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Transcript

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0:01Who are the characters behind science? This is Science Behind the Glass, Illuminating the Human Side. In this podcast, we unveil the human side of laboratories and science. Scientists share personal experiences and will discuss their meanings from different perspectives and fields of research. Welcome to another exciting episode of Science Behind the Glass, Illuminating the Human Side.

0:34Today, we are diving deep into the fascinating world of venom research. with a scientist whose journey is as intriguing as the creatures they study, Dr. David Wilson. Dr. Wilson is a visionary researcher whose passion for venomous creatures has taken him on an extraordinary voyage of discovery. From the venomous layers of Australian funnel -web spiders to the hidden depths of scorpion stings, Dr. Wilson’s work pushes the boundaries of scientific exploration. But what sets Dr.

1:02Wilson apart isn’t just his groundbreaking research. It’s the human stories that lie beneath the surface. From his early days studying chemistry and biochemistry at the University of Melbourne to his entrepreneur ventures into the world of biopharmaceuticals, Dr. Wilson’s journey is as diverse as the creatures he studied. I also have to mention that David Wilson, or Dave, brought me into the world of spider venoms and my favorite spider, funnel web spiders. Dave, thank you for accepting the invitation. So, Dr. Wilson, many might find the idea of studying venomous creatures intimidating.

1:42What inspired this field and what keeps you motivated to delve deeper into it? I think my dissociation with venomous things has been almost a lifelong interest. So when I was quite young, I was quite interested in looking at spiders and studying spiders. I used to collect them in little patches of things at school. That probably stemmed a little bit from my father’s interest in science in general. He was a high school science teacher.

2:10And yeah, the interest always stayed there. And then as I was… Growing up, I had the opportunity to live on a farm for a while. And on our farm, the four main snakes that were on the property were all in the top 20 most venomous in the world. So it sort of paid to be aware of what was around and what could happen if you got bitten. And then I didn’t really intend on following it up.

2:40I wanted to become a vet. I managed to get into the University of Melbourne and to study science. And the vet dream kind of fell away. But in second year, I decided to do pharmacology subject. And I was very fortunate that one of the guest lecturers they brought in to do the venomous creatures section of that course was Professor Strawn Sutherland, who is an absolute guru of Australian toxinology.

3:11So he was the person who developed the funnel web antivenom and initiated and set up the Australian Venom Research Unit in Melbourne. So his lectures sort of got my venomous bug back again. And I wanted to work in sort of a toxin field. flash drug development type field. And everything just kind of fell into place. Then I got to go to Brisbane to do a PhD. I was initially going to be working on cone snails. My supervisor there, Paul Elwood, was working on cone snails. But when I arrived, they had just discovered I got one of the first specimens of far web spider from Gary or Fraser Island. at the Queensland Museum and got to go and have a look at that.

4:00And yeah, the rest is history. That sounds amazing. And you never feel any fear about these tiny little creatures? It’s not a fear, it’s a respect. So yeah, I’m not frightened of them, but I certainly have a lot of respect for them. And you need to keep your wits about you when you’re handling them. Your research spans across various venomous animals, from spiders to cone snails. Could you share a memorable moment from your research that truly showcased the unexpected beauty or complexity of these creatures? I think unexpected beauty, that’s an interesting question. Probably something that most people don’t associate with venomous things. More apt for you and me. Probably something that’s… Dan’s out at JCU, James Cook Uni. They have an aquarium facility and I was over in that one day and they had a couple of little Irukandji jellyfish in a big circular tank. And I was just watching, I was trying to take photos of them and the tank had a current running through it and the jellyfish kind of just… float around in the current and the Irukandji jellyfish have a very small bell so the head of the jellyfish is only one to two centimeters long but their tentacles can be up to a meter long and these two little jellyfish were floating around and their tentacles became all entangled so it was just a massive knot of tentacles and I was kind

5:33of looking at them and thinking oh geez they’re gonna be in a bit of trouble you know probably not be able to get away from one another and not be able to feed anymore and yeah they just came floating past and both of them just pulsed and just separated it was it was incredible it was just like watching fishing line that it was all knotted just spontaneously unknot it was it was awesome so yeah that’s probably something that really stands out i think when you see a male sydney funnel web for the first time and you you see exactly how off their tree they are with their aggression um that also stands out yeah but it’s it’s so beautiful how they change when for example they’re mating they’re the most gentle animal making all this core shape and moving and dancing God, you’re falling in love.

6:24Okay, so passing to another topic. Many people know or heard at least that venom molecules have the potential, a therapeutic potential, I mean for pain treatment, for example. And this sounds both intriguing and groundbreaking. Can you explain to us the process of identifying and characterizing these substances? Sure. There’s a couple of approaches to discovering and identifying. slash characterizing toxin molecules. The classic approach has been to collect venom in some sort of relatively significant amount and then either test the crude venom or fractionate it, so separate out some of the components and then test them on a particular assay or target of interest, so some sort of receptor of interest.

7:15So certain groups tend to focus on, or pharmaceutical companies tend to focus on particular receptor or target that’s associated with some disease that’s trying to cure. So you test the venom or the venom fractions on your assay and if you get a positive result, so some sort of activity, then you take that fraction and try and work out what’s in it and what the active component is, which in the case of venoms… It’s usually some sort of protein or peptide, but it may be a small molecule. Then you may have to make it synthetically and then structurally characterize the molecule and go on from there. Yes. And how difficult it is, like, well, you find a molecule, you isolate it, trying to find the structure, and then you run the test from there to becoming a drug or a potential. the discovery alone can take over how easy it is. Yeah, so it’s a long, slow process. One of the really difficult things following that approach is that you might determine the sequence or the structure of the compound, that’s great, but then you don’t know what it does. Trying to find what it does can be very, very difficult because… A lot of these molecules are really highly specific or selective to the target that it’s designed for. And unless you

8:45have the exact one or something that’s very, very, very similar, you won’t see any activity. So working out that can be quite challenging. So you’re looking at usually up to five years, maybe characterize something that’s maybe with full activity characterization. Then if you wanted to develop it, you have to start looking at doing. early stage growth, animal data, clinical trials, those sorts of things. They take anywhere between 20 years and they cost significant amounts of money. I think the going average is around about a billion dollars to get a drug on them. Wow.

9:25Just in development costs. But you’re keeping the track. Transitioning. From Venom research to management roles and master of business administration in finance, entrepreneurship seems like quite a shift. How did your diverse academic journey influence your approach to scientific research and management? It’s been a bit of an interesting ride. So I’ve found that it’s all well and good to have plans about where you want to be and what you want to do. But sometimes making that happen can be a bit difficult. I’ve been quite fortunate to kind of… fall into pretty much every position that I’ve ever had. And I didn’t particularly want to follow a traditional academic role. So when I finished my PhD, I was interested in going into industry. And it just so happened that somebody that I worked with during my PhD had left their job to head up a small startup by a pharmaceutical company. They wanted me to work at the company. So the timing just worked out. I transitioned there. I was there for seven years. And while I was there, the work was interesting and the idea of developing something that might help people, you know, thousands of people worldwide is quite an inspiration. But it became obvious that there’s challenges in managing that process in drug development and running a small company.

10:55particularly in Australia where venture capital funding can be quite limited. And it sort of occurred to me that I wanted to learn more about that. So the obvious choice was to do a Master’s of Business Administration. And it just so happened that the subjects that I was interested in meant that I focused on entrepreneurship and finance. The MBA has been… very useful, I think, after now returning back to sort of an academic environment, because it gives you more of an understanding of how difficult it is to spin off companies and to get startup companies running and to obtain funding. And because the corporate funding world is very, very different to the academic funding world. I think that’s a very important distinction and thing to understand. Yeah, we rarely think about that. Because they never teach us. If you want to work in the industry, how to do that transition or, for example, thinking about starting a startup or like a company. The fact that they don’t teach you that means that I think it contributes to a lot of early failures, those sorts of things, because pretty much everybody who then heads off down that road is reinventing the wheel.

12:13making the same mistakes as the 20 people before them. But having said that, I mean, one of the things that came out of the MBA was that particularly around entrepreneurship is that even in the corporate world, the failure rate is really high. You’re only looking at maybe a 10 % success rate if you’re lucky. So just because you’re an academic and you don’t have that sort of training doesn’t really mean that you’ll be less successful or more successful. Nice experience. Sounds rough.

12:44Well, in other topics, behavior in Australian spiders is a fascinating aspect of your research and Linda’s as well. Could you share how is this aspect of the research and any surprising discoveries or insights that you have gained in this area? So that work all stemmed from working with spiders for years and having multiple different species and all that sort of thing and talking to other people. interested in spiders it was was kind of there was lots of anecdotal evidence of personality in spiders so you’d see a particular individual from a species that you had that you know was different to the others or they or they were all slightly different and i have one one particular example of i had a blue mountains funnel web at one stage that was given to me during my phd and that That’s the only funnel web that I’ve ever really been hesitant about working with.

13:47It was, she learned how to climb my tweezers. And so anytime I went to do anything with her, she’d… start scaling up my uh forceps my tweezers so i didn’t particularly like what and she was big as well there was like i say there was lots of anecdotal evidence and when i started uh at jcu and started talking to asmund reimer who was linda’s primary supervisor and she her specialty is uh animal behavior and so we started talking about it and these little characteristics and traits and things in the different spiders and we’ve been throwing around some ideas about trying to do some experiments to actually measure if there was personality in arachnids and we’ve done a few preliminary tests and things and then quite out of the blue I got an email from a young Colombian lady who was interested in that particular aspect and so we worked on getting Linda out for for a phd and that went incredibly well so yeah it was uh you know linda’s work showed that a lot of the anecdotal evidence had some some credibility and yeah there’s there’s certainly repeatable behaviors and personalities amongst various species of australian funnel whip Yes.

15:13And I remember that he was trying to convince me to work with Huntsman. And I was just so obsessed with Huntsman. Like, no, I don’t need to do anything to milk them, to turn the van on. They just release the van on easily. And I have so many amazing spiders. Cranky one was the classical one that when I was measuring heart rate, it just jumped.

15:39but they were they were the sweet ones that always cooperate so that’s been a pleasure but huntsmen are easier to collect yeah good luck very very upset on a on a field trip after spending two hours trying to dig up a funnel web to only find two slugs oh yeah over the bar that was so frustrating i was just like yes I got it. I almost get into China and I think it’s a big sloth. I’m like, what? It sounds fun. Venom regeneration and plasticity in Scorpion sounds like something out of the science fiction, a science fiction movie. Can you explain how understanding these processes could contribute to medical advancements and other fields? Yeah, so regeneration of venom is the… very interesting topic that hasn’t really been explored in depth too much. There seems to be in the scientific community there seems to be this underlying assumption that every species has like a baseline venom composition and that once they use their venom for some particular purpose be it catching prey or defending themselves that it will then return to that baseline composition at some point. in the future. What we’ve done is shown that that’s not the case. It’s always in a constant state of flux and there’s no real

17:13baseline. Even for an individual, there is no standard baseline composition, particularly in relation to relative abundance of the compound. So the venoms are really quite complex. They often contain several hundred components. And so what we tend to find is that in general, you will have components that are standard, I guess, are always there, always present, but the relative amounts of each one will vary at any particular time. And then you have other lower abundance compounds that sometimes will not be visible on the time scales that we’re looking at. That can become very, very important in medically significant species. You mentioned scorpions.

18:00I’ll just use a funnel web example for this particular point. In the male Sydney funnel web, there is one toxin that causes the toxicity and the medically significant implications to humans. So if you happen to get bitten by a male Sydney funnel web at a time when it has a lot of that particular component in its venom, then that particular bite is going to be far more dangerous than if it’s… only expressing a very, very small amount of that toxin. So if we can get some sort of understanding of what’s driving these expression levels, even being able to potentially model how much might be there, then we can have a bit more of an idea of how to treat sting victims.

18:49And just coming back to the scorpion reference, then in Australia, scorpion stings are not really a medical issue. Not many people get stung by them. Most of our scorpions aren’t really highly toxic to humans. You might get a bit of a sting, a bit like an ant sting, or a bit of discomfort for a couple of days. We do have a couple of little scorpions that can cause quite significant pain, but generally nothing life -threatening.

19:21If you then contrast that with other regions of the world, such as Africa and Middle East, And in particular, Mexico, scorpion stings are a significant medical problem in those areas. Mexico used to have over 1,500 fatalities per year just from scorpion stings alone. And they still, to this day, have over 300,000 medically significant stings a year, which is quite a burden on the health system. So if we can get more of an understanding of how these toxins regenerate and how they might fluctuate under certain conditions and certain pressures, then it’s likely to help with the treatment of things. Wow. It’s like a cocktail that you change and vary the quantity so it’s one of the components. And it can be more lethal or not. Yep. Absolutely. Yeah, that’s very interesting. So you told us that protein structures are fundamental in understanding venom composition. You already explained a little bit about its importance for drug development and human health. How are these molecules important in other components of venom research, for example, in evolution or population dynamics of these species that have venom? The thing with the structural

20:51aspect of the toxins is that we find families of toxins that have similar structures and you find very conserved structural aspect in a lot of the toxins. And it’s not the structure that drives the activity. It’s the sequence, the amino acid sequence, generally, of the peptide that drives the activity. But the structure is what holds everything in place. And I guess the simple explanation of how these things work is you can think of your target as a kind of a lock. So the receptor is like a lock and the toxin is a key. And you need a very specific key to fit in the right lock in order to make it work. So understanding the structure of these things can help you understand how they are binding to the receptors. That sort of information is very important for particularly in drug development because you need to know what the mechanism of action is, how everything’s binding, how the activity is working. And one of the things that happens in drug development is that you often change to perform subtle changes on the native toxin.

22:09So you might trim. the the ends of it or change out certain amino acids because they are causing some sort of detrimental effect whether it be solubility so your you know your your compound might have solubility issues which make it hard to deliver or it might have some unwanted activity lower level activity on another receptor that you you don’t want and so you can play around with the sequences and make little changes to drive or make things more active on a particular receptor, improve your cell activity, make the compound more potent, that sort of thing. But in doing that, there is the potential that you change the structure. So we need to know how it’s interacting with the receptor from a structural perspective in order to know whether certain changes are likely to ruin the interaction. So it’s like also important at evolutionary level, how these animals have evolved, these toxins to target the specific prey, but also like developing for defense, right? Or specific predators that are trying to attack them. Yeah. So there’s a constant battle going on between predators and prey. So you have predators figure out some way of circumventing. some sort of defensive mechanism that the prey item has, whether that be some

23:40sort of physical attribute or they’ve developed a toxin that causes a problem to the predator. The predator then, not consciously, but will look to evolve some sort of mechanism to circumvent that defense mechanism. And as that becomes a… Arm grace. Yeah, it’s an arms race. So as that becomes a sort of a dominant trait that allows the predators more access to prey, then the prey has to come up or has to evolve some other mechanism to stop being predated upon. And so we have this ongoing race. And in the case of venomous animals, because a lot of them use their venom for both prey capture and defense, it’s these toxins are constantly under some sort of development, I guess, natural development. Yeah, and that’s because it’s important to make the connection with understanding the evolutionary point of view, how it’s changing all these venom molecules and in that way understanding how they can possibly act or how can be a potential lead molecule to develop a drug, right? Yeah, it seems like they are key traits to all. to keep watching evolutionary timescales and all this kind of research. And nature is amazing with some of the things that it comes up with, the way things kind of evolve and develop and what works and what doesn’t.

25:11We, as the human race, think that we’re quite intelligent and that we like to try and control these sorts of things. But the type of stuff that nature comes up with is just mind -blowing. Sometimes we just can’t think of it. Talking about the venom research, with your expertise, where do you see the future of venom research heading? What do you think are the potential breakthroughs or applications that you envision?

25:40I think we’re going to see more development of venom -based therapeutics, so molecules from venoms that get taken through to some sort of drug. There’s groups around the world working on developing particular. toxins at the moment for some uh for treatment of certain disease states and medical problems i think with the advancing technology and the ability to access or work with much smaller amount we’re seeing an increase in access to venomous sources so things that weren’t really possible in the past because of the sensitivity of the instrumentation and you know the amount of toxin that you could get from from a particular creature where that wasn’t possible in the past it’s now possible i think that’s also leading a little bit to a re -evaluation of things that considered to be completely characterized in the past so what what used to be thought of as you know we’ve we’ve studied everything there’s nothing else to look at there it’s not actually true because there’s a lot of underlying smaller things that are available that just weren’t visible with the technology in the past. And with artificial intelligence, it’s going to help speed up a little bit more of that dynamic with the molecules.

27:02And as you said, like a key lock interaction. That’s still at an early stage. So, you know, there’s the alpha fold AI that’s doing a lot of people are very interested in looking at it to use and using it for. structural prediction of proteins and peptides, but it doesn’t always get things right. But it’s an AI, right? So it has to learn. And so we have to show it where it’s wrong. Yeah, let’s see what happened with that. So in your extensive research on venom, I guess you have encountered a number of challenges.

27:39So could you share an example that you’ve faced during your career and how you overcame it? Challenges. There’s always challenges. Nothing’s easy. And there’s always something that doesn’t work or makes life difficult. I think that’s part of the interest, though. If everything was easy, then you’d lose interest. It’s the trying to solve the puzzle. I can actually give you an example. So when I was doing my PhD, I started working on this rare species of funnel web that’s found on the central coast of New South Wales.

28:14They’re quite small. They’re hard to keep. and barely ever give you very small amounts of venom. But their venom is quite unique because it has a very, very strong odor to it. Incredibly strong. I used to stink out the office complex that I was in if I milked them. And it’s quite a bizarre smell. So some people find it really nice. I actually quite like it. But other people can’t stand it. They find it quite offensive. So yeah, it divides the room a bit. And we were interested in… in trying to find out what it was. But it’s so hard to work with. It’s volatile, incredibly volatile. So you’re in a situation where you can’t get much of it and then it’s incredibly volatile. So what you have disappears very quickly.

29:00We tried doing some work, some mass spectrometry work with a guy who worked on insect pheromones to work that out. And, you know, insect pheromones are small, volatile molecules. So you’d think… This should work fine. Nope. No, it didn’t work. So I’m still technically working on that. So I started working on that in 1998. Wow. Technically, I’m still working on it. I haven’t solved it.

29:32I’d like to figure it out. But yeah, it’s just burning in the background. It never goes away. So it’s the unsolved mystery, right? Finally. Could you give one piece of advice or an advice about aspiring scientists or researchers? What would be? And could you share a lighthearted or amusing anecdote from your lab or fieldwork experiences that highlights the human side of scientific research? Advice -wise, my advice is science is a career of love. You don’t go into it for fame and fortune. It’s a hard road.

30:13It’s basically solving puzzles every day and not all of them get solved. In Australia at the moment, the funding situation is not great and it’s a difficult, challenging road. If you’ve got the passion for it though, then it can be quite rewarding. As for a lighthearted anecdotal story, one of the best aspects that I’ve found is some of the people that you get to meet. So this… particular Illawarra wishartai spider that I was working on, the one with the smelly venom. They were on the property of a retired pharmacist down in central New South Wales coast.

30:56And he and his family were some of my biggest supporters during my PhD. They used to let me go down and stay with them multiple weeks during the breeding season to collect. He would help me collect. He was such a positive person and such a positive influence on my project and me.

31:22He had such a strong belief in what I was doing. And yeah, I think that was definitely one of the highlights of the career that I’ve chosen and the path that I’ve taken was being able to meet people like him. Unfortunately, he passed away a number of years ago. And you have the pleasure to meet that person. And you’re amazing students, I think. That’s right. Thank you very much, Nathan, for accepting this invitation.

31:49It has been a pleasure having you here. Thanks for having us. Thanks, Dane. Discovering new molecules is a complex process not only because it is the use of multiple skills like structure analysis, but also because of the difficulty of leading with the function or role of a particular molecule. In diverse venom studies, one of the constraints is understanding the ecological role of venom. Focusing only on isolating the molecules without understanding under what habitat and context occurs, like predation or feeding, makes difficult the identification task. Yes, every species has its particular context, habitat and interactions. This makes unique traits for the venomous molecules as well as for the animal itself. And that has implications on how people should address research and management of these species. There are complex examples, like scorpions, which deliver stings on females’ abdomen during courtship. That’s crazy, right? Yeah, why not?

32:54We don’t know why they do that. But probably it’s because they stimulate the female or help them to drug the female to convince her to mate with the male. But these stings don’t have any damage on the female. So we need to know more about this behavior. Or another bizarre example is the platypus. The males are mammals that deliver venom by stabbing, which they do with a spoon on their hind wings. And then they usually do that for male -male competition. And there’s millions of examples with different contexts and functions. So we are quite sure understanding what is the ecological role of venoms. Part of my thesis was understanding the behavior of funnel -web spiders under different ecological contexts and the association with the spider’s physiology during behavioral experiments. So, for example, I exposed the spider to a physical stimulus and that stimulated a predator or another spider.

33:51So I was annoying and fucking the spider. And while I measured the spider response to this stimulus, I also collect the venom and measure heart rate to try to understand the association with the behavior and the use of the venom. This is very interesting. Indeed, there are a lot of questions still to ask about the mechanisms, the ecology, and the behavior of venomous animals. This kind of knowledge can help complete the picture to have a better management of these species and the special molecules that they produce.

34:22It is important to respect venomous and poisonous animals. I think that the lack of resembles to us make us feel threatened. And in the case of some venomous animals, evolution, culture, and even religion have reinforced the fears of venomous creatures, such as snakes, scorpions, or spiders. Yes, that’s true. There is a lot of things to know about these animals, and there is a lot of myths that surrounds them. So, it is important to know them better. This episode was inspired by the book Venom, the Secrets of Nature’s Deadliest Weapon by Ronald Jenner and Ivan Unheim. We’ll leave reference to this in the episode description.

35:01This podcast is self -funded and self -published by Dithop. Support us by clicking the like button and subscribing. You can listen on Spotify, YouTube and our official website. Follow us on our social networks on X, Facebook and Instagram. Original music by our colleague and friend Bernardo Aguirre.