Zebrafish - Breakthroughs In Epilepsy Drug Discovery?! - Prof Deborah Kurrasch, University of Calgary, Canada
Neuroscientist Prof. Deborah Kurrasch from the University of Calgary talks about her cool research into the epilepsies using zebrafish! She explains the challenges faced in acceptance of using zebrafish as a model system for epilepsy research and shares how we need to explore new mechanisms of action if we are going to figure out how to help the remaining 30% of people who cannot (yet!) have their seizures controlled using anti-seizure medications! Transcription and links to Deborah are below! 👇🏻
Reported by Torie Robinson | Edited and produced by Carrot Cruncher Media.
Podcast
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00:00 Deborah Kurrasch
“If a human has these five symptoms and a mouse has a very mild version of two of them and none of the other two, how well are we recapitulating that disease to study it and make inferences, right?”
0:12 Torie Robinson
Did you know that tiny little zebrafish are key to researching the epilepsies?! Well ,today we hear from prof Deborah Kurrasch who explains how the valuable data gathered using zebrafish is generally undervalued by pharma - despite a potential translation to humans! Plus, we hear why we have so many epilepsy drugs but still 30% of people don’t have their seizures controlled by them!
If you’re new and you haven’t done so already, please do like and comment on this episode, and subscribe to our channel, so that we can get way more people learning about and developing a further factful understanding of the epilepsies!
00:48 Deborah Kurrasch
So I am a professor at the University of Calgary. I run a basic science research program where we use model systems, so zebrafish, mice, cell lines, more recently human brain organoids - which I'm happy to talk about - to study development of our brains and diseases of our brains. And we're focused on the pathways that might cause these diseases and ways that we might be able to treat, especially epilepsy.
01:13 Torie Robinson
And in addition to epilepsy (because you said diseases); what other things are you looking at?
01:17 Deborah Kurrasch
We look at a lot of neurodevelopmental disorders. So, that's actually where our bread and butter is. So, we do some autism research. We do some rare genetic disorders. We study Prader-Willi syndrome, which is one that affects hypothalamus…
01:33 Torie Robinson
Oh yeah.
01:34 Deborah Kurrasch
And then a wide range of different developmental epileptic encephalopathies (DEEs).
01:39 Torie Robinson
You use zebrafish, right? And I'm reading this out “Zebrafish versus 2D culture versus 3D brain organoids”. What does that mean?
01:48 Deborah Kurrasch
So, zebrafish are a fish, as its name implies. You see them at your pet store. People buy them often to feed fish in their fish tank. They come from a river in India. And in the 1980s, a professor in Oregon actually decided these would make a really interesting model system. And so, they brought them into the lab. They decided that we needed something that was between the simplicity of like a C. elegans, like a worm or a fruit fly (which has been heavily used in the lab setting for genetic reasons). And we need something between that simplicity and a mouse or a mammalian system. And they decided zebrafish were going to be it! It took them almost 20 years to get a publication and they convinced the community that this was going to be a good thing. And since then (we're now to the late 1990s, early 2000s) it's just been a boom. And so, lots of people use zebrafish as a genetic model system, a developmental model system. They actually develop very similar to humans and they have a lot of shared programs, processes in terms of how cells divide and they move and they form the proper organs. So, we use zebrafish to study epilepsy. We also use mice models to study epilepsy. And then we use cell culture. So, 2D is cells that just kind of lay flat in a monolayer. And then 3D are these new fandangled brain organoids. And so they're supposed to recapitulate some of the cytoarchitecture of our brain. You take these cells and they kind of cluster in such a way that they form connections and they self-sort to create regionalisation that you would find if you took a biopsy or a plug from your brain.
03:05 Torie Robinson
What type of specific research are you doing using this material? So, are you causing abnormal electrical activity? Are you looking at genetic makeup? What are you focusing on?
03:46 Deborah Kurrasch
Yeah, it depends. It depends on the project, what we're trying to do. In the zebrafish, we very much wanted to see if we could create better models. So, interestingly enough, mice are very protected (or at least the common wild type mice strains that we use in the lab, are protected) against seizures. So, if you take, like, a DEE where these kids can have, you know, 100 seizures per day, the mice will have four.
04:08 Torie Robinson
Wow!
04:09 Deborah Kurrasch
I know, to be a mouse, right?!
04:13 Deborah Kurrasch
And so, there's always questions when there's that much of a difference between the phenotypes or the symptoms, right? If a human has these five symptoms and a mouse has a very mild version of two of them and none of the other two, how well are we recapitulating that disease to study it and make inferences, right?
04:32 Torie Robinson
Mmhmm.
04:33 Deborah Kurrasch
So, we like zebrafish actually as a model system for human epilepsy in particular. They have hundreds of seizures. Their seizure profile seems to match humans better than the mice. And they generally recapitulate the disease better! So, something I find very interesting, though, is that as much as some of the scientific community really recognises the advantages of zebrafish as an epileptic model system, pharmaceutical companies in the community that drives drug discovery forward, they don't like the zebrafish! They don't think it's relevant. They think it swims in water and how can it have any kind of translation to humans. And so, you can explain to them, like I just did, these very clear differences. No, they want to see it in a mammalian system. And so, it's interesting. So, zebrafish is widely accepted in one community and not widely accepted in another community.
05:31 Torie Robinson
Does one need to display something, show something or prove something in a zebrafish and then replicate it in a type of rodent in order to convince pharma companies, et cetera? Like try and replicate it. I mean, you said it's difficult because they're refusing…
05:45 Deborah Kurrasch
Yeah, exactly!
05:45 Torie Robinson
…to have seizures. So, what do you do?
05:48 Deborah Kurrasch
It's kind of a catch-22, because if we do what you just suggested and we replicate it in mice, then they say “Why didn't you just do it in mice?”. And so you kind of go “Well, that's a good point. I guess we probably could have just saved the effort.”. And if it doesn't replicate in mice, then they say “Well, maybe it doesn't matter in fish. Maybe it's not relevant.”.
06:08 Torie Robinson
Which could be true in theory, right?
06:10 Deborah Kurrasch
Yeah. So, you know, I'll give a shout-out to Scott Baraban. He's at University of California, San Francisco. He's really pioneered zebrafish as an epilepsy model. He's done drug discovery in zebrafish for epileptic conditions. He's taken… he's written papers on “aquarium to bedside” as a spin…
06:29 Torie Robinson
Ah!
06:29 Deborah Kurrasch
…on “bench to bedside”. And so, he's taken some of the drugs that they've discovered in zebrafish and they've moved it right into clinical trials. So, these are repurposed drugs that are already approved. And he's showing that you can go straight from fish directly into humans. And I think one of their trials - it was just a small open-label proof of concept trial - but they had a positive signal in the primary endpoint of decreased seizures in their kids. So, now they've spun up a company and they're doing much more large clinical trials around their lead drug. So, I think some of that work as it starts to go from fish into humans, I think if he can get drugs approved, that were discovered and proven out in the fish and that they work in the kids, I think that will go a long way to put this issue to rest. But he probably needs more than one. He needs people like me and others to follow behind to show that it wasn't just an isolated incident.
07:23 Torie Robinson
Okay, well, you have me supporting you, and listeners; I say follow Debbie online…
07:29 Debbie Kurrasch
Hahahaha!
07:30 Torie Robinson
…because we should support her in everything that she's doing. And we can achieve, like, things much more quickly in in fish, right, than in rodents, you know, and… yeah, so… it just sounds a bit nuts to me.
Loads of people have been asking this, and maybe you've got the answer; why on earth, after decades, do we still have 30% (approximately) of people with epilepsy who don't have controlled seizures. Despite research. What's that about?
07:55 Deborah Kurrasch
There's, like, what, 37-some anti-seizure medications on the market now. And when I talk to my neurology friends, not epileptologists, but just, you know, other neurological conditions, they're always like “What's with you epilepsy people? How many drugs do you think you need?!”, right?!
08:11 Torie Robinson
Well…!
08:12 Deborah Kurrasch
If you think about schizophrenia or bipolar or even depression, like from the SSRIs in the late eighties, there really hasn't been a lot of innovation in the space. And so, there is a paucity of neurological drugs for neurological conditions. And here's epilepsy with this, you know "treasure trove” and yet it's all kind of the same, right? You respond or you have, but you have, you know, side effects to juggle or you don't respond and you're kind of, you know, SOL a little bit, you know, I don't know if I can, what I can say at your show, but…
08:44 Torie Robinson
Hahaha!
08:45 Deborah Kurrasch
So, the reason is if you look at these 30-some drugs that are on the market They have very similar mechanisms of action and so what that means is that they work very similarly inside the cell and so their mechanism of action is as name applies the what is the target of the of the drug and what is it trying to do neurobiologically speaking.
09:07 Torie Robinson
Mm-hmm
09:07 Deborah Kurrasch
So, when you think about epilepsy; like, our brain has, you know, natural electrical activity, right. And epilepsy, as your listeners very well know, is this hyperexcitable state. And so you have, like too much activity. And so very intuitively, the solution to that is to dampen or block or somehow curtail that hyperactivity. And so, the way to do that is to, you have a synapse, you have a presynaptic cleft and you have a postsynaptic cleft and you have energy that goes across this cleft. And so, the strategy is to dampen that transfer of electrical activity at the synapse. And that will then block seizures and it will calm down the hyperexcitability and decrease seizure frequency. There's various ways you can do this. You can block some different proteins on the presynaptic side. You can block some proteins on the postsynaptic side. And that's what these drugs do. These drugs target different channels, different neurotransmitters, different receptors, but they're all (in terms of their strategy) very similar. And they are all targeting either the presynaptic or the pro synaptic cleft or postsynaptic cleft, and they're trying to block that transfer of a seizure across it. And so, basically, the answer to your question is that in 30% of the time, blocking a seizure at the cleft doesn't help. And so, we need to go away from that strategy. It is well tested. We have a lot of good drugs on the market that work for 70% of the patients. And so, we now need to think outside the box and to go inside the cell or in different manner to affect the hyperexcitability.
10:52 Torie Robinson
Do you think that we are starting to do that, as a whole?
10:56 Deborah Kurrasch
I think so. You hear a lot about it. Pharma is very interested in it. So, if you talk to pharma, you you know, you say “What's kind of hot for you guys right now?” and they say “New mechanisms of action.” to use the, you know, the pharmaceutical term or “drugs that work differently” to use a different term. So, they're very much hunting right now for that. I think that there is a decreased appetite for more of the same. So, yeah, I think there is… Pharma drives research priorities. And so, I think the more that they're interested in, the more you'll see this change. Yeah.
11:31 Torie Robinson
Well, to our pharma listeners, please come on board with us and sometimes look at things from another perspective as well, you know, and, like, I've spoken to researchers who spoke, who told me about how “Gosh, it's not down to the fact that there is overactivity in this area. There's actually underactivity in another area, which means that the activity becomes too much.”. So, yeah, it's all about looking at things from a different perspective, isn't it? Rather than just dulling down the entire organ, which is kind of, generally, what medications tend to do, isn't it?
12:03 Deborah Kurrasch
Yes, yeah I think that's a problem across you know brain science entirely right we just kind of bathe the brain so you have an issue here… I mean, like, the analogy I've heard is like putting oil across your engine block right instead of into the right chamber we just kind of like dump oil and hope that you know it kind of has some effect in the right spot and maybe not too bad of an effect in another spot. It's not very precise.
12:29 Torie Robinson
Well, we will keep our eyes on you and your team, Debbie. Thank you for all you're doing and for understanding the need to have new treatments, perhaps even preventions and things like that. Oh, and, everybody: also make sure that you check out Debbie's discovery program. It's called Stream Neuroscience and I'll put a link to it on the website. Thank you so much, Debbie.
12:49 Deborah Kurrasch
Thank you very much for having me, nice to talk with you.
12:52 Torie Robinson
Thank you to Debbie for such a cool overview of her work and for explaining the clear value of zebrafish for further understanding the human brain and the epilepsies!!
Learn more about Debbie and her work on the website t-or-i-e robinson.com (where you can access this podcast, the video, and the transcription of this entire episode) - ooo, and the link to her website(!), all in one place. And if you’re new and you haven’t done so already, please do like and comment on this episode, and subscribe to our channel so that we can get more people learning about and having a better understanding of the epilepsies, around the world!
See you next week!
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Deborah Kurrasch is a Professor in the Department of Medical Genetics at the University of Calgary and a Scientist at the Alberta Children’s Hospital Research Institute. She received her PhD in Molecular Pharmacology from Purdue University and conducted two postdoctoral fellowships, one at the University of Texas – Southwestern Medical Center in Dallas and one at the University of California, San Francisco.
Deborah’s teams’ current research program can be broadly divided into three domains: basic, translational, and drug discovery. On the basic science side, they seek to understand how neurons organise themselves into nuclei. Although two-thirds of our brain is functionally organised into defined neuronal clusters (versus layers such as in the cortex), we know comparatively little about the cellular and molecular mechanisms that guide newborn neurons into their respective nuclei. They study this question using the hypothalamus as their model system in zebrafish, mice and human brain organoids. As they learn more about hypothalamic development, their translational program seeks to apply this knowledge to study how environmental challenges during development (e.g., maternal stress, maternal obesity, environmental toxicants) change hypothalamic cytoarchitecture, leading to diseases later in life. Through this work, they have uncovered a role for microglia in shaping hypothalamic development, and now study the involvement of the maternal microbiome. Finally, they have developed a neurometabolic drug screening platform to uncover novel anti-seizure drugs for the treatment of refractory epilepsy. They are now pivoting this platform to models of autism and other rare diseases for which no therapeutic options exist.
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