Epilepsy Via Somatic Gene Mutations - Karl Martin Klein, University of Calgary
Learn about somatic gene mutations, how they can lead to an epilepsy, and how this is being researched by lead clinician scientist of the University of Calgary: Karl Martin Klein.
Reported by Torie Robinson | Edited and produced by Pete Allen
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Torie Robinson
Now onto our star of the week, Karl Martin Klein.Karl Martin Klein
Thank you very much, Torie, for having me. So, I'm a neurologist and epileptologist working in the Calgary Epilepsy Program at the University of Calgary. I'm also a member of the Hotchkiss Brain Institute and the Alberta Children's Hospital Research Institute. And so, I am a clinician scientist. So, basically, I'm involved in seeing patients with epilepsy, looking at their pre-surgical workup ( if they potentially qualify for epilepsy surgery), and I'm also doing research in epilepsy genetics.Torie Robinson
Gosh, it's a pretty diverse range of roles and responsibilities. Do you look after children or adults?Karl Martin Klein
I'm clinically, primarily looking at adult patients for the research however, we're also working closely with the Alberta Children’s Hospital and the colleagues there, so, for the research, we're also recruiting children.Torie Robinson
Okay, and are there specific types of epilepsy that you're working on?Karl Martin Klein
No, it's actually broadly all types of epilepsy basically for the clinical work. You know, from the generalised epilepsies, focal epilepsies, up to the patients who are investigated for the possibility of epilepsy surgery. And for the research, it's kind of, is of course having a certain focus on patients where genetic factors are considered to be more relevant, although there is often also an overlap with acquired factors and genetic factors, so we're basically trying to recruit all the patients who are seen in the Epilepsy Clinic in Calgary and on the seizure monitoring units for the research. We're also having a project where we're looking at potentially predicting which medication is going to work in that individual patient. Yeah, but the project I kind of thought might be most interesting to talk about today is our work in so-called somatic mutations in epilepsy.So, these are changes, genetic changes, that are actually not inherited but they occur at some point during the development of the embryo. So, basically, the development of the embryo starts with all healthy cells and then at some point there is a little arrow happening in the DNA/in the genetic information of one cell, that might just be in the cells that are just in the future kind of developing into the brain. So, you will only find it in the brain cells and it will not be possible to see it, for example, in the blood as we can, as what we usually use for genetic testing. And then depending on when it happens, it can affect more or less cells in the brain. And then this has been recently shown in the last few years to be kind of a cause of focal epilepsies where the seizures are starting in a certain part. And these variants have been found in the cells where the kind of, where the epilepsy is coming from.
Torie Robinson
That's just amazing. I mean, I've heard of, I don't know if this is a fair comparison, but there was an article I read a while back about how there was a child who had a certain genetic disease, and both parents were tested blood-wise to see if they had the mutation. Neither did, but anyway, they found out that the dad was carrying it in his sperm. So, only his sperm were affected by this disease: that's where the mutation was. Is it kind of along those lines, but it's just a place in the person's brain that we're talking about with the epilepsy?Karl Martin Klein
Yeah, exactly. So, these kind of mutations, they can happen at any point and they might just affect the sperm cell, basically the sperm genetic information, or they might just affect the genetic information in the brain. And it just depends on when exactly during development it happens. It's the same mechanism basically, but has of course completed different effects.Torie Robinson
And so, and just to clarify this grant that you got, I believe it's called the New Investigator Award 2022, is that right?Karl Martin Klein
There's the one, from Epilepsy Canada and one from Brain Canada. Therefore, our work in trying to use Stereo EEG or Depth Electrodes to find these variants. So, what we know, most of what we know so far in this field with brain somatic mutations has come from tissue that was removed during epilepsy surgery. But of course not, you know, every patient is going to have epilepsy surgery and many patients have epilepsy that's refractory to our medication, and we can't get hold of course of the brain if there isn't a reason for it to be removed anyway. So, what we sometimes do is in patients where the, we're not quite sure yet if we can do surgery of the brain to treat them, so, we need to really clarify where exactly it's coming from, we sometimes have an intermediate step that we, that the neurosurgeon basically implants electrodes into the brain, so they do some burr holes in the skull. And then these very thin electrodes are put into the parts [of the brain] where we suspect the seizures to be coming from in multiple areas, and then record the EEG from these regions. And then, sometimes that results in surgery, but sometimes the findings also indicate that the surgery isn't possible. And these electrodes at the end are removed and there are actually brain cells sticking to these electrodes. And there has actually been a method suggested by a group in the United States (the Richard Gopin's group) to actually harvest these cells and get their DNA and look at this DNA or these cells to identify these genetic changes that are present in the brain. And we did see, I mean, it does work: there's also a publication from Michael Hellebrand's group in Melbourne who found a variant in these cells. But in our experience when we look at it, we often see that there's a lot of contamination on these electrodes. Basically, there can be blood as well, or there can be immune system cells, and then if there's lots of them, then it's very difficult to find the brain cells. So, we've kind of worked on a method to purify these samples and really pull out only the brain cells. And that's what we're currently doing. That's what we're working on, that's what these grants are about.Torie Robinson
Wow, so I'm just imagining: so you take these, you know, electrodes out, which have been pretty deep within the patient's brain, and they have remains of bits of the brain that they've been scanning, just like stuck to them. It's, and why are they stuck to them? Is it just like, that's what happens if you stick anything in anything, or is it like, is it something else that makes those neurons stick to them, to the electrodes?Karl Martin Klein
The aim of course is to have the least amount of brain possible sticking to these electrodes! Of course, we don't want to do harm with these so it's really just a very, very small amount, but I mean you probably know that from a cheek swab: if you just swap your tissue in the mouth you're gonna have some cells sticking to it. So, this is just unavoidable and of course, the aim is to have it as least as possible, and then kind of the research tries to make that little amount work for the actual analysis.Torie Robinson
So, it's like two in one, basically. You're doing intracranial EEG, but you're also getting brain cells, which you can use for research too.Karl Martin Klein
Yeah.Torie Robinson
How long is this project of yours? And how far into it are you? How much longer is there to go? What are your anticipations for what may be discovered?Karl Martin Klein
Good question. So, at the moment we have these startup funding or the startup from this new investigator funding to get this project running. So, we're basically looking at a limited number in 1 grant it's 18 patients and in the other grant it's 9 patients. To see how the method is working to develop the first data idea, the best strategies for analysing the data we get. And then, of course, we're working on larger projects in collaboration with other centres who have higher number of patients included, and then of course a much broader overview in the end on the variants that are actually playing a role. And I think the field so far, because we're kind of so dependent on the tissue, is really just showing us a certain spectrum of genetic changes that we… are kind of happening more likely in the patients who can have surgery in the end, often in the patients where there is an abnormality seen on the MRI. Whereas now with this technique, we can also look at the patients who don't have any changes seen on the MRI, we just identify the focus by looking at the EEG activity. And I think that's going to give us a much broader idea about the variants that are playing a role in the brain in epilepsy. And then of course, the idea is to use that information to improve the treatment in the future. You know, of course, this is the first step that we're looking at [in] which genes play a role. And it's the same as it was with all the inherited or so-called germline changes in epilepsy or the development in epileptic encephalopathies where identification of the gene came first and then the research focused on understanding what the genes are doing. And now we're really in the germline field! It's a really, very important part of the clinical practice. It helps with diagnostic workup, it can inform treatment, and I think at some point, we hope of course that the work on the somatic mutations is gonna be kind of similar. Still gonna be having the issue of identifying it - if somebody is not gonna have a stereo EEG investigation or surgery then we still won't potentially find it, but maybe we can even find certain types of epilepsy that are more likely to have the changes in the brain than if we have a treatment code applied based on that.Torie Robinson
There may be a limitation in terms of... because you can't look at all the tissue in the whole brain, right? So, does that limit, potentially, the discoveries in your work?Karl Martin Klein
Yeah, that's a very good question. So, it's basically… the difficulty with looking at these genetic changes in the brain is that it's very typical that not all the brain cells actually carry these variants. So, they're only present in a fraction, for example, 5% of the cells. So, if we do the standard genetic testing that we do in blood we may we're only looking at a certain number of cells (simply explained). And then if you just look at 50 cells, you might not see that there's a small percentage of the cells that have the variant because you might by chance just look at the ones who are having the normal genetic information. So, it's really dependent on the so-called “depth” of the sequencing that you're applying. And if you want to do that broadly across all the genes that we know of, it gets quite expensive. So, what we can do is we can focus on a certain number of genes, and then we can have it much more… can look much more densely at these genes. Or we go broad, where we have a chance to find something new. But then it gets expensive when you wanna, to look very carefully. So, these are the limitations. And of course, in the future, I mean, you know, the future would be to look at the whole genome. So not only at the so-called exome (which is only the parts of the genetic information that is kind of making the proteins in the end), it’s also all the regulatory information in between. And then it's much more data that we have to generate and then doing that at a very high depth is actually quite expensive. But, I mean, the cost for the sequencing is going down continuously, so I think we can probably do way more in the next few years than we can do at the moment.Torie Robinson
And I think that gives us a perfect reason why you should get more grants in the future as well. More funding for your work because it sounds utterly exciting, and I really do look forward to hearing more from you. Thank you so very much, Karl Martin. It's been great.Karl Martin Klein
Thank you very much for having us. And I would really, really like to thank all the patients who are supporting this work by actually participating in our projects by actually allowing us to get a blood sample for the DNA, allowing us to use the electrodes and potentially the tissue, allowing us to use that for the research as well. Because of course, without the participation of the patient, that would all not be possible. I'd like to thank Epilepsy Canada and Brain Canada for the funding for this project. Yeah, and also, I wanted to mention that I'm a member of the Hotchkiss Brain Institute and the Alberta Children’s Hospital Research Institute who are also supporting that research. And of course, I'd really like to thank our collaborators: the neurosurgeons in Calgary who are really collaborating with us because it's a lot of organisation to be around, and when they actually pull out the electrodes and, you know, process them immediately for the research, All the clinicians we're seeing, the patients who are working with us to make it possible that we know when the electrodes are pulled out, giving us the information on where the seizures are coming from, because we also kind of need to decide how we combine all these different electrodes for the research. -
Karl Martin Klein is a Clinician Scientist in the Departments of Clinical Neurosciences, Medical Genetics, and Community Health Sciences as well as a member of the Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute.
He completed medical school at Philipps University Marburg, Germany, in 2002, followed by a residency in Neurology at Philipps University Marburg. He specialised in epilepsy and EEG at the Epilepsy Center at Philipps University Marburg and continued to work in this area as a consultant at the Epilepsy Center at Goethe University Frankfurt, Germany, from 2015. He also performed a fellowship in epilepsy genetics at the Epilepsy Research Centre, University of Melbourne, Australia (2008-2011). He obtained an MD degree from the University of Marburg in 2003 and a PhD from the University of Melbourne in 2012. Karl was recruited to the University of Calgary in 2018.
Karl’s research focuses on the genetics of epilepsy. He is particularly interested in multiplex families with epilepsy as well as adult and pediatric patients with epileptic encephalopathies. A backbone of his research is detailed phenotyping i.e. the detailed clinical characterisation of each participating patient. Karl also has a strong interest in precision medicine not only in patients with monogenic causes of epilepsy but also in patients with complex inheritance. He is a member of multiple international epilepsy genetic consortia.
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University of Calgary: kleinkarlmartin
Clinical Genome Resource: klein
Loop: Karl Martin Klein
Epilepsy Canada: grants-awarded
Alberta Epilepsy Education Webinars: karl-martin
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