Shipworms, sponges and snail venoms: The search for marine medicine

Tiny Matters

For millennia, humans have looked to the sea to find medicine. Today, medical treatments that come from the ocean have been clinically approved for pain, cancer, and Alzheimer’s disease, and over a dozen more are in clinical trials. In this episode of Tiny Matters, Sam and Deboki are tackling marine natural products—things like proteins, fats, and other molecules that marine organisms produce—that humans are hoping to use to treat the diseases that plague us.

Transcript of this Episode

Sam Jones: For millennia, humans have looked to the ocean to find medicine. In Ancient China and Japan, eating seaweed was seen as a way of warding off a bunch of diseases including cancer. In Ancient Rome, Pliny the Elder suggested that ash from the burnt spine of a stingray mixed with vinegar could get rid of toothache pain.

Deboki Chakravarti: Since then, things have progressed … quite a bit, and today medical treatments that come from the ocean have been clinically approved for pain, cancer, and Alzheimer’s disease. And there are well over a dozen more of these drugs currently in clinical trials.

Welcome to Tiny Matters. I’m Deboki Chakravarti.

Sam: And I’m Sam Jones. Today’s episode is about marine natural products. These are, generally speaking, things like proteins, fats, and other molecules and chemicals that are biologically active, meaning they are important to the organism producing them. Maybe these products help fight off a predator or a disease, or they’re a way to communicate with other organisms. And we humans are asking, “is this molecule relevant to our health?”

Deboki: Let’s start off with a little marine natural product history. So in 1960, the first conference was held on the biochemistry and pharmacology of compounds derived from marine organisms. From there, the field started to take off.

The first marine-derived compound was approved by the US Food and Drug Administration in 1969. That drug was cytarabine, also marketed as Cytosar U®, and it’s used to prevent and treat leukemia that has spread to the meninges, which are the membranes that cover your brain and spinal cord.

Cytarabine was first isolated from a marine sponge, and it works by blocking an enzyme that our cells need to replicate. Because cancerous tumors arise from our cells replicating and growing out of control, researchers realized that it could kill cancer cells.

Sam: Today, there are eight marine natural products clinically approved for cancer, pain, and Alzheimer's disease—the majority of which also have FDA approval—and there are more than twenty marine compounds in different stages of clinical trials. This is a field that continues to grow, and the amount of information about what marine natural products to go after has increased a ton over the last five or so decades.

Eric Schmidt: There's a huge body of knowledge now about chemicals that are found in marine animals and where to look for them, and so that's very helpful, you know, standing on the shoulders of giants.

Deboki: That’s Eric Schmidt who is a professor of medicinal chemistry at the University of Utah. His research generally focuses on marine animals as well as microbes that live in them and on them, like bacteria. And he told us that to figure out what organisms or types of compounds to go after, it’s important to not just look at all of the previous data on potential marine natural products collected, but to really look at how an organism interacts with things within its ecosystem.

Eric Schmidt: For example, we never would've thought to work with small molecules in cone snails. But some ecological insights from our coworkers led us to look at this in more detail and find some interesting molecules there. So I would say it's a mixture of this immense knowledge that's been generated in the field, and then really thinking hard about the ecology of the organisms and where we might be able to find the molecules for a specific therapeutic area.

Sam: We promise we’re going to get back to cone snails in a few minutes, but first let’s talk a little bit about one of Eric’s interests: shipworms.

Eric Schmidt: I've worked with some amazing biologists—Margo Haygood and Dan Distal, and they're experts on shipworms. They're basically clams that eat wood, and pretty much everyone has seen them because when you see driftwood on the beach, it's full of holes. Or if you see a wooden pier, you can often see these little filters hanging out of them, little tubes hanging out of them. And those are the tubes of shipworms that have burrowed into the wood. And they're responsible for most of the wood degradation in the world when, you know, trees fall into forest and wind up in the ocean, shipworms are the main degraders of that material.

They live in wood, they eat wood, and the microbes, the symbiotic bacteria that live with them help them to do that. They make the enzymes that let them digest wood. The microbes live in the animals and they defend their turf, they amazingly somehow clear the gut of potentially competing microbes. And so Margo and Dan had this hypothesis that this would be a rich source of antimicrobial agents. And so we've been looking at these for antimicrobials for a few years now.

Sam: So you might be wondering how a scientist could go from ‘oh those bacteria in ship worms might produce incredible antimicrobials that humans could use!’ to ‘we’ve identified what that antimicrobial could be!’

Amy Wright: The very first step is always to make an extract of the organism. We have to get out the organic molecules so that we can then test them in our biological assays. So if someone makes a cup of coffee, they are extracting coffee beans and they are making an extract that you could test. And of course you might know, I'm sure you do that they have caffeine. And caffeine is a stimulant for humans. It’s not why coffee beans make caffeine.

Deboki: That’s Amy Wright, a natural products chemist at Harbor Branch Oceanographic Institute at Florida Atlantic University. I love that metaphor of making a cup of coffee and how our goal is to get caffeine from it, but our human caffeine addiction is not the reason coffee beans have caffeine. Just like how some compound we’re looking for in a sponge or shipworm microbe might be doing something very different for those organisms than we would want it to do for us.

So once you have an extract, there are a variety of things you can do. Eric told us he and his lab will start out with DNA sequencing of the bacteria in shipworms to try to distill out the important potential antibiotics they might be producing.

Sam: Amy told us that once they have an extract they use techniques to separate out different classes of compounds based on the different things they might do, and then work closely with biologists to see if any of those compounds might, say, kill a cancer cell or block the growth of a dangerous bacteria. To clarify, they’re not just looking for something that’s quote “toxic.” They’re looking for a more specific effect, on a particular protein, for example, that if it’s blocked will stop the cancer cell from dividing and the cancer from spreading.

As new scientific tools have developed, the field has been able to hone in on individual compounds they might not have considered in the past. Like…the ones in venom.

Deboki: I think the idea of using venom as a potential therapeutic is pretty cool, so to learn more about marine natural products in venom, Sam and I called up biochemist Helena Safavi at the University of Utah.

Sam Jones with Helena Safavi: What would you define venom as? What is venom?

Helena Safavi: I think at the core, venom is a very complex mixture of compounds that have evolved by one organism to disrupt the physiology and behavior of another organism.

Sam Jones with Helena Safavi: Getting a little bit more narrow, what types of marine venoms are you and your lab studying?

Helena Safavi: So there are quite a few different marine venoms out there. We are mostly interested in snails, so venomous marine mollusks. Recently we've also started to look at Octopus's venom and squid venom, but the majority of our work has been on snail venoms.

Deboki Chakravarti with Helena Safavi: So how did you get interested in snail venoms in particular?

Helena Safavi: I've always been interested in the marine environment, particularly in coral reefs, because of the richness of biological interactions at the coral reef. And so I'm coming from a biology background, and then I thought about human health a bit more during my studies, and then I stumbled across these cone snails that people had used to find new drugs to treat human diseases. So I thought that would be a perfect opportunity to kind of combine my passion for the coral reef with advancing human health.

Deboki Chakravarti with Helena Safavi: You talked about venoms being used to disrupt another animal's physiology for this cone snail. Who are they looking to disrupt?

Helena Safavi: Right. And that's a good question because they're so diverse. So there are around 850 known species of cone snails, and each one of those has a different type of behavior and a different type of prey. Broadly we can categorize them into three different types. So there are the worm hunters, snail hunters, and fish hunters. And within those hunting or prey categories, different snails use different strategies and accordingly have different venoms that they have evolved. So each of the 850 different cone snails has another mixture of venom components. So you end up with this massive biodiversity of compounds that you can study in cone snails.

Sam: Cone snails are so cool. They’re actually all carnivorous so they have to hunt to survive. Like Helena mentioned, there are a lot of cone snail species and that means lots of venom mixes and reasons that they use that venom. Helena and her lab are interested in the toxins cone snails use for predation. She told us that her favorite of the cone snails is Conus geographic, which has a super potent venom that is deadly to humans. This is a snail that has been studied for decades but about 8 years ago Helena and her lab found something new in its venom: a type of insulin. In humans the hormone insulin is created by your pancreas and is essential for controlling the amount of glucose or sugar in your bloodstream.

Helena Safavi: So this cone snail uses insulin to induce very low blood sugar in the prey. And that was a whole new mechanism of prey capture that had not been observed in nature before.

Sam Jones with Helena Safavi: What made you think, okay, we should be looking for what's in venom to find a therapeutic compound for humans. This venom, you just said, if a human is stung by these cone snails it could kill them. So how is that connection made? Because I think my immediate impulse would be, “I need to stay away from this cone snail!” And not, “I need to investigate how I may be able to harness something in this venom to help people.”

Helena Safavi: I think that's probably the most common misconception that we face as venom researchers. People associate venoms with something that is maybe just a very simple mixture that just kills, right? Whereas venom is a very complex mixture that if given all together can have pretty bad outcomes for the prey, but when we separate all of these components into their individual entities, we find very interesting things that individually can be therapeutic.

Deboki: We asked Helena a bit more about going after marine natural products in general, how you make the decision to focus on a specific organism. She told us something along the lines of what Eric had told us. That it’s not just about mashing up an organism so you can find some interesting chemical compounds. Knowing the behavioral and ecological context really, really matters.

Helena Safavi: I think lately we've observed, what does the venomous animal actually do? And from that behavior can we try to kind of narrow down our searches. So let's say for cone snails, there are some that very rapidly induce paralysis. So they inject a venom, and then within less than a second the fish becomes completely paralyzed. So if you want to find your next, like Botox for example, that inhibits the muscles in your skin, that would be the Conus that you would want to look at. Whereas if you wanted to look at Conus geographus, for example, that releases venom into the water and it takes a little bit longer for the venom to act, that's where you might find something that lowers blood glucose. So we've tried to connect the behavior of the venomous animal with what compounds we look for.

Deboki Chakravarti with Helena Safavi:
Does that mean that you're usually looking at them in the wild or are you looking at them in the lab or both?

Helena Safavi: I would love to do more work in the wild that's really not feasible. So often we collect them and we maintain them in the aquarium, and then we give them different things to potentially hunt and go after we set up like night cameras and then we just observe their behaviors. A lot of it also other people have observed. So when we go out, we always ask the fishermen and the scuba divers about anything that they might have observed that would help us in our lab when we look for new compounds.

Deboki Chakravarti with Helena Safavi: Do you find people still reluctant to think of venoms in a therapeutic context? Or is it a little bit easier now that we can point to Botox as this example of something that people will readily inject in themselves?

Helena Safavi: So I think there are a couple of examples specifically from venoms that have made it into the clinic that we use in almost every article we write or every grant application we write that have helped the field a lot. And so there's one very famous antidiabetes drug called Exenatide that was isolated from the Gila monster, which is a venomous lizard that you find in the southwestern United States. And there's one from cone snails that has made it into the clinic.

Sam: The one Helena’s talking about is Ziconotide, which was discovered in Conus magus or the Magician’s Cone snail that prey on small fish. It was approved by the FDA in 2004. It’s a non-opioid drug that blocks pain signaling in the spinal cord and is typically given to people that don't respond to the opioid drug morphine because they’ve developed a tolerance to it. Ziconotide is marketed as Prialt® which gets its name from ‘Primary Alternative to Morphine.’ Unlike opioids, this drug does not cause respiratory depression or withdrawal. Eric also mentioned the story of Ziconotide when we talked with him.

Eric Schmidt: Just with pure scientific curiosity, investigating how cone snails pursue and kill fish, which is amazing, and then translating that finding into an actual pain drug that helps, especially cancer patients, deal with intractable pain—I think that's an amazing and inspiring story.

Sam: This is all very cool and very important work. So now you might be wondering, “why aren't more marine derived products approved or in clinical trials?”

Eric Schmidt: I would say there's two classes of bottlenecks, and one of them is what I would describe as social. And the other one is technical. Natural products themselves, after a Supreme Court ruling 10 years ago, aren't patentable anymore. They used to be, and usually pharmaceutical companies don't wanna touch something where you don't have good intellectual property. They might spend, you know, the better part of a billion dollars plus or minus bringing a compound into the clinic, and they don't wanna take the risk that somebody else can undercut their intellectual property at a late stage.

The technical factors, I would say the main issue that we struggle with is the supply problems. You're getting these small amounts of chemicals from these tiny little animals that you've obtained or from cultivated bacteria if you're lucky. And you have to have enough to really test and validate them and then get them into the clinic. And how do you turn that into a multi kilogram scale endeavor that's needed to really supply a drug? That's very difficult. Obviously, it's not ethical to supply things by harvesting them from coral reefs, for example. So there's a lot of synthetic chemistry, there's a lot of biotechnology that underlies bringing these things into the clinic and they're quite difficult as well.

Amy Wright: I think for many, many years, and I think a lot of us will agree on this, that the biggest bottleneck is getting a large enough supply. So if it comes from a deep water sponge and we used a submarine or a submersible to go get it, you're not going to be able to just keep popping back down there as you need more compound. So then you're gonna have to find a way to get more of the compound. And I'm actually really much more optimistic these days.

Deboki: One of the things that makes Amy more optimistic is synthetic biology, like Eric also mentioned. That’s very exciting to hear because I worked in synthetic biology when I was in grad school, and part of what drew me to it is the possibility of taking inspiration from nature to make new things. The way I think of it, synthetic biology is a field of science where we’re learning how to use what an organism already has as the basis for getting it to do something new, something we’d like it to do for us. For example, scientists could engineer the DNA in cells to produce bulk amounts of a marine natural product they wouldn’t usually produce.

So what does the future hold for the marine natural product field? We’ll start with Helena and venoms.

Helena Safavi: I think some of the things that the venom compounds do, we don't even understand yet. I don't work on wasps, for example, they're parasitic venomous animals and they completely change the behavior of the hosts. I find that utterly fascinating that you could have a compound that changes the behavior of the host. You could think of parasites as venomous creatures too, because they start secreting things. Once they're in your body, they manipulate your behavior. And so I think there will be exciting new mechanisms of action that we'll stumble upon in the future that venomous animals have evolved.

Eric Schmidt:
Personally, I think that the best and the most potentially intellectually rewarding area is in sensation and neuroscience. All of the compounds that are out there that we're interested in there is a sensory component to them.

Thinking about chemical defense, a sponge is sitting there full of toxic chemicals that ward off predators—they might be good and translatable into cancer therapeutics, but underlying that the predators need to know that the compound is present. There's a sensory component. There are many more complex stories about sensation where organisms are communicating with each other or with their prey using small molecules.

Deboki: I love the idea of using natural products used in marine communication for neuroscience endeavors.

Sam: Me too. I’m excited to keep following this field and see where it goes.

All right. It's Tiny Show and Tell time.

Deboki: Cool.

Sam: As always, I never remember who went first last time.

Deboki: Maybe I went first last time. But I'm also happy to go first because I think mine is slightly in the same mood as what we've been talking about.

Sam: Let's do it.

Deboki: So I will go first because I feel like there is a thread in my Tiny Show and Tell that is related to what we were just talking about. I'm going to display a lot of my own biases here, which is that my husband is vegan and I don't eat beef. So I have been eating a lot of fake meats for a while now, even before the Impossible and the Beyond and all of that. And I also really like them. They don't weird me out. I know other people, it makes them uncomfortable or it weirds them out. I'm not one of them. With that said, I was very intrigued by the title of this article in The Atlantic, which was The Secret Ingredient That Could Save Fake Meat. And the article is written by, I believe, Yasmin Tayag. So I'm going to spoil the surprise. Basically, the secret ingredient that we all need is real pork fat.

How would you do that in a way where you could still call this vegan? Well, the point is that it's not going to come directly from the pig. It's actually going to be fat made from cultivated pork fat cells. And I kinda disagree with a lot of this article when it talks about fake meat in terms of its quality, especially because I think it's being very emphatic about opinions that I personally think are subjective. It says outright, the fake meat on the market now is lacking in the flavor and texture departments. And maybe it's just because I didn't grow up eating beef, but I don't know. I like it, but that's not the point. The point is that this article is really interesting if you want to understand how this works. I think it reminds me of what we were talking about with this idea of synthetic biology.

And part of what's always drawn me to it is this idea of, what can we replicate from nature and what's worth replicating for nature? There are reasons to not just take the fat from the pig. There are a lot of reasons to maybe reduce the amount of farming that we're doing or how much meat we're raising and killing just for the sake of eating. There's a lot of arguments about that, and I'm not here to weigh in on the arguments. But I think the idea of the technology is really interesting. Also, the article talks a lot about why, at least in the opinion of people, the fat that is currently used in a lot of these fake meats are not really up to stuff, and why turning to pork fat is not just about being tasty, it's more about how it binds everything together. And I just thought that was really interesting.

Sam: So I do eat meat. So I'll eat some chicken, but I feel like I eat red meat maybe once every couple weeks or something. So it's not that frequent. But I have started eating Impossible meat. And I'll use it, if I create a ragú or something, I'll add it in as I would have added ground beef. And I've started to really develop a taste for it. And so now sometimes if I have actual beef, it tastes a little weird to me for some reason. Anyways, it's interesting thinking about using pork fat cells. You're not taking it directly from a pig anymore because you're cultivating these cells in a lab.

But if you trace it back far enough, there was a pig involved at some point. Can you call that vegan? I don't know. If you're worried about harm to the environment, if that's your big concern, comparatively you're in the clear, right? But if you're really concerned with not eating anything that is an animal product, that feels like cheating. But at the same time, if this does make some alternative meat products more appealing to people, and it means we're not slaughtering as many cows and pigs and chickens every year, weighing the risk and benefit, I think there's something to that, too.

Deboki: Sometimes an article that you disagree with in some points is also still really good. What I liked about the article is the way it was making me think about the issues overall. One of the challenges with some of these plant-based meats is, how much healthier are they? And especially once you're then turning to pork fat, would we be negating whatever health benefits there are from cutting back on real meat and especially red meat? And the question of what do we call vegan at that point, I've learned that there's a lot of nuances around what people consider vegan for themselves. Because for some people who are vegan, the idea of eating fake meats entirely is completely weird. But fake meats have this very long history that predate Beyond Burgers, predate bean veggie burgers. There are a lot of cultures that have different versions of fake meats. So I find it fascinating to see how we evolve with that.

Sam: Cool. Well, thanks for sharing that. I like that it's marine natural product adjacent for sure. So I'm going to share something that has nothing to do with any of this, and it's related to space. So the James Webb Space Telescope, I think it was six months ago that some of the first images came in. Essentially, we're seeing a lot more of space than we've ever been able to see before. We're seeing it in, I guess, you could think high definition as someone who knows nothing about space would explain it. I guess maybe they saw this a little while ago, but they're just reporting that six galaxies that formed within the universe's first 700 million years, they appear to be about 100 times more massive than any standard cosmological theories would've predicted. I think one of the scientists in the article that I read said adding up the stars in those galaxies would exceed the total amount of mass available in the universe at that time.

So these researchers spotted these objects that looked super bright and red, which is a sign that they'd be really big and far away. And I won't get super into it, but essentially measuring the amount of light that these objects are emitting in different wavelengths can give astronomers an idea of how far away galaxies are. So then of these objects, six of them, they were able to identify that it looks like their light comes from no later than about 700 million years after the Big Bang, but they seem to hold up to 10 billion times the mass of our sun and stars. And one of them might even have the mass of 100 billion suns. So there are a couple of different explanations that these scientists have put forth. The idea is that matter in the universe forms by smaller bits of matter clumping together, merging together, forming larger bits of matter. So one explanation for why these super-duper massive galaxies exist is that there's another way to form galaxies.

But it could also be that some of the galaxies have maybe a super massive black hole in their core. And so what looks like it could be starlight could actually be light from the gas and dust that the black holes are devouring. And apparently, the James Webb Space Telescope has already seen a potential active super massive black hole. To know if this is real, if these really are galaxies that are enormous, or maybe if there's some alternative way that they formed, astronomers need more data. They need more precise measurements of the galaxies' light across a bunch of different wavelengths. This is just the start, but it seems like there's a lot more information that is incoming. And I'm very excited to see if this mystery can be solved. I assume it can be solved. I don't know when it would be solved. The fact that someone even said maybe galaxies form in a way that's different from how we think they form is just wild in itself, right? Wait, are we really debating this right now? Are you sure? Can we debate this? Yeah, I just liked that.

Deboki: When you were saying the thing about the mass being 100, it was 100 billion suns, right?

Sam: Yeah. So they appear to hold most of them 10 billion times the mass of our sun. And then one of them looks like it could be the mass of 100 billion suns.

Deboki: You know when people make those representations of what a billion dollars is and it's like a grain of rice next to a whole pile of rice? That's the only way I can conceive of that. And even that is nowhere near. It's suns. We're talking about suns. I don't know how to even imagine.

Sam: I think our brains are just not wired to be able to conceptualize certain things, and this is definitely one of them for me.

Deboki: Thanks for tuning in to this week's episode of Tiny Matters, a production of the American Chemical Society. Our exec producer is my co-host, Sam Jones.

Sam: This week’s script was written by me and was edited by Deboki and by Michael David. It was fact-checked by Michelle Boucher. Episode audio was edited by Russell Silber. The Tiny Matters theme and episode sound design are by Michael Simonelli and the Charts & Leisure team. Our artwork was created by Derek Bressler.

Deboki: Thanks so much to Helena Safavi, Eric Schmidt and Amy Wright for joining us. If you have thoughts, questions, ideas about future Tiny Matters episodes, send us an email at You can find me on Twitter at okidoki_boki.

Sam: And you can find me at samjscience. See you next time.