why would you have these like syringe like teeth if you didn't have something to inject? That's right. It's a really good point, right? And so you could think about like what step would probably come first. Having really sharp fangs does seem reasonable as a thing to catch animals with alone, but really it does seem that the evolution of fangs, so between those alapids and those fibers, the evolution of the fangs seems to be a convergent situation. So morphologically, they're different enough that it seems that fangs evolved twice. And so colubras, those guys in the middle, your garter snakes, they don't have big fangs either, right? But it seems like alapids did. And then they, and associated with that, that venom, that oral gland became this really powerful venom gland and the same thing along the lines of fibers. So they develop a slightly different tube-like tooth that can inject, you know, using all the muscles around a big and large venom gland. And from that, they can, you know, subdue their prey. And so it does seem that maybe while venom might have evolved, the sort of the capacity for some kind of venom evolves first, we then see the fangs develop. So wait, before you have the like syringe to inject the venom into the animal, venom is still beneficial because you're like biting something and your whole mouth is coated in venom and you're smearing it on the surface. And it's not as effective, but- Well, we don't know if it was used to kill prey at the time. I see. Or if it was just really a digestive thing, or if it was some other purpose. Could just been like a seasoning. That's right. Ooh, I like spicy food. I even, because I've read this report of, you know, so we all, we have enzymes in our saliva as well, right? And we don't think of ourselves as toxic. However, I guess there's these reports of people that used to take human saliva and inject it in their skin. This was, the report read it was like to get out of prison, but it would, it were to get like to the hospital in the prison because it would create an, a reaction. So if you inject enough of something, right? And you inject enough enzymes into you, it's going to have some kind of effect. And so what we've always questioned early on was, well, you know, the key thing about alapids and vipers, so they have massive amounts of this venom that they can inject. And are these venom proteins actually super dangerous? Are they that much different than the proteins they evolved from? Or is it just the amount that you're injecting in? Interesting. And why hasn't anybody made a snake venom based hot sauce yet? This, this is a great question because I mean, I'm sure you'll get tingling mouth. I mean, it sounds like, wow, delicious, right? I mean, capsaicin evolved as, you know, animal plant warfare toxin. And so like when I double down on that, I think this is a billion dollar idea. Let's give the extraordinary's a moment to ponder this amazing question that Daniel has shared with us. And when we get back, we will return to chatting about venom with Matt. The Southwest famous for our countryside. So if you want to create in green skills, working with nature, animals or clean energy, study where it all happens. Cannington College from our borough culture to animal management, hands on learning with cutting edge facilities, including the Cannington AirQuine Center and National College for Nuclear. Register now for our next event Wednesday, the 29th of April from six until 8pm. Such UCS college group.ac.uk Okay, we're back and we're talking to Matt Giorgiani about snake venom and whether it would be tasty on a hot dog. Matt, give us some insight into the chemistry of venom. You've talked about it as proteins. We've talked about how enzymes in your mouth do stuff. What is venom doing? Why is it so bad to get injected with venom? What does it do to you? Right. So there are two major flavors of venom and spicy and extra spicy. So one of those, one of those main types is a neurotoxin. And so these are, there's a few selected proteins and peptides that are targeting nerve receptors. And so anyway, they're disrupting the nervous system. And this can result in paralysis and shock or various organ failure. That happens to me after I eat a big burrito anyway. Or this might help re-inject the system, I don't know. It might start you right back up. No, we're joking, but this is quite serious, right? Yeah, it certainly is. I mean, it is fun to joke about this stuff and there's a real, obviously there's a real human component to what venoms can do. But the other major flavor are what we call, let's say broadly we'll call them hemorrhagic. And so these are proteins that target the blood and the hemostatic system. So it's very important for us to have our blood flowing nicely. And then if you get cut, you have to be able to clot that blood and prevent it from having hemorrhage, for example. And a lot of these proteins are targeting elements of that system. Some of them are causing massive clotting, which can then disrupt all your other blood systems, as well as throwing clots throughout your system, which is never good. But some of them are kind of doing the reverse where they are essentially disrupting the clotting system completely such that there is, you just bleed. I mean, you just have massive hemorrhage because, and so this creates obviously a lot of problems if you can't clot after a wound or especially if the damage starts to spread. And then there are many other components that are then targeting that sort of the vascular system or the muscle system and degrading cells and chopping up parts of the cell membranes that are essentially really important for the integrity of your body. So these are two very different mechanisms, targeting the nervous system or targeting your clotting. I thought earlier we were saying that we thought there was a common origin of venom because the fundamental mechanisms of them were so similar. But now there's two different ones. Are they isolated in the two different groups of snakes or how does that all fit together? I mean, this is why it gets, it's where it gets so exciting. So that, what I talked about the commonality is that like at the base, there are some components of this system that are shared. But when the vipers in a lapid split, they each start to recruit new genes into their venom. And those are the ones that are the real, are the ones we really talk about, the real dangerous guys. And along the alapid lineage, they develop some really powerful neurotoxins. And largely speaking, but not exclusively, they are neurotoxic venoms. And they have components of that hemorrhagic venom and they have elements that are disrupting cell integrity. But they also have really powerful neurotoxins. And that's why those snakes can be really, really deadly and act quite quickly. Can you remind me, alapids are vipers? Is that right? So alapids are going to be your copras and crates and some sea snakes. So anything in Australia, I don't know why people would ever go there. Some of the deadliest snakes. Because everybody who lives there is smart and good looking. That's why people would go there. No, that's true. Pandering to our listeners. Because they are surviving snakes all the time. They even have like venomous trees in Australia, like poisonous trees, not venomous. Yeah, anyway, crazy. They probably already put venom on their hot dogs down in Australia. They just don't even talk about it. They're made of stern or stuck down there. It's so boring to think so. So, um, cobras and Australia stuff. So there's a lot of these things and they have the super potent neurotoxins. So they're very dangerous in that respect. So vipers along that line is they developed a lot of like, they included in a lot of proteases and other genes that help really disrupt that hemostatic system. But they also have taken some of those and turned those into neurotoxins as well. So they've, they've mutated some of these proteins that we're initially, we think, used for disrupting the hemostatic system or disrupting the cells and change them and modify them and turn them into neurotoxins as well. So we see neurotoxicity within vipers in addition. So vipers again are our rattlesnakes. And, but then there's a ton of those snakes over in Europe and in Africa and Asia. So all of these snakes are kind of all over the world for the most part. But there are no vipers. There are no vipers in Australia. I see. So the answer because it's biology is it depends or it's complicated. And so it seems like if I'm understanding, there is some common origin to the venom, but then after the split, they continue to evolve and the vipers become neurotoxins and the, no, the cobras become neurotoxins and the rattlesnakes become hemorrhagic. And so now they've also separated, right? And so there's some elements of both to the story. That is fascinating. Yeah. Each lineage, you know, and this is only, they split maybe 30 to maybe it's 40 million years ago. And the, each lineage starts to develop just really starts to experiment and play with the things they can do with this venom. And so this is the part that we came in as being very interested. And my focus initially was in mostly in vipers, but they took one gene, for example, one metalloprotease, and it seems to be ever rooted into the venom gland, something they would excrete. And if you look at it, if you look in a human, we have this metalloprotease in the same genomic location. So we have a few flanking genes that are conserved across all vertebrates. And we can say, oh yeah, there's gene X and gene Y, and then there's this metalloprotease. And then there's some other genes. But in a rattlesnake, in the Western Diamondback, for example, there might be up to 30 copies of that metalloprotease. And they're all different. They have really conserved areas, but they have the proteins have been modified and changed. And we don't know why. We have no idea why they have so many copies of this gene, and why they're also different from each other. And so more copies doesn't mean you necessarily mean you make more, but it means what you make, you make different versions of it or? So right, they're slight, they're like different variations in the same way that there are thousands of variations of hot sauces. These are different variations of these proteins. And we assume, we don't know really how they function differently, but we assume it has to do with the prey that they're eating or the predators they're avoiding, and that they are constantly tweaking these genes to be more effective against different types of prey, potentially, in the same way that the prey is kind of going like, I really should figure out how to stop this. So that's the other part I wanted to ask about, because the missing part of the story is the evolutionary context in which they're evolving, right? The things that they're injecting the venom into. So do we understand, for example, why these two lineages split and develop different kinds of toxins? Are they effective on different kinds of prey? Were they in different parts of the world? Why do we understand the motivation for that split at all? Well, they split in the way that every, that species split all the time. Who knows exactly, we have no idea exactly what context led this, you know, to split initially, it was one little snake hanging out, and occasionally, if you look soon after the split, it would seem like the exact same couple of sister species or something like that. What led, maybe once the lineage for vipers starts to evolve one type of venom, maybe they focused on one kind of prey that was different than what a lapid did. And a lapid behavior, and it's very different than viper behavior in many ways. So the venom evolution could either just be like, look, we went in a random different direction because we were separate species, or it could be that it worked better on the kind of prey that they were tending to snack on. I mean, you know, these mutations and these recruitment events are random, we think, right? And so that they are, that they just happened in one lineage versus another might just be all that they needed to slowly start to delineate these two groups. And there might have been other elements, like, you know, the snakes do have some other physiological differences with that between each other. But, you know, they largely, yeah, exactly what led to the split between the two is hard to say. Do we see any patterns where like, if you are, for example, a snake that goes after rodents versus a snake that goes after, I don't know, birds, is there certain kinds of venom that are more helpful depending on what kind of prey you're going after or what kind of predators you're trying to avoid? Yeah, there certainly seems to be some correlations, but it's not great. It's not, I think people have done some nice studies where they've tried to look at the prey that's, you know, that what they're eating and then see if the different venom types are correlating. But it's not, it's not great. It's like, there's some correlations there, but it doesn't seem like some smoking gun. Like, this is clearly what's driving the differences. And what about non-snake venoms? I know we talked about lizards and you mentioned trees or whatever. In other species that develop venoms, is there any similarity to snake venom in terms of the chemistry or the history? The chemistry is, so there's, so one of the genes, one of the interesting genes that we study is called phospholipase A2. And so phospholipase A2 is a part of this large family of proteins and that's in the viper venom, they use one of these. The elapids also recruited a phospholipase A2, but a different family member, a deeply diverged version of it. So we call that a group, a group one, PLA2. And the viper's use group two. And bees use group three in there, in the venom that they have. So there, in that case, you have a convergent use of a similar enzyme that can be used when injected to cause pain or to disrupt the prey or whatever you're trying to sting. But other molecules, especially like in cone snails and stuff, they use very different kinds of molecules that work effectively at, you know, they can often work as neurotoxins or some other effect. But we suspect that, so I don't know a lot of the chemistry about all the different kinds of venoms, but that I suspect that the evolutionary sort of effects of these are the result of gaining toxin or gaining venom and then what we see following that in terms of the diversity of toxins or the evolution of those toxins once acquired, we might have some similarities in there. I probably shouldn't have used the word venom for the trees. It's probably some other word was the right word. But so you mentioned that the prey are probably wanting, quote unquote, you know, to evolve away around being susceptible to the venom. Do we see prey evolving ways around the venom? Like can you get bit by a rattlesnake and just kind of shake that off if you're a mouse, for example? So it seems that at least in the one good example is the California ground squirrel, which has evolved the resistance to the Pacific rattlesnake. So this is in Oregon and Northern California. And in some of those locations, what we have are a ground squirrel that can take a bite and survive. Wow. So it's invented by like sort of recruiting in some little proteins, some small proteins that act as inhibitors to those hemorrhagic toxins. So that's a pretty cool invention and very really good for the squirrel. Yeah, I'd say. And why isn't that more widespread? So that's a great question. And it seems that, well, it's unclear because let's say that we have a lot of snakes are hunting small mice. And it seems at least to me, naively, that a big bite from a big rattlesnake is going to be quite damaging to you regardless of whether or not it has venom. Now a viper, generally speaking, will strike, hit an animal and then kind of pull back and the animal will walk off and die somewhere and it will follow and find the prey that it killed and then eat it. And this is largely because they don't really want to tussle that much, you know, because you have potential for injury. If all you are is a hot dog with teeth, it's really easy for something to get you. With no marshmallow armor. You try to belittle it. You try to belittle it, but that's still, that's the inspiration for a horror movie right there. Huzzah with teeth that follows you. So, you know, viper's are also often ambush predators. So rattlesnakes don't go seeking out their prey, but they kind of hang tight. They wait for animals to go by and they nip at them. Whereas the lapids tend to hunt and stalk things out. So the things that rattlesnakes are eating, why is there not more, there may be more resistance. And it might be that the history, that the reason that that venom is so complex might reveal an evolutionary history of prey resistance and then trying to overcome it with by either recruiting in new toxins or duplicating and multiplying the toxins you do have and changing them. So you have an arms race going on. Right. So we think this might really, truly be a really good example of an arms race. But we don't know, it's hard to look at the history because all the animals that kind of came in along the way are all dead now. But where we also see a lot of resistance is actually in predators of snakes. And so these are ones that are like in Africa, there's like the honey badger or the mongoose or even meerkats have evolved, I think in some cases convergently ways to prevent the neurotoxin from affecting them. And these are all animals that eat, you know, cobras and other snakes because essentially they're really juicy, tasty hot dogs. And so if you want to eat a hot dog that can bite you back when you're trying to eat it, like you, that's a very thin, if you're depending on that for your diet, there might, it might as possible, there's even stronger sort of pressure to, to sort of evolve a resistance. All right, we're going to take a break. And when we come back, we're going to ask Matt all the really weird snake venom questions we've been holding back on. We're back. We have been hitting Matt with all the hot dog related questions we could think of, but now we are going to hit him with the weird venom related questions that we've got, including venom related questions from the listeners. So first, all right, Matt, if a snake accidentally bit itself, would it be immune to its own venom? Perfect, it seems valuable, right? And if I told you especially that rattlesnakes are living in these big dens often, right? You know, there's tons of them around. If you ever see videos, you can see videos of these guys swarming all over each other. And the young ones, you might are nipping at each other. You don't want a ton of death. So it does turn out that rattlesnakes have a resistance to their own venom. Wow. And this seems like that's probably important. It might be because the big fangs and they're trying to chomp at something, maybe they bite themselves occasionally. Maybe it's happening. We don't really know exactly where and when they might be nipping each other or getting their own venom. But it does seem like they really do have a few layers potentially of resistance, which makes perfect sense. Which makes perfect sense. And now a question that requires a qualifier that you're not a medical doctor and not giving medical advice, but what should you do if you are bitten by a venomous snake? Should you cut it with an X and suck it out? I think you should just cry a little bit first. But don't take too long because class is good. So the most important thing, of course, is just stay calm. And if you're in the United States and if it's a rattlesnake, you're gonna live. If you can get to a hospital, there's anti-venoms. And there's generally speaking, there are, I think, I looked it up for this, so there's some 7,000 to 8,000 bites a year within the US. And there's five or six deaths, which is tragic, but is a good survival rate for sure. And as long as there's access to some medical care, you're gonna be just fine. That's fewer people than are killed by sharks, I think, otherwise known as ocean-based hot dogs. Daniel, I've been listening to some of our past episodes and you often compare things to shark deaths. Do you actually know how many people are killed by sharks every year? This isn't the first time you've used that as a baseline. I use that as a baseline because it's something people think of as very rare and it is quite rare, but they're still terrified of. And I think people don't have a great sense of the frequency at which you can be killed by various things. And so it's just a fun example. And no, thank you for putting me on the spot. I do not have that number off the top of my head. I'll have to, I'll send you, I have this diagram that has like human deaths caused by animals. And it's really great because it, well, not great, but it's great in that it does put all of it into a framework. And so obviously the number one, of course, is mosquitoes, right? Mosquitoes are killing than us. And then it's like humans. Yeah. Killing other humans. Depressed. They're dangerous. But then snakes is third, right? So as much as snake bites in the US are not really, they're not, not you should be like, it's nothing, but it's, it is like not the problem it is in Africa or in Asia where it's a significant problem, of course. And do we know how antivenoms work? Like, is it just some chemistry where this chemical attacks that chemical and breaks it apart? Or does it like go into your system and the way it does in this squirrel and like block it somehow? No. So by and large, what we've done is created antibody-based antivenoms. And so what this is essentially is they'll take venom, they'll inject it in a horse initially, initially people do these in horses or sheep. And then you're essentially just creating, asking the animals immune system to create a series of antibodies that'll, that'll block the toxins. And so they'll take, you know, they'll take a few of the snakes that are here. So the one, the main one in the United States takes venom from four different animals, four different snakes, puts it together, puts it in sheep or ant or horse. And then it does some, it will try to do some purification. Then you take that, that polyclonal antibody and then you essentially just put that in vials and then you, you have to take it if you get bit. And this system is sort of just working around the world where they take the venom from the snakes in the area and then they try to, try to put it, try to create antibodies against it. Unfortunately, it's not like, well, it's very good in that it saves or saves lives and prevents damage. Like to some degree, it is also, it's not like the most perfect system because people can develop allergies to these kinds of antibodies. And they're extraordinarily expensive. I mean, even if in the U.S., like you're getting, I think you might have to get like 10 vials of an antivenom and if there are a few thousand, a pop, that's gonna, it's significant. And they require refrigeration. So this is like why snakebite is such a problem in the developing world where they don't have access to this sort of, these sort of antivenoms for their costly, they have to be handled correctly. And the bigger problem in many cases is that the diversity of snakes, even regionally, the venoms are different enough that your antivenom might not be sufficient to cover you if you're bitten in a slightly different area by a slightly different sister species. So for horses, I had imagined maybe you go with horses because they're gigantic and so you can hit them with a little bit of venom and they, you know, their bodies are big enough that they can handle it and survive. Why, why sheep? I think you can just have a lot more sheep. Okay. All right. I think it's just easier. I honestly, I don't know. Okay. Because they survived this, right? They need you to mount an immune response. They do. They do. After that though, we need to get the blood out to get the antibodies. I'm not sure how much, I don't want to, I shouldn't speak for their industry, but I don't know that it's great. Got it. Okay. And do antibodies developed by sheep always work for humans? Is it transfer that way? I was reading about this crazy guy who like injects himself with venoms to develop antibodies. Right. So this guy's, he's great. I mean, I don't know about great, but he's insane. Right. So a human antibody is way better for humans because we don't have the same allergic reaction to having a foreign body, foreign antibody being used. So if we can develop human-based antibodies as the best and there are people doing that and there's someone that's, they've been doing that recently for neurotoxin that Cobras have and they've done it against a synthetic library of human antibodies. But that means injecting a human with snake venom intentionally, right? In this case, it's actually just taking a, like a library, like a library of antibodies. So it's not in a human, but it's rather on, you know, in a tube, essentially. And then testing to see which ones are reactive or which ones can bind and then using those specifically as therapeutics or treatments. And so those might be much better. The, you know, the other issue is here that we're, I talked about a cocktail of proteins, right? And we actually, as much as we know that the different kinds of actions that the different kinds of toxins can do, we don't really know what contributes the most to like a fatality. We don't really know like specifically, is it all of them are needed or some of them? So some of these, like, and when you throw a bunch of snake venoms in there and you put a bunch of antibodies against all of them, or you hope that you're gathering all of them, you don't know exactly what you're stopping or blocking. And so I think some people are now trying to like specifically target a few proteins alone and say like, maybe this is the worst one. And this is the one we should stop. But the best end of venom comes from humans, which is why we're so ingratiated to Tim Freed, who's injected himself more than 700 times voluntarily with venom to develop an unparalleled snake antivenom. That's amazing. Thank you, Tim. But that's, that's not going to be sustainable for an industry. It's not very sustainable. I mean, I don't know all what's planned with it. But while that might be good, it's, I think there will be other methods too. And I think there are some, there's some work now with what are called nanobodies. And so this is if you inject llamas and alpacas, they have a slightly different immune system, like they're, the antibodies that they generate are different enough that they can be essentially broken up so that they take away the animal, like the lab on a specific part. And so they might be able to function without the same kind of allergic reactions and side effects that are possible. So there's some of that. And then I think there's also some people trying to develop like, just small molecule inhibitors, things that are just like, you can generate as a chemical, and then it may be give that to people. And so those are the kind of things that might be even better because we're, especially when we're talking about like snake bite as a, as a health issue, it is the biggest issue. And the main reason why so many people are dying injured is because they just have no access to medical care, or it's so delayed that by the time they're given it, it's, it's too late. And part of that is like those, there's the rural hospitals don't have the venom stopped and all this other stuff. And if we can come up with things that are, that you might take into the field with you or things that you don't have to be refrigerated, that's like the real goal, the real, then you can really save, you know, a million lives a year or a hundred thousand lives a year. Well, if you think that an anti-venom industry based on one guy named Tim is impractical, here's an idea for you. What if you made snakes out of antimatter, so you have anti-snakes, and their venom is anti-venom? Couldn't you just use that as anti-venom? It's amazing. Wow. Because I suspect you could keep an anti-snake with you at all times. And then you have like a little pan anti-snake, and if you ever get bit, you can just have the anti-snake bite. You're an anti-snake in some sort of magnetic bottle. I mean, I just come up with the idea is the engineers need to figure it out. Right. I think that part's the easy part. This is why we need integrative research projects. Yes, exactly. Cross-disciplinary ideas. You can see how useful they are. Every biology project needs a physicist and vice versa. So then let's get to the actual question of the episode. Now that we have some understanding of snakes and venom, if a rattlesnake bit an octopus, would its venom have any effect? First of all, this is like one of the greatest questions you could ever ask. And imagine a scenario where this happens. Yeah, I'm already, it's just amazing. Snakes on a plane and crashes in the ocean, I don't know, dot, dot, dot. Man, I really, we do got to figure this out. This is important. Are you saying this is not currently the top question in snake venom science? But that's a failure of top venom science and not a failure anyway. So to try to get at this question, I obviously can't really know. But if we think about those vipervenoms that are designed around sort of mammalian blood systems and disrupting clotting or causing it, those hemorrhagic type venoms, you know, you might, you might, an octopus doesn't really have the same kind of clotting systems, but they do have cells that are still made of like same kind of membranes that these venoms do target. So I suspect it could still do quite a bit of damage and probably just really disrupt those tissues. Octopuses, of course, can kind of, some of them can grow their limbs back, so they may not actually care too much. Amazing. That might be one thing. That as far as the neurotoxic snakes, you know, these are still, they still have muscles and that still have, you know, neurotoxin, you know, they have receptors on them that these neurotoxins could target. Now, they certainly haven't evolved to do that or, you know, and this is definitely outside of the sort of, outside of mammals, let's say mammals and reptiles that most snakes are eating, let's say. So all bets are sort of off on how effective it would actually be, but there's reason to think that even these venoms would still be pretty damaging to an octopus. Amazing. So you wouldn't recommend to an octopus to get bitten by a rattlesnake? I wouldn't, but I mean, honestly, an octopus with all those tentacles and the snake, I don't know how that hot dog, it's, the picture I have is a marshmallow surrounding an octopi, a hot dog. And I don't know, I don't know what the snake could do. You know, Australian octopi probably shrug it off. Yeah. Yeah. There are some venomous sea snakes, right? There are, yes. So there are a lapids that are, especially come off the coast of Australia, and those things are super deadly, primarily because they're in the ocean and they're just, they mostly hunt fish, but this is the closest we're going to get to like if this thing is happening in real life. Okay. So, I mean, you know, when I was a kid, it was about the giant squid and the, and the sperm whale, and like no one had ever seen the battle. So I think this is really on par with that. whales also lost their legs. So I feel like we're really kind of into this like legless animals versus squids and octopi is, I think we got to try to sell the movie rights. Pretty good. And also we should add a qualifier. Matt is not an octopus doctor. So if you're an octopus and you're listening, don't take his advice as medical advice. Just chop off one of your legs and grow it back. Not medical advice people, don't listen to him seriously. The listener also sent us an extended question and wanted to know, so we already established that like if a diamondback rattlesnake bit another diamondback rattlesnake or bit itself, it would probably be fine. But what if like a diamondback rattlesnake bit a cobra or a cobra bit a diamondback rattlesnake? What would happen then? This is a great question. I suspect that if we go between alapaz and fibers, we might see that they don't have the same kind of resistance to that venom. The one that I'm not sure about is this. So the king cobra is called a king because it eats other snakes. And it probably, so I should really know this, but it probably has, it probably could have some resistance to other vipers if it could be eating. You're totally going to do this experiment this afternoon, aren't you? Yeah, I do have a few in the back, so I will just make sure I throw them together and see what happens. You need an eye to cook for that. But even within rattlesnakes, we don't know, you know, within within rattlesnakes biting each other. I think the further they are apart from each other, evolutionarily, it's possible that they won't have that same resistance. And there are some rattlesnakes that are neurotoxic, have neurotoxic venoms, and so how those two would react with each other, I don't know. I'd like to say that I think it's probably good we don't have the answers to some of these, because it suggests perhaps a lack of ethics that we've like, you know, thrown snakes together and been like, what happens now? Like, I'm kind of glad we don't know. It's probably for the best. We probably shouldn't know. Yeah. So within ethical guidelines, what kind of questions are being investigated at the cutting edge of snake venom science? What are the big arguments at the snake venom conferences all about? I think that, well, there's, let's see. And is this a nice community or is it toxic? Oh, geez. I don't even think I can respond to that. I think the state community is quite nice. It can be, there's a lot of collaboration that I see out there. These many snake scientists, many of these guys are true herpetologists. So these are the guys that do really love to get the snake hook out and pick them up and show pictures of themselves holding snakes, which I cannot do. I will not do. But there is a lot that's into, so there's a lot of the snake world that is into the populations of snakes and how they move and react and tracing the evolutionary history of those snakes. So there's a lot of, I think in today's world, there's a lot of genomics has become a lot easier to use to study variation and distribution of animals. And in the snake world, that's so different. And so there's a lot of work that's breaking down these genomes and then trying to compare them across different snake lineages and try to learn the history of those snakes and where they've come from. Very cool. And then with respect to venom, then there's always cases of trying to understand where venoms are coming from. And it just, there's so many ones you could study. So there's a number of different lineages or lines of studying different venoms. So I want to know, my last questions are, as a rattlesnake venom person, what question do you get asked most often and what is the most common misconception you encounter? Yes. So I most often am asked if I ever get to hold the snakes or carry. It's what everybody wants to know. But it's the right question because if you talk to my, I have a co-worker who is very much the guy like, oh yeah, oh, absolutely. And we have a big debate because I like to, I like to tell, Vipers is the better venom snake and he is a big, a lapid fan. And part of that has to do with the joy of holding on the lapid, which I'm like, fine, you could do that. So that's one of those things that's always asked, of course. And then a lot of like, you know, what is, what is venom or what does it do you? Those kind of questions are great. In terms of misconceptions, I think generally speaking, the idea that, I mean, if you watch any kind of movie about what snakes in it is often somehow incorrect and they're hunting, they're usually like looking for humans and trying to bite them. And of course, snakes are really gentle and they're really fearful. They just are trying to hide. They just want to be basking in the sun. But they react to prey, predators that are things that they perceive as predators. And so oftentimes they get perceived as a danger when they may not be and they just need to be moved away or sort of gently encouraged to not do, not to sit where they are sitting. The poor, misunderstood venomous snake. Yep. Yes. I like snakes. Well, then let me ask you my favorite question, which is, you are landing on an alien planet on which you think there's probably life. Do you expect there to be snakes? Do you expect there to be venom? How universal do you think this is across the universe? Well, snakes, like as a, you know, as a tube, like worms, I think a tube is a really great simple body system. So the snakes obviously came from a more complex evolutionary history of having legs and having used to swim in the sea and now they're walking on land and now they lost the legs and now they're crawling in the dirt into the sea again. So they've done all kinds of stuff. And so tubes, I think, are really probably pretty cool systems we'll see in any, on any alien planet. But you're not giving up your legs, right? You know, becoming tubular. I prefer my legs, you know, so I'll keep them for now. But, you know, whales did great things without them. So have snakes. Big fan of whales work. Yeah. Yeah. They're neat. Everyone should be. So you think there probably are tubular animals on alien planets? It just seems like a very easy body system, right? So essentially all we are are tubes with just ornamentation, right? You know, all animals essentially are just a tube from mouth to butt, whatever you say here. And then, and we just decorate it with different kinds of legs and pinchers or other teeth or whatever you want. But like, it's all just basically a tube to get food through and reproduce. So if you meet a biologist in real life, folks, they are thinking about you as an ornamented mouth to butt tube. Yep. That's exactly what you are. That tells me a lot about how biologists see the world. I think of you as a parasite host. So it depends on you, the biologist. And so many parasites are just a little worms, so they're little tubes. That's a good point. That's a good point. But do you think that those tubes are going to be venomous? I mean, look, venomous seems to be a system that works in a lot of different animal systems. If you can use chemicals as a defense system, great. And if you need to bite into something or if you're tussling with something and you depoke it and make it stop, then venom is a really great system. So I would expect that you would see, you know, venom kind of anywhere you see conflict between animals. Well, I have learned a lot about snake venom and a lot about ways to cook hot dogs. And I will never see a human the same way again. Good. So thank you so much, Matt, for being on the show. This was fantastic. It's my absolute pleasure. Thank you guys. Thanks everybody for listening. Please go and do us a favor and rate the show on whatever podcast app you're using. It really helps people find us. Daniel and Kelly's Extraordinary Universe is edited by the amazing Matt Kesselman. He really is a wizard. You can also find us online on Blue Sky Instagram and X, D and K Universe. Come engage with us. You can email us at questions at Daniel and Kelly.org. We really do want to hear from you. And you can find our website www.DanielandKelly.org, where you'll also find an invitation to join our Discord where everybody comes and talks about the amazing universe. And we also have the most amazing moderators. This is an I Heart podcast. Thanks for joining us. This is an I Heart podcast. Guaranteed human.