Ologies with Alie Ward - Conotoxinology (CONE SNAIL VENOM) with Joshua Torres & Sabah Ul-Hasan

Episode Date: May 18, 2022

Predatory. Sneaky. Deadly. Lifesavers? You think you don’t care about cone snails. But that’s about to change. Conotoxinologists Dr. Sabah Ul-Hasan and Dr. Joshua Torres study these spiral-shelled hunters of the sea. Why all the fuss? Because their venom -– and the microbes that live in it — may hold medical magic that can help us solve problems related to pain and insulin and much more. Also: how long can you live after a cigarette snail strikes you? What happens to researchers who get stung? How is venom harvested? Should you ever pick one up? The docs have all the answers. Follow Dr. Joshua Torres on TwitterConnect with Dr. Sabah Ul-Hasan via LinkedInMore episode sources and linksYou may also enjoy our episodes on Malacology (SNAILS), Medusology (JELLYFISH) & Toxinology (JELLYFISH VENOM)Donations were made to Helping Women Period and OCA-Asian Pacific American AdvocatesSponsors of OlogiesTranscripts and bleeped episodesSmologies (short, classroom-safe) episodesBecome a patron of Ologies for as little as a buck a monthOlogiesMerch.com has hats, shirts, masks, totes!Follow @Ologies on Twitter and InstagramFollow @AlieWard on Twitter and InstagramSound editing by Jarrett Sleeper of MindJam MediaTranscripts by Emily White of The WordaryWebsite by Kelly R. DwyerTheme song by Nick Thorburn

Oh, hi, it's me, the guy in the grocery store parking lot who pointed out that the moon looked cool. Alleyward, we're back with an aquatic, toxic episode of oligies. It was so mysterious, so dangerous, so hopeful, we had to have twoologists for it. One studies the chemistry and the molecular composition of this very niche, but trust me, intriguing sea snail venom, and then another who investigates what microbes have to do with the whole shebang, because there are roughly a thousand species of cone snail. Who are they?

What are they doing? They each have perhaps their own signature venom, and today we're going to make you care about every single one of them, and not just because they could kill you. They could also save your life if they don't kill you first, as one researcher found out. We'll get into it. But first, to the lifesavers out there, thank you to everyone at patreon.com slash oligies for submitting your questions and always supporting the show. You also can join for as little as a dollar a month, and for no money, you can rate the

show, you could subscribe so that you always get new episodes, or you can review because you know I read them all, every single one. Like for example, such as Steve Musical Arts, who this week left a review that said, oligies is hope and dares us to be curious instead of fearful. Thank you for the intrepid pursuit of wonder, and Steve, thank you. Also, this one is fearful. I'm scared of cone snails, but I'm definitely in wonder of them as well, as you will be too.

Also, Kayle Neuro left a three-star review because the urology episode was skipping on you. Kayle Neuro, I love you. That's a Wi-Fi and a streaming issue, aka that's a you problem, my babies. But if you have spotty Wi-Fi, just let her download fully. I'm just saying. Love you. Okay.

Kono toxicology. The word, as far as I can tell, has been used legitimately one time in a 2001 publication called Kono Toxins in retrospect, which happened to be authored by a certain Dr. Toto Oliveira, more on him in a bit. But essentially, I found out about it. It was on. So get ready to hear about patterned shells, poisoned proboscisies, tongless diving, near-death experiences, how doctors use a snail painkiller 1,000 times more powerful than morphine, what

bugs have to do with it, Rembrandt's enchantment with cone snails, and why working together is better with Kono Toxinologists, Dr. Joshua Torres and Dr. Saba Ulhasan. I'm Saba Ulhasan, and my pronouns are they, them, theirs. I'm Joshua Torres. My pronouns are he and him. And okay, this ology, we've gone back and forth. What do you both think the best ology for cone snail venom would be? Well, that's because we were trying to figure out a one word term.

Kono Toxinology came pretty close, but then we also want to talk about venom microbes a little bit as well. And so figuring out how to do that, that's the tricky part. We're deferring to you, Allie, you're the ology. It's all the pressures on you. I liked the Kono Toxinology one. Wow. It's decided then.

How big is the cone snail toxicology, venomology community? How many people are working on this? Oh, that's a good question. I'm pretty sure there's more than 50 groups around the world. I just moved to Copenhagen in Denmark, and we just had our first venom conference here. And I'd say there are a lot of people working in different aspects of cone snail venoms here. And in Asia as well, where actually I originally from, I'm from the Philippine, there's been a lot of groups doing cone snails, venoms.

Well, perhaps then it bears asking, where are cone snails? Where around the world do we find these critters? I'm going to defer to Joshua to answer since he is from one of the hotspots for finding cone snails. Most of the cone snails, you'll find them in the warm waters of the world. So you're looking at tropical regions of the world, but you could also find them in temperate waters, and even in the Mediterranean. So we would not find them, say, off the coast of California, say, but maybe Hawaii too?

There is one species off the coast of California. That's the one I'm working on. Really? So, quick backup. At a venom conference, Saba saw a video on brown recluse spiders and got captivated by microbes and venom. And they got their PhD from the University of Merced in 2019 with the thesis, the utility of marine snail californiconus californicus as a model system for venom.

And that species name struck me because I don't want a cone snail too. We're off the coast in California. I'm only asking because I am based in California because I have feet. You can find californiconus californicus, which is the california cone snail. The only cone snail species currently known that is endemic to California coast. So you can find it as far north as about Monterey, but I would say mainly Monterey area down south through Baja, California, you start to see overlap with other species there, a few other species once you get more south.

In the other side of the U.S. as well, right, I mean, Florida, I know you'll find a lot of them in Hawaii, especially in Guam, I've been to those places collecting these things. So Joshua had been a research assistant in the Philippines and the lab there was partnered with one in the States. So in 2020, got his PhD in medicinal chemistry at the University of Utah, where he met Saba, and they both had connections through faculty and researchers there, including famed Filipino biochemist and cone snail expert Dr. Toto Oliveira and Dr. Eric W. Schmidt of the Marine Natural Products Laboratory.

So their cone snail partnership was born in Utah. I thought I was going to go swimming in the Indo-Pacific collecting cone snails and they're like, no, actually, we work with fishermen and they're going to give those samples for us. And I was like, oh, okay. No. But since then, of course, they've both gotten to do plenty of field work and lab work. Saba even started a group called the Initiative for Venom Associated Microbes and Parasites, which is a bunch of cool researchers helping each other out.

So does one of you have to analyze the components just of the venom from a molecular level and then do you try to grow the microbes to see what's living in there? Where do you kind of pass the baton? So in my case, I was able to get funding and support and I did want to do things kind of from scratch. So I collected a lot of the animals. I collected the majority of the animals myself and then I collaborated with people to do kind of the processing, depending on what I was interested in.

If it was proteomics, if it was microbiomes, if it was transcriptomics, I didn't get a chance to do as much as I would have liked, but just kind of trying to collaborate to paint a holistic picture of basically the venom as a microenvironment. And then I think in Joshua's work, he did a lot of really good microscopy follow-up, which is really important to kind of visualize where those microbes were in the venom. So those are very exquisite science terms that mean studying their proteins and what instructions their RNA is giving out. Now what about Joshua?

That started because I joined the ICBG group. It's called the International Cooperative Biodiversity Group Program that's funded by the NIH. And it's a really big group that does bioprospecting and drug discovery in weird places in the world. And for this particular group that I was in, we were mostly interested in the drug discovery in marine animals. And this is where the cone snails come in.

So I started studying the microbes in these animals, see what compounds they can produce. And the overall arching theme of my work back then was to really figure out how are they made and what are they making and can we use it for something. Let's start with what a cone snail is. I figure they're called a cone snail because of their shell. Is that correct? That's true. It is.

Okay. It is true. It's the same because of what they look like. It's a shell that looks like a cone. But don't so many shells look like cones? I mean, I feel like there's so many other snails out there being like, excuse me, like, have you seen? Yeah, that's a good point.

I feel it's one of those things where, and I don't know what your thoughts are on this, Josh, but I feel it's one of those things where it's like, once you see it, you can't unsee it. It's just more cone-like, I guess you could say, than a regular cone. There might be more waves to it or curves to it. And so I would just say it's more cone-like. And once you see it, you'll go any shell shop and you'll be like, oh, that's a cone snail.

Really? They come in different colors and shell patterns, but, you know, like what Saba said, they have less flair on the world, but they're basically like a cone. It always reminds me of a cornetto, you know, that's basically what a cone snail looks like. If it looks like that, then it must be a cone snail. You know, once you see it, you can't really unsee it, and then you see it everywhere and you notice this thing of, you know, they're very kind of clean in being this desirable color and pattern, and they kind of stay that way even after they dry.

So cone snails. I was picturing pointy, pointy, sharp shells, kind of like a high heel, but no. Cone snail shells, they're more like a broad V or like a teeny waffle cone, but shellacked and patterned and with rounder edges or like a cornetto, which is a drumstick of ice cream I learned today. So just Google image search it and you're going to be like, oh, yes, one of those shells that you would see glued onto an accent mirror or a lamp at your rich aunt's beach house. Got it.

But with predatory, venomous, sneaky smart cone snails, it's about what's inside those shells or flippin around just outside of them. And they're venom. Let's talk about why they have it because there are a lot of snails out in the oceans and lakes that don't have venom. Can you explain what their hunting style is like? So generally cone snails would have to have venom. I don't think there's any cone snail out there that doesn't have a venom.

They make it in this particular organ, we call it the venom gland and they use it to actually hunt either fish, other types of mollusks or shell things and marine worms. So those practically are their diet. So they would make several forms of these venoms and tailor it according to the diet that they would like. Each individual snail can do that? Yes. Really?

That's true. There's one venom in there, so the gland would make several hundreds of these. So it comes out as a cocktail of things. Wait, that's like incredibly fucked up and cool. That's like one of those soda machines where you're like, do I want like a minute-made light with a shot of cherry and some Dr. Pepper? What the fuck? Yeah, that's true.

You know, in my background, it's in chemistry. My fascination about these snails really is the idea that these little things can actually make so many different components in a venom and tailor it according to what they want and how they actually use it, which is the really interesting part for us for people who try to make drugs out of this thing. So what they do primarily is to actually load the venom into what we call a radula. You could think of it as a harpoon. It's like a hypodermic needle that shoots out and targets the fish or the worm or another

snail and instantaneously paralyzes them. Other cone snails would just have to open its mouth really big and lace the surrounding water with those venom and then the fish, usually the fish would just be paralyzed and it could not move. It's like an opium den that you cannot escape and then the snail would just swallow it. And other things that we just figured out just last year, part of the venom are also like mimics of the pheromones, sex pheromones that the worms use. So they would hijack that horny process during a full moon.

That is low, maybe it's so low. They're really clever. So these little fuckers can shoot a syringe of paralyzing poisons at you or they can release an aquatic cloud of sedatives and swallow you whole or they can use venom to seduce horned up worms. And then just be like, psych, you're my dinner. So the California cone snail, it's considered an extreme generalist. So what Joshua was mentioning about, they can be fish hunters, worm hunters, they can

eat other mollusks. So the California cone, it's really weird in that the Hunts and groups, otherwise cone snails are fairly solitary. So Hunts and groups, it can scavenge and then it can also kind of eat multiple types. It can eat fish, it can eat mollusks like all of the above. So there was an experiment I did where we starved the animals and then I felt bad. I always felt bad during this experience, but I guess it's, you know, we got to do what you got to do.

But we starved the animals and then we exposed them to different prey types. Would you like to hear tonight's specials? And so I was reading that they usually capture their prey within, you know, five to 10 minutes. And we had the starved animals as a control, you know, just regular fed animals as another control. And then we had them exposed to three different types. I think one was like shrimp. So those would be kind of in one category.

Then we had another was snails, another that was fish. And we see a different proteomic profile. So that corresponds to their venom profile. And that was only after five minutes of exposure. At an individual level, they can basically, you know, gear up their little harpoon and get it lodged and ready for whatever they're wanting to eat, which is an interesting thing. This harpoon, you mentioned it was a radula. Is that essentially a tooth that they're using as a harpoon?

You could think of it, but it's generally made out of chitin. So it's like a harpoon that's hollow inside. You can think of it as a hypodermic needle where, you know, they could load the venom into that thing and it ejects out. It comes out of that really long proboscis and, you know, ambush a fish or something like that. Yeah. If you look at an aquarium and you see the little snails kind of scraping off the algae,

just to piggyback off of Joshua, and they're like screaming off the algae, that's the radula. And so, yeah, it is different from a tooth, but I guess you can think of it as like it's scraping stuff off and it's using it to eat. It's some sort of tool to help them eat. And then in the cone snails case, it's like a little purse, the radula sac. So it's like little purse that carries around filled with little harpoons. And then it gets one ready to lodge, or depending on its, you know, predatory scheme, if it's using the netting scheme that Joshua mentioned or another scheme to be a slightly different.

Like why isn't every school team named the cone snails? What a little badass. That's what we want to know. I love that that's what you're investigating is why doesn't every high school archery team or football team? This is amazing. Well, of course, it's easy to get obsessed with them, which is good for two people who research them because day in, day out, it's cone snail o'clock for you.

But when we're talking about this incredible ability to dial in the venom that they want, how do the microbes come into play? What's living in the venom? I've studied a good deal of, you know, what kinds of microbes can be found on every conceivable, dissectable part of a cone snail. But the venom gland was really interesting for me because there's some form of diversity there, but there's one like consistent group of microbes that's always in there, regardless of where you get this species.

Like for the same species that you get from Hawaii or in the Philippines or in Guam, you'll find the same microbe there. We look at where exactly they are localized in the venom duck. That's a really long duck. Anyway, I did sections of that, did microscopy, and, you know, they're there, but what they're doing exactly is still a mystery for me at least. What are you doing here? What are you doing here?

I don't really know what they're doing there. It's almost tempting to suspect that they might have to do something with venom production, but that remains to be tested. And even he isn't sure. And he is one of the world's experts in this, having authored the 2021 paper, Small Molecule Mimicry Hunting Strategy in the Imperial Cone Snail, Conus Imperialis, which explains that fish hunting cone snails use venom that targets vertebrate ion channels and receptors, which is why the FDA and the pharma world sees promise in similar chemical pathways for pain medicines.

And one article, which was in The Atlantic, was written by Catherine J. Woo, and it bore the headline, quote, cone snails are liars and murderers. They lure their prey with the promise of sex and then kill them cold. And in that article, they, of course, quoted Joshua, who said, cone snails have mastered chemistry. They are smarter than we are. And I'm starting to believe that too. So Josh's paper is really cool and extensive, and so I definitely encourage people to check

it out. And he's a nice person. So if you have any questions, just ask him. Eric's also pretty nice. So basically, from my end, I was coming in a little bit on the microbial ecology side, or that was the angle I was taking, trying to collect the animals from the field, see if they were just focused on the California cone snail species as a potential model system for looking at venom microbes and then seeing if that aligned generally with what Josh was

seeing too. And so it was exciting in that I also kind of independently was seeing that there are definitely microbes you see only in the venom that you don't see in other parts of the body, that you don't see in the seawater or the sediment. And these animals, they can vary in the sediment too. That's what we just want to encourage people, you know, yeah, venom microbes, because there's very few venom microbiome studies generally, which is crazy to think about when you think about there's hundreds of thousands of venomous animals.

There's so many different types of microbes out there. And we know so little, like maybe there's like, I would say five explicit venom microbiome studies. I think one just came out this past year. But there's very few that are kind of these comprehensive high throughput sequencing venom microbiome studies. And Josh is one of them, which is great. But then also in terms of, you know, what are they doing there?

So, you know, you see these certain groups that are in certain parts of the venom gland. And so like Josh mentioned, it's really long. So then I got curious, and if you stretch out, at least for the California cone, if you stretch out the venom ducts of the animal, it ends up being two to three times the size of the animal. So California cone, yeah, so California cone, it's probably on a range of like an inch to three inches, depending on where you go. So if you stretch these out, it ends up being about two to three times the size of the animal.

And then look, think about what's in the human body, right? What is really, really long if you stretch it out, the gut, the GI? We know a lot about human gut microbiomes and just gut microbiomes generally at this point. But we know very, very little about venom glands and venom microbiomes, which is kind of interesting when you think of this parallel of the venom gland is an incredibly specialized organ convergently evolved across very different animals, like, you know, you have snakes, you have spiders, you have cone snails, you have marine, you have terrestrial, and they're

very, very different. And yet you still see these very specialized organs. And yet we only have a few studies that are explicit microbiome, venom microbiome studies. And so going back to the thing of Josh making the comment, like, what are they doing there? So one interesting thing that is speculative, I would say still is with the California cone, I was trying to do kind of like a multi-omics study. So you know, you have genomics, you have transcriptomics, et cetera, et cetera. But what I was able to do with the time I had was really looking at the microbiome or

kind of a general microbial community. So Saba's analysis focused not just on the chemistry of the venom, which can include over a hundred thousand different bioactive compounds, but also which tiny, tiny critters, which microbes are hanging out in the venom and what molecules and metabolites are floating around. And so what we saw, there was one experiment that I did where I wanted to basically sterilize the animals and see what happened when the animals were in a sterile environment and what microbes they retained.

So you can think of this analogous to, you know, if you go to the hospital, hospitals are very sterile environments, right? And then in aquaculture, people, they use antibiotics for making sure that, you know, the fish are healthy enough or don't get sick so that they can be used for seafood. So one of the main antibiotics people use in aquaculture is tetracycline. So that's what I used for my experiment. So I had three groups, three categories. One was just a wild type with the natural seawater.

I was able to use a facility in San Diego, thanks to collaborators there, where I had access to fresh flowing seawater and the population of the animals were also from San Diego. So I had fresh flowing seawater and then I had sterile seawater that I synthetically made and then introduced to the animals. So it's clean and there's no microbes in there, hypothetically. And then I had another category that was the sterile seawater with the tetracycline added. And then we looked at what the microbial profile was, the proteomic profile was for the venom and the metabolomic profile was.

And then I was looking at the results and then I was like, this can't be right. And I was like, did I contaminate something? So I added tetracycline, the antibiotic to only one group. And I was seeing tetracycline and the metabolomic profile actually be present in the wild type controls as well, the wild type and the sterile controls, like this can't be right. I'm sure I didn't contaminate it. What's going on? And then I was like, wait a second, where is tetracycline, how is tetracycline made?

And so it's made from streptomyces, which is a part of this group actinobacteria. And then I looked at the micro profile and the cone snails and I also saw streptomyces. And so again, the speculative needs to be reproduced and redone, but it was kind of some hypothesis that potentially the microbes could be contributing to keeping the integrity of the venom gland to prevent other microbes from coming in and basically messing up the environment. So if they're naturally making tetracycline, which is this antibiotic in the venom gland, maybe they're keeping other pathogenic microbes out as a competition. So wait, they didn't contaminate their sample with tetracycline.

The call was coming from inside the house. But yes, making micro friends means cone snail DIY antibiotics. And Saba says that the researcher, Dr. Michelle Casada has done great work in this area and a lot more experimentation can be done to figure out why they do it, why the microbes are making tetracycline. They could be making antibiotics to keep their niche competition free of other microbes. They could be making compounds that enhance the venom itself or they might serve as natural medicines for the cone snail to have a clean venom duct, which is why medical chemists

and me are getting stoked. So antibiotics, possibly anesthetics or analgesics, I mean, don't kill me cone snails, but please kill my germs and my pain. So I was really curious about why are there basically little to no or so few venom microbiome studies, right? Because coming in from the angle of why I was really interested in microbes and microbiomes, microbial ecology, I was like, what microbes are everywhere? Why are people not looking at venom?

So generally, people in the venomics community, I really interested in drug discovery and natural products. And in tandem, another big issue right now is antibiotic resistance, right? So you have these groups, E. coli, staff, et cetera, they're called the escape groups. And you see them a lot in hospitals where they're kind of superbugs that are antibiotic resistant and you have to take like a lot of different combinations of antibiotics to kind of kill them off in the hospital settings. And so people are really trying to look for solutions for this.

I think one popular solution that's coming up is phage therapy. Phage therapy, side note, is when specific antibacterial viruses are deployed, kind of like tiny hitmen for bacteria. So that's one idea, but... But then also people are looking at other types of natural products from different sources, such as venoms. And so when you look in the literature, one thing that comes up a lot in the literature is that people are looking at venoms as a source for killing off these antibiotic superbugs

in hospitals. But then they're doing these experiments where they're taking the venom and they're saying, can I kill off this strain of staff from the hospital? But they're not looking at what's already in the venom. So then in these studies, they're isolating certain venom toxins, but they're not looking at the holistic picture, which makes sense in the context of what they're doing. But then there's just a whole other side of the story that could also be helpful in this fight against antibiotic resistance.

And so that's where we're thinking that, okay, maybe there's so few studies on this topic because people have this kind of cultural thought that, oh, because we've found so many compounds in venom toxins that have antibiotic properties, that means the venom is sterile. And that's just not true from what we know from a microbial perspective, because microbes live everywhere. So just kind of having more of these studies pop up to show that, okay, there are microbes there, and then what are they doing? We've almost a decade of work on the microbes of not just cone snails, but a lot of different

snails in the marine world. And on the other hand, we also work on those, the venom itself, which is, of course, another different field of work, not because for the antimicrobials, but like what Ali alluded to for analgesic, the venoms are really nice platforms to build peptides that can be used to treat pain and other types of diseases, human diseases. In fact, one of the earliest compounds from the marine world that made it into the clinics is actually from a cone snail. You don't say.

So this is called ziconotide, or prealt. And it works by blocking calcium channels in these pain-screaming nerve cells. And it was formulated from discoveries made right in the same university of Utah lab. And it was approved by the FDA in 2004. Can you pick some up at CVS alongside tampons and chocolate? No, you cannot. It's administered directly into the spinal fluid, straight to the dome, but it's said to be 1,000 times more powerful than morphine from a freaking cone snail.

Prealt, it's just short for primary alternative for morphine, unlike opioids or morphine, it does not develop tolerance, which is really great. A lot of us are really finding the next prealt and even the other types of peptides that are found in the venom like insulin, even certain types of hormones that are similar to humans are being clinically developed for medicinal purposes. Evolutionary medicine is becoming more popular, which I think is really exciting and really great. Because when you think about it from an evolutionary biology perspective, these animals, these

cone snails, they're considered in the category of neogastropoda, which means new gastropods or like that they're more recently evolved compared to others that are evolutionary relatives. You have spider snakes and all sorts of groups that range across this evolutionary timeline. These are animals that have these systems that have been evolved for millions, if not hundreds of millions of years. Of course, there's going to be really good resources in there that we could then apply to these more recent within 10, 20, 30 years for antibiotic resistant issues, for example, that we can use to tackle that have already been, you could say, perfected in an evolutionary

context. I mean, I was here thinking you're going to learn about how they can kill us, but really they can end up helping us. Kill and cure. Yeah. Can I ask you some questions from listeners? Sure. Okay, amazing.

Before we dig into your questions, let's spend some money on some good causes chosen by theologists. Saba selected helpingwomenperiod.org, which is a nonprofit committed to supplying menstrual health products to people that menstruate who are either unhoused or low income. Joshua chose the OCA National Center, and that was founded in 1973. The OCA Asian Pacific American Advocates is the second oldest civil rights organization dedicated to advocating for social, economic, and political well-being of all Asian Americans and Pacific Islanders.

May happens to be Asian American and Pacific Islander Heritage Month, which celebrates community milestones, but also remembers the adversity endured in the past and today. I will include links to both of those great charities in the show notes. Those donations were made possible by sponsors of the show. Okay, you had questions, patrons. Let's dive into the cone zone. Here we go. You ready?

Let's do it. It's scary. They're not as scary as a cone snail might be. And on that note, Jess Wan wants to know, do you have a sense of where the cone snail sting might fall in comparison to the jellyfish, I guess there's a Schmidt sting pain index? But any idea? How much does it hurt? Have you ever been stung by one?

I have not. I haven't too, but I don't think you'd want to be stung by a cone snail just because there are certain species of cone snail that can actually kill people and that had been recorded, you know? Really? There's no answer for that, unlike snakes. So even if you're really close to the hospital, but if you got stung by a geographer snail, like conus geographers, that's going to kill you.

And that's the one that's nicknamed cigarette cone, right? It's like a colloquial thing that they say that a cigarette snail or a cigarette cone just because... You can enjoy a last cigarette before you die. But I think you actually, you know, last more than that. I don't know how quick a cigarette is actually, maybe 15 minutes, but you know. That's what, yeah. They said like 13 minutes.

Yeah, because I think in terms of lethality to humans, I think the ear congee or the box jelly is the quickest death for humans in terms of lethal dose. And then cigarette cone, I think, is the second most. For more on jellyfish and their venom, you can see the Medusology episode with Dr. Rebecca Helm and the companion episode toxinology about jellyfish venom with anaclompon. It will bless so many myths, especially about peeing on your friend's legs. And I'm going to link those on the webpage for this episode. But yeah, the box jelly sting will escort you to heaven in about two minutes.

But what about this cigarette snail? Okay. So I looked it up. One hour down a time, it takes to smoke a cigarette is six minutes. And the good news is, if you do get harpooned by one of these conus geographis snails in a shallow reef somewhere in the Indian Ocean or off the coast of Australia or the Red Sea or in the Indo-Pacific region, you can actually smoke at least 10 cigarettes, maybe even 50 cigarettes, because it actually takes about one to five hours to die.

That's great. What a relief. So then California cone, if you get stung by a California cone, I have some friends that have been and they said it's like a bee sting. I haven't ever been stung because I, you know, choose safety. But yeah, there are people out there who do, there's like a subgenre of people who are like really interested in like intentionally injecting themselves with venom. And that is some of those people are scientists, you know, I don't know, but that is some controversial

stuff that I choose. I choose life. So I don't do it yet. If I may add, I mean, like this is a really interesting question because, you know, people would say cone snails are deadly. But I'd like to add most of the cone snails that would eat fish or whose diet is mainly fish are the ones that's going to sting or hurt really bad. It's just because the components of those venom snail hunting cone snails can actually

be good substrates or ligands to the kind of sodium channels or receptors or target that we as humans also have. I didn't know what any of those words meant. So I was just going to cut that part out. But you know what? We're here to learn some shit. So a ligand is a chemistry term and it means a molecule or an atom that binds things together and a substrate is a molecule that an enzyme acts on.

So Dr. Torres, someone with a PhD in medical chemistry is saying that cone snail venoms that act on fish can also act on us because we're made of the same stuff. Our receptors are related to those receptors and fish. So you'd expect it to be more lethal or potent when you get stung by fish hunting cone snails versus a worm hunting cone snail. Evolution. Yes. And do they use it for self-defense at all or is it just predation?

So most of the known documented cases of cone snails that actually harm humans is because people would pick them up or I guess some stupid person would look at the cause, oh, this really looks good. So I'm just going to take this out while diving, hit it under my wet suit and then that's going to get you into trouble. But if you work on the snails, they have certain types of personalities really. I've observed that for the years that I've been looking at the snails. Really?

Yeah. You know, there are snails that are quite aggressive and these are the really venomous ones. The geographer snail and the magician snail, which is cone snails. They are really temperamental I think. I guess that's a word. When you really like put them or poke them or hold them, you'd see the proboscis. That's where the harpoon comes out would literally be pointing where it feels like the threat

is coming from. Wow. But most of them are really docile. The worm hunting ones, if you like touch them, they would just like hide in their shells. The shells themselves are really tough for some of these species. So they would try to just be hiding and if they need danger. But for some, they're really aggressive and they're going to put up a fight. Which is why researchers, when collecting, use tongs, keeping their distance, preserving

their lives. But what if you are clueless and or tongless? Well patrons, including Lisa Inglise, Christian Krupp and first-time question asker Blu-Rain, aka Maren, asked about first aid tips if the Grim Reaper happens to saunter up to you with a cone snail in his pocket. Well, Gerald Thompson wants to know, what should you do if you get stung by a cone snail? Don't pee on it. You don't have to pee on it.

Do you have to pee on a cone snail sting or no? There are no standard protocols for life-saving measures if you've been stung by one. I know there is a protocol that has been developed at the University of Utah Hospital because there was one case where in someone actually got stung by the cone snail. I think I did hear about that. Yes. They did the hospital unlike snakes, you know, there's no snake antivenom. I think what they did was to rehydrate or I think they had to wait, you know, if it's

going to make it. Yeah, I think I should have said, yeah, I think you're right. I think I remember, because I think I was at the U when that happened actually, and I think I might remember what I said, yeah, but we could probably ask them. I would agree with Josh and I would say the nice thing in this is that it's one of those things where it's like, you know, enjoy and look at nature but don't touch, right? And it's just one of those things where, you know, you leave them alone, they leave you alone for the most part.

Like that's how it is. They're not going to, you know, Josh mentioned they do have, there are ones that have personalities, but unless you're, you know, going and you're diving or snorkeling and you're, and you're touching everything and you're really low to the ground, you know, it's very low risk. Same with, you know, if you're, a lot of these cases where people get stung, it's because they pick something up and, you know, they want to take it home or it's just one of those things. So just respect the environment, that's what I would say, and you'll be fine.

And you really have to think, you know, it's a very energetic process, you know, they're going to use a lot of their resources in trying to come up with this venom cocktail and they would not just use it to something that's really big, that they could not even swallow like a human or something like that. That would take some, a lot of venom to knock the human out. So generally they would try to evade danger into the shell and they're really docile, except for really when you provoke them. That's good to know.

They're like, if I want to protect myself, I'm not going to give you my minute made cherry, Dr Pepper cocktail. I'm going to hide in this like incredibly top shell I have. That's why I have a shell. Exactly, right? But if you're going to pick me up and do something where, you know, it's crushing my shell or something, you're going to have it, I guess. Yeah, and to that end too, you know, I was wondering with the California

Coast Nails, I had all these questions like, well, how often do they even eat? They're pretty hardy, they're hardy species, and I'm not encouraging anything here, but they're pretty hardy species, I would say they're pretty tolerant. They can withstand a lot. I mean, if they're living healthily off the LA coast and whatever water is, you know, they're doing okay, I guess, but I kind of like tested a little bit and you can think of them similar as like a boa or something where they don't seem to need to eat that often.

And I think just to Josh's end, a comment of, you know, it does take energy for them to make these venoms, right? And so, okay, how often do they actually need to use that? And what is that process for them? That's something to consider just similar, or I think what snakes do, it's like how much do they want to be using that all the time. Just respecting animals and not provoking them is a good way to go, and it's low probability. I mean, wood sting rays, for example, you know, it's usually because you're not doing

the shuffle and you step on one by accident, right? Which is, I think, a reasonable reaction. If I got stepped on by something, I probably will fight back a little bit, too. It's so funny that it's called the shuffle. Yeah. It's something that like marine scientists just know about, you know? The shuffle. Look this up, and yes, keep your feet in the sand as you walk, because one, the vibrations

will scare the sting rays away. And two, you don't want to Godzilla down onto an unsuspecting flippy-floppy who's forced to say no, dude, via their venomous tailspines. Don't surprise them. Also, I did reach out to the researcher who was stung. I got their name, I found their email, and confirmed that, yes, they are okay. They preferred to remain nameless, but told me, I got the whole scoop, that they were studying the fish hunting conus magnus, and one managed to land a harpoon right through

their latex glove, which is unsurprising, they said, because it can penetrate fish scales. At first it felt like a bee sting, but they immediately knew, quote, I am in life threatening trouble, as they wrote, because no anti-venom exists. And they had numbness and paralysis of the stung hand, and they felt progressing into their arm when they were getting to the ER. And they said that they lost 30 to 40% of breathing capacity during this episode and had a really dangerous heart rate all over the place. But they say that they survived because, luckily, they just must not have gotten a lethal dose

of the venom, and they had the ER and the medical center right there, which were ready to intubate them in case they stopped breathing or in case their heart stopped. So they say that they barely survived, and let that be a lesson. If you work with cone snails, always be careful, and if you see a cone snail, just leave it be. But what a champ. What a story to live to tell. Well, we mentioned Anna Klampen, who is a toxinologist who was in the Jellyfish Venom

episode, and all caps wrote in, I'm so excited about this, and wants to know about the process of milking the venoms from these animals. And Summer Fouvet said, I'm sure we've all seen the videos of rattlesnakes being milked, how do they extract snail venom. And Julie Burton wrote in and said, there's a lab in South Carolina that milks cone snails for venom, and even weirder, the cone snail has learned to trade the venom for food. My God, I had no idea. When you say weird, you're not fooling around.

Have you heard of any of that? How is the milking happening? So there are two ways to actually milk. That I know. Two ways to milk venom out of the cone snail. First, requires that you actually have to sacrifice the cone snail. You open them up, and I guess that's a really safe one, because if you want to take out the gland and work on it, the snail has to be dead, at least preventive measures for

you getting being stung by a snail. We haven't really described what the venom gland is, but you could picture it as something as long as a spaghetti noodle, and it has a kidney pain at the other end. But the venom itself is made on that really long spaghetti. The kidney pain, we think that it's just like some form of muscle that can contract and push away, squeeze out the venom into those radulas, into those hypodermic needles. But the venom itself, the fluid itself, is found in that spaghetti noodle. And so you open up one snail, take it out, and just squeeze it through, and that's how

you get most of the venom. And the other way that the commenter was actually eluding to was milking it from a live cone snail. What they do is they get an epitube, it's just like a small tube. They actually put fish in there or something, usually meat, fish meat, and then wrap one end of that tube with a film, plastic film. And that's how the cone snail would realize there's some form of food in the epitube. It bites that film that covers the lining of the tube and melts it out.

So yes, the old, hey, you want a snack, JK? It's a tube covered in saran wrap. Thank you. Now, do cone snails have enemies that are not researchers trying to milk them? Well, patron Eli Jonathan had a two-part question. Firstly, asked what? Secondly, asked, do they use their venom on other snails, be they cone snails or vanilla non-venomous ones?

What about other cone snails? Are other cone snails susceptible to being venomized? Are they so immune that it doesn't even faze them? Are they immune to attacking each other? Mm-hmm. Yeah. Is that used in mating at all? Is there like an aphrodisiac?

The other type of cone snail, the one that actually hunts for other castropods, their venom is specialized for hunting other mollusks underwater, including other cone snails. We've actually seen this in laboratory settings wherein you accidentally put a snail hunting cone snail in another tank that has a snail in it, and it actually eats that cone snail. Oh, wow. So you have to be really careful when you have a collection and you have live snails bring them into the lab. You really need to separate those snail hunting cone snails from the rest of the cone snails

because they're going to eat it. So the worm hunting snail would go well with the fish hunting snail, but never with the snail hunting cone snails. You're basically giving them food. Yeah, but who wants to eat snails for breakfast? Well, you know, on that note of eating cone snails, Timothy, Wang, Kelly, Yulig, and Talia, Daniak all wanted to know, can we eat them? Are they tasty?

Um, Talia wanted to know if I eat one, would it kill me or just be vaguely spicy? Yes, you can eat cone snails. I've tried it before. What? Yeah. But not all parts of it. Okay. Just shells, I guess, right?

Only eat the venom. Yeah. Well, if anyone's going to be prepared to actually cut that up with a scalpel and take out the venom and be you, Joshua, like, who else is going to be in the kitchen being like, I got this. I'm going to take out the spaghetti noodle filled with poison and just gently put that aside. The edible part, at least for my experience, was actually the foot of the cone snail.

Oh, that makes sense. That makes sense. So that's actually a really nice part of the snail that people can eat. You don't want to eat the stomach and stuff like that. But the foot is something that you can eat from the really big snails, like the geography snail. And they taste like, you know, like any other mollusk that we eat, like a squid or a tentacle of an octopus.

The texture is like that. A little chewy. Yeah, they're chewy. I'm glad that at least one of us on this call has eaten them. So we know. Well, I would also caution people, because there are certain species that are endangered or they take a while to develop and things like that. So just like with other seafood, you know, I would encourage people, you know, California

Cone Snail is an incredibly common species. You can find it pretty much everywhere. You don't have to worry about putting it in this population anytime soon. And there's other ones. There are some papers that come out where they're even with, you know, the research that scientists have done, if we've made a dent in cone snails and their populations because of all of these collections we do for our research. So yeah, definitely encourage people to check that out.

The IUCN website is a good place you can see if you want to try a cone snail and see that it's going to be okay to eat them without feeling as much guilt. So that is the IUCN, the International Union for Conservation of Nature, which is a global authority on what species are doing okay and which ones are getting a raw deal from species of least concern to vulnerable, endangered, critically endangered, extinct in the wild, extinct, et cetera. And this website I poked around is kind of like a sad yearbook, checking on people's statuses.

But I was relieved to see that a lot of the cone snails seem to be doing okay. But for inexperienced hunters, I would not put them high on your list of favorite munchies. It has been something that has been done in the past, like culturally, there are places in the world that would actually eat them, I mean, like the Philippines where I grew up. So, and even cone snails have been part of culture already, like, you know, they've been used for jewelry, as means of money, and even Rembrandt has a painting, has an etching of a cone snail.

Really? Yeah. Where did you see a cone snail? When was that guy out hanging around cone snails? Cone snails were mostly like feist possessions, because it was really hard to trade something from outside of Europe. I think those were, that's how they actually got these snails before. There's an etching, it's an etch by Rembrandt, it's called the shell.

And it's the only still life etching that he did. It's a cone. It's a marble cone, it's cone smart more, yes. Wow. That's a great pop cultural reference. There's a lot of pop cultural reference of cone snails, even dating back, way, way, way, way back. I mean, cone snails are even expensive back then, like certain collectors or shell items

would actually fetch so much, there's a species of cone snails. We're really digressing with the question right now. No, no, this is a great question. Mary C. wants to know if you're aware of any movies, books, et cetera, where cone snails are used as a plot point. And if it was realistic, so anything in pop culture that's cone snails, we're here for it. Okay.

So I'll continue with that. Some shell collectors, there's this particular cone snail species, it's called Conan's Gloria Maris, or Gloria of the Sea. So it's so nice, it's like mathematically perfect cone snail, they would say, if you look it up, and it used to fetch like back then, the price, if you like compare it to now would around be like a million US dollars, because it was so rare, but then in the 1960s, they actually found out there's a lot of these in the warm waters of the Pacific, but they're still expensive a little bit right now.

You could see them in eBay, they would fetch around less than a hundred dollars. I'm not rich. For a shell. But that was the most expensive cone snail, Conan's Gloria Maris. The Beanie Babies of the Mollus World, people are like, this is going to be my investment from retirement. People don't know about this, or only a few people know about this, I guess. There was a mention of cone snails in Jurassic Park, the movie.

Really? Yeah. Really? Yes. There was a part where, I think that's the lost world, then you were one, some Jack Cobblom. I think they were trying to kill one of the dinosaurs, and this one guy actually gave him a gun, and it has been loaded with a corn toxin from Conan's corporatis. Oh!

He's supposed to kill the dinosaur. Yeah, it's like trying to take a clip. I love that. That's really cool. Some scientist was like, this is a really good, what's it called, Easter egg. Easter egg, air rifle, fires a subsonic flugor impact delivery time. Does it work any better than your satellite phone? That's funny.

I loaded it with the enhanced venom of Conan's purple arson, saucy cone shell. Most powerful neurotoxin in the world, that's within a 2,000th of a second, which is faster than the nerve conduction velocity. So the animal is down before it even feels the flick of the dart. Is there an antidote? What do you mean, like if you shot yourself in the foot? Don't do that. If you did that before, you can realize you had an accident.

The way they delivered the line was so convincing, but totally BS. The world needs an action hero who uses weaponized cone snails. Am I right? And both doctors agree. Sabah says that both they and Joshua are available for consulting, and also nominates comedian Julio Torres to be that action hero, which they say would be really sweet. Speaking of sweet. Last listener question, Julie Burton wants to know, is it true that some cone snails shoot

insulin at prey fish to make their blood sugar plummet? And also, how are they seducing each other? Is it through a similar method? We would go with the easy one first, before that was how they would attract. Cone snails are hermaphrodites, so they would just lay eggs by themselves. Really? So there are also instances where they are male and female? I think California cone are male and female.

Yeah. But have you seen it like made? Nobody has. So, yeah, I have seen basically they just have like a cone snail orgy. Oh, wow. I'm going to see piles of them. That was cool. Where's the party?

Whenever I've seen it, it's usually between, I would say April to June that you see them in the water. They're just like these piles, and then you see them following each other's traces, too. So they're the little slime trails, because they are a bit more social, I would say, than versus the other cone snail groups. So they do seem to kind of socialize or they hunt in groups. So that might be a distinction that I would say is a little unique from regular cone snail groups, but they do follow each other's trails, I've noticed.

Oh, that's so cute. Yeah. That is so cute. And to answer the other question for the insulin, that is true. So they make insulins, they have endogenous, you know, the thing, the insulin that they use for the system, but they've also recruited this insulin gene that they make for themselves into their venom dogs and evolved it to look like insulin of a fish. And they use that as part of their venom to actually cause hypoglycemia in their prey

fish. So what we think is happening or how they use this is that they would make those fish like insulins that have been weaponized. This is like the first instance that an insulin was weaponized by a predator. So they would open their mouths and they would just lay the water around them. And you could imagine that the insulin, because they target fish, it would just go through their gills directly to the bloodstream and would just cause that hypoglycemic shock. And you should see the videos of this wherein the fish is just like a zombie, not a zombie,

but you know, it's just not moving and the mouth of the cone snail is so big. It's so impossible that the fish could not see it. The eyes are still open. And you can still see the, you know, the gills breathing, the eyes moving, but it's not swimming away. And it's slowly being engulfed by this really big mouth. Wow. That is so fascinating.

So fascinating. Yes. Oh, such cool creatures. I didn't know that I had a favorite snail. Now I do, you guys. That was our, that was our mission this entire time. I'm team cone snail. You're team cone snail staff.

And you know, but last question is, I always ask it, there must be something that sucks about them. There must or something that sucks about working on them. Any petty annoyances you have complaints you'd like to file with a cone snail department? I think I have one if someone doesn't have any. I wish they would just produce more of the toxins because, you know, they produce so little and, you know, we have to study them. We really have to stretch out the, the better for our, for our science.

If they could just make their own cell line for us, that would be really helpful. Yeah. Cause I don't want to go through that work. I mean, they could, and you know, then we don't have to kill them really as much. And they could just, you know, just if they could just work on that in the admin department, that'd be good. Now for Saba, having started in Dr. Toto Oliveira's lab with molecular biology and then entering the fields of biochemistry, neuroendocrinology, microbial ecology, venom

microbes and even biomedical database creation. They say the most exciting aspect about their job is collaboration with other scientists. And while cone snails may be called liars and murderers, other scientists are your friends. A good piece of advice that Amanda had told me was, you know, when you're doing something, just let people know because then people know you're doing it. And even if something happens, you know, there's always, where someone takes, or it publishes on the same stuff you're working on, there's always more ideas and you're going to learn

a lot more than what you would just on your own. And I think that's really good advice, especially now that I basically do all my research is open source and open to the public. I think for me, the really exciting thing about this, which is maybe not specifically on the, on the cone snails, but the really exciting thing about this for me has just been, you know, I just started asking around, you know, I would read a paper and I like cold email people or be at a conference and like, Hey, I'm looking at microbes and venom. If anyone out there wants to do this, let me know.

And you know, that's how I chatted with Josh. That's how I chatted with a lot of people in the venom micro group that we have now. And people are just really, really great and open for me. It's almost like a reinforcement that, you know, sharing knowledge and being collaborative is really in the best interest of good science as well. So for me, that's, that's a really exciting part because at the end of the day, it's about the science and think good science also comes from just being open about this kind of stuff. And it's been really exciting.

Hence, they started the initiative for venom associated microbes and parasites. Because the more we help each other along the way, the farther we'll all go. We're all one big social pile of snails. Now what about Josh? My life goal really in trying to study these things is to actually do discover compounds or peptides that are medically useful to humans. But really what, what drives me every day to go to the lab is those tiny, not tiny, but you sell them once in a lifetime moments when you get to discover something.

That's a really, really good feeling. I remember when, you know, when I had elicited my first new molecule, when I understood what the pheromone mimics were for, it was just like, for the first time, nature shared you her secrets and nobody in the world knows about it than you. Oh, wow. That is so cool. Right? I remember it, it's like, it dawned into me like 3 a.m.

I was in Salt Lake. I could not sleep. Really, my, my, my brain was like over, it was over sensitized. I couldn't sleep for, you know, because I solved something, but I think I solved something and probably nobody cares about it in the world, but I care, care a lot. You know, that, that kind of fascination was, was really, what's really, was a high. It was enough for me to actually go for another year with a series of frustrations, you know, I go to the lab, ending up with, you know, bad results, I eat for station for breakfast.

I would always say that, but, you know, once in a while discoveries, it's, it's going to wipe it all away, those frustrations. I think that's, that's why I really like doing this thing. Oh my gosh. What good life advice is collaborate, reach out, eat frustration for breakfast and just keep going. This has been so, so fun. I am 100% on your cone snail PR team now.

Let us know. I think you just turned a lot of people into cone snail phonetic. So ask quality people, aquatic snail questions. Really you have nothing to lose and all of the caution to gain. So thank you Dr. El Hassan and Dr. Torres and all the researchers and cone snails out there who are making better medicines for us. There's a link in the show notes to our website at alleyward.com slash ology slash conotoxinology and that will have links to research papers and social media handles and the charities

the ologists chose and more. And we are at ologies on Twitter and Instagram. I'm alleyward with 1L on both. You can join us on patreon.com slash ologies to submit questions for the ologists. It costs a dollar a month to join. Our hearts are cheap. Also hello the ologies podcast redditors and the ologies podcast Facebook page. That's adminned by Aaron Talbert with help from Shannon and Bonnie from the podcast You

Are That. Thank you to Emily White of The Wordery who makes and oversees the transcripts and Kayla Patton who bleeps episodes. Those can be found for free at alleyward.com slash ologies dash extras. Susan Hale and Noel Dilworth handle so much ologies business from scheduling to accounts payable. Thank you Zeke Rodriguez-Thomas of Mindjam Media for handling this shortened kid-friendly small ologies episodes that come out every few weeks.

Apologies to him that we're a little behind because of some family emergencies. Thank you all for your patience on that. Stephen Ray Morris assists on those. Thanks Kelly Ardewire for website design. She can make yours too. And giant love darts to lead editor Jared Sleeper of Mindjam Media who puts these all together each week. And Nick Thorburn made the music and if you stick around to the end I tell you a secret

in this week. It's that I just found out nobody ever told me that when you do laundry and you have that sticky cup of soap that you use for your detergent apparently you can just throw the cup into the washer with your clothes especially if it's one of those really rubbery silicone ones. You just toss it in there and then you don't have a drippy cup it just it just gets cleaned in the wash. Nobody tells us this shit.

Nobody. It's boggling. I'm forever changed. I love you Ardewire too. Okay.