Interviews

Professor Irina Vetter on pain, stinging trees and ion channels in Australia

BY      |     June 7, 2021

Irina Vetter is a Professor of Pharmacology at the University of Queensland, Australia. She is also the group leader of the Sensory Neuropharmacology Lab, a NHMRC R.D. Wright Career Development Fellow and the Director of the Centre for Pain Research at the Institute for Molecular Bioscience, University of Queensland.

Other than that, Irina is a brave scientist who can deliberately sting herself with a stinging tree for the sake of science. She characterizes herself as “interested in everything”, loves reading books, looks forward to seeing people again at conferences and hopes that her research might have an impact on patients.


I spoke with Irina Vetter about her career, pain research, venomous stinging trees, ciguatera disease, automated patch clamp, ion channel research in Australia and more. I greatly enjoyed talking with Irina and happy to share this interview with you.

Have a good read.



Irina, let me start by asking you about your academic background and sort of trajectory by which you arrived to the place you are at now. I know that you lived in Germany and then moved to Australia. Why is that?

Yes, that’s true, I was born in Germany and lived near Ulm until 1999. I moved to Australia right after high school cause I wanted to continue my studies in an English-speaking country. The options were obviously the US, the UK or Australia. I came here on a holiday and I really liked the weather. Actually, that was a major contributor to my decision to stay here. Warm and dry winter, hot and wet summer with thunderstorms in the afternoon – I’m still enjoying the weather, 21 years later.

I really enjoyed research and I loved being able to correlate the results I see in a dish with what I experience every time I have a hot curry.

IRINA VETTER

I always knew that I wanted to work in drug discovery and I had been particularly interested in natural products. And so, I studied Pharmacy which gave me fairly well-rounded view, I suppose. During my Honours year, I also did a research project in the lab of Prof. Peter Cabot (School of Pharmacy, University of Queensland) where I first got exposed to capsaicin and TRPV1 channels, and was hooked on sensory neurons and ion channels ever since then. I really enjoyed research and I loved being able to correlate the results I see in a dish with what I experience every time I have a hot curry.

After my undergraduate degree, I worked in a hospital pharmacy and then community pharmacy for a little while before I decided that I would like to do research. And so, I got back to Peter Cabot’s lab and did a PhD on functional interactions between TRPV1 and the mu-opioid receptor, which I have to say there wasn’t very many (see here).

I did my first postdoc at the Queensland Brain Institute in the group of Prof. Geoffrey Goodhill (who’s actually a mathematician studying axon guidance using DRG neurons as models) and then, my interest in natural products brought me to Richard Lewis’ lab (University of Queensland) working in the field of cone snail venoms.

The unusual side of my career is that I did all my studies (undergraduate, PhD, postdoc) in the same town, Brisbane, and I continue working here to this date, aiming to understand the molecular mechanisms behind pain.

Brisbane, Australia.

Would you tell me more about your pain research?

Sure. I kind of sit between two chairs. First, my group is aiming to understand disease-specific pain mechanisms. At the moment, we’re particularly interested in chemotherapy-induced pain but I’m sort of a pain-type-agnostic. I’ve worked on lots of different things in the past and I’m planning some new adventures in different types of pain.

The other aspect of our work is on venom peptide pharmacology. I’m mostly interested in venom peptides that act at targets on sensory nerves, either to understand signaling pathways and activation mechanisms or to develop new analgesics.

So, one aspect of your work is related to chemotherapy-induced pain, and more specifically to vincristine-induced neuropathy. Could you tell me more about vincristine-induced inflammation and pain? Is it any different from other types of chemotherapy- induced neuropathy?

Vincristine is a type of a chemotherapy drug used in mostly leukemias and brain cancers. It’s used in adults as well, but a lot of kids get it as part of their treatment. And one of the major dose-limiting side effects is a neuropathy, which can be painful. To be honest, all the chemotherapy drugs seem to be similar in some extent that they affect the longest sensory axons first, so you start to get symptoms in the hands and the feet, and then they progressively move further up. We previously worked on different types of chemotherapy-induced neuropathy. One of them was oxaliplatin, and the motivation for that was because it causes a really striking hypersensitivity to cold. So, we were interested in understanding how that arises. We found that oxaliplatin works on NaV1.6-expressing sensory neurons specifically and now we use various toxins to try to unravel the contribution of the different ion channel subtypes to oxaliplatin-induced neuropathy.

So, going back to vincristine, I had a PhD student, Hana Starobova (who is now my postdoc) who wanted to work on vincristine-induced neuropathy, mainly because she had a member of her family who really suffered from that side effect. And I thought we could perhaps show that its effect is very similar to oxaliplatin, and that vincristine affects sensory neuron excitability by acting at ion channels. But as it turned out vincristine-induced neuropathy seems to develop quite differently and it appears to involve different pathways and mechanisms compared to oxaliplatin. The work on vincristine-induced neuropathy has taken us in a slightly different area of pain, which is predominantly focused on the interaction between immune cells and the peripheral nervous system. In contrast to oxaliplatin, vincristine-induced neuropathy seems to be a type of inflammatory pain, and we are currently trying to understand these mechanisms using gene expression analysis and various knockout animals targeting these specific inflammatory pathways.

You know, I’m quite excited about the work we do on the vincristine-induced neuropathy, because we think that we can repurpose existing drugs that are used for, for example, rheumatoid arthritis, to try and prevent or treat the neuropathy, and to improve cancer outcomes for children. And I’d like to acknowledge the funding from “The Kid’s Cancer Project” supporting our research in this area. I’m hopeful that my research, which is usually very basic and fundamental, might have an impact on patients, relatively soon.

When you say “relatively soon”, you mean months, years?

Well, the proof is always in the pudding, right? So, while we do a lab-based preclinical research we would still need to validate that what we are finding in various cellular and in vivo models holds true in humans. So, we would need to do a clinical trial, but I’m definitely hoping that that is possibly on the cards for the next couple of years.

That’s terrific. I wish you the best of luck with this. And, what about another aspect of your research, which is venoms? Seeing the growing interest in natural compounds from the pharmaceutical industry I’m curious, where are we now in terms of venom-based drug discovery?

Well, venom derived drug discovery is an area that is still growing quite a bit. There’s quite a few venom derived drugs at various stages of the development process. And I think in the last few years we’ve increasingly realized that venoms are a really great resource where you’ve basically got an evolutionarily defined library of bioactive molecules. So, instead of screening synthetic libraries, where you get a hit rate of 1% or 0.1%, if you screen a venom library you get a hit rate off somewhere between 50% and 100%, most of the time. It’s just a really great resource, and I think we’re also increasingly appreciating that peptide drugs do have attractive features. Because they’re slightly larger than the small molecules they have bigger interacting surfaces, so they tend to be more selective and specific. And while we’re still working on some of the delivery and pharmacokinetic difficulties associated with peptides, I think there’s great potential in these venom derived drugs.

In relation to ion channels, the first FDA-approved ion channel-targeting venom peptide was ziconotide (the synthetic form of an ω-conotoxin peptide from cone snails), which is a Cav2.2 inhibitor. It was discovered by Michael McIntosh and Toto Olivera quite a number of years ago now (see here) and it is used for the amelioration of severe and chronic pain. Another ion channel-targeting venom peptide that comes to mind is XEP-018, which is a biomimetic of a natural mu-conotoxin from cone snails. XEP-18 selectively blocks the voltage-gated sodium channel Nav1.4 and is used is cosmetics for reduction of facial wrinkles, just like Botox. Then, a couple of ion channel drug candidates inspired by venoms are now in clinical trials, such as Dalazatide (Kv1.3 inhibitor) for autoimmune diseases or SOR-C13 (TRPV6 inhibitor) for cancer.

I imagine that in order to get venoms for your research you deal with different kinds of venomous species. Is it dangerous to work with scorpions, spiders, cone snails or other venomous animals? 

I don’t, actually. I’m an arachnophobe. I stick to plants and things that don’t move. I’m really lucky at the University of Queensland because I’ve got really great collaborators who have access to lots of these venoms: Bryan Fry, who works with all sorts of venomous snakes 🐍, Glenn King, who collects and milks the spiders 🕷, and Richard Lewis, obviously, is a cone snail expert 🐚. So, I personally don’t typically go out and collect things from the wild. Except for plants.

Yes, your recent paper on venomous stinging trees attracted a lot of attention from both scientific and non-scientific worlds. How come that you started studying these fancy trees?

I’m interested in anything that works on sensory neurons and the more painful – the better.

IRINA VETTER

Well, as I’ve said, I’m interested in anything that works on sensory neurons and the more painful – the better. About 10 years ago, I started to dabble in these Australian stinging trees, because somewhere I read about how particularly painful they are. I came across a paper, published in the 50s or the 60s, that said that there was a molecule called moroidin in the stinging hairs of these trees and it was what causes pain. And I thought: “Well, I’d be curious to know what this moroidin actually does,” because there was nothing known about the pharmacology of it. And so, that was my weekend hobby – I went out to find these stinging trees. I’m not a plant scientist at all, so the very first time I found one, I thought it pretty much looks like the pictures but I guessed there’s only one way to find out if it really is a true thing. I put my hand into it and then I was pretty confident that I got the right thing. That was my very first encounter with it.

We set out to find this moroidin, and I had various attempts of isolating it but I basically couldn’t find it. It just wasn’t there. I was starting to doubt my own scientific capacity in isolating peptides from stinging leaves. And then, a couple of years ago, I teamed up with Tom Durek, a chemist, and we decided to use a different approach – the activity-guided fractionation. Basically, instead of looking for the moroidin, why not just take an agnostic view and try and work out what actually causes symptoms from the sting? In the end, there was only one fraction that was active, and I very clearly remember the day that Tom came to the office and he said: “It’s an inhibitory cysteine knot peptide”. I was totally blown away. It’s this peptide scaffold that you would normally find in venomous animals like spiders and scorpions and cone snails. It was totally unexpected.

And what was even more unexpected is that the sequence of it is completely different to anything we’ve seen before, but it seems to work in a very similar way: it acts at my currently favorite pain target – the voltage gated sodium channels. So, that was a bit of serendipity. These tree-derived peptides have really really interesting pharmacology. Watch this space – I think we can learn a bit more from them about how nociceptors function.

That’s very interesting story. And it’s also interesting that you deliberately stung yourself with a stinging tree. So, in terms of evoked emotions or pain sensation are stinging trees any different from mosquitos, bees or ants?

To be honest, they’re all very similar. What sets the stinging tree apart is that it lasts for a really really long time. I mean, if you get stung by a bee 🐝 or an ant 🐜 (by the way, we have some nasty ants in Queensland, so there are picnic hazards and I’ve gotten bitten by those plenty of times), the ants can last a couple of hours and bees maybe 15-30 minutes or so. It’s mostly the duration that differs. But another intriguing thing that sets the stinging tree apart is that you get some weird other sensations of crawling and tingling and shooting pains that sort of come in waves. You feel nothing for a while, and then all of a sudden it gets a little bit itchy and you scratch it and then BANG, it’s back. So that’s the really interesting phenomenon that we get with the stinging trees, and at the moment I’m trying to understand why it lasts for such a long time and exactly what populations of sensory nerves actually become activated by this. But otherwise, it’s much of a muchness in terms of how it feels.

What do you mean by saying that the pain sensation lasts for a “really really long time”? Hours, days, weeks?

Irina with her favorite stinging plants

For the stinging tree, weeks, for sure. After we published the paper, there was a local TV crew who came to film a story about it and they asked us to bring some plant specimens because, you know, it’s always much more attractive to have something that you can show. And actually, I’m growing one of these trees as a pot plant in front of my house, strategically placed in front of the window as a burglar deterrent. So, I brought my plant to work to film and I got stung, because you can basically not avoid getting stung by these things. And I have to say, that four weeks later I could still feel the pain.

There’s not a lot of scientific literature on stinging trees, but on the internet, if you have a look there’s a few people who report that it hurts for months or sometimes even years. I mean, all the stings I’ve ever gotten were quite mild, so I can imagine that, if you get a really bad sting, it could last a very long time. There’s one paper describing how there was a couple that were skinny dipping while intoxicated, and fell into a bush . I can only imagine that that would be extremely unpleasant. But it can definitely last for weeks. I’m not yet quite sure why that is, although I have a couple of theories. Remains to be seen.

Yes, these stinging trees are quite peculiar. But it’s not the only peculiar thing that you’ve worked on. You said that you are aiming to understand disease-specific pain mechanisms. And one of the diseases that you were investigating was painful marine toxin disease – ciguatera. What is ciguatera and have you got any new insights into the mechanisms of pain from your ciguatera studies?

Ciguatera is a fish toxin disease. If you eat fish contaminated with the ciguatoxins you get this condition (ciguatera) that’s characterized by muscle aches and pains and also hypersensitivity to cold. One of the reasons why we were interested in that is because we were thinking that maybe ciguatoxin might give us some clues as to how oxaliplatin causes cold pain. With these cold hypersensitivities, cool temperatures that are not normally painful cause pain, so patients report, for example, that they can’t walk barefoot on bathroom tiles because it’s too painful. Or, drinking a cold beer might cause them too much discomfort.

We were interested in understanding the molecular mechanisms leading to this cold hypersensitivity. Being a pharmacologist we used toxins as molecular tools to dissect the signalling mechanisms involved, and in the end what we determined was that even though the symptoms of oxaliplatin-induced and ciguatoxin-induced cold hypersensitivity are quite similar, it turned out that they’re mediated by completely different sets of neurons and completely different mechanisms.

Even though the symptoms might appear similar the molecular mechanisms can actually be quite different.

IRINA VETTER

So, what I’ve mainly learned from those projects, is that even though the symptoms might appear similar the molecular mechanisms can actually be quite different. That’s an extra challenge in treating these painful conditions clinically. At the moment, we’re trying to stratify our treatments based on the symptoms. And it’s obviously better than completely ad hoc, or random treatment choices. But I think we need to be mindful that the symptoms alone don’t necessarily tell you the mechanisms. That was the main learning from those two projects, actually.

So, when you say that your “research has already challenged a traditional understanding of pain pathways and sensory neural physiology”, you are talking about your findings that similar symptoms could arise from different mechanisms.

Yes. Ciguatoxin-induced cold allodynia seems to develop through traditional nociceptors or pain sensing nerves. And as you would expect, it involves cold sensitive ion channels that activate pain sensing nerves expressing Nav1.8. Kind of classical cold pain signalling really.

On the other hand, oxaliplatin-induced cold allodynia seems to involve Nav1.6. And Nav1.6 is a subtype of the voltage gated sodium channels that’s expressed mostly on myelinated neurons, including some that are typically thought of as touch-sensitive nerves. And, at least in our hands and in our model, oxaliplatin-induced cold allodynia actually developed independently of these cold stimulated ion channels.

A different perspective would be that you don’t actually have to activate your classical, cold sensing pain nerves, and you can still end up with cold hypersensitivity in painful conditions.

Oxaliplatin, vincristine, stinging trees, ciguatera… you have a lot of different projects. Do you have a big lab? And also, what kind of technologies do you use?

Do I have a big lab? It feels very big, but in actual fact it’s probably not that big. This year I’ve got four and a half postdocs and about four PhD students, so it’s usually somewhere between 10 and 15 people. So, as far as labs go it’s not huge, I would say.

Irina Vetter.

As for technologies, we’re really lucky that we’re at a research institute that has a lot of technology available to us. My bread and butter, so to speak, is calcium imaging. I’ve done a lot of work with high throughput calcium assays and the FLIPR. We’ve also got some manual patch clamp rigs, so we do whole-cell patch clamp as well as single fiber extra skin nerve extracellular recordings. And then, we’ve also got a couple of the middle throughput automated electrophysiology platforms that are shared between different research groups: a Patchliner from Nanion, and a QPatch from Sophion. Otherwise, the institute has lots of high-end microscopes, and we’ve got sequencing facilities, we’ve got a CRISPR facility etc. So, we’ve got quite a lot of technologies at our fingertips that we can use.

Oh, you have automated patch-clamp systems from both Nanion and Sophion. That’s interesting. What can you say about these systems? Which one do you prefer?

Well, I can tell you a lot about that but not sure how much of that you want to disclose 🙂. The first encounter with automated patch clamp did not go smoothly for us. We had a QPatch 16, which we got a number of years ago, and for a long time it just wasn’t working properly. We weren’t getting any seals and the cells were dying and we didn’t know what’s going on. But, at one point it turned out that there was antivirus software on the computer, and it just wreaked havoc with the software preventing the QPatch from doing its job. And so, in the end, the simple uninstalling of antivirus software has dramatically improved the performance of the machine.

And now I should say that it’s fabulous. I mean, obviously there are certain situations when you can’t replace manual patching, for example if you want to co-express certain accessory subunits or you just have separate populations of cells you want to look at. But if you just have a stable cell line and you just want to do pharmacology, if you just want to do concentration response curves and maybe an I-V curve, the QPatch is just great. 

I’ve hosted plenty of students in the lab who said I would like to come to your lab, but my supervisor said I can’t possibly do patch clamping because it takes so long to learn. And, then I usually tell them: “Don’t worry. You know, you can learn the QPatch in about half an hour.” So, if you have students coming through who want to collect data, but they don’t know how to patch, I don’t know if there’s any other way you could actually get that amount of data.

I mean, it’s really very productive for us for straightforward pharmacology experiments. And in terms of throughput for us, probably, a 16 or 48 cell patching is about right. I don’t know that doing 384 wells wouldn’t really make sense for us. I mean, if I want to do things in 384-well format, I use the FLIPR and imaging and it does the job of getting hits quickly. So, I haven’t got much experience with 384-well patching but I don’t think that it’s something that we would need.

As for the Nanion’s Patchliner, we could only afford a four-channel system. The Patchliner is a bit of a hybrid for us between doing more complex protocols, or more complex experiments that require a bit more critical input and monitoring while you do them, but can be done by people if you haven’t got the rig available. And the Patchliner works really well for that. It’s pretty robust and quite flexible. So, my personal view is that the flexibility of the Patchliner is a great advantage of it.

So, you asked me which one I prefer, and I actually think it’s ideal to have both. The two systems are different and they are used for different kinds of experiments in my lab. Having both is definitely good.

And what kind of cells do you use when doing experiments on QPatch or Patchliner?

All sorts of cell lines. I wouldn’t be game to try primary cells but we use various overexpression systems like HEK, COS, CHO. Obviously, CHO are the best. But we get pretty good success rates with HEK cells as well. We’ve tried neuronal cell lines, for example F11 and ND7-23 DRG-derived cell lines. And they work fine as well.

OK. And now, let’s talk a little bit about collaborations. I think you have lots of academic collaborations, but I also want to know about industrial ones.

Sure. I always feel like collaborations are the best way to do science. I don’t try to reinvent the wheel – just work with people who compliment you in their expertise. I also really enjoy industry collaboration and I’m actually always looking for industry partners. There is also a lot of funding that we can get for industry collaborations, and I’m very keen to tap into some of that funding, but you know, Australia has not that many companies in the ion channel space.

So, our collaborations are actually with companies overseas. For example, I have a really great relationship with SB Drug Discovery (formerly Scottish Biomedical), who offer lots of different ion channel expressing cell lines. We got our sodium channels cell lines from them and they’ve hosted one of my PhD students in their lab for six months. And yet another reason I like them as my collaborators is that I can strategically go on a whiskey tasting tour, when I go to visit them 😊. We’ve also got a really good relationships with Nanion and I’m hoping that we can set up some more formal collaborations with them, and Sophion as well.

So, I really like collaborating and working with people with different expertise. And if you think that we publish a lot of papers it’s in no small way because we have a lot of outstanding collaborators. Teamwork makes the dream work, as the saying goes.

So, there are not many ion channel companies in Australia. And, how are things going with basic ion channel research in Australia? Could you tell me a little bit about local ion channels groups, associations, networks, etc.?

Well, I really like the ion channel community in Australia and they’re all really great people to work with, really engaged and collaborative. At the University of Queensland, we of course do a lot of venom work, and that’s also the theme of some excellent groups in Melbourne, for example Ray Norton comes to mind. In Sydney there’s fantastic groups working on potassium channels, for example Jamie Vandenberg, or mechano-sensitive channels – Kate Poole and Charles Cox are two great young scientists who I hope to perhaps work with in future. And then of course there are a number of groups around Australia who are working in the pain and ion channel space, for example Stuart Brierley is a fantastic long-standing collaboration. I’ll stop here because otherwise I’m afraid I will forget too many people!

I see that most of the scientists you’ve mentioned are men. So, has been a woman caused any challenges in your career in Australia?

I grew up thinking that being a girl or a woman, make no difference. I cannot put a number, or quantification to you whether or not being female has affected my career, but I’ve certainly come across sexist behaviors and sexist attitudes. Even just little things, for example one time I had the toolbox in my hand, because I was fixing the rig. And somebody said: “Oh, what have you got? Is it your sewing kit?” And I thought that was offensive. Anyway, honestly, I think there’s challenges. The statistics say that there is still unconscious bias. But I don’t know how many more grants would I have gotten if I had a male name. I don’t know, I can’t tell you that.

OK. So, what do you do when you don’t do science? Maybe you have some other fancy hobbies besides putting your hands on unknown venomous trees?

Yes, that is definitely a hobby. Otherwise, I’ve got two sausage dogs and I like playing with them. And, I like reading, I read a lot.

Could you recommend a book?

Well, I am part of a book club, and my recent recommendation to this club was Terry Pratchett’s “The Truth”. One of my favorite books. I’ve read that plenty of times – I’ll be interested to see what the book club think of it.

So, at the end of this interview I wanted to ask you about the 2020. For obvious reasons, 2020 has been really challenging for many people. But I will not ask you about the challenges you had. I’m curious if there was anything good in 2020 for you? What’s the best thing that happened to you in 2020?

Well, 2020 wasn’t so bad, actually. I mean, other than missing out on students and people not coming back. I realized in 2020, that I don’t need very much to be happy. And, actually, I’m not even needed in the lab for it to run very well. I realized that in 2020. I think that’s a good thing. And then, in 2020, I have a fantastic team of people. And we’ve had quite a number of papers published in 2020, so that was really great. We’ve got some good data in 2020 so I’m excited about taking that further, and obviously we started 2020 with some grant funding that we got last year so that’s also really good. Lots of good things happened in 2020.

Australia

And what are you looking forward to in 2021?

I’m looking forward to publishing more papers. I’m looking forward to following up on some of these research themes that we’ve talked about. We’ve got some exciting data with new ion channel modulators, including the ones from the stinging tree that are really interesting pharmacologically. Maybe talking to people about translating some of our vincristine research into a clinical trial, that would be great. I’m really really looking forward to maybe seeing people again at conferences. That’ll be nice.



I’m thankful to Prof. Irina Vetter for taking the time to talk with me and sharing her story and insights.

If you have questions to Prof. Irina Vetter, you can contact her at i.vetter[@]imb.uq.edu.au.

Watch Irina talking about the mechanisms underlying vincristine-induced neuropathy here.

Learn about Irina’s research projects here.

Follow the Vetter Lab on Twitter: @SensoryNeuroph1.


Pictures by Irina Vetter, as well as from Unsplash and Pixabay.


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