Venom and Blood Clotting

HELEN: Welcome to Talking About Blood. I’m Helen Osborne, host of this podcast series and a member of the advisory board for The Blood Project. I also produce and host my own podcast series about health communication, and it’s called Health Literacy Out Loud. Today, I’m talking with Professor Bryan Fry, who has conducted venomous animal field research in over 40 countries, from the Amazon to the Antarctic. Bryan has published two books and more than 300 scientific papers. He’s received numerous scientific awards and been inducted into several elite professional research societies. Bryan has been featured in over 150 documentary films, including the upcoming series, Pole to Pole, where he guides actor Will Smith through the Amazon in search of anaconda and giant spiders. Bryan, I am delighted that among all of this, you agreed to be a guest on Talking About Blood. Welcome.

BRYAN: Thank you very much for having me.

HELEN: I am fascinated. I’ve never had a conversation about anacondas and giant spiders before. I’m someone who knows as much as you. But this is all about venom and blood clotting. So let’s start at the beginning. What is venom?

BRYAN: That’s actually an age-old question and something that’s of a lot of no small amount of debate because in its simplest definition, it’s something produced by a specialty gland by one animal that’s delivered through a wound created by any number of structures into another animal to facilitate feeding or defense. So that means of course we have animals like rattlesnakes and stingrays that easily fulfill this definition, but the conversation gets broader when you actually look at that and think that okay, well, that means technically a mosquito is a venomous animal. A leech is a venomous animal. A vampire bat is a venomous animal. And when you dive into it, it makes sense when you think of this sort of toxicogenomics multiverse because the target selects the toxin. So certain physiological sites are much more amenable for disruption than others.

HELEN: So I want to stop you there. Okay, you said that the target selects the site. Say that again and how there’s the selection of the venom.

BRYAN: So the target selects the toxin, which means that the evolutionary selection pressure comes from the receiving animal site because there’s of course no intelligent design of any sort, let alone venom. There’s not like this little hungover fairy going here, poof, have another toxin. No, it doesn’t work that way. So the same pathophysiological actions that are useful for a puff adder in Africa, which is basically Ebola with fangs and kills by hemorrhagic shock, the way it causes such rampant internal bleeding and anticoagulation are some of the same pathways that are disrupted by something like a leech, a flea, or a vampire bat. So you see this incredible convergence using these different proteins to act on the exact same sites.

HELEN: That is absolutely fascinating. And I don’t know if you know this, but there has been a Talking About Blood podcast on vampire bats. So I think that we’re, you know, keep looking at that. Bill Aird, who oversees all the Blood Project, he’s fascinated about anything about blood, whether it has to do with people or animals, you know, all of that. So this is fascinating about the venom. You talked about how and why they use venom, and it’s about prey and it’s about defense. Can you talk about that?

BRYAN: Well, sometimes you actually get an interesting overlap between the two. So with defensive venoms, they’re typically incredibly painful. I know, like, other than the time that I broke my back in three places, the most pain that I’ve ever been in was from the various stingray evenomations that I’ve had. I mean, they were just mind-blowingly painful. And that’s typical because they’re trying to deter, in the case of a stingray, tiger sharks, killer whales, and other large marine predators, while the venoms that kill typically are doing so in painless ways, just, you know, all about prey subjugation and mobilizing the prey. But sometimes you get these really cool convergences and diversifications. Probably the best example of that are the cone snails, where they originally evolved with these neurotoxic venoms for killing worms, but then they’re always getting harassed by these small predatory fish. So they evolved a defensive weapon that we showed that the cone snails can switch back and forth between their predatory worm-specific venom and this defensive fish-specific venom. But then some of the cone snails eventually switch to secreting just the fish-specific venom and feeding on those same fish that they’re originally just trying to deter. So it goes to show how dynamic of a trait venom really is.

HELEN: Wow. So they do the venom. Does one venomous animal insert its venom in another venomous critter?

BRYAN: Oh, absolutely. You know, you do get animals that specialize on feeding on other venomous animals, such as the long-glanded blue coral snake of Malaysia, which is the most beautiful snake we’ve ever worked on. It’s a specialist feeder on other venomous snakes, such as krites and baby king cobras.

HELEN: So what happens? Make it real for all of us who don’t live in this world of venom, except we’ve all been stung by mosquitoes. But tell us a story about this.

BRYAN: Well, this particular case, it’s a fascinating one of evolution in action because it’s feeding on venomous snakes within the same family that it’s in. So it’s immune to its own venom and the other snakes would be immune to the same ancestral type venom. So in order to be a specialty feeder on other venomous animals, there was a selection pressure for a radical shift in the venom. So instead of being the typical paralysis, it’s like a barbiturate overdose or heroin overdose, this limp type of paralysis. Instead, the venom is now using different types of toxins to produce a tectonic, a rigid type paralysis that rapidly incapacitates its very dangerous prey. But of course, you know, we keep moving away from blood. Sorry about that. But you know, venom is where this whole landscape is.

HELEN: We’ll get there. Before we move on to all those blood questions and about clotting, I am so curious about you, how you became an expert on venom and worldwide venom. What’s the backstory?

BRYAN: Well, short answer is I was a very weird kid, but there’s no more of a backstory. Every weird kid has a backstory. So in my case, it was my very first memory is actually being in the hospital, being absolutely torn apart by toxins because my first memory is being strapped to a hospital bed with spinal meningitis as a toddler, which is just an absolutely agonizing disease. And it’s one that still strikes fear in the hearts of doctors and parents, even nowadays, where like in Queensland a few years back, there was a camp where 18 kids came down with spinal meningitis, six of them died. And of the survivors, you don’t get away from that untouched. So my first memory is, you know, in the hospital bed, they’ve strapped me down and heavily investigated me because I kept pulling out the IVs that they had to surgically implant into my temples and the inside of my ankles. My little veins were too small to get IVs into.

HELEN: And you’re a real little guy.

BRYAN: Yeah, but it left me permanently deaf in my right ear and with pretty dodgy balance as a consequence of that too. So I was left with this permanent nerve damage. And actually that’s getting away pretty light for a severe of a case of spinal meningitis that I had. Like Helen Keller, the very famous disability advocate, she was deaf and mute because of spinal meningitis.

HELEN: I had no idea.

BRYAN: So I had this early formative experience of this interaction with these invisible substances that had these magical like properties that just changed the trajectory of your entire life. And then combined with that, my mom was the daughter of Norwegian diplomats and they lived in Africa all over the world, traveling continuously. They actually ended up living in Africa three times. And I remember looking at her photo albums where they had cobras in their garden. They had a gaboon viper in their tennis court one time. They had a black mamba come into their house. So I was just struck by these incredible animals that I thought were just beautiful, but also were even more amazing because they were able to inject you with these same kinds of mysterious compounds and affect other animals and people that way. So it was just a natural intersection of these unlikely series of events. But I love these animals. I think they’re phenomenal. But also I’m one of the few people that I know of that’s managed to turn that childhood passion and use that as a fuel for a career.

HELEN: I’m curious on so many fronts. Like what can the world learn about your scientific explorations that you’re doing and the knowledge that you’re bringing? So your backstory, thank you for sharing that. It’s wonderful that it’s turned into your life’s work and your life’s passion. I can tell from this. But what does this mean for other… How does advancing our knowledge about venom make a difference in medicine and science?

BRYAN: Well, a number of different ways. What makes venom so fascinating from an evolutionary perspective of this incredible dynamic variation is also what makes it such a clinical challenge. Like one of the snakes that we’re working with, the Southern Pacific rattlesnake, down around the Los Angeles region, where you can travel two hours from the desert floor and up into this San Jacinto mountain and you transition just in that short drive from venom, within these snakes that are otherwise genetically indistinguishable. The ones on the desert floor are causing extraordinary anticoagulation, but the ones up at the top of the mountains are neurotoxic and they’re causing vesiculations and all other kinds of really bad problems in the envenomed patients there. And you also transition from ones that are covered okay by the antivenom to ones where doctors can pump 60 ampoules of antivenom, which is an extraordinary amount, in a three to four hour period and the patient will still die. So that clinical nightmare, that dark cloud, however, has a silver lining with that same variation that makes it so interesting but so challenging, also makes it a rich treasure trove for bio-discovery. And a simple example of why we should care about venomous animals is, if you know of anybody who’s taking high blood pressure medication…

HELEN: Which is about everyone I know these days.

BRYAN: Yeah, and odds are they’re taking captopril or one of its many derivatives, but that founding molecule was discovered over 40 years ago and remains today a $10 billion a year annual market and it’s a modified snake toxin.

HELEN: Really? Whoa. So let’s talk about the blood part. The blood, the clotting, the antivenoms. Just talk us through this. And I want to tell you about our listeners. Our listeners could be very seasoned hematologists or those in medicine for a long time. You know, they know a lot, but they always want to learn more. Our listeners might also be those much newer in their careers, whether they’re heading towards medical school or early in their medical training, or they’re heading into the sciences. And then it might just be people like me who are just simply curious about everything about blood. Make this real for us. Talk about the blood part, the clotting, the antivenoms. What can we all learn from this?

BRYAN: Well, when we’re talking about that convergence of different toxins, a simple example of how fascinating that gets is that to block certain types of platelet receptors, the RGD amino acid tripeptide is a classic way to bind to these integrin receptors. And we’ve seen that motif evolve on, I can think of, 10 different occasions across different venomous animals using different protein scaffolds. But eventually with that target selecting the toxin, a random mutation of ending up with that mutation, that tripeptide motif presented at the end of a loop means that those proteins, regardless of what the rest of the protein looks like, is going to bind to platelets and cause anticoagulation. So there you have not only a convergence of the target, but a convergence of the tool used to affect that same target. So this new biochemical, functional, and molecular convergence, all happening from a vampire bat to a leech to a rattlesnake.

HELEN: So somebody seeing a patient in their office, been bitten by something, how do they know what to do?

BRYAN: Well, it’s actually, if you Google “inland taipan bite” in South Carolina, it’s a bite that I’ve been consulting on and actually put up a long post about on my Facebook page, where this was a private keeper keeping what is literally the world’s most toxic snake, something found deep in the Australian outback. He had no bite preparedness plan, and even worse than that, he even mocked people who did and said, “Antivenom is for p… ” and fill in the rest of the word. Literally, he posted that and he was putting up videos of attention-seeking videos of him free-handling, which means letting the snake crawl across his arms and everything. Ten minutes after his last feed, he puts up a post asking if anybody knew where he could get antivenom. And this created this countrywide frantic search. They got some out of Florida. Some zoos refused to send their own private antivenom because they were under no moral obligation to do so, because it would put their own workers at risk. Some responsible private keepers had stocked their own antivenom for protection. Again, they had a bite for their own snake. So it was this worst-case scenario that you can imagine, and it’s been all over the news. But then you’ve got doctors in South Carolina going, “He got bit by a what from where, how?”

HELEN: Right. I’m just seeing that. And you also talked about a bite prevention plan. And I’m also thinking of the time. I’ve done a fair amount of traveling and some guide was walking us through maybe a rainforest or something and saying, “Here’s a snake and here’s another kind of a snake. You might need a different antivenom for those, but you might need it right away.” How does this guy who was just bitten by this snake have time to contact people all over the country and maybe talk his way into getting antivenom?

BRYAN: Well, luckily it was a small snake. It was a baby or else he wouldn’t have lived long enough to even become international headlines while they search for the antivenom. That was one aspect of it, because he didn’t tell the authorities for hours because he was hoping he didn’t actually get evenomated.

HELEN: Evenomated? I’ve never heard that word. It’s a new one. I love it.

BRYAN: And then when he did present at the hospital, he didn’t fess up that it was an exotic venomous snake for a few more hours. So there was about a 12-hour delay before they even realized what antivenom he needed. And by now, the venom has a chance to do its job. And what’s fascinating about taipans is that the bite pathology to a prey is very different than the bite pathology to a human. So these taipans are very dangerous snakes because they’ve evolved to feed on extraordinarily dangerous prey. They specialize on animals like the Australian long-haired rat, which is a formidable rodent that is easily able to severely injure or kill a snake. So they’re going the nuclear option to overwhelm this very, very potent or very dangerous prey. So taipans have long fangs. They do long distance strikes over half their body length. They bite repeatedly. They have incredibly toxic venom, and they have so much of it. To put it in perspective, the lethal dose of an inland taipan is about one milligram, and an adult can deliver over 100 milligrams. It’s even worse with a coastal taipan where the lethal dose is about two milligrams, but the most I’ve ever gotten out of one milking was 750 milligrams. So you’re talking 375 lethal human doses at one bite. Now, when they bite a prey animal, what happens is that it triggers massive amounts of normal endogenous thrombin because the venom is loaded with prothrombin-activating enzymes. In fact, what the venom is loaded with is a weaponized version of the prothrombinase complex. They have factor Xa and factor Va, both in their active forms, in the venom. So it’s as if we walked up to you with a needle and gave you a huge injection of recombinant Xa and Va, you would have a massive out-of-control blood coagulation going on. So in a prey animal, they stroke out almost immediately. It triggers massive blood clots that long before the rat is even dead, it’s immobilized. It can’t fight back or run away because, as you know, of anyone who’s had a stroke, the effects physically are catastrophic. But with a human bite victim, it’s very different evenomation because the venom is diluted into a much larger blood volume. It doesn’t have several liters of blood. So instead of a bunch of, you know, a few big strokes, instead, there’s millions and millions and millions of micro-thrombi. It’s a very fancy way of saying very small blood clots. That itself is not going to do anything. But what it does is cause complete defibrination. You’ve used up all the blood clotting at this point in time. There’s no factors left. And human victims instead die from cerebral hemorrhage or internal bleeding, or they also die from the huge amounts of presynaptic neurotoxins that are also in the venom, as well as cardiotoxins that are in there, as well as myotoxins.

HELEN: Okay.

BRYAN: Taipans are just about the worst thing to be bitten by because it’s this multidimensional attack on every part of the body. You can imagine some doctor in rural South Carolina going, “Huh?”

HELEN: Well, I’ve got two questions for you. And this is fascinating. I want to know what should doctors or, you know, health care providers where I am in Boston be doing about this? This isn’t, I don’t think this is an everyday occurrence, but when it happens, you need to know what to do and be prepared, I assume. And the other part that maybe we can just kind of wrap this up with is what’s the upside of venom? So, let’s talk about first, what does someone, I don’t know how many snakes we have around here. I see some in my garden, but, you know, what you’re talking about is not part of my everyday life.

BRYAN: Well, the what they should do, that’s a good question because you can contrast Florida with South Carolina, where South Carolina, there’s no permit system. Now, they’re probably just going to bring in a blanket ban, which is actually worse. But versus Florida, which has a permit system, which means they know every snake that’s in the state. They know what antivenoms are required as part of the permit system. There’s a central stock of antivenoms that’s funded in part by the permit fees. So, therefore, there’s awareness of what’s out there and there’s medication that’s available. Versus South Carolina, there was no idea what was out there and no medication available. But if you make a ban on people keeping these snakes, you’re actually going to make it more attractive to the outlaw biker mentality type, who will be attracted to keeping a cobra because they’re not supposed to. So, you actually create a worse situation. We’ve seen this in states that have implemented a ban because there’ll be no training of the people of how to care for these snakes and work safely with them. People aren’t going to present to the hospital because they’re afraid of losing their snakes. So, as with anything else in life, awareness, education, dissemination of information is the key because a doctor in Florida is going to know, “All right, we have puff adders. Here’s the symptoms. Here’s the supportive care needed. Here’s the type of antivenom and here’s the starting dose.”

HELEN: Okay. Well, this is fascinating. And you’re based in Australia. You’re talking about Queensland. I know you’ve done this work all over the world. I’m based in the U.S. Thank you for giving some U.S. examples. Are venomous animals everywhere?

BRYAN: Oh, except for Antarctica, New Zealand, Ireland. Pretty much wherever you have life, there’s venomous animals. Actually, there’s no venomous animals on land in Antarctica, but we’ve done work under the water there, collecting polar venomous animals down in Antarctica. So, there are actually venomous animals down there as well. Pretty much wherever you have life, you’re going to have a venomous animal. And actually, there are venomous animals in New Zealand and Ireland too, just not snakes. New Zealand’s got some extremely dangerous spiders. So, anywhere you have animals eating other animals, there’s a strong selection pressure for the evolution of venom because it means that instead of having to kill your prey using mechanical means in close quarter combat where you’re at risk of being killed or injured yourself, you can inject venom, sit back, let your prey get immobilized, and then eat it at your leisure.

HELEN: Your stories are fascinating. Okay, so you’ve talked about toxic and dying and paralysis and clotting and all that awful stuff and pain. Any upside to venom?

BRYAN: Well, as I mentioned, you have the capture pill. Another example is Glen King here at University of Queensland has discovered that as a total fluke, one of the toxins from the Australian funnel web spider, the most dangerous spider in the world, one of the toxins, it binds to an ion channel that an insect does one thing, but it does a completely different thing, a non-dangerous thing in humans. And it actually blocks the ion channel in the heart muscle that triggers cell death. Well, when we have a heart attack, that ion channel gets triggered rampantly and time is tissue when it comes to heart attacks. So they’re actually entering clinical trials using this toxin to slow down and it looks like they can almost pretty much stop the triggering of this ion channel leading to heart tissue death. So this means that the recovery from a heart attack, this could be an absolute game changer.

HELEN: Wow, Brian, it wasn’t great that you were so sick when you were a child, but look what you have done to make this your life’s work and exploration and sharing it with the world with all your many publications and films and books and articles and being a guest on Talking About Blood. Thank you. Thank you. Thank you for all you’ve done and sharing it with us.

BRYAN: My pleasure.

HELEN: As we just heard from Professor Brian Fry, it is so important to be looking at venom too, putting into place all these different species and toxins and way they interact with other animals and with people. To learn more about The Blood Project and explore its many resources for professionals, for trainees and for patients, go to thebloodproject.com. I invite you to also listen to my podcast series about health communication at healthliteracyoutloud.com. Please help spread the word about this podcast series and The Blood Project. Thank you for listening. Until next time, I’m Helen Osborne.