Epigraph Vol. 24 Issue 2, Spring 2022
Epigenetics in epilepsy and the Michael Prize: Dr. Katja Kobow
Reported, edited and produced by Nancy Volkers, ILAE communications officer
Though she became involved in epilepsy epigenetics research “by accident,” Dr. Katja Kobow is already one of the leading researchers in the field, and the most recent recipient of the prestigious Michael Prize. Sharp Waves talked with her about the prize and her research.
Listen below or download the episode.
In this episode we talked with Katja Kobow, the most recent winner of the Michael Prize, an international award in epilepsy research. Her work focuses on epigenetics and epilepsy, and she talked about the prize, her research, and how far this field has come in only the past 10 to 15 years.
Dr. Kobow: My name is Katja Kobow, I’m assistant professor at the Institute of Neuropathology at the University Hospital Erlangen in Germany.
Can you tell us a bit about the Michael Prize and the research you submitted in your application?
Dr. Kobow: The Michael Prize is awarded by the Michael Foundation, which is a private foundation and ask far as I know it’s the oldest private foundation for epilepsy. It’s a German foundation, named after Michael, who suffers from epilepsy, and it was founded by his father, I think. It is still maintained by his sister and other people. It was more in the beginning a German prize, but became an international prize and is awarded every second year, and is I think by now the biggest prize in epilepsy research.
And it’s not only for researchers, basic scientists, but also for clinicians doing research on epilepsy. It always has some topical focus, which is changing regularly so that it will not always be about the same things, because some topics are more prominent than others and this type of rotation gives the opportunity to include more interesting research.
It’s a prize where you don’t have to be awarded but you apply yourself, so that’s maybe a big difference to other prizes. It’s the biggest prize in the epilepsy field and for me it’s a big honor to receive it because when I read the list of names that have received it so far, it’s like the Who’s Who in epilepsy research, and to be a part of that makes me really proud.
You submit usually three papers on a specific topic, and I submitted three main publications focused on epigenetics in epilepsy. My research in the beginning was focused on mechanistic aspects of epilepsy development and how epigenetics contributes to that, but because of where I work, in neuropathology, it has shifted towards molecular diagnostics of epilepsy – using epigenetic signatures to be able to diagnose epilepsy and specific lesions associated with epilepsy, and to rationalize the diagnostic process by not just relying on histopathological features which may sometimes not be very well defined for some entities.
Here, you have a chance to use molecular signatures to become more confident in your diagnosis, and also let’s say to liberalize the process a little bit. So people who do not have the knowledge or experience of 40 years diagnosing structural brain lesions in epilepsy can still have some idea of what kind of lesion they are looking at, even if they’re not too familiar with the microscopic process. So that’s kind of the vision of that work.
So can you explain what epigenetics is and how it might relate to epilepsy? In ten words or less? No. Take as long as you want.
Dr. Kobow: So, epigenetics is the bookmarking system or the data management system of our genome. It decides which part of the genome is read, at which time point during development, and in response to certain cues like environmental cues or things like that. While our genome is static more or less, the epigenome is what makes it versatile in terms of regulating gene expression as an adaptive response to environmental cues.
It [epigenetics] is very important for all aspects of brain development and function, and so if there is a malfunction of the brain it’s logical to consider epigenetics as one of the mechanisms that is failing here. The interesting part about epigenetics and epilepsy, beyond the part of the diagnostics that I’m using, is in looking for new therapies, because epigenetics is by nature a reversible mechanism. So it always has enzyme pairs working one way and the other way, so modifications can be established but they also can be removed. so here we have maybe a new target to modify the epileptic process, targeting a mechanism and not just ictogenesis.
I’m concentrating on DNA methylation, so that’s methyl groups added to cytosine nucleotides in the genome. And that’s regulating gene expression by usually silencing genes. This is the most stable epigenetic modification that we have. Biology uses DNA methylation to silence developmental genes for 100 years—once they’ve been used at the beginning of our development and need to be shut down for the rest of your life, that’s what DNA methylation does. So it’s considered stable.
We have knowledge from cancer research and other research that there also are epigenetic signatures that contribute to what we call “the molecular memory” of a cell. A cell remembers things that it has experienced, and this is kind of written in our epigenome.
The idea behind my work is that if we have an epileptic network and cells that are part of the network and participating in generating seizures, they have molecular knowledge of this type of activity. So what we know from other diseases is that we can use these epigenetic profiles, these DNA methylation profiles across the genome, as something to diagnose and classify disease.
So what I’ve done is I checked structural brain lesions, mainly malformations of cortical development, and looked for their specific DNA methylation profiles. I had some evidence from animal models where I compared different animal models that all have their specific DNA methylation signatures.
There’s evidence that the DNA signature associates with the phenotype, but also the underlying etiology. So different models had different signatures. That was kind of the basis, or the first evidence for me, that I could maybe also use this to classify different lesions in human epilepsy.
We tested that in patients with focal cortical dysplasia and have extended the research to other malformations of cortical development and we can see specific DNA methylation profiles in these different brain lesions. This helps to diagnose these lesions, because some of them are really badly described for their histopathological hallmarks.
Someone who’s not a trained neuropathologist for the past 40 years will maybe not recognize some of these lesions under the microscope because they look almost normal. These molecular signatures help distinguish these entities, and can even identify new disease entities which we haven’t recognized before.
What are the implications of being able to diagnose these different lesions using epigenetics?
Dr. Kobow: All of our understanding, whether it’s mechanisms, or treatment, or prognosis, really relies on an accurate diagnosis of the patient. And the diagnosis of the patient for me, for focal epilepsy patients with a structural brain lesion, doesn’t stop with an EEG and an MRI and maybe a decision for surgery. The diagnostic process ends with the histopathological workup of the tissue. We can only be sure about the diagnosis when we see the histology, and then we can try to understand what has been seen beforehand in the EEG or MRI, to try to make sense of those signals, but also to make a prognosis. Will the patient be seizure free after surgery? What’s the likely outcome? This depends on what type of lesion we identify. At least that’s our current knowledge, that the type of lesion is one of the prognostic features for outcomes.
One could also think that beyond using these methylation signatures for diagnosis and classification of epilepsy, one could think of identifying in this signature, parts that give a prognosis of drug response or other things. I think we can later identify many more associations which are then clinically meaningful. For the moment it’s speculation, but we know from cancer research for instance that this is possible, so I hope we can use this in epilepsy as well.
So someone has a lesion considered operable, they have epilepsy surgery and you can look at the lesion and use epigenetic techniques to understand where the lesion came from, why it’s there, and if the person is still having seizures, what drug they might respond to best?
Dr. Kobow: I can maybe add that the idea and the next step for research is that maybe we don’t have to do the surgery first and then look for the epigenetics. Maybe we find parts of the signature in the blood of the patient. There is cell-free DNA that we could identify.
Because of the blood-brain barrier leakage in epilepsy, there is some sort of communication between blood and brain, so I would not exclude that we can, if we have sensitive methods, identify part of these epigenetic signatures also from the blood. Then this would be so much more important, because you could do the diagnosis, classification, and prognosis before surgery and that would be so much more useful. So that’s something I will look into in the future.
How did you get into epigenetic research initially?
Dr. Kobow: By accident! It was really by chance, because my job interview for the job where I am now, 16 years ago, was not the normal job interview that I had experienced before. The first question was: “This is the technical problem: We have a gene that is downregulated in epilepsy and it has this and that function, why do you think it is downregulated and how could we check for that?” And I said, “Well, I would start with DNA methylation.” And that was my start into epigenetics research. Since then I’ve been studying DNA methylation in epilepsy.
I am not just honored to receive this prize. But knowing or remembering that this has been a very bumpy and difficult journey to do epigenetic research in epilepsy and convincing people that this is a relevant topic, it is a big joy for me to receive this prize and see this type of research really valued. And hopefully it will help to boost the attention, that people will be more aware of epigenetics and more interested in the topic.
Yes, it’s sort of a validation of the topic, right?
Dr. Kobow: Epigenetics is so big in developmental biology! It’s so big in cancer research! And to really convince people that we should sometimes look more broadly and not just in our own field and try to learn from other research areas. Here I think there’s a lot to learn from epigenetic research in other areas. For me it’s a promising field for so many reasons, and the data we’ve seen is just so convincing, that I’m really happy to be working in this field and push this further.
So it’s sounds as if it’s taken some time for the news to spread about the potential of epigenetic research in epilepsy?
Dr. Kobow: One of my first international talks I had, I remember it was in 2009 or 2011, We had a chapter meeting of the German, Austrian and Swiss League Against Epilepsy. I had organized a session on epigenetics and I had a wonderful lineup of speakers who were experts in their field, not from the epilepsy field, but giving insight into what epigenetics could mean to brain function and disease, including epilepsy. The disappointing thing was, we were speaking in front of an empty room. There were two people sitting in the room, nobody else, it was an empty room. I was so disappointed.
The funny thing was, the two people who were listening were so impressed by what they heard, they were running around and telling everyone about the cool session they’d been in. So at the end of these several days of meetings somebody came to me and said “Oh, did you hear about the epigenetics session? It must have been great! Did you go?” And I said, “Well yes, I’ve been organizing it, and I know it was a cool session, but unfortunately nobody came!”
But I’m happy that [epigenetic research] is gaining momentum, and the group of people doing epigenetics research in epilepsy is growing, and that’s really cool.
That is cool.
Dr. Kobow: And even in the Jasper Basic Mechanisms of the Epilepsies, there will be a chapter on epigenetics, so things like that are just my personal [victory], you know. It makes me really happy to see that.
That’s amazing. I mean it does take time for topics to be accepted by the community sometimes, although those topics are always the ones I’m most interested in, but in general it does take some time. It’s great you’ve been able to see that transition and that momentum.
Dr. Kobow: I have the same feeling like you – when there’s something new, and especially the topics where nobody else is listening, those are the topics that are interesting to me. And I really like working with people outside of epilepsy. My best collaborators are from the diabetes and heart disease area, and it’s been really interesting [to work with them], because metabolism has such a big role in epilepsy as well. And it’s also linked to epigenetics. It’s been really a great collaboration and gave me many new insights, and you just look differently at the whole thing.
You can find links to Dr. Kobow’s research in our show notes. Applications for the upcoming Michael Prize are now open and available until the end of 2022; you also can find more information about the prize in our show notes, or by visiting ilae.org/Michael.
To hear more from Dr. Kobow, watch the 2021 Michael Prize award symposium lecture on epigenetics.
Selected recent publications:
DNA methylation-based classification of malformations of cortical development in the human brain (Acta Neuropathologica, 2022)
Molecular diagnostics in drug-resistant focal epilepsy define new disease entities (Brain Pathology, 2021)
Epigenetics explained: a topic “primer” for the epilepsy community by the ILAE Genetics/Epigenetics Task Force (Epileptic Disorders, 2020)
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