Fighting Epilepsy With MicroRNAs?! - David Henshall, FutureNeuro SFI Research Centre, RCSI, Ireland
Molecular physiologist and neuroscientist, David Henshall discusses the role and importance the role of microRNAs in epilepsy (which act as master regulators of gene activity and help stabilise the gene pathway), plus the potential of RNA therapy in treating epilepsy! This is episode 1 of 2 with David.
Reported by Torie Robinson | Edited and produced by Carrot Cruncher Media.
Podcast
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Amazon: finetuning+life+david+henshall
Synopsis
Take a journey into the fascinating world of microRNA, the genome's master controllers. Discovered in 1993, our genome's master controllers are critical to the evolution of complex life, including humans. This captivating book tells their story, from their discovery and unique role in regulating protein levels to their practical applications in brain health and other branches of medicine. Written by a neuroscientist, it provides an in-depth look at what we know about microRNAs and how we came to know it. Explore the impact of these molecular conductors on your life and gain a new appreciation for the precision they bring to the molecular noise in our cells. Perfect for students of neuroscience, life sciences such as biochemistry and genetics and the curious public alike, this is the captivating tale of the conductors of life's molecular orchestra. -
00:00 David Henshall
"Here are some genes which we seem to be very tolerant of changes in them. We can kind of put up with there being a little bit “out of whack”, either because we've got maybe another gene a little bit like that, that can do some of the same job, you know. Or maybe we have a lot of it in the cell so that a small change in the amount of that particular RNA doesn't make a lot of difference."00:25 Torie Robinson
Fellow homo sapiens! My name is Torie Robinson, and welcome to, or welcome back to: Epilepsy Sparks Insights.
Now, who knows about MicroRNAs, their relation to worms(!), how they were discovered, and how they are involved when it comes to the epilepsies?! Well, today we do hear all about it - from an person who can apply his knowledge of neuroscience, molecular neurophysiology, pharmacology and genetics to figure out the answers for us - David Henshall!
Please don’t forget to share your thoughts on this episode with us in the comments below because I enjoy reading your thoughts and responding to them! Do subscribe so that we can educate the masses and empower way more people affected by the epilepsies around the world, and, indeed, more clinicians with patients who have an epilepsy - to provide the best care possible.01:13 David Henshall
My name is David Henshall. I'm a professor at the RCSI University of Medicine and Health Sciences, which is a big medical school in the heart of Dublin in Ireland. And I do research on epilepsy. The area I'm most interested in is understanding what happens to genes in the brain during the development of epilepsy and that's what we do research on: trying to find new ways to treat epilepsy.01:40 Torie Robinson
When it comes to genes ([which is] obviously a rather complex topic in itself), I have to keep reminding myself, what is the difference between different types of RNA? Could you just give us a bit of a low down for people who aren't aware, haven't heard of them or have forgotten (like me!), what are RNAs and what are the different types?02:01 David Henshall
What I could do is try and tell you the simple gene pathway, if you like, and kind of tell you where RNA comes in in that pathway. So, when we think about a gene, what we're usually talking about is a sequence of DNA that has the instructions to make a protein. So, the way that this works is that the DNA gets read in a process called transcription and this produces an RNA which we call an mRNA for messengerRNA. So, this is a long RNA molecule, ribonucleic acid, long RNA molecule. And then that gets shunted out, away from the DNA out into another part of the cell, where it meets a big structure called a ribosome and within the ribosome the messengerRNA is red and amino acids are glued together into a long chain which forms a protein. So, the gene pathway is sort-of DNA, messengerRNA, protein.03:09 Torie Robinson
You say protein, I just think of like, you know, slabs of meat or something. So, like, how do… what's the difference between the protein we refer to in a slab of meat and the protein that you're talking about?03:20 David Henshall
They could be one and the same!03:21 Torie Robinson
Huh!03:21 David Henshall
So, one of the types of proteins that we talk about is, or one of the types of proteins that we have is the proteins that make up the muscles in our cells. Okay, but proteins can do all sorts of different things. So, some proteins are enzymes that produce energy in your cells. Other proteins (and this is maybe most relevant to the brain), other proteins produce neurotransmitters which are released by nerve cells when they communicate. We also have proteins that form little channels that allow the movement of molecules into and out of the cell. One of those molecules is sodium. Sodium - just like the salt that you put on your food.04:03 Torie Robinson
Or shouldn't put on your food!04:04 David Henshall
Or shouldn’t! And sodium moves in and out of cells during the firing of signals in the brain. In fact, it's one of the most important things. And actually, one of the best-known genetic forms of epilepsy is caused by a fault in the gene that makes that sodium channel.04:22 Torie Robinson
Which form of epilepsy is that?04:25 David Henshall
Dravet Syndrome. Dravet Syndrome is mainly caused by a fault in this gene called SCN1A and so that gene, that encodes a protein that forms one of these sodium channels on nerve cells.04:39 Torie Robinson
What are the benefits of these RNAs when it comes to us - as the animals that we are, and, you know, looking at evolution over time; did they always exist within organisms, more-or-less all the time? Because they seem to be a bit annoying (to put it politely) sometimes when it comes to a epilepsy, because they play around a bit.05:00 David Henshall
Haha, so yeah, there's lots of different types of RNA, right; the one that most of us talk about is mRNA - most of us knew that name from the COVID vaccines, right? And the mRNA is the type of RNA which, you know, encodes a protein. But there's all of this other part of the genome that can be read, make RNA, but that RNA doesn't make protein. That RNA stays as RNA and does other jobs in the cell. So, it's a bit like a gene. So, there's a sequence of DNA that can be read. It makes an RNA, but the RNA doesn't then go on to code for a protein. It stays as an RNA and then the RNA does jobs within the cell. And microRNA are one of the key types of those RNAs.05:55 Torie Robinson
Okay, this needs to get more complex. So, what exactly do these RNAs have to do with whether a person has an epilepsy or doesn't have an epilepsy? And how are you using that knowledge in your research? Tell us about06:08 David Henshall
RNA is a measure of gene activity. So, the RNAs that we were talking about (messenger RNAs); they code for proteins. So, if you have epilepsy, there may be a fault in the sequence for that RNA and so that RNA maybe doesn't make the protein that it should do.06:28 Torie Robinson
Hm!06:29 David Henshall
And, so, then you can end up with problems in brain function and, for example; seizures. But there are also other types of RNA that we're learning more about; the type that doesn't code for protein; we call that non-coding RNA. There are lots of different types; some of it's quite long, soome of it's shorter. And those non-coding RNAs are really important for regulating the gene pathway. So, they sort-of serve to either: activate it a little bit more or to dampen it down a little bit less. And so, if you have changes in that type of RNA (if you have changes in non-coding RNA), that can also cause problems. It can lead to too much gene activity or too little gene activity; the wrong things being switched on or off.07:24 Torie Robinson
We're pretty sensitive creatures, right? With all these little things that could go wrong or malfunction.07:30 David Henshall
Yeah, but it depends a lot on the gene. So, there are some genes which we seem to be very tolerant of changes in them. We can kind of put up with their... being a little bit “out of whack”, either because we've got maybe another gene a little bit like that, that can do some of the same job, you know. Or maybe we have a lot of it in the cell so that a small change in the amount of that particular RNA doesn't make a lot of difference. But then there are other types of RNA where small differences make a huge impact on brain function. And actually, the SCN1A gene is a nice example of that because that gene is particularly important for the firing of our inhibitory neurons within the brain. And anything changes in how they fire then we start to have problems!08:23 Torie Robinson
I went to a conference and I met lots of people with SCN2A and SCN8A (mutation). And one of them was a data scientist and everybody else had severe intellectual disability, autistic traits, mostly nonverbal. And I just thought “Wow, this really shows you can have what appears to be the same on paper (at least to the layman) but the variety of how that can impact people is huge!08:58 David Henshall
Yeah, absolutely, and we're only just starting to sort-of understand or make sense of, you know, why a mutation in one particular gene can cause something really catastrophic, whereas another mutation or variation can be really well tolerated. A lot of it comes down to… so, for some of the proteins that are important for movement of molecules inside and outside of brain cells, there'll be a particular amino acid that sits right at the centre of it that sort-of acts as a gateway, and if you get a mutation there then the entire protein stops working properly. So, there are sort-of some areas of genes that can handle a bit of variation, [but] in other areas where any kind of variational mutation can completely damage the function of the gene.09:49 Torie Robinson
And so, the type of research that you do, do you look at a particular gene that commonly causes epilepsy - And we'll get onto your marvellous book in a moment - or are you looking at the whole spectrum of things? Or…10:01 David Henshall
So, we don't tend to concentrate on a single gene or a single cause of epilepsy. In fact, the area of epilepsy we work most on is temporal lobe epilepsy, which is a very common form of epilepsy (particularly in adults), it's very often drug resistant or difficult to control seizures with. And we don't see a very strong genetic component to that type of epilepsy. It's generally understood that that epilepsy has resulted from a combination of environmental factors; maybe things that you experience growing up, mixed together with your genetics and perhaps something else that we still don't fully understand. So, the sort-of working hypothesis for our lab (as well as several others on temporal lobe epilepsy) is that actually what's happening there is there are multiple different changes within the brain. Maybe changes to neurons, changes to their support cells called glia. There's maybe an inflammatory component, maybe something to do with the blood supply, the sort-of energy balance within that tissue. And so, you've got a lot of things changing a little bit. And that makes it particularly challenging to fix as an epilepsy. You know, you certainly, we don't think you can just go in with a sort of a 1 gene approach. And that was one of the reasons that I became really interested in the area of microRNAs for reasons that I can explain.11:39 Torie Robinson
Do these things just faff about in your brain or are they, like, going to other organs and other tissues?11:44 David Henshall
They're in every cell in the body. So, every cell produces microRNA. The brain produces the most microRNA molecules and the most different types of microRNA. And one of the reasons is that the brain is (in terms of its complexity, in terms of the different cell types), it's absolutely packed with these microRNAs - which are very important, in fact, for producing all of the variety; the rich variety of brain cell types. Vbut they can be detected in other places; so they can be detected in the fluid that surrounds and circulates through the brain called CSF, or cerebrospinal fluid. You can detect them in the blood. You can also detect them in things like tears and saliva.12:29 Torie Robinson
Gosh.12:29 David Henshall
So, there's a whole area of research on microRNAs as potential diagnostics. And one of the reasons that we think they might work is that we know that particular cells generate very particular microRNAs. So, if you imagine there's a microRNA that's only produced in one part of the brain; if you can detect that in the blood, that could tell you straight away that there's a problem with that part of the brain if no other part of the body makes it.12:58 Torie Robinson
Right!12:59 David Henshall
And microRNAs are also… they're quite sort-of chemically stable; so, they can survive quite a long time in fluids and that's an important factor to consider for sort-of practical use of these things - you know, If you want to take a test in a hospital, that molecule has to survive for a while in that fluid.13:21 David Henshall
So, there's a couple of really exciting stories that I cover within the book about particular experiments that were done. So, I could mention a couple of them now. One of my favourite experiments was an experiment that demonstrated the effect that even a single microRNA can have on a cell. So, a group of researchers took one of the microRNAs that's only made in the brain, and they put it in a common cell that's used in most labs around the world. It's called a HeLa cell. There's a story around the origins of HeLa cells that I could tell you a little bit more about, but essentially this is not a brain cell, okay? So, they took one of these microRNAs that's made only in the brain, and they put it into this other cell type, HeLa cell. And then they looked at what happened to the gene activity. And it reduced the level of all of these genes that are not made in the brain. So, what this told us was that what this microRNA is doing is keeping brain cells, brain cells, and stopping them make things that shouldn't be in brain cells.14:35 Torie Robinson
Which is a good thing, right? Yeah.14:37 David Henshall
Which is a very good thing, yeah! And there's a large amount of this particular microRNA which is continuously made inside neurons within the brain. And it stops other “non-neuron” genes getting made in that cell type. And if you, in fact, if you remove that microRNA then the genes begin to sort-of bubble back towards something that isn't neuron. So, that was one of these really cool experiments that was done really early on.15:08 Torie Robinson
So, like without this microRNA, we could potentially have, like, any old weirdo cell growing in our brain.
15:15 David Henshall
Yeah, without that particular microRNA - and there's one or two others that are a bit similar - our neurons wouldn't have all of the properties that we need them to have. So, it's sort-of like leaky genes would start to come through, and then the microRNA is just like, no, not on my watch.
15:35 Torie Robinson
So, the microRNA is the boss of what goes down. And what was the next one you had to share?!
13:39 David Henshall
So, one of my other favourite experiments was to try and understand what controls the amount of microRNA in a particular brain cell. And what they did was they connected a little coloured substance onto a microRNA and they watched with a microscope little flashes of that colour as that microRNA got made. And what they learned was that that microRNA was getting made just as a signal came through from one neuron to the next. So, the production of a microRNA is actually connected to the signals between brain cells. And this is really important for things like learning and plasticity and memory because we know that brain cells can change shape slightly (in terms of their connections) and that's an important thing, that those connections can strengthen as we learn things. So, what their experiment showed was that actually microRNAs are really important for that strengthening process. They need to be able to switch on and off and by doing so they can strengthen or weaken the connections between brain cells.
16:56 Torie Robinson
So, something goes, an experience happens, something affects one particular part of your brain, brain cell, and the microRNA that already exists will go “Yo, I'm here!” - or not, depending upon what is happening in your brain at that time.
17:12 David Henshall
Exactly, so, to sort-of learn and to make memories we know that new proteins need to get made, and so, microRNAs are sitting right at the centre of that process controlling it all and making sure that it happens smoothly and correctly.17:27 Torie Robinson
That is so cool! That is kind of scary-cool, but very cool. Yeah. Okay. And we'll hear about that in the book, right?17:37 David Henshall
Yes, yeah, there's a good description of that experiment as well as the other experiment with the HeLa cell.17:42 Torie Robinson
Thank you so much to David for managing to explain to us what microRNAs are, their significance, and giving us an enticing sliver of his new book! Do make sure that you join us next week for part 2 of 2 with David where he shall be telling us much more about incredible discoveries, microRNA therapy today, and exciting us more(!) abuot his epilepsy research going forward!
Do check out David’s book on the website torierobinson.com (where you can also access the podcast, the video, and transcription of this episode), and if you haven’t already, don’t forget to like, comment, and subscribe to our channel, share this episode with your friends/colleagues/family members(!) and see you next week! -
David’s undergraduate degree was from the University of Bristol, graduating with First Class Honours in Pharmacology in 1994. Postgraduate training on stroke modelling and neuronal injury was under Drs John Sharkey and Steve Butcher in the Department of Pharmacology and the Fujisawa Institute for Neuroscience at the University of Edinburgh, leading to the award of a Ph.D. in Neuropharmacology in 1997. Post-doctoral training in cell death signaling in epilepsy was under Prof Roger Simon at the Department of Neurology, University of Pittsburgh, USA. Following NIH funding in 1999, David was appointed Assistant Scientist at the newly established Robert S. Dow Neurobiology Laboratories, a private non-profit research institute in Portland, Oregon, USA. An RO1 award for research on apoptosis signaling in epilepsy established an expanded research team and in 2003, promotion to Associate Scientist. In early 2004, David moved to RCSI as Senior Lecturer in Molecular Physiology & Neuroscience. David has authored over 195 papers and 10 book chapters. He is the Chair of the International League Against Epilepsy Neurobiology Commission''s Task Force on Genetics/Epigenetics and a Benchmark Steward for the National Institutes of Neurological Disorders and Stroke. He coordinated the European FP7 large-scale collaborative project EpimiRNA (2013 - 2018) and co-organised the international conferences EpiXchange I and II which brought together Europe’s major epilepsy research projects and which is now supported as a flagship “Cluster” by the European Brain Research Area (EBRA). In 2017, he became Director of FutureNeuro, a €13Mio Science Foundation Ireland Research Centre and the first to be hosted by RCSI, focused on chronic and rare neurological diseases. The Centre is an industry-academia partnership model working to translate findings for patient benefit and includes world-leading investigators in the areas of clinical neurology, genetics, materials science and eHealth based at RCSI, TCD, DCU, UCD, NUI Galway, WIT and UCC.
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