New Matter: Inside the Minds of SLAS Scientists

A Lesson in the Use of Venom in Drug Discovery with Steve Trim

December 19, 2022 SLAS Episode 135
New Matter: Inside the Minds of SLAS Scientists
A Lesson in the Use of Venom in Drug Discovery with Steve Trim
Show Notes Transcript

In this episode, we're joined by Venomtech Founder and Chief Scientific Officer Steve Trim, for a lesson on the use of venoms in drug discovery and other fields! He explains the many uses of animal venom including cosmetics and crop protection. Also, Trim shares the story of the Ventomtech exclusive hot sauce that simulated a venomous spider bite!

Key Learning Points:

  • Why venom isn't widely used for drug development
  • What the ethical implications of using venoms are
  • What you need to know to use venom in your own research

About Steve Trim:
Trim is the Founder and CSO of Venomtech, where he leads the scientific efforts to produce automation-compatible biological libraries, targeted to drug discovery therapeutic areas to maximize hit potential and a wide range of biopesticides. He founded Venomtech to deliver value to drug discovery programs struggling to find novel lead material after 10 years as a pharmaceutical molecular biologist and safety delegate, followed by a research associate position in a comparative genomics lab.

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*For a transcript of this episode, please visit this episode's page on Buzzsprout.

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Hannah Rosen: Hello everyone and welcome to New Matter. The SLS podcast where we interview life science luminaries. I'm your host Hannah Rosen and joining us today is Steve Trim founder and Chief Scientific Officer of Venom Tech, who is here to teach us about the use of venoms in drug discovery and other fields. So welcome to the podcast Steve.

Steve Trim: Yeah, fantastic yeah. Thanks Hannah, thanks for having me on.

Hannah Rosen: Well, it's our pleasure. So, to start out I wanted to know, what first got you interested in using Venoms for drug discovery research?

Steve Trim: That's a great question. A great place to start because it's not always an obvious choice. So, for me, I always, as a graduate, wanted to do applied research, and that led me into a drug discovery position at Pfizer and their, what was their global research European hub in Sandwich E Kent. And most of that time was in pain and neuroscience and key targets there are ion channels and one of the big problems with ion channel drugs. So, you think, like lidocaine, which are really potent, really great, but not too selective. So, you can't really take lidocaine as a tablet. That sort of stops all like sodium channels, whereas injected low plans, I think it's fantastic. And so finding something that was more selective to the pain targets was the key thing in small molecules were struggling and still...still...still do struggle. The academic literature, on the other hand, were finding a whole host of peptides, principally from spiders, what people called tarantulas, we would call theraphosid spiders, but they're actually more selective at these key targets, and partly because we got a bigger interaction surface, and it was with sort of obscure to me. Certainly at the time, I, nothing I'd heard of. And so, we started looking into the literature seeing, you know, it was quite a collection of these interesting targets, the peptides to hit these difficult targets. Then we started wondering, what...what can we do about this? But it wasn't really, the supply line and, it's sort of investigate a few things, but, it's sort of just filed away as an idea really. We've got a few venoms in that could get hold of and it sort of dabbled along but didn't really...really go anywhere. But that sort of sparked an interest for me of, could we do more with these? If we could get hold of the starting material better? And what can we sort of do to try and improve drugs for...for chronic pain patients? And it sort of started an idea bubbling along and actually the, you know, getting ion channel ligands from venom peptides is something I've actually just been invited to write a... a book chapter on. So, it's still a a key thing, key part of...of what we're doing. So that sort of got us thinking about how can these drug like and...and just opened a a new world of...of pharmacology from venom peptides.

Hannah Rosen: Wow, so then what inspired you to start venom tech from there?

Steve Trim: So yeah, it's sort of, as you well, yes. It feeds nicely into that, but there was a few serendipitous things that happened, so I absolutely loved my big pharmaceutical job. You know, I was running the projects as principal scientist, sort of doing the science I wanted to do to achieve the targets of the company, so I was never looking at leaving. However, when Pfizer drastically downsized their operations in East Kent, I found myself facing redundancy. I wanted to stay in the area, so my wife's a principal lecturer. And want to stay in science, but also unsure quite what else to do. A few ideas. And I thought, well, actually, it's not just one company, I guess it's a... a global need to get better drugs to patients where small molecules are failing, and you know just that these venoms could be more useful in other disease areas as well as ion channels. And I had a few core skills, so I was a medical biologist and doing a lot of pharmacology biochemistry as well at that time of, on the... on the targets. I was a safety officer or toxins we... we did have and other stuff we were doing in pain. So, a lot of strong background in laboratory safety, and also, I had an interest in non-dangerous spiders and snakes, which we were keeping as pets and still do now, as you can see behind me, but nobody else can. 


And so I sort of went, hang on a minute, sort of in that typical stereotypical light bulb moment, I've got the three things here to solve this: Problem I understand, biology. Basically, have... have tried to be the customer. I understand safety is very important, and I understand supply. So I set up venom tech by putting those three things together. And we started in the back of the pet shop because that's where the animals were, with a bit of kitchen workbench, sort of words in in my head from a good friend Ed Hawks that works with Pfizer, saying you can do good science and you should if you know what you're doing, and we weren’t far off. So with kitchen work bench and some, a lab kit in the back end, and yeah, captive bred spiders, and snakes, and scorpions that we could find from pet trade wholesalers, breeders, and that's... that's how it started, now back in 2010. And the idea of... of what we set out to do then is still exactly what we do now, is fractionate the venom into their component parts and target them against either ion channels, we do a lot of work in cancer, biology, antimicrobials now as well, and many other targets as a ready-made screening library. So... so 12 years on the vision, the idea is... is still held out. It, it's a yeah, an adventurous road setting out on your own and at that time, yeah, it was just me and I realized that I was spending too much time looking after the animals, and not enough time actually, you know, building the... the business. And so then I had to work out how to employ people and all that stuff, which is a great adventure. Because at Pfizer, if you needed to do something new, you were set on training course first and you had everything at hand to go do it. And it was quite a shock that out in the... the small business world, if you, you know, send off your form to get a small business you... you get the registration form, you've got a business and now you need to be responsible. It doesn't come with a handbook or training, you have to work that out yourself.

Hannah Rosen: Yeah, very intimidating, but I mean I guess you work with highly venomous animals every day, so I assume you're not easily intimidated. So, you found, I... I'm just curious, with this whole thing with the pet shop, did you find a pet shop that like, had a lot of venomous animals just on hand? I can't imagine, do, are venomous animals that popular as pets?

Steve Trim: So in Europe, there's not too many in the UK because we've got a dangerous wild animals act. And rightly so, less to keep control on... on dangerous animals in in the public. But in... in Europe, there's a... there's a lot. There's, you know, there's big trade shows in... in Germany, which is where we sourced a lot of our early animals from, but keeping non-dangerous snakes and spiders, I've been going to this pet shop in Ramsgate for years, in sort of, yeah 7-8 I think by that point. I noticed he had a cobra and a rattlesnake. And yeah, he’d not lost his fingers and hadn't died, so he clearly knew how to look after these. I think the... the scary thing for me was sharing my idea because I... I never worked with anything dangerous. Yeah, I realized that I couldn't do it on my own, and so yeah. And I went a talke to the guy, Pete, who was a good friend of mine and we've been working together for 12 years now, so that I've got this idea, what do you think? And he's like, oh, we're looking for a reason to keep more of these, that's fantastic! I've got a room at the back if you want to do it up. You can make use of it.

Hannah Rosen: That's so funny, perfect match.

Steve Trim: And yeah, that's how that crazy idea started. So, it was a real surprise to me to see, you know, to go around people's houses and the places where people had a a green mamba as a pet where people would have a budgie or a hamster.

Hannah Rosen: That's interesting.

Steve Trim: And yeah, and the license and it was all fine, but it's... it's not until you start looking, you start seeing that, yeah, and then go to the the... the German trade shows and they were huge. And yeah, we bought a load of snakes, spiders and scorpions and popped them in the car and... and drove back.

Hannah Rosen: That's... that's adventurous, I'll say. Yes, so you know you started out doing this drug discovery research, what led you then to branch out to some other fields of research such as, you know, cosmetics and crop protection?

Steve Trim: Yeah, that's a very good question on something that was not on my horizon at all in the beginning. So, in 10 years of... of drug human drug discovery I'd not looked to these other areas, but they're two very different answers. So, tackle the cosmetics one first. So it's a very good friend of mine was a cosmetic chemist and, you know, the classic thing over a beer, he was saying oh, cosmetics would love what you do. That yeah, the power of venoms looks like a powerful marketing story and he said, well, bee Venom's been on the market for 100 years I think, particularly in sort of aging, traditional cosmetics and treatments and stuff, but also there's a synthetic snake peptide called SYN-AKE which is already licensed by that point. And I was like, I know nothing of this market, you're gonna have to show me how. And yeah, if you think it's good, yeah, show me. So we... we set up a just yeah commission only deal if you find a deal, great, we'll, you know, we'll pay for it and we'll see how it takes. Sure enough, he did. That led us to launch SensAmone P5, which is a tricky one, blocking peptide to soothe sensitive skin from sea anemones, because what was interesting in the marketing story there is that, you know, although they like the power of venoms, the Mibelle Biochemistry, who we work with, they said that you know, spiders and snakes are quite scary, what else have you got? So, it became a... a sea anemone because they felt they were sort of a bit more ethereal and... and flowing, and pretty for the cosmetic marketing market. But what we really see is, there's an east-west divide there that our sort of Japanese customs and stuff we're working with really like scorpions because they have a mystical power and their fascination, which for me, is fantastic that you know, they're amazing animals and they're actually more appreciated, and therefore that there's a bias, so we do have scorpion venom cosmetics in in the pipeline as well, but yeah, so it's drug discovery like in... it's in vitro phase and then it takes a a big leap into the bold and goes from in vitro data with some safety and pharmacology straight into human trials, in the loosest sense of the term of the human trials. It's not, yeah, you’re not looking for clinical validation, you're looking to see if people like it and it feels nice, but yeah.

Hannah Rosen: Yeah, that's crazy. And it... it's so interesting too, this divide between, you know, when you're doing the drug discovery, it's such a bigger emphasis on does it work, and then we can rebrand it. Like probably a lot of people who are taking drugs derived from venoms don't know that they're... it's from a venom. But then when you've got the cosmetics, it's so much more of a marketing thing where it doesn't really matter if the snake venom is more effective. If nobody wants to put some snake venom on their skin, it doesn't really matter.

Steve Trim: No exactly, yeah.

Hannah Rosen: That's so interesting. And what about crop protection?

Steve Trim: Yeah, so crop protection... It, for us had more evolved into biopesticides. And this was more organic and driven by our customers because people coming to us saying, you know, we know you're doing, you know, sort of venoms in drug discovery, they'll see me presenting at conferences and stuff, can you help with sort of biopesticides? We know these venomous animals eat pest species. What can... what can be done? And... and... and that shows that there's a... a lower hurdle getting into that market with venoms, because the link between venom and toxin and the therapeutic is... is quite high. Although, you know, it's, you know, toxicity is always down to dose. And a lot of drugs are... are toxic at at too high doses. Whereas, in the biopesticides, these animals, they have spiders eating flies and caterpillars and snakes, eating rodents, and so to go from those venoms to a biopesticide that kills those animals as a synthetic version, it's a... a lower hurdle to... to entry. And so it was people coming to us saying can you do this for us? And they led us into that market.

Hannah Rosen: And are those then, you know, specialized enough, the targets, that they, is there any danger to humans? You know, with a lot of pesticides we get this concern of it being, you know, dangerous to the people who are then working in the crops or in the fields. It is there a lot of, you know, cross over with the targets, or are they pretty much exclusive to the... the insects or the other pests?

Steve Trim: What we found is a lot of selectivity there, and there's a lot of spider venom peptides that are insects selective and don't hit any of the human channels, so you don't have that pharmacology. But also, the wonder of using pesticides is they're biodegradable, so they don't stick around in the environment. They break down to amino acids just like any other protein in the environment does, so you don't get persistence. Importantly also, the bioavailability, so it's a... a challenge that's achievable to engineering oral availability of these peptides into the pests. But to get the second order they're... they're already starting to... to break down because they are biological sequences of amino acids underneath it all. So, you know, in trials and stuff, what we're seeing so far is that a... a lack of bioaccumulation, so therefore it's more environmentally benign to non-target species. And the company Vestaron has got a product out on the market from a a spider venom as a crop pesticide registered in the US and registration in Europe is pending soon, so it's the first. It's great because it's proof of concept. You know, there's people, not just a good idea, here's a... a product that has made it into the US market and is shortly coming over here so.

Hannah Rosen: Yeah, that I mean, that's pretty amazing. So, you know, when you are using these venoms, what's... what's the process like for using these venoms to develop new drugs? Or I imagine maybe it's different for a biopesticide, but you know what... what's the process like?

Steve Trim: So, the process is very similar. Because the key thing is... that stopped people in the past, is starting material. So, drugs like captopril, the... the ACE inhibitor series, a lot of people don't realize they come from snake venom. And, in that case, it was people understanding how this snake venom causes a catastrophic drop in blood pressure as part of the envenomation pathology, so you could see human pharmacology already in... in the bite patient and then it was just a case of how do we extract that and tune that? Whereas, what we're doing is actually separating the venom out into its component parts, into three or four well assay plates. So, screening a venom library is just showing the screening a compound library that's you've selected it based on the target, and then the next day building the lead series is already very similar, but you've got some shortcuts you can make with peptides. Because we've got a... a phylogenetic and geographically diverse species collection, that means you actually end up with a variety of different hits with subtly different amino acid sequences, and that immediately gives you the opportunity to make those modifications for building the lead series. But also because they have proteins and peptides, and most of the sort of drug like molecules are small peptides below about 40 amino acids. And they can be made by solid-state synthesis or... or in recombinant systems, and you can then put in mutations to actually build a chemical lead series and take it from there. So, the discovery phase is very similar to small molecules. 

The development challenge of peptides, you know the Holy Grail of getting orally available peptides, is coming closer. And there are a few, you know, the... the sort of post a compound of cyclosporine that those cyclic peptides have that oral availability in them, and so that's where the the... the challenge is. But also when I got made redundant, Pfizer was saying and... and several other companies were saying, you know we're going to be #1 in biologics as the next thing. So, I was coming out and I said absolutely, perfect, everybody's moving from small molecules to biologics, here we've got biological library. Yeah, it's... it's going to be, you know, Footsie 100 in you know two years times. But what actually happened there was those biologics were antibodies, and that was the next big wave. And so what you see with the antibody therapeutics is a... a patient demographic that, they're happy with injectables, and therefore the... the peptides can also be injectables, just... just the same, so it's opened the door. It wasn't, yeah, it wasn't the wave I was hoping to ride at the time, but that's starting to come now. People are looking at, can we make antibodies smaller? A bit more bioavailable? These sorts of things, and when you start looking at those smaller proteins, you start to come into the realm of the venom peptides with a lot of stable cystine knots in them and bonds and so yeah, there, there's a door open that wasn't there before of the injectables market for the protein, as well as there's a lot of people working on oral availability of... of peptides and some that have achieved it, which is really, really promising through a variety of different ways. And we're doing some work ourselves actually looking at protease stability and absorption I think of... of peptides. So that's a bit, that's different, so the discovery phase is... is very similar very.

Hannah Rosen: Wow, yeah. That's so interesting just to think about all of the different things that have to come together to adopt something new is, you know, I... I didn't even think about the injectables aspect of it is, you know, people... like what routes are people OK with for taking their medication? I... that's really... it's really interesting perspective. So, do you think that, that's part of why venoms for drug discovery isn't more common? Are there other reasons?

Steve Trim: So I think that's that is... is part of it. You know the Lipinski rule of five? Everybody's going for all available small molecules where you can get target engagement and good pharmacology with your small molecule. Then that's obviously a... a better route where people can just take a tablet and it's a lot easier, a lot less invasive in people’s daily routines. But with the antibodies and injectable side of things, it does open up other routes, but I think there's a a couple of things to this question, and one is, a lot of people don't realize there's seven or eight drugs out on the market that have come from venoms, and some of those are very close to their original native peptide. So captopril, as I mentioned earlier, was a... it's a small molecule mimetic, a peptidomimetic if you will, that binds the same targets of the... the angiotensin converting enzyme. Whereas on the other end of things there is Byetta, which is a glucagon like peptide from the venomous lizards. So, people don't realize that there are some venomous lizards out there, not many, but a few, and this has a much greater plasma half-life than the... the human peptide. And this comes down to a... a benefit of biology and serendipity for us by using venoms as drug discovery tools, is that a venom is secreted into the venom gland and it waits there ready for action. There is a slow turnover, but essentially it's waiting ready for action. The glucagon like peptide in humans is a... a burst signal that's evolved to be rapidly metabolize, because you don't want that signal persisting, and so the stability of venoms because they are secreted and wait ready for action basically. So yeah, the Byetta, the GLP one from the gila monster, already had the superior stability compared to the, the human molecule that hit the same target. So, it was easy to then, you know, make use of that and then Prialt, which is, so the compound name is ziconotide, it's a calcium channel 2.2 blocker from venomous cone snails. And again, it's a really stable peptide for the same reasons, and it potently blocks calcium channels, and there's a wonderful bit of sort of serendipity here that the... the animal evolved this for stopping its prey principally, and it just so happens that those sort of ion channels that evolved to stop its prey, the sort of muscular calcium channels, are actually used in pain... pain processing in humans, and because you've got a a soft squidgy snail that has taken an opportunity beyond its normal means to feed on bony fish, the only way it can do that is to kill it very, very quickly. And... and so you have a very potent neuromuscular block, and it turns out that part of that actually blocks a pain specific pathway in humans, and so that is a... a recombinant version of the native peptide that is made as a... as a drug. So there's, you know, the opportunity out there, and I think part of it is people haven't thought to... to look, but also it's all taken sort of new advances in peptide chemistry and drug delivery to open up more opportunities with venom peptides.

Hannah Rosen: Yeah, that's... that is really cool. So with... when you do the... the... when you create the recombinant peptide, is that then, are you trying to kind of tone down the effect on the... the muscles and make sure that it's only targeting the pain receptors, or you know, like what do you... what do you do to... to kind of eliminate the potentially toxic effects of the... the peptides.

Steve Trim: With ziconotide, it was actually fractionating the venoms and finding which component was actually selective, and the... the... the drug itself was selective for Cav 2.2 which is a... a... a pain target in humans within the spinal cord. And the challenge there, that they developed the drug to be entropical delivery so it's a mini pump infusion, so it's only licensed for chronic intractable pain because you need a surgical implant to deliver the drug, whereas if it was in the systemic circulation, it showed some cardiac toxicity. So, by keeping it within the spinal cord and within the CNS, then it evolve... it avoids that exposure. But, in general, with other... other peptides we can do structure activity relationships just the same as is done with small molecules, but we do it at the peptide sequence level rather than the reactive group level, because that just means that if we find a... a particular amino acid that is problematic, we can just swap it out and you know, from from our point of view, we get a lot of peptides made with a third party supplier, and it's just an e-mail with a different line... a different letter in one place and say, can you make this one instead? And it turns up and we can... we can work with it. That was a really good example in the... in the literature looking at modelling of a... a scorpion peptide that blocks calcium channel KV 1.3 for inflammatory disorders. There is a closely related KV 1.1 which is a neuronal target, and therefore a bit of a challenge. That's, you'd... you'd get, you know, off... off target effects and... and toxicity which would reduce your therapeutic window. And through molecular modelling they were able to realize there was one amino acid that sticks in the pore of KV 1.1 and interacts with the channel, but it doesn't in 1.3, and so switching that arginine for an alanine, it reduced the reactive group and therefore got a 2000 fold selectivity over the of 1.3 / 1.1 and is now into the clinic.

Hannah Rosen: Wow, that's just incredible. That's so cool.

Steve Trim: So, there's... there's definitely more coming through.

Hannah Rosen: Yeah, I'm curious, you know, it's become a big trend nowadays in drug discovery to develop machine learning algorithms or models to try to kind of jump ahead and identify novel targets for like small molecules or or other things. Do any of these algorithms exist to identify novel targets for these peptides or proteins found in venoms?

Steve Trim: So, that would be great if we could just sort of type in and go, I've got this venom, what type does it hit? Unfortunately, not yet. I've definitely had a few conversations with people at conferences. Who have opportunities in this space, but the diversity of venoms is... is huge. And it's, yeah, it's comparable to small molecule libraries getting up into the millions of peptides. So, it's not so much of a repurposing where you'd look for what target does this venom hit, where you'd look the other way round and go, I've got a validated target, which venoms hit this? Some of the SAR selectivity and sort of bioinformatics tools can... can do that, and those techniques that we use when people come to us with a new drug target and say, you know, I've been, you know, I've often, for typical cases, I've screened this my molecular library, I've got no hits on this target. Have you got something that can help? We can sort of get involved in that side of things but what's happening now is a move to rational drug design and optimization. So, when you've got a ligand that hits your particular target, you've got to understand the protein sequencing, the structure, and using a lot of cryo-electron microscopy, it's built some wonderful structures, even with big complex ion channels. And through that modeling you can use the AI to understand the interaction between the amino acids, and then make those modifications that improve the binding pocket fit or avoid a binding to an off-target channel, and so the AI is being used in the developmental... so drug development stage rather than the sort of hit ID phase from what I'm seeing. 

And this is something that really struck me early... early on that, and my background's in genetics, I have a degree in genetics, and I was initially employed for doing gene expression profiling and... and stuff to these models. And so I'm used to, you know, DNA is great, and... and nucleic acids are fantastic, you've got binary pairing, if you know one sequence, you can just write down what the other one is so that they'll bind to it. And it's... it's just that easy. When I talk to my wife and I was sort of thinking about setting up, and so she's a biochemist, and I go well, so what's the rules for protein? Which, I mean, acids bind to each other ones? And she was like, we don't really know. What do you me we don’t know? Surely there's just a rule! And it's like no, proteins... proteins don't work like that. And so, I've been trying, and I often challenge people who are building AI training sets and stuff, can you teach it what is the pairing rules of amino acids and can we just sort of start there to... to predict which... which sequences bind to which targets? And that would be absolutely amazing, but we're not there yet. It's definitely a... a work in progress, and it's an absolute wonder of biology because you can screen against a target and find often, find hits that are closely related and that makes sense. And then some, but there's no sequence in common, and yet it's still engaging the same target in the same, with the same pharmacology, and that's to do with the... the atomic structure of how that protein is displaying itself, how it's folded. That's where that complexity comes. So, I... I would love to have had that sort of 1 to 1 amino acid pairing rule because it would sort of make everything so much easier, but it is still a Holy Grail to aim for.

Hannah Rosen: Sure would solve a lot of problems and if you could figure that one out.

Steve Trim: Yeah, there'll be a lot of people jumping on there very quickly because you could just type in the protein sequence you wanted to... to hit your target and... and away you go, it would be fantastic. So yeah, some... some good tools out there. People are looking at free energy perturbations in the binding pockets and things which are allowing that structure guided drug design to improve the... the peptide hits. But we're not there, as predicting entirely new ones yet.

Hannah Rosen: I'm curious, so this is a little bit of a different track, but I understand that, at least when it comes to snakes, there can be a lot of differences, variety in the venom composition, not just between different species, but even within the same species with... between different individuals of the same species. So, is there, when you're... you know, you’re producing these drugs, is there any way to control for this variety between different individual animals so that you can kind of create some consistency with the venoms that you're... you're developing? And is this a problem with other venomous animals as well, like in spiders?

Steve Trim: Yeah, there are differences, and it... it stems from our... our approach being, humankind needing to put things in boxes, and an evolution being continuous. But there's a a gradation. Evolution hasn't stopped, the species we've got are just a snapshot in time that we're currently looking at, so you get geographical differences on individual variation within the venoms. And so, the way we control that is to have the animals on site. So, we collect venom from the same animals every time, so we know exactly the provenance of those venoms and control for that... that... for that change as much as possible. There are examples out there of... of locality differences of single amino acid changes that can make differences in... in... a in a binding profile. If you've not gone back to the same stock you might not see that same hit again.

Hannah Rosen: Could this be a problem then if, you know, when producing medications at a large scale, drugs that are utilizing venoms, is this create a issue with batch consistency?

Steve Trim: No, because as soon as you get to drug scale, you'd make it synthetically or recombinantly. So yeah, actually using the... the... the whole venom or... or the... or venom fractions really just part of the discovery phase allows you to find something completely novel, understand its sequence by mass spec, so we use a double digest, and intact mass spec to understand the mass and sequence. And then from there you can make it. And once you've got synthetic control of it, you don't need to worry about the... the animal side of things, and that's for a couple of reasons. One is sort of practicality of... of, let's say, batch consistency and... and control from the drug discovery point of view. The other is, you'd have to have massive warehouses of the same... the same animal and people to look after them and... and extract their venoms to... to produce a clinical trial grade venoms, let alone product launch scale. It's just not... not practical, so we moved to synthetics very early on.

Hannah Rosen: That's cool, so you're basically just using the live animals as a way to literally discover what peptides they have, and then once you have zeroed in on one, then you can just use it as a blueprint essentially to... to manufacture them.

Steve Trim: Yes, exactly yes. So, it is, you know, we're using the animals as the chemists to make new compounds that we've not seen before, we don't know about and new pharmacology. And then once we understand that, we can then make it in vertically or recombinantly to take it forward into building a lead series and those sorts of things. So yeah, it is a discovery tool. So, venom library is usually though with snakes, sort of pairs, and with spiders for sort of five or fixe,s some of the smaller spiders with some 10 or 12 of each species for just producing enough for the compound libraries follow up on ID. And then the bulk work is done in a... a human controlled manner, either recombinant production or... or synthetic.

Hannah Rosen: I'm curious, so it, I mean, this sounds like good news as far as the ethical considerations going that you only need a small number of these animals in order to help with this drug discovery process, but you know, what... what are the ethical concerns potentially surrounding using animals to produce these venoms and... and what are you guys doing to mitigate those?

Steve Trim: Yeah, it's... it's a good question. The key thing for us is that essentially happy animals produce better venoms, so it's not just a... a moral need to... to look after them. Well, there's a... a business need as well, and so if you're collecting them from the... from the wild, obviously you've then got the... be aware of the biodiversity control and access and benefit sharing versus the... the Nagoya Protocol, you can't just go to a country and acquire a load of animals to... to make a new drug from, and rightly so, you know, we need to protect these... these species. And then you've also got the connection of trade in endangered species, the CITES as well, which is why we use captive bred stock. So, we've got animals that have come from additional captive bred sources. And with regards to the, sort of, ethical treatment and husbandry side of things, we actually won an award early on for improving husbandry of arboreal tarantulas and showing they respond to environmental enrichment much like rodents do, and... and by giving it a three dimensional space to live in, a sort of complex 3D structure, mimicking the tree branches, they... they sit at at rest more often, and we got better venom from them. Yeah, so. And we also, yeah, so we won the most significant impact on animal welfare award back in 2012 in the Institute of Animal Technologists, which was great.

Hannah Rosen: Yeah, that's wonderful. That's cool. And that's interesting that... that happy animals equals more venom, yeah? That's, I mean, it makes sense, but....

Steve Trim: Yeah, so we sort of milk them like a herd really, I suppose. As... as a sort of a... a simplistic model of how we manage the collection.

Hannah Rosen: That's really neat. I'm going to shift gears quite a bit now and ask you a little bit about this venom inspired hot sauce that you invented a few years ago.

Steve Trim: Yeah, I wondered If you going to bring that up. Yeah, it... it's fantastic. It came out of a... a presentation I was giving to the Institute of Directors here in the UK. The local group of them and they were, I was the only scientist presenting. So, to explain how we use venoms for drug discovery, I took a step back and explaining sort of what drugs are without, you know, moving away from medicines and making that distinct. And... and so I used the example of... of capsaicin. That is the hot component of chili. It activates the TrpV1 receptor and causing thermal pain, so the... the taste we have is a... is a thermal pain sensation. It just so happens that us humans seem to like it, and so we sort of, you know, explain that capsaicin is a drug that the plant produces to stop predation, and it binds to this receptor, so, and this is how we... we... we have hot... hot sauce and... and chilies are just a... a weird thing in the human wiring that we actually like this... this pain sensation. And then I went on and made the link. So, there is a couple of spiders, and my favorite one being the Trinidad chevron, so this is a arboreal tarantula from, as the name suggests, the Caribbean islands of Trinidad, and its venom contains a TrpV1 agonist, so the... the venom peptide opens the same channel as capsaicin, in slightly different binding sites, but have the same activity. So, you know, I said that, you know, what we think has happened is that this to the spider to defend itself against mammals has got a venom that feels like an injection of Tabasco sauce. So you've got a direct pain causing mechanism as a... as a defense, because venoms have evolved for both prey capture. And... and... and... I then went on to talk about other venoms and how we use them as drug discovery tools because they hit other receptors and those things. 

At the end the host came up to me and went, we really need to make a venom chili sauce, that's a great idea. And I was just like no, that's a silly... that's a silly idea, we can't... we can't do that. And he... he basically didn't let it lie and what we ended up doing, because of the sort of, he actually went to the Food Standards Agency, like what would it take to produce a... put a venom in a chilli sauce? And they... they didn't get to say go away. That's great, they, you know, there's a... a set standard of toxicity testing you've got to do to put a new and non-food item into the food chain, rightly so. But that was pretty expensive and not the way we sort of looked at doing because also, the amount of venom we would need to do it... so it was based on the idea that because the venom acts at the same receptor as the chili, and therefore the venom acts like chili sauce, and therefore capsaicin acts like venom. You could sort of flip it on its head so it is a branding story that explains how venoms activate TrpV1, made into a... a really tasty chili sauce. So then we sort of branded out with a nice spider and a caricature of me I got a friend to draw. As a... as a venom chili sauce that ended up being called Steve’s Scientific Sauce because Stephano, who came up with the idea, thought that would be a... a funny thing to do. And it was. And so for us it was just a... a little local thing to, a bit of interesting branding and a few quid on it. Not much, but just, I mean, to make it worth doing. And that was that really. It's just a sort of a little local idea and you know, sort of selling a few in the Eastern Area, UK where we are. 

And then I was on a train to a conference, I remember distinctly the Biopesticide conference, and I thought, well, I'll just sort of look through and sort of plan my day on the... on the train on the way into London. And my phone was absolutely red hot, and what had happened is that our website and branding somehow had been picked up by LADbible, which is I guess is how you may know about it, and it just blew out of all the bushes. So, we had people from... from all around the world phoning us up wanting like, palettes of this stuff. And now, we were making it in a little farmhouse, this boat kitchen. We were sort of, you know, baking batches of 50 or 100 bottles, not tens of thousands. And it... it just took off beyond what we uh, prepared for because it's a... it's not a... we're not a food company, and so it was a couple of months of just craziness doing radio and TV interviews around the world talking about the... the... the new hot sauce, which was very funny indeed. Unfortunately, coming into... to COVID, we had half a batch left. And we... we sold them out to our local distributor and people at the Discovery Park, where we're based in East Kent, and we've not made any since. So we're thinking that we might make some again for... for a conference, branding a conference trade stand, but sort of bit more low key because we know it's so had that potential to just blow up. And if... if we, you know franchised it out or something to a big wholesaler, it's something it could... could take off, but it's... it takes our... our focus off of the... the drug discovery and crop science. So it's something we're not looking at doing. But yeah, just a hilarious couple of years. And let's say, like you mentioned yourself, that it still goes on and people still ask me. I've done some great after dinner speeches at conferences and things based on the... the pharmacology of... of venom and... and food and focusing around the... the chili sauce. It's... it's a story that captured people's imagination and excitement, and yeah took off beyond anything we could have expected.

Hannah Rosen: Were you ever... were you ever irritated during that time of, like, you spent all this time developing all of these really important, you know, drug discovery, your crop protection, and the thing that like, people care about is this silly hot sauce that you made on a whim?

Steve Trim: Yeah, there are moments where it's just like, what are we doing? Why don't we just make hot sauce? But also, it opens conversations. And still now, oo you know, 2-3 years later talking to people, going to conferences and when they see the Venom Tech. name they go “Oh, you guys made the chili sauce” so it... it's still opens doors for us now for two years since we stopped doing it. So it is, yeah, it's... it's a great marketing story. I think in hindsight you can say, you can never really predict the future, but if we'd been ready for the... the scale it got to, it could have made more of it, but it just caught us by surprise because it's just a a silly idea we were doing on the side.

Hannah Rosen: Yeah, I guess you just never know, but it's funny it... it goes to show, you know, people don't want to put spider venom on their face, but apparently they're happy to put it in their mouth.

Steve Trim: Yeah, that is quite a surprising thing.

Hannah Rosen: So you know, we're... we're unfortunately... we're starting to run out of time, but before we go, I want to know, you know, if there's a researcher out there listening to this podcast whose heard all of this, and now they're super interested in starting to use venoms for their drug discovery. What do they need to know to get started?

Steve Trim: Then the key thing is that a venom peptide library can act like a small molecule library. We produce them into 384 plates, they are echo compatible, so we won the ELRIG Technology Award back in 2012 for showing we've got acoustically dispensable venom library, so they can go straight into an HTS screen for... for hit finding just the same as small molecules. The added benefit, and I think is more of a benefit by it for biologists rather than chemists, is that you don't have to use DMSO and so they are aqueously soluble so you can use your assay buffers, which is much kinder to your cells, you're doing cell based assays. For instance, because DMSO obviously has lots of different activities you need to keep the concentration down low, so it has that... that benefits. And the other thing is that the... they are larger molecules so they have larger interaction. And some of the data we produced, the poster conference post a couple of years ago, showing that we screened our venom library with a high throughput times resolved fluorescence, some of the HTRF assays for PD1 is a protein-protein binding, and it wasn't a surprise to us, but a lot of people go “oh wow, that's really cool” when we're showing you later that we got interactions because the... the peptides that have a large... larger interaction surface, they can block protein-protein interactions quite well because ultimately, it's what they've evolved to do. So it is, yeah, it's just plug and play. Use it like a... a compound library. And people say, “oh, you're gonna have to talk to our safety people because there's venom.” It's like well, you should talk to your safety people with a new compound library too. That's, you know, the amount of venom that we're using in the... in the library for a screen is tiny compared to the amount of snake will in... in... inject, so they are just as safe to use as a... a small molecule compound library. Yeah so, give it a try. Basically we challenge people to throw new targets out as new ideas. We did some work on epigenetics and bromodomains. There's nothing in the literature connecting venoms and bromodomain signaling, and we found some selected hits in there by just trying it and going to see. As was with PD1 and any sort of protein-protein interactions. Again, there isn't the literature, it's... it's a Venom Tech internal that said that if this was a... a target to add. So, if you've got a... a target and no one else can help, give us a shout. Because the... the venom peptide libraries have a, yeah, have a high, high hit rate and I like being challenged with targets that we've not tried to prosecute before.

Hannah Rosen: That's fantastic. Well Steve, thank you so much for taking the time to come and talk to us, I learned so much. This was a super, super fun conversation. But yeah, so if anybody out there is listening and wants to give Steve a challenge, then I would say reach out to him. And... and Steve we hope to see you at some future SLAS events where we can keep this conversation going.

Steve Trim: Yeah fantastic thanks. Thanks for the invitation. I'll definitely be coming over to SLAS in San Diego next year, so look forward to catching up with people there.


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