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Why Zebrafish are Particularly Well Suited for Anti-Seizure Research with Dr. Deborah Kurrasch

Tune in to episode 64 of 17 Minutes of Science as we talk with Dr. Deborah Kurrasch about her recent paper and why she enjoys working with zebrafish so much!

Dr Deborah Kurrasch is a Professor in the Department of Medical Genetics at the University of Calgary and a Scientist in the Alberta Children’s Hospital Research Institute and the Hotchkiss Brain Institute. Dr Kurrasch’s research is focused on characterizing the genetic programs that govern hypothalamic development, and how exposure to environmental chemicals changes these programs, using zebrafish, mice and human brain organoids as model organisms. Her lab has also developed a novel drug screening platform to uncover therapies for children with refractory epilepsy. Her work is funded by the Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada, and Canadian Foundation for Innovation, among other Foundations.

Dr Kurrasch 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. Dr Kurrasch has received various awards for her scholarly work and supervision of graduate students, most recently receiving the ASTech Women in Innovation award, 2021.

Transcript

Hannah Huston (Host): [00:00:10] Hello and welcome to 17 Minutes of Science, our show that explores the world of science and how it affects both the starting academic and the seasoned professional. I am Hannah Huston and today I am joined by Dr. Deborah Kurrasch. Kurrasch is a professor in the Department of Medical Genetics at the University of Calgary and a scientist in the Alberta Children’s Hospital Research Institute and the Hotchkiss Brain Institute. Dr. Kurrasch’s research is focused on characterizing the genetic programs that govern hypothalamic development and how exposure to environmental chemicals changes these programs using zebrafish mice and human brain organoids as model organisms. Her lab has also developed a novel drug screening platform to uncover therapies for children with refractory epilepsy. Her work is funded by the Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada and Canadian Foundation for Innovation, among other foundations. Dr. Kurrasch 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. Dr. Kurrasch has received various awards for her scholarly work and supervision of graduate students, most recently receiving the ASTech Women in Innovation Award 2021. As of last week, so extra. Congrats. Welcome, Deborah.

 

Dr. Deborah Kurrasch (Guest): [00:01:33] Thank you. Thanks for having me.

 

Hannah Huston (Host): [00:01:35] We are very excited to have you on our show. I am going to start my timer now, and we can start with just you telling us a little bit more about your research.

 

Dr. Deborah Kurrasch (Guest): [00:01:47] Yeah, of course. So fundamentally, we are a neuroscience lab. We’re interested in how the brain develops and how it functions. We use zebrafish, mice, human brain organoids as model systems, so we can take advantages of these different models, depending on the question we’re asking. The core of our lab is hypothalamic development, so the hypothalamus is a powerful brain region that sits at the base of your brain, and it’s important for basically everything you need for survival. All your homeostatic processes. Are you hungry? Are you thirsty? Are you tired? Are you cold? And it also controls a variety of social behaviors, such as parenting and attachment and emotional states. On the other side of the lab, we also have started modeling CNS diseases, and particularly epilepsy. And so we’ve developed a drug screening platform that’s part of a commercialization project. So we kind of have two sides to the lab, like the fundamental basic science around brain development. And then we have the – using animals and models to conduct drug screens.

 

Hannah Huston (Host): [00:02:53] Fascinating. You get to see both sides.

 

Dr. Deborah Kurrasch (Guest): [00:02:56] Yes, exactly. My people do as well. It’s it advantageous for the trainees because they kind of can, excuse me, bridge both worlds.

 

Hannah Huston (Host): [00:03:04] I bet that is really helpful for them in their future career choices as well.

 

Dr. Deborah Kurrasch (Guest): [00:03:08] Yeah, it is. And it’s interesting. You know, it seems, in general, that the students and postdocs come down on one side, which I think is helpful, right? They either really like the academic science or they really like more of a commercialization angle to the science. And so it’s interesting to see them kind of develop and move between projects as they mature in the lab.

 

Hannah Huston (Host): [00:03:28] What a great experience for them. So can you tell us what type of tests do you use in your research?

 

Dr. Deborah Kurrasch (Guest): [00:03:36] Yeah, well, you know, early on we were basic histology and some behavior, and we really expanded our repertoire, so we we do the gamut. So we start with – we can do molecular studies, you know, single cell sequencing. Most labs are adopting this technology. We do a lot of that. We do histology, which can be anything from whole brain clearing to immunohistochemistry gene expression type studies. We’ve moved into microscopy, so we do a fair amount of computational analysis and time lapse imaging, behavioral analyses. And then now, most recently, we’ve added ephys [electrophysiology]. So we do patch clamp and we do extra cell recordings and EEG in our mice model. So it’s really – it’s been quite nice to watch the students take the projects in different areas and learn the tools they need to to answer the questions.

 

Hannah Huston (Host): [00:04:28] Oh, I love that. So you use a number of models in your research. Can you tell us more about why you choose a multimodal model approach and why these specific models work well?

 

Dr. Deborah Kurrasch (Guest): [00:04:40] Exactly, so by training, I’m a mouse geneticist, so I started back in the day where we would use homologous recombination to make knockouts and knockins. More recently, of course, we have CRISPR technology, which makes that a lot easier. But in my postdoc, I expanded into zebrafish and then my lab has started to do these organoids, brain organoids, and it’s interesting we can really move between these models. Initially, when we first started to use zebrafish and mice in parallel, we thought that they would be pretty complementary and they are in many ways. But we’ve learned over the years that you really have zebrafish questions and you really have mouse questions and that we don’t jump back and forth as seamlessly as as I thought we would when I was first starting my lab. And I think in hindsight, that makes sense because zebrafish is a very powerful and robust model in and of itself. And mice is a powerful and robust model in and of itself, and they each have their own unique tools and they don’t really need a complement, in many ways. We can do behavior, we can do efforts, we can do molecular and cellular studies in both models. And so I think that sometimes we do move from the zebrafish into the mouse to get a mammalian perspective on some social behaviors or that might be helpful, like parenting, but that’s not necessarily a requirement. I do think the jury’s out on the brain organoids, and it’ll be interesting to see how those fit into the mix. We’ve been working with them for about two years now. And so we’re very comfortable with the technique. There are some reproducibility – or not reproducible – but variation across the models that has to be taken into account, and it’ll be interesting to see over time how will these models, how that type of a system flushes out in terms of translation and actually back to the human brain?

 

Hannah Huston (Host): [00:06:35] I’m glad you mentioned that because I was going to bring up the human brain organoids if you didn’t bring them up because I was intrigued as as to how those fit in as well. You recently published a paper: ‘metabolism based drug discovery in zebrafish, an emerging strategy to uncover new anti-seizure therapies.’ Can you tell us a bit more about this study?

 

Dr. Deborah Kurrasch (Guest): [00:06:57] Absolutely. So this is the cornerstone of our drug screening platform that we developed in our lab, and we became interested in developing this platform around the idea of how do you find new targets in, uh – how do you find new druggable targets for CNS drug discovery programs and, you know, a basic example of this would be Alzheimer’s disease, where five billion dollars have been spent on numerous phase three clinical trials. Based on this idea that beta amyloid or tau is going to be a good druggable target to decrease symptoms of dementia. And I think we can all agree, you know, Biogen success aside, that there hasn’t been a lot of success in this field. So if not beta amyloid, where do you go for new druggable targets? And so we became interested in this idea that cellular homeostasis, that is how well the cell is functioning, might actually be a readout for, uh, to identify new drug targets in a pathway agnostic manner. So the cornerstone of cellular homeostasis is mitochondria, and mitochondria are the powerhouse of the cell because they generate ATP along the electron transport chain, and their role is to maintain a cellular – healthy cellular function. So we developed assays that would enable us to measure mitochondria output in a healthy state and in a disease state. And then we asked, how can we screen these assays to identify protein targets that improve mitochondrial function? So this is a non-biased phenotypic way that we can ask – what is the best target for a certain disease that’s going to restore cellular homeostasis? And so that’s basically what the paper shows. It’s how can we measure mitochondria output in a disease state? How do we target different proteins? How do we know when it’s improved? And can this be used not only to identify targets, but also to conduct drug screens to find drugs against those targets down the road?

 

Hannah Huston (Host): [00:08:49] That’s fascinating, and so you use three models in your lab, but for this study, you just used zebrafish. What, um, why are zebrafish particularly well-suited for anti-seizure research?

 

Dr. Deborah Kurrasch (Guest): [00:09:05] Excellent question. So many reasons, actually one is, well, of course there’s a high conservation. I think zebrafish are a great model for CNS disorders in general. So like I said earlier in the interview, we use zebrafish mice in these brain organoids. And my favorite model is actually the zebrafish. They recapitulate the disease quite nicely. We can – um, 70 percent of the genes are conserved. They have many behaviors that are similar to what we would see in mammals and even humans that we can that are robust and trackable. So there’s many advantages, I think, to zebrafish in drug discovery programs in general. For us in particular, zebrafish are advantageous because we need a fully networked brain to measure the mitochondrial output. We don’t want to say ‘how are the mitochondrial performing’ and measure them in isolation or measure them in cells or neurons that we’ve isolated. We want to measure how the mitochondria are performing in neurons that are part of an overall circuit. To do so – we couldn’t possibly do this in mice because they’re too big, um and we couldn’t begin to measure their mitochondrial function – but in zebrafish, we can put them in 96 Wells and we can use probes that measure oxygen consumption in the water. And so that’s an indirect measure of how well the mitochondria are functioning because they’re consuming this oxygen to generate ATP. So it’s advantageous for us because fish are small, they have a network brain. We can put them in 96 Wells and we can measure mitochondrial function in the whole living organism.

 

Hannah Huston (Host): [00:10:40] That’s fascinating. They definitely sound like the perfect model for that, then what are the next steps for this research?

 

Dr. Deborah Kurrasch (Guest): [00:10:48] Well, we have a commercialization project that we’re moving forward on. We have identified a half a dozen new druggable targets in epilepsy. So we’re – we validated those targets in mouse models of disease and also in our patient derived organoids. So then we move into target based drug discovery, much like any other biotech company does. We have medicinal chemists on the staff and and a Head of chemistry. And so we designed molecules for these targets and we move forward. And so the proof is always in the pudding. And so we’ll see how these targets behave once we start to get into the clinic. We, in our preclinical models, they look to be very promising – that perhaps we have identified some really interesting intracellular protein targets that have never been explored before for epilepsy. So we’re pretty excited about these programs and we’re busy fundraising and hopefully we can get some investors who are excited to.

 

Hannah Huston (Host): [00:11:42] Sounds like some very exciting research to be part of.

 

Dr. Deborah Kurrasch (Guest): [00:11:45] Yes, thank you.

 

Hannah Huston (Host): [00:11:46] So we have just a couple of minutes left and my final question for you here: zebrafish have been relatively slow to gain popularity in drug discovery research compared to other models, such as the traditional gold standard mouse model. Do you think the field is changing towards more adoption of the zebrafish model?

 

Dr. Deborah Kurrasch (Guest): [00:12:11] Um, maybe slowly, um on my more optimistic days. I think that part of the problem is that zebrafish were used in the early 2000s, pharmaceutical companies brought them into their programs and adopted them as a model system. And I don’t know that they saw a lot of success or fruitful productivity coming off of that. And so they – I think I don’t know how many pharma have colonies still in their basements, but for the most part, I think they’ve moved back to mice and organoids and iPSCs are, are of a lot of interest to most drug discovery programs instead of fish these days. I do think that’s a shame. I think that zebrafish have a great potential. I think one of the problems before was that zebrafish were used mostly as a behavioral model, and so – drugs were screened and behaviors were monitored. And I think we have a whole collection of new tools that can be used for zebrafish these days that is more advanced and robust and perhaps behaviors. And I think with CRISPR Cas9 and a lot of new genetic tools that we can now use in zebrafish, I would like to think that there will be a movement back to them as a model and complement with mice. I mean, if we’re being honest with ourselves, it’s not like mice are working out swimmingly great either. I mean, 95 percent of neuroscience therapeutics fail in phase two or three clinical trials, suggesting that whatever looked amazing in the mice models isn’t translating either. I think that there’s a bit of a – the look towards human brain organoids. We’ll see how that pans out. But those are an artificial culture and it’s not a fully networked interacting brain. And so I still think zebrafish have some advantages that I hope they bring back into the screen pipelines.

 

Hannah Huston (Host): [00:13:58] Yeah. I mean, you make a bunch of really good points there and you have seen the benefits of a multimodal approach because each model can truly bring you some very unique answers and very unique data. And so using multiple models or even just different models for different types of research is really important.

 

Dr. Deborah Kurrasch (Guest): [00:14:17] Yeah, I agree completely.

 

Hannah Huston (Host): [00:14:20] Well, my timer is about to go off, so I will pause it there. Thank you so much for joining us today. It was a wonderful treat to have you on our show.

 

Dr. Deborah Kurrasch (Guest): [00:14:31] Well, I appreciate the invitation. It’s always nice to talk to people about our research and I know InVivo Biosystems well, and so it’s great to be part of your outreach.

 

Hannah Huston (Host): [00:14:41] Thank you so much. Well, thank you everyone for tuning in today. We will see you next time on 17 Minutes of Science.

About The Author

Hannah Huston

Hannah is the Marketing Manager at InVivo Biosystems. She received her Bachelor of Science in Science & Management specializing in Biotechnology from Scripps College in 2017. She has been with InVivo Biosystems since June of 2018. Outside of work Hannah coaches youth soccer and enjoys being active and outside with her dog, Siri.

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