Treating Epilepsy With Spider Venom?! - Glenn King, Institute for Molecular Bioscience, University of Queensland, Australia
Glenn King discusses his research in epilepsy and how animal venoms can be utilised to develop new treatments! He explains the mechanisms of ion channels, the diversity of venoms, and the process of identifying effective compounds. The conversation also touches on the challenges of drug development, the potential for personalised medicine, and the future of epilepsy treatment.
Reported by Torie Robinson | Edited and produced by Carrot Cruncher Media.
Podcast
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00:00 Glenn King
“So, we started exploring these venoms in the mid-90s, and I, like you, thought “Why does a spider need more than a couple of insecticidal compounds to kill its prey? Surely! I was absolutely shocked when I separated the venom for the first time and saw that there were literally hundreds of components in there!”
00:17 Torie Robinson
Fellow homo sapiens! My name is Torie Robinson, and, welcome to, or welcome back to: Epilepsy Sparks Insights.
Now, who relates spiders to epilepsy?! It turns out that spiders (amongst some other cool organisms) can contain amazing compounds that could help stop seizures in people with a refractory epilepsy! Today we hear all about itfrom the cool biochemist, lead researcher, PI, Glenn King!
00:43 Glenn King
Hi Torie, lovely to be here. My name is Glenn King and I'm a professor in the Institute for Molecular Bioscience at the University of Queensland. So it's a research institute of the university.
00:54 Torie Robinson
And what do you actually research? What's your job?
00:56 Glenn King
We're interested in human diseases, what I'd broadly call neurological diseases, where the underlying defect is in this receptor called an ion channel. These are things that sit on the outside of your nerve cells and let ions like sodium, potassium, calcium across many diseases are actually caused by defects in those ion channels, and of course, one of those diseases is epilepsy! But, our unusual take on this is that we use animal venoms as a source of compounds to correct those defects. And you may say “Well why animal venoms?!” Turns out that after 20 years of researching on animal venoms, we've realised what they're full of (particularly invertebrate venoms, things like spiders, scorpions, assassin bugs, centipedes); they're full of molecules, little proteins called peptides, that actually modulate the activity of ion channels, the very things we're interested in. In fact, they're the best known source on the planet of things that will modulate the activity of epilepsy ion channels.
01:59 Torie Robinson
Of any other species that we know of; these guys, these are the creatures that do it?!
02:03 Glenn King
Absolutely. They're the creatures that do it. And the cool thing is they're some of the oldest creatures on the planet! So spiders have been...
02:09 Torie Robinson
I was just thinking that!
02:11 Glenn King
Yeah, yeah, they've been around a long time. Like spiders, centipedes have been around for 400 million years! So they've been actually working on the problem of making these ion channel modulators for a heck of a long time! And so they've tuned them up really nicely for us!
02:25 Torie Robinson
How does this product, how does it benefit these species? Like, why do they have it?
02:31 Glenn King
Yeah, great question, Torie, yeah! So, a lot of these things are, actually… either will paralyse or kill insects, so they have the same ion channels as we do (or closely related ones), but they use them in different ways. So, something that might kill an insect might actually be beneficial for us. So they have a purpose for them but we are repurposing them for something different.
02:57 Torie Robinson
So, this is something brilliant to come out of the evolution of these species because it's a benefit to us.
03:04 Glenn King
Absolutely. Look, there's a classic example: there's a drug at the moment that comes from a deadly cone snail. So the cone snails are these little venomous cones, slow moving molluscs, that live at the bottom of the ocean, and believe it or not, they catch fish! And the way they catch fish is they have venom, and they actually (this sounds like science fiction, but it's true!), they load it into a harpoon and they actually shoot it at the fish to paralyse the fish. Can you believe that?
03:32 Torie Robinson
That is so cool!
03:34 Glenn King
And the cool thing is, in that venom of that cone snail, there's a toxin (it's a toxin in an ecological context), that actually paralyses the fish by paralysing the neuromuscular junctions. Now, we have the same channel, but in us it's in the spinal cord and it's used for transmitting pain to the brain. That same molecule's now being developed as an analgesic for humans, because it's a painkiller in humans (but deadly to a fish)!
04:03 Torie Robinson
It’s amazing. So, we're getting stuff from a snail (for example), that is benefiting us as a comp.. I mean we're all related somehow, right - but just like, that dis- there's that distance between us yet…
04:15 Glenn King
It's huge, yeah.
04:17 Torie Robinson
Which type of spider is it that you are working on or with?
04:20 Glenn King
We're pretty agnostic about the source of the ion channel modulator. So we have a collection of more than 500 different venoms from different species of arthropods around the world. So, as I said, they'll be spiders, scorpions, assassin bugs, caterpillars, bees, wasps, ants, whatever. And when we have an ion channel that we want to target, we'll screen our venom collection against that ion channel looking for a venom that might have the activity we're looking for. The hard part is when we have a venom that we know has something in it that has the right activity, we've got to find that thing, that compound in the venom. And some of these venoms can have hundreds to thousands of compounds in them! So, now we've got to do a deep dive and say “Which is the molecule that has the activity that we're really interested in” - and that's where most of the hard work is.
05:11 Torie Robinson
Gosh, yes, I just have to say, I feel so ignorant! You, know, the more you learn, the more you realise you don't know. And I was, you say “Oh, I have to go through all these different compounds within the venom” and I was thinking “Yeah, I never even thought about that. That's… okay… a lot of work!”! I mean, how many different compounds or things within a venom may there be for you to have to identify that one thing?
05:33 Glenn King
I mean, to give you an extreme example, the spider that we've worked with most is the Australian Funnel-Web spider, particularly one found on K'gari (which is the biggest sand island in the world, just north of Brisbane) and that spider has more than 3,000 peptides in its venom. So, when you're looking for a molecule that has a particular activity, you've got a lot of work to do to narrow it down to find the right compound!
05:56 Torie Robinson
Wow.
05:58 Glenn King
And look, I was the same as you; when I started working on venoms, my interest in venoms initially was to try and develop more eco-friendly insecticides! And I thought “Well, spiders are the best insect killers on the planet, surely, they've worked out the chemistry and pharmacology of making insecticides a long time ago.”. And so we started exploring these venoms in the mid-90s, and I, like you, thought “Why does a spider need more than a couple of insecticidal compounds to kill its prey? Surely! A dozen at most, maybe!” and I was absolutely shocked when I separated the venom for the first time and saw that there were literally hundreds of components in there!
06:34 Torie Robinson
It sounds really …like, really impressive, and quite humbling really, just to hear you talk about it and the diversity of these venoms.
06:42 Glenn King
Yeah, they’re amazing, absolutely amazing. And even the latest venomous animal we've been looking at is caterpillars! There are actually quite a lot of venomous caterpillars!
06:48 Torie Robinson
Huh!
06:49 Glenn King
So, they’re venomous at the caterpillar stage because they're very sedentary and very easy to be preyed upon. They're not venomous as adults though, so when they turn into moss and butterflies, they're not venomous anymore. And very few of them have had their venom looked at and it turns out they've got really interesting and complex venoms. And so, we're adding those to our venom collection as well now!
07:12 Torie Robinson
So, these venoms, you've been testing them, I believe, in upon epilepsy in rodents, is that correct?
07:19 Glenn King
In the past, that's right, we would have a receptor that we're interested in (an ion channel), we'd screen a venom, we'd find the venom that was working, and we'd isolate the component from that venom that did the job… And so, this was all in vitro work, just testing it directly against the channel. And then you're right, then once we got something that we thought was good, then we tested in a rodent model of the epilepsy.
07:41 Torie Robinson
And what were the results of that?
07:43 Glenn King
So, the original one we worked on was Dravet Syndrome, which as you probably know is a deficiency in a voltage-gated ion channel called NaV1.1. And we were looking (so, patients have less of it than they should)… and so, we're looking for something that would just spice up the activity of the remaining amount of NaV1.1; what we call an “agonist” in pharmacological terms. And we found this beautiful, very selective molecule that just potentiated the activity of that channel. And so, we tried that in a mouse model of Dravet; it's a very severe Dravet model in the genetic background we have it in. And so, the mice start to seizure at about postnatal day 17, it gets pretty bad by about 19 and they rarely last more than a week (it's a very, very severe form of Dravet). So, we started infusing this peptide from a tarantula into the brains of these mice at day 19. Within 4 days we'd eradicated the seizures completely and the mice survived (unlike the control mice who all died within a week). So, we're able to pretty much completely eradicate seizures in that model of Dravet.
08:55 Torie Robinson
Were there any side effects to treating them with this venom?
08:58 Glenn King
Well, we only did it for about a week or so, so we don't know whether there's anything long term. And this is where we ran into trouble because this was done just prior to COVID.
09:08 Torie Robinson
Ah….
09:08 Glenn King
We decided we needed a molecule that had a more long-lasting effect (we didn't think the effect from that was going to be long enough clinically). So, we developed a better molecule. And when it came to thinking about testing that in that rodent model, COVID happened. And of course, we could not get access to animals during that period of time. That's when we started thinking about perhaps a better way of doing it.
09:30 Torie Robinson
Tell us more! So, your better way of doing it…?!
09:32 Glenn King
I mean, the problem with the rodent mods of epilepsy is, as you know, that for each particular type of epilepsy… I guess we should pull back a bit and say (you know, for people who aren't used to talking about epilepsy); there are many, many different types of epilepsy. And even within a class of epilepsy, say, Dravet, there are many hundreds, even thousands of different mutations that can lead to that class of epilepsy. And so...
09:56 Torie Robinson
Mm.
09:57 Glenn King
…when you test a rodent, when you use a rodent model, you're testing just 1 mutation from that patient group. So, you know, it might work for that mutation, but maybe it's not gonna work for all patients. And so, what we can do now is take advantage of the revolution in stem cell biology. And we can take blood samples from individual epilepsy patients and from them we can derive a brain organoid, a little mini-brain, just a few millimeters that contains all the cells that are in the human brain that talk to one another in the way that cells talk to one another in the human brain. But the good thing is we can make those organoids from lots of different epilepsy patients (all with the same nominal epilepsy, but with different underlying mutations). And then we can actually take this little mini-brain and we can put it on something called a multi-electrode array (all it is is something that measures the electrical activity of that brain). And we can see for the epilepsy patients, it's a bit different; it's overexcitable. And then we can just put our candidate drug on there and say “Does it correct the phenotype in that mini-brain from that patient?” and if does, we can say “Well, that's great. But what about the 5 other patients that have that epilepsy with different mutations? Does it correct the phenotype for those ones as well?”. So, we can look at a broad array of patient mutations now and develop more what we would like to call personalised medicines that we know are going to work for that particular epilepsy. So, I should make that point: we're not interested in making generic epilepsy drugs, we're interested in making personalised epilepsy drugs for specific types of epilepsy.
11:26 Torie Robinson
But I have to say as a person with an epilepsy, that sounds beautiful to me. Having a drug that is specifically, well, basically designed…
11:36 Glenn King
Correct.
11.36 Torie Robinson
…literally, right, for…
11:38 Glenn King
Yep.
11:38 Torie Robinson
the individual. So…
11:40 Glenn King
Yes.
11:40 Torie Robinson
…and I presume with that, it's likely to be (one would hope), more effective in seizure control, but also, I imagine, like, side effects; you'd be looking at those to minimise those for, for people as well, right?
11:54 Glenn King
Correct, yeah. So, we're working with peptides, not small molecules. So, small molecules tend to be easy to make and permeable to the brain, so they're good from that point of view. But because they're small they often bind to lots of different things (because they can fit into lots of crevices in all sorts of receptors). So, that's where you get the side effects. The peptides we're working with are bigger and they bind to a greater surface on the receptor and therefore they tend to be much more specific, usually more potent, and also much more specific (so you don't get the side effects that you were talking about, that's for sure, or least less likely to).
12:32 Torie Robinson
So, you've got your organoids;...
12:34 Glenn King
Yes.
12:34 Torie Robinson
…lots of people will say (especially if they're not so familiar with research) “Okay, cool! How long before, now with the organoids (and assuming, like, of course it's going to be successful!) before it gets to humans?”! So, could you just break that down for us a little bit and tell us where we are in the grand scheme of things please?
12:51 Glenn King
Yeah, yeah, look, it's still a long way to go. what we have in the case of Dravet, for example, we have a drug that we know works in the animal models and it also works in the organoids. But then you have to do a whole bunch of safety testing, of course, before you even go into clinical trials. And then there are 3 stages of clinical trials; so, called: Phase 1, 2, and 3. Phase 1 is just to look at the safety of the molecule in (usually) healthy volunteers (not necessarily epilepsy patients) and that alone can take a year. And then you've got the 2 Phases where you're looking for efficacy: Phase 2 and then a much bigger Phase 3, and that can take up to 3 to 5 years. So, the whole process from discovery to having a drug is 10 years plus typically.
13:40Torie Robinson
And not all of them make it, right?
13:43 Glenn King
Absolutely.
13:44 Torie Robinson
IHowever, I always say, though: we do learn a lot about diseases in the process, and that information can be used in other studies or to develop an idea further.
13:56 Glenn King
Absolutely, no question about that. You learn from… they're not necessarily errors; it may be that the pharmacology of the rodent doesn't translate fully to humans, right? So, your drug might work brilliantly in a rodent… I mean, cancer has been cured in rodents so many times but it doesn't always translate to humans, unfortunately, and that's the risk you always take.
14:15 Torie Robinson
We such frustrating organisms aren't we?
14:18 Glenn King
Hahaha!
14:21 Torie Robinson
The over complexity does my head in (excuse the pun)!
14:24 Torie Robinson
Thank you so much to Glenn for making epilepsy research cool and relatable, and for sharing with us his work using both rodents and organoids!
Also, if the term “organoids” rings a bell, that might be because a few weeks back we also chatted with the fab clinician and researcher Patrick Kwan - who is working with Glenn! Check out that episode here if you haven’t already!
You can find out more about Glenn and his work on the website torierobinson.com (where you can also access the podcast, the video, and the transcription of this episode), and if you haven’t already, don’t forget to like, comment, and subscribe to the channel, share this episode with your friends/colleagues/family members(!), and, see you next week!
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Glenn King is a professor, a biochemist, and a structural biologist whose expertise lies in translating venom-derived peptides into human drugs and bioinsecticides. His lab maintains the most extensive collection of venoms in the world, which includes venoms from more than 600 species of venomous spiders, scorpions, centipedes and assassin bugs.
Glen’s primary focus is on the development of drugs to treat three pervasive nervous system disorders: chronic pain, epilepsy, and stroke. His lab is working closely with several pharmaceutical companies to develop drugs for clinical use.
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LinkedIn: glenn-king
The University of Queensland: Glenn King
Institute for Molecular Bioscience: Bugs & Drugs
The Florey: using-lab-grown-organs-to-test-new-spider-venom-epilepsy-drugs
ResearchGate: Glenn-King
Genetic Epilepsy Team Australia (GETA): Glenn King