WEBVTT - Special Episode: Snake Venom Evolution 0:00:43.200 --> 0:00:46.680 Hi, I'm Aaron Welsh, and this is this podcast will 0:00:46.760 --> 0:00:50.199 Kill You. You are listening to the latest and last, for 0:00:50.320 --> 0:00:53.920 now bonus episode in our mini series of bonus episodes 0:00:53.920 --> 0:00:56.240 that have been coming out over the last several months. 0:00:56.960 --> 0:00:59.800 I've had such a great time putting these episodes together, 0:00:59.840 --> 0:01:03.480 and I've learned so very much along the way. I'd 0:01:03.480 --> 0:01:05.640 love to pick up this series again in the future, 0:01:05.920 --> 0:01:09.440 so let's just consider this a break for now. If 0:01:09.440 --> 0:01:11.479 this is your first time tuning into one of these 0:01:11.480 --> 0:01:14.560 bonus episodes, I'll give a brief explanation of what they're 0:01:14.600 --> 0:01:17.160 all about. And if this is not your first time, 0:01:17.240 --> 0:01:19.240 then I'm sorry that you've had to hear this intro 0:01:19.440 --> 0:01:23.399 over and over again. In these bonus episodes, I'm taking 0:01:23.520 --> 0:01:26.360 some aspect of the topic we discussed in our previous 0:01:26.360 --> 0:01:30.160 week's regular season episode and bringing on an expert guest 0:01:30.200 --> 0:01:34.039 to help me investigate this subject in more depth. For instance, 0:01:34.200 --> 0:01:36.520 my guests and I have gone further down the rabbit 0:01:36.520 --> 0:01:39.640 hole of mixed andmatosis by following up with an episode 0:01:39.640 --> 0:01:43.679 on rabbit heemorrhagic disease virus. We've explored in more detail 0:01:43.760 --> 0:01:48.040 how electricity actually works, and we've re examined the origins 0:01:48.040 --> 0:01:52.200 of epidemiology. I'm also rounding out many of these discussions 0:01:52.240 --> 0:01:55.680 by asking my expert guest about their own journey into science, 0:01:55.880 --> 0:01:58.280 what they like about it and what they don't, and 0:01:58.360 --> 0:02:01.440 any advice they may have for people interested in pursuing 0:02:01.520 --> 0:02:05.400 a career in this field. And this week, I'm especially 0:02:05.440 --> 0:02:09.680 excited to learn more about the absolutely fascinating world of 0:02:09.840 --> 0:02:14.800 snake venoms. In our regular season episode last week, Aaron 0:02:14.840 --> 0:02:17.320 and I covered the different groups of venoms that some 0:02:17.440 --> 0:02:20.400 snakes produce and what happens to your body if you 0:02:20.440 --> 0:02:23.160 are unfortunate enough to be at the receiving end of 0:02:23.200 --> 0:02:26.240 a bite from a venomous snake. If you haven't listened 0:02:26.280 --> 0:02:28.920 to that episode yet, I recommend that you go back 0:02:28.960 --> 0:02:32.240 and listen to it before continuing on here, since that 0:02:32.320 --> 0:02:35.799 will provide some good background information on what's actually in 0:02:35.840 --> 0:02:38.880 these venoms and how they work, which turns out to 0:02:38.919 --> 0:02:43.240 be a pretty complicated subject, too complicated even for me 0:02:43.360 --> 0:02:46.040 to begin to scratch the surface of the different types 0:02:46.080 --> 0:02:49.240 of venoms in a recap here. But in addition to 0:02:49.320 --> 0:02:52.359 talking about the action of these different venoms, as well 0:02:52.400 --> 0:02:56.000 as the significance of snake bites as a neglected tropical disease. 0:02:56.639 --> 0:02:59.880 We also spent some time talking about how snakes may 0:02:59.880 --> 0:03:03.680 have played a role in primate evolution, specifically in the 0:03:03.720 --> 0:03:08.440 evolution of our visual systems. What we didn't discuss, however, 0:03:08.840 --> 0:03:13.560 was the big question of venom evolution. So many snakes 0:03:13.600 --> 0:03:16.919 and other animals have evolved the ability to use venom, 0:03:17.400 --> 0:03:21.800 and the resulting diversity of venoms is simply astounding, which 0:03:21.840 --> 0:03:24.720 is why for this bonus episode, I really wanted to 0:03:24.760 --> 0:03:28.120 take the time to dig into how these venoms evolved 0:03:28.120 --> 0:03:31.640 in the first place, why there is such diversity across 0:03:31.760 --> 0:03:35.560 venom type and function, and what happens when venoms evolve 0:03:35.640 --> 0:03:39.160 as a defense mechanism rather than as an aid and predation. 0:03:39.880 --> 0:03:42.600 And I'm absolutely thrilled to have one of the world's 0:03:42.720 --> 0:03:47.400 leading experts on venom evolution as my guide, Professor Nick Casewell. 0:03:47.840 --> 0:03:49.960 And with that, I think we'll just take a quick 0:03:49.960 --> 0:03:51.800 break here before diving in. 0:04:15.280 --> 0:04:18.120 My name is Nick Casewell. I'm a professor of Tropical 0:04:18.120 --> 0:04:21.839 disease biology at the Liverpool School of Tropical Medicine and 0:04:21.920 --> 0:04:24.839 I'm the director for the Center for Snake Bite Research 0:04:24.839 --> 0:04:29.039 and Interventions. This is a research group at LSTM, where 0:04:29.080 --> 0:04:32.240 we essentially study snake bite and try and develop new 0:04:32.279 --> 0:04:37.000 interventions to improve the lives and livelihoods of snake bite victims. 0:04:37.720 --> 0:04:41.159 Awesome, thank you so very much for joining me today. 0:04:41.839 --> 0:04:44.120 It's a real pleasure. Thanks for the invitation to talk 0:04:44.200 --> 0:04:45.800 snake venom and snake bite with you. 0:04:46.920 --> 0:04:50.039 Of course, I am so excited to learn more about 0:04:50.040 --> 0:04:53.520 these fascinating compounds. And so can you start us off 0:04:53.560 --> 0:04:55.920 by talking about exactly that, like, what do we know 0:04:56.000 --> 0:04:59.800 about the earliest emergence of venomous snakes and what is 0:04:59.839 --> 0:05:02.680 the about why this trait emerged when it did. 0:05:04.080 --> 0:05:06.800 So we start on a really tricky subject really in 0:05:06.880 --> 0:05:09.119 terms of we know lots about what's in the venom 0:05:09.160 --> 0:05:12.560 of snakes today, and actually we don't know all that 0:05:12.720 --> 0:05:16.720 much about the whys and the wares venom evolved in 0:05:17.800 --> 0:05:21.320 snakes and in fact, in many venomous animals. So what 0:05:21.360 --> 0:05:24.599 we do know is that venom evolved in snakes on 0:05:24.600 --> 0:05:28.400 one occasion. So all these venomous snakes we find today 0:05:28.440 --> 0:05:31.080 are all related to one another, and their venom systems 0:05:31.080 --> 0:05:34.360 are related to one another as well. And this probably happened, well, 0:05:34.360 --> 0:05:37.560 it certainly happened at least forty to fifty million years ago, 0:05:38.080 --> 0:05:40.560 so it's a relatively old trait and it may go 0:05:40.720 --> 0:05:45.240 back even further than that, But we don't know for sure, 0:05:45.320 --> 0:05:47.560 and we don't know why only this group of snakes 0:05:47.880 --> 0:05:51.080 have evolved a venom system compared to others. But what 0:05:51.120 --> 0:05:54.360 we do know today looking at snakes is that although 0:05:54.360 --> 0:05:57.320 those venom systems are effectively the same, or they evolve 0:05:57.400 --> 0:06:01.040 from the same common ancestor, they're actually rereadibly different. The 0:06:01.080 --> 0:06:03.400 toxins that you find in the venoms of these different 0:06:03.440 --> 0:06:06.400 snakes are very different. And the effects that these venoms 0:06:06.440 --> 0:06:10.400 have on a prey item they're trying to kill or immobilize, 0:06:10.640 --> 0:06:12.920 or on someone who's bitten by one of these snakes 0:06:12.920 --> 0:06:15.520 can be really really different depending on which snake you're 0:06:15.560 --> 0:06:16.080 bitten by. 0:06:17.200 --> 0:06:20.880 What are some of the drivers for this diversity? What 0:06:20.960 --> 0:06:21.800 is thought about that? 0:06:22.800 --> 0:06:26.200 So we think the primary reason that snakes ultimately evolve venom, 0:06:26.920 --> 0:06:30.760 and the primary driver that's kind of honing the competitions 0:06:30.760 --> 0:06:34.839 of venom we see today is for predation. So snakes 0:06:34.839 --> 0:06:37.599 are primarily using their venom systems to catch prey, to 0:06:37.680 --> 0:06:39.400 help them to catch prey, and if you think about 0:06:39.400 --> 0:06:41.719 a snake, it's pretty obvious why that might be right. 0:06:41.760 --> 0:06:45.560 These are limbless animals. They don't have claws or arms 0:06:45.640 --> 0:06:48.680 or legs to help them to catture their prey. All 0:06:48.760 --> 0:06:52.720 snakes are predators. They're all eating other animals. And what's 0:06:52.760 --> 0:06:56.200 interesting is that while some snakes use things like constrictions, 0:06:56.240 --> 0:07:00.360 so they wrap body coils around prey to immobilize them, 0:07:00.960 --> 0:07:03.720 many snakes have taken a different strategy, which is the 0:07:03.839 --> 0:07:07.880 use of a chemical weapon, which is injected into the 0:07:07.920 --> 0:07:11.120 prey and ultimately has the same effect. It immobilizes that animal, 0:07:11.400 --> 0:07:13.320 or it kills the animal, or in some way just 0:07:13.440 --> 0:07:17.240 enables the snake to actually feed on it relatively unharmed. 0:07:17.280 --> 0:07:20.160 So we know that the venom is really crucial for 0:07:20.240 --> 0:07:23.320 these snakes to catch their prey. Snakes can use their 0:07:23.400 --> 0:07:26.400 venom defensively too, but this is not the primary purpose. 0:07:26.720 --> 0:07:29.880 And the reason we think that is because there's been 0:07:29.880 --> 0:07:33.040 a number of scientific studies done over many years that 0:07:33.160 --> 0:07:36.960 show that there are associations between, for example, the potency 0:07:37.280 --> 0:07:41.320 of venom and the diet of that particular snake species. 0:07:41.360 --> 0:07:45.520 So you can start to see associations whereby certain snakes 0:07:45.520 --> 0:07:48.880 that feed predominantly on one type of animal, have venom 0:07:48.920 --> 0:07:52.880 toxins that are honed towards that particular prey type or 0:07:52.920 --> 0:07:57.560 even specific to that particular prey type. We also see 0:07:57.560 --> 0:08:01.920 evidence in some species where venom is no longer being 0:08:02.040 --> 0:08:07.640 used that venom system has started to degrade or disappear. 0:08:07.840 --> 0:08:11.720 So in c snakes, for example, that feed on fish eggs, 0:08:11.720 --> 0:08:15.160 they don't need venom to catch their fish egg prey anymore, 0:08:16.120 --> 0:08:18.000 and we actually see that the toxins in their venom 0:08:18.000 --> 0:08:21.960 have begun to degenerate, so they're not functionally intact anymore. 0:08:22.000 --> 0:08:24.720 They're not functionally active. And also the venom glands in 0:08:24.760 --> 0:08:27.640 the snakes themselves start to reduce in size too, so 0:08:27.680 --> 0:08:31.200 they did trophy. So there's this clear association between diet 0:08:31.920 --> 0:08:35.840 and venom itself. It may not be the only factor. 0:08:36.160 --> 0:08:38.600 There may be other things that come into play that 0:08:38.840 --> 0:08:42.079 may hone that final composition of venom, but without doubt, 0:08:42.080 --> 0:08:45.320 we think that the prey is the key thing that 0:08:45.360 --> 0:08:47.280 has driven venom evolution in snakes. 0:08:48.320 --> 0:08:50.800 In terms of the types of venoms that we see, 0:08:50.840 --> 0:08:54.560 you know, we have these neurotoxic or cytotoxic venoms. Is 0:08:54.559 --> 0:08:57.960 there any association between the type of prey you know, 0:08:58.000 --> 0:09:01.800 whether it's fast moving dents or something else, you know, 0:09:02.080 --> 0:09:05.559 and the actual type of composition of the venoms among 0:09:05.600 --> 0:09:07.560 different snakes or is that just sort of like an 0:09:07.640 --> 0:09:08.720 accident of evolution. 0:09:10.000 --> 0:09:13.120 Yeah, more the latter than the former. So there are 0:09:13.200 --> 0:09:17.280 lots of different kind of classes of venom, toxins and 0:09:17.280 --> 0:09:21.120 what they do. And there are different groups of venomous 0:09:21.160 --> 0:09:24.480 snakes as well. So the most famous ones we think 0:09:24.520 --> 0:09:27.480 of from a human context of vipers and a lapids. 0:09:27.559 --> 0:09:30.600 These are the two most medically important group of snakes 0:09:30.600 --> 0:09:33.280 to people. There are types of snakes that can put 0:09:33.320 --> 0:09:36.920 us in hospital and killers, and broadly speaking, they have 0:09:37.000 --> 0:09:40.520 quite different venoms with lapid snakes, so these are things 0:09:40.559 --> 0:09:44.280 like cobras or coral snakes or mambers. They typically have 0:09:44.360 --> 0:09:47.920 a neurotoxic venom that causes your nerves to be paralyzed 0:09:48.000 --> 0:09:51.440 and this causes particular issues when you're breathing, muscles ultimately 0:09:51.480 --> 0:09:56.040 stop working. Their venom is quite different to viper venoms. 0:09:56.080 --> 0:09:58.720 So with vipers, we're talking about things like rattle snakes, 0:09:58.880 --> 0:10:05.120 puff adders, Russell's vipers. These venoms broadly are hematoxic venoms. 0:10:05.600 --> 0:10:08.079 They have toxins in there that are causing damage to 0:10:08.080 --> 0:10:11.360 blood vessels. They're causing people to bleed internally or prey 0:10:11.400 --> 0:10:16.000 to bleed to cause strokes. And these two did very 0:10:16.000 --> 0:10:19.600 different groups of snakes ultimately are feeding on similar prey. 0:10:19.760 --> 0:10:22.800 So you know, some might be mammal specialists within a lapids, 0:10:22.800 --> 0:10:25.040 some might be mammal specialists within vipers. Some might have 0:10:25.080 --> 0:10:28.600 broad diets within lapids, some might have broad diets within 0:10:28.640 --> 0:10:34.640 the vipers. That kind of hemotoxicity versus neurotoxicity, Both those 0:10:34.679 --> 0:10:38.480 strategies are really great at killing prey quickly. Either you 0:10:38.559 --> 0:10:41.480 paralyze the prey or you cause it to have a stroke. 0:10:42.200 --> 0:10:45.240 Both strategies work equally well. And so although we do 0:10:45.280 --> 0:10:49.480 see some examples where certain snakes have very prey specific venom, 0:10:50.160 --> 0:10:53.680 it's not that this group of snakes only feed on mammals. 0:10:53.720 --> 0:10:56.040 They must have a neurotoxin. This group of snakes only 0:10:56.040 --> 0:10:59.920 feed on reptiles, they must have a blood acting venom. 0:11:00.080 --> 0:11:01.640 It's not quite as simple as that. So we see 0:11:01.640 --> 0:11:04.800 a lot of variation within those different groups. And I 0:11:04.840 --> 0:11:07.480 suppose there are a number of ways that a snake 0:11:07.520 --> 0:11:10.480 can rapidly kill its prey no matter what that prey is, 0:11:10.520 --> 0:11:15.360 and ultimately those snake families diversified many millions of years ago, 0:11:15.400 --> 0:11:19.920 when one snake family, the lapids, has evolved neurotoxins and 0:11:19.960 --> 0:11:24.240 really increased the abundance of neurotoxins in its venom, whereas 0:11:24.240 --> 0:11:27.280 the vipers have gone down a hemotoxin rout and they've 0:11:27.280 --> 0:11:30.120 really increased the abundance of those hemotoxins, and that's what's 0:11:30.160 --> 0:11:33.080 dictated those different kind of venom pathologies. 0:11:34.080 --> 0:11:37.800 So earlier you talked about sea snakes having slowly lost 0:11:37.920 --> 0:11:40.760 or losing their ability to produce venom or deliver venom 0:11:40.800 --> 0:11:43.280 because they don't use it as much, meaning that venom 0:11:43.360 --> 0:11:46.720 is probably a fairly costly thing to produce and maintain 0:11:47.240 --> 0:11:50.200 as a tree. And there's this thing I want to 0:11:50.240 --> 0:11:52.960 mention that's sort of in line with that, the economy 0:11:52.960 --> 0:11:58.000 of venom in the overkill hypothesis, where it seems like 0:11:58.120 --> 0:12:01.720 the deadliness or the toxicity of venom is much much 0:12:01.760 --> 0:12:05.880 greater than would actually be needed to kill a particular prey. 0:12:06.320 --> 0:12:08.840 Can you talk about why this may not fully capture 0:12:08.840 --> 0:12:11.480 the relationship between venom of snakes and their prey. 0:12:12.520 --> 0:12:18.000 Yeah, absolutely, so. This overkill hypothesis proposes that because snake 0:12:18.080 --> 0:12:22.600 venoms are so toxic, and because snakes, well, certain snakes, 0:12:22.640 --> 0:12:25.480 we are able to inject a lot of venom when 0:12:25.480 --> 0:12:28.960 they bite. When you kind of extrapolate that, you know, 0:12:29.120 --> 0:12:32.720 certain toxicity at a certain amount scale to how much 0:12:32.760 --> 0:12:37.520 they actually inject, it seems that for many snakes they're 0:12:37.600 --> 0:12:39.760 just they just have way more venom than they would 0:12:39.760 --> 0:12:43.959 actually need. And therefore, this idea that venoms are honed 0:12:44.000 --> 0:12:48.400 towards certain prey doesn't really hold, because no matter what 0:12:48.440 --> 0:12:50.520 the prey is, their venom is going to be sufficiently 0:12:50.559 --> 0:12:54.520 toxic to kill it. But this is quite a simplified view, really, 0:12:54.679 --> 0:12:58.640 because the toxicity of snake venoms is often modeled just 0:12:58.760 --> 0:13:03.079 basically in terms of their toxicity to laboratory animals. Usually 0:13:03.360 --> 0:13:07.120 this will have historically been lab mice, and these snakes 0:13:07.160 --> 0:13:09.160 aren't feeding on lab mice in the wild, and we 0:13:09.280 --> 0:13:13.640 know that from lots of different species. There's quite compelling 0:13:13.679 --> 0:13:17.280 evidence that prey items and on a predators have evolved 0:13:17.280 --> 0:13:20.360 at least some degree of resistance to many snake venoms. 0:13:21.480 --> 0:13:24.720 So to simply say that because a lot of venoms injected, 0:13:26.320 --> 0:13:29.559 you know, these snakes all kind of wasting their venom 0:13:29.640 --> 0:13:32.760 is simply not true. There's a lot of different prey 0:13:32.800 --> 0:13:36.120 out of there that have mechanisms that have enabled them 0:13:36.160 --> 0:13:40.600 to evolve resistance to snake venom, and we suspect probably 0:13:40.640 --> 0:13:44.080 that snake venoms are also responding and evolving further in 0:13:44.160 --> 0:13:48.079 response to that resistance. You have this kind of arms 0:13:48.200 --> 0:13:51.199 race between prey and predator in terms of the potency 0:13:51.240 --> 0:13:53.680 of the venom. And we also know that from a 0:13:53.720 --> 0:13:55.960 few studies at least, that there seems to be some 0:13:56.080 --> 0:13:59.120 evidence that snakes can meet to the amount of venom 0:13:59.160 --> 0:14:02.880 they might inject, and so certainly snakes will not use 0:14:02.920 --> 0:14:05.080 all of the venom they have in one bite. They 0:14:05.240 --> 0:14:08.640 may bite multiple times. But also lots of feeding attempts 0:14:08.640 --> 0:14:12.520 from snakes are unsuccessful, and so they need to retain 0:14:12.600 --> 0:14:14.640 enough venom to then go on and try and feed 0:14:14.640 --> 0:14:17.960 on the next prey item too. So we know snake 0:14:18.040 --> 0:14:22.040 venoms are toxic, but ultimately a lot of that extrapolation 0:14:22.120 --> 0:14:24.800 has been based on an artificial scenario. These snakes are 0:14:24.800 --> 0:14:27.800 not feeding on lab mice in the wild, and there 0:14:27.840 --> 0:14:31.160 are studies that have shown that certain snake venoms it 0:14:31.200 --> 0:14:34.160 may take, for example, half an hour to kill a 0:14:34.200 --> 0:14:36.960 scorpion which might be a natural prey. And clearly if 0:14:37.000 --> 0:14:39.920 these venoms were super toxic and overloading prey with a 0:14:40.000 --> 0:14:42.120 huge amount of venom, it would take much less time 0:14:42.160 --> 0:14:42.440 than that. 0:14:43.560 --> 0:14:46.520 So you mentioned arms races. So can we now kind 0:14:46.520 --> 0:14:50.160 of shift to talking about venom as a defense mechanism 0:14:50.400 --> 0:14:53.720 and sort of some of the ideas about spitting cobras. 0:14:54.440 --> 0:14:57.600 Why is venom spitting so unique and what are some 0:14:57.640 --> 0:14:59.680 of the drivers for its evolution. 0:15:01.040 --> 0:15:03.640 Yeah, venom spitting is a really interesting one because you know, 0:15:03.680 --> 0:15:07.120 we talked already about why venoms have evolved in snakes, 0:15:07.120 --> 0:15:11.400 and it's for predatory purposes, and there doesn't seem to 0:15:11.400 --> 0:15:15.680 be much evidence really that venom composition is evolving secondarily 0:15:15.720 --> 0:15:19.720 for defense, although snakes will use their venom defensively, right, 0:15:19.800 --> 0:15:22.920 every human snake bite that happens many millions every year, 0:15:23.280 --> 0:15:25.960 These are defensive snake bites. The snakes aren't trying to 0:15:26.000 --> 0:15:29.760 eat us. But there's actually very little evidence that the 0:15:29.840 --> 0:15:33.040 composition of venom is evolving in response to the use 0:15:33.080 --> 0:15:38.680 of that venom defensively, except with the spitting cobras. So, 0:15:39.320 --> 0:15:42.600 the spitting cobras are this one group of pretty closely 0:15:42.640 --> 0:15:46.720 related lapid snakes. So these are very highly venomous snakes. 0:15:47.560 --> 0:15:51.840 And within this group, on three independent occasions, we see 0:15:51.880 --> 0:15:55.680 the evolution of venom spitting. So this is the ability 0:15:55.720 --> 0:15:58.880 of these snakes to eject their venom in a stream 0:15:59.000 --> 0:16:02.400 of liquid from them mouth, directly targeting the eyes of 0:16:02.400 --> 0:16:05.280 a predator or aggressor over a couple of meters. So 0:16:05.280 --> 0:16:07.360 it's a really effective way. And what that venom does 0:16:07.400 --> 0:16:09.480 when it hits the eye or the area around the 0:16:09.520 --> 0:16:13.080 eyes is it causes extreme pain. And so this is 0:16:13.120 --> 0:16:16.120 a really nice strategy to deter a potential aggressor or 0:16:16.120 --> 0:16:19.640 a predator from eating you. It's by causing pain and 0:16:19.720 --> 0:16:23.000 to be left alone. But what's interesting here is that 0:16:23.040 --> 0:16:25.480 we find that there is some evidence that the venom 0:16:25.520 --> 0:16:28.920 composition has also changed in response to the evolution of 0:16:28.960 --> 0:16:32.120 this venom spitting trait. And so this goes against everything 0:16:32.120 --> 0:16:35.000 I've said. This is the exception. There's always in biology 0:16:35.000 --> 0:16:37.800 there are exceptions. This is a perfect example. And each 0:16:37.840 --> 0:16:40.200 of these three groups of spitting cobras, so the African 0:16:40.240 --> 0:16:43.560 spitting cores, the agent spitting cobras, and also in a 0:16:43.720 --> 0:16:47.080 closely related cobra species called the wrinkles, they've all evolved 0:16:48.240 --> 0:16:51.600 to increase the abundance of a particular toxin which works 0:16:51.600 --> 0:16:55.160 together with another toxin to cause this pain enhance pain 0:16:55.320 --> 0:17:00.960 causing effect. And so it's likely we think that only 0:17:01.000 --> 0:17:04.399 spitting cobras have evolved the ability to spit because of 0:17:04.440 --> 0:17:07.920 a variety of these what we would call preadaptations, if 0:17:07.920 --> 0:17:10.160 you like. There are a few things that these snakes 0:17:10.200 --> 0:17:13.760 had to have before spitting could evolve. So one of 0:17:13.760 --> 0:17:16.639 them is this toxin that can kind of cause a 0:17:16.640 --> 0:17:19.720 bit of pain and then could be enhanced upon later on. 0:17:20.400 --> 0:17:23.280 And the other thing is this defensive behavioral posture that 0:17:23.320 --> 0:17:26.119 cobras have in that they can kind of raise the 0:17:26.160 --> 0:17:28.640 first third of their body up in the air, which 0:17:28.680 --> 0:17:32.640 gives them a very nice kind of position from which 0:17:32.680 --> 0:17:36.040 they can spit. If you imagine most snakes lying flat 0:17:36.080 --> 0:17:38.159 on the ground, and if they open their mouth to 0:17:38.160 --> 0:17:40.040 spit their venom, it's just going to go straight into 0:17:40.040 --> 0:17:41.480 the ground. So they have to be able to raise 0:17:41.520 --> 0:17:43.520 their body up, and so this is kind of a 0:17:43.560 --> 0:17:46.560 defensive behavior that cobras would already have done prior to 0:17:46.600 --> 0:17:49.560 the evolution of spitting. So probably those two things have 0:17:49.720 --> 0:17:52.920 enabled this particular group of snakes to evolve this special 0:17:53.000 --> 0:17:57.439 defensive adaptation that we don't see in any other venomous snakes, 0:17:58.200 --> 0:18:01.280 and so we think, we think possibly that the driver 0:18:01.640 --> 0:18:04.760 for having a specialized defensive use of the venom in 0:18:04.840 --> 0:18:08.280 cobras it may have been stimulated by our ancestors, so 0:18:08.800 --> 0:18:14.000 ancestral hominins which in Africa came out onto the planes, 0:18:14.000 --> 0:18:18.280 they were bipedal. And we know that certainly many primate 0:18:18.359 --> 0:18:21.760 species will defend themselves from snakes. They will actively identify 0:18:21.840 --> 0:18:23.960 them and mob them, throw stones at them, try and 0:18:24.080 --> 0:18:28.200 kill them. And we suspect that for cobras it may 0:18:28.240 --> 0:18:30.800 well have been an advantage for them to have a 0:18:30.920 --> 0:18:35.640 long distance defensive weapon that could protect themselves from from 0:18:35.680 --> 0:18:39.560 our ancestors. And indeed, we know that the timing of 0:18:39.600 --> 0:18:43.360 the origin of venom spitting in Africa in African cobras 0:18:43.400 --> 0:18:47.200 about fifteen million years ago, correlates quite nicely from when 0:18:47.359 --> 0:18:53.280 our ancestors diverge from chimpanzees. So this remains a speculative hypothesis, 0:18:53.320 --> 0:18:58.080 but it may well be that human ancestors may have 0:18:58.119 --> 0:19:01.200 shaped snake ancestor as many million years ago. 0:19:02.240 --> 0:19:05.960 In terms of trade offs, are there tradeoffs that we've 0:19:06.000 --> 0:19:09.200 observed in terms of you know, where a more prey 0:19:09.200 --> 0:19:13.040 specific venom could mean a less effective defense venom. 0:19:14.040 --> 0:19:16.280 Yeah, I would really like to know the answer to 0:19:16.320 --> 0:19:20.639 that question. I think it's a great question. So if 0:19:20.680 --> 0:19:23.040 I go back to the example of the spitting cobras here, 0:19:23.080 --> 0:19:27.520 there's clearly potential for a tradeoff, right because you have 0:19:27.560 --> 0:19:30.320 a venom that's working to dual purpose that the snakes 0:19:30.440 --> 0:19:33.600 is still using that venom to catch their prey, but 0:19:33.680 --> 0:19:37.359 we know that they've also evolved certain venom components that 0:19:37.400 --> 0:19:40.760 are increased in their abundance to help them defend themselves. 0:19:41.320 --> 0:19:43.879 And so you know, in theory there should be a 0:19:43.880 --> 0:19:47.439 trade off there with a reduction in terms of the 0:19:47.480 --> 0:19:51.000 content of other toxins. And I think ultimately we don't 0:19:51.080 --> 0:19:56.199 understand this yet. We don't understand to what extent in 0:19:56.240 --> 0:20:02.240 a natural prey capturing scenario the evolution of a toxin 0:20:02.280 --> 0:20:05.280 that's helping that snake to defend itself might have upon 0:20:06.000 --> 0:20:09.640 capturing a prey item. And what's quite interesting with many 0:20:09.640 --> 0:20:12.360 of these venom toxins is that they can be multifunctional. 0:20:13.440 --> 0:20:15.840 There are toxins that have evolved to enhance the pain 0:20:15.920 --> 0:20:18.240 causing ability of the venom if it hits the eye 0:20:18.240 --> 0:20:22.000 of you or me. Actually, when that toxin is injected 0:20:22.040 --> 0:20:24.879 into the prey item, it's almost certainly still going to 0:20:24.920 --> 0:20:27.880 be helping the snake catch the prey. And whether that's 0:20:27.920 --> 0:20:30.800 just by destroying cell membranes and letting the snake permeate 0:20:30.880 --> 0:20:33.480 further into the prey, or whether it's by having a 0:20:33.520 --> 0:20:36.359 much more specific effect, it's likely not to have any 0:20:36.400 --> 0:20:39.600 detrimental effect on the ability of that snake to catch 0:20:40.160 --> 0:20:44.000 the prey item. Ultimately, there are still destructive venoms, but 0:20:44.080 --> 0:20:46.120 we do know there has been a change. Again using 0:20:46.119 --> 0:20:49.399 this example, if you look at all non spitting cobras 0:20:49.560 --> 0:20:52.159 and most of lapid snakes, we've talked about what their 0:20:52.240 --> 0:20:56.480 venoms usually do, and it's to cause neurotoxicity. So if 0:20:56.520 --> 0:21:00.239 you're bitten in Africa by a non spitting cobra, an 0:21:00.280 --> 0:21:04.240 Egyptian cobra, or a cape cobra, you will suffer from 0:21:04.280 --> 0:21:08.639 neurotoxic effects. If you're bit of my spitting cobra, chances 0:21:08.640 --> 0:21:11.800 are you won't suffer any neurotoxicity at all, And in 0:21:11.840 --> 0:21:14.040 fact what's likely to happen is you're likely to have 0:21:14.480 --> 0:21:17.840 a local tissue damage around the BikeE sites, you're likely 0:21:17.840 --> 0:21:21.280 to have swelling, pain, maybe some blistering, and maybe some 0:21:21.320 --> 0:21:25.679 destruction of your flesh. You're unlikely to die, whereas from 0:21:25.720 --> 0:21:29.199 a neurotoxic bite the risk is much higher. So the 0:21:29.240 --> 0:21:32.080 evolution of defense has had a knock on effect in 0:21:32.160 --> 0:21:36.359 terms of venom composition and in terms of venom functionality 0:21:36.480 --> 0:21:40.840 for humans. But to what extent that applies to natural 0:21:40.920 --> 0:21:43.440 prey is a far more difficult question to answer because 0:21:43.440 --> 0:21:46.960 there's very little research that's been performed upon how these 0:21:47.040 --> 0:21:52.040 venoms actually are incapacitating or killing prey items in the wild. 0:21:53.200 --> 0:21:57.880 So we're talking about some very complex things, right, complex behaviors, 0:21:58.000 --> 0:22:03.320 complex venoms themselves are incredibly complex. Can you walk us 0:22:03.320 --> 0:22:07.840 through how venom evolution happened in a genetic sense, or 0:22:07.920 --> 0:22:10.600 may have happened in a genetic sense. A non venomous 0:22:10.600 --> 0:22:13.840 snake didn't turn venomous overnight, So what might that process 0:22:13.880 --> 0:22:14.439 have looked like? 0:22:15.520 --> 0:22:19.679 Yeah? Absolutely right. So we're talking here about timescales of 0:22:19.720 --> 0:22:23.480 you know, forty to fifty million years from at least 0:22:23.520 --> 0:22:26.280 from the earliest inception of venom, if you like, in 0:22:26.480 --> 0:22:32.000 a snake ancestor to modern day snakes today. But in principle, 0:22:32.040 --> 0:22:34.720 we do understand at least some of the bases for 0:22:35.600 --> 0:22:39.720 how this may have happened. So venom glands are essentially 0:22:40.840 --> 0:22:44.159 modified salivary glands, the same as you or I have 0:22:44.240 --> 0:22:50.199 in our mouths, and these salivary glands produce proteins that 0:22:50.240 --> 0:22:52.200 are used for different purposes for us, that used to 0:22:52.240 --> 0:22:56.159 help digest our food, for example, And we believe that 0:22:56.200 --> 0:22:59.600 on many occasions snakes may have repurposed some of the 0:22:59.600 --> 0:23:03.480 protein that were being expressed in these salivary glands to 0:23:03.560 --> 0:23:07.320 turn them into kind of incipient or primitive venom toxins. 0:23:08.119 --> 0:23:11.040 And that doesn't mean that these proteins were only present 0:23:11.080 --> 0:23:14.159 in the slavary glands. There's quite good evidence that the 0:23:14.320 --> 0:23:17.239 kinds of toxins that evolt there are present today have 0:23:17.320 --> 0:23:20.639 evolved from proteins that are either expressed at low levels 0:23:20.640 --> 0:23:23.960 in lots of our different internal tissue, so whether that's 0:23:24.000 --> 0:23:26.240 the heart or the pancreas, lungs, wherever it might be. 0:23:27.320 --> 0:23:29.920 But there are certain examples. So there's a protein in 0:23:30.280 --> 0:23:34.440 our saliva called calikreine. This is a syriene protease, and 0:23:35.920 --> 0:23:39.359 this protein, amongst many of its rules, one of the 0:23:39.400 --> 0:23:41.639 things that it does is it drops your blood pressure, 0:23:41.840 --> 0:23:45.199 so it helps to reduce blood pressure. And we know 0:23:45.359 --> 0:23:50.119 that that calakrine protein is related to caliqreines that are 0:23:50.119 --> 0:23:54.200 found in snakes, that are toxins now found in snake 0:23:54.320 --> 0:23:58.080 vent And so what we think happened was that in 0:23:58.240 --> 0:24:01.440 early venomus snakes there were handful at least of these 0:24:01.520 --> 0:24:04.760 kind of incipient proteins that are probably doing a role 0:24:04.800 --> 0:24:08.159 that might be somewhat helpful to enable a snake to 0:24:08.200 --> 0:24:11.080 catch its prey. And then gradually, over a period of time, 0:24:11.119 --> 0:24:14.840 there's probably an increase in the abundance or the expression 0:24:14.920 --> 0:24:21.560 of these particular proteins to reinforce their use for capturing prey. 0:24:22.160 --> 0:24:23.840 And so in the case of caliquin, you can imagine 0:24:23.840 --> 0:24:28.480 a scenario whereby if you are using your saliva at 0:24:28.480 --> 0:24:31.560