How Worms Helped Us Understand Epilepsy! - David Henshall, FutureNeuro SFI Research Centre, RCSI, Ireland
David Henshall shares how information gathered when researching worms led to the discovery of microRNA, a far improved understanding of the epilepsies, and potential treatments - all explained in his new book (link below)! This is episode 2 of 2.
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. -
David Henshall
“So, the genes are sort-of whirring away, we're getting proteins made and then microRNAs kind of come in and they sort-of stabilise things and dampen things down and keep things as they should be. They sort-of fine-tune the system and that's the idea behind the title of the book,Fine-Tuning Life. They're sort-of nature's fine tuners.“
00:19 Torie Robinson
Fellow homo sapiens! My name is Torie Robinson, and welcome to, or welcome back to: Epilepsy Sparks Insights.
The RNA Revolution has given us an entirely new, exciting, way to treat - or at least look at treating - many diseases, including the epilepsies. In today’s episode and part 2 of 2, David Henshall conveys his passion and excitement for MicroRNAs and their regulation of the human genome - talking about his new, cool book: “Fine-Tuning Life - A Guide to MicroRNAs, Your Genome's Master Regulators”!
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 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
“Fine Tuning Life, a Guide to MicroRNAs, Your Genome's Master Regulators”. So, that's quite an enticing title. What's the purpose of your book and who is it targeted at?
01:51 David Henshall
The purpose of the book is to tell the story of these remarkable types of genes that we've been working on for many years now called microRNAs. So, to try and tell the story of them, I think we think that they're fascinating genes, that they're a bit different to the type of genes people typically are doing research on. And the story of how they were discovered, how we learned what they do, how they work, how they evolved in the first place, and what they do within the cell, I think, is an exciting story that I thought I had reached a point that I could tell. And because it links to the work that we've been doing on epilepsy over the last 15 years or so, I could see that you could tell the story and move it towards the areas that I'm of course most interested in, which is what these genes do in the brain, and (more importantly), what they might be useful for in epilepsy in terms of explaining what can cause epilepsy and maybe targeting those new types of genes as a new way to treat epilepsy. There's even a little bit of a story that they could be useful for diagnosing epilepsy as well, which I can tell you more about.
03:08 David Henshall
So, the book begins with a description of the gene pathway really, so, it takes you from DNA to protein and then tells you where it is that microRNAs sort-of act in that pathway. Because, they sort-of work at a particular point and they work by sticking on to messengerRNA and reducing the amount of the messengerRNA. So, essentially, they dampen down gene activity within the cell. And they're an important fine-tuning system, so, they sort-of stabilise gene activity within the cell. And experiments have shown that without this molecule, gene activity becomes rather unstable and slightly chaotic. So, microRNAs work as a sort-of negative feedback loop to stabilise gene activity within cells. And they evolved hundreds of millions of years ago alongside our protein coding genes.
04:14 Torie Robinson
Ah-ha!
04:15 David Henshall
And so, they're sort-of there the whole time looking after things, keeping things stable, keeping watch over the gene pathway.
04:24 Torie Robinson
They're mates.
04:25 David Henshall
And there's a rather nice analogy that sometimes people use to describe microRNAs that they're “the conductors of the molecular orchestra”.
04:32 Torie Robinson
Oh, I really like that thought. I went to a concert (a classical concert) recently. I love some classical music. And it's so true: like, unless you're all following the same hymn sheet and following the rules, things so easily fall apart and just sound dreadful. And so, it's the same within one's body, right?
04:50 David Henshall
Exactly, you've sort-of got this molecule that - using the music analogy - can speed things up, slow things down, make things louder, make things quieter. So, the genes are sort-of whirring away, we're getting proteins made and then microRNAs kind of come in and they sort-of stabilise things and dampen things down and keep things as they should be. They sort-of fine-tune the system and that's the idea behind the title of the book, Fine-Tuning Life. They're sort-of nature's fine tuners.
05:20 Torie Robinson
What has been the impact on us as a species over the past 10-20 years with a better understanding of RNAs and the impact on people affected by the epilepsies, on the brain, on us as a species really?
05:36 David Henshall
There's been an enormous… there's been what people have described as the “RNA Revolution”, which is that RNAs now represent a completely new way of treating disease, not just brain disease, of course (I mean, the COVID vaccines are the best example of this or the most obvious example). But we can now target RNAs to create very precise types of gene therapy where we can design molecules that will lock on to specific RNA, stop it from working - or, activate it (make it work better)! And by doing that you've really got a single gene sort-of precision therapy! A lot of the drugs that… well, really, almost all the drugs that we use for epilepsy, act very broadly
06:23 Torie Robinson (19:06.691)
Yeah.
06:23 David Henshall
…you know, they dampen down brain excitability, they sort-of jam things in the neuron to neuron communication, quieten things down, but they quieten things down everywhere! They don't know to just go to this one place and interfere there!
06:38 Torie Robinson
“Cheers mate, yeah, thanks, dampen down my life, great!”
06:45 David Henshall
So, the promise of RNA therapy is that you can target (in very, very specific ways) a molecule inside a cell, stop that from working, or boost it from working, leaving everything else on its own. So, you in theory would get less side-effects. The downside (!) of these types of RNA therapy is that the drug, if you like, to target that, is a large molecule, it's complex, you probably can't just take it as a pill. It might be something that has to be sort-of injected somewhere and perhaps injected even into the brain itself (because otherwise it won't get into where it needs to be).
07:23 Torie Robinson
And by “big”, do you mean… sorry, are you talking [about], like, a centimetre? Are you talking [about], like, a couple of millimetres?
07:30 David Henshall
We are still at an atomic scale here. We're still at the atomic scale.
07:31 Torie Robinson
Right. So, so, why can't that be, like, absorbed in another way then?
07:37 David Henshall
We have this barrier that separates the blood from the brain called the blood-brain barrier. So, basically, the blood cells that make up the vessels in the brain are really tightly glued together and things just can't pass through them very easily. So, small molecules can get through pretty well but these big molecules that we're designing - and in a way what we're designing is something that looks a little bit like DNA itself. So, these are very large molecules and they won't pass simply from sort-of the blood into the brain. So, we have to figure out ways to get that therapy into specific brain cells and people are working on solutions for that.
08:19 Torie Robinson
Well, I'm just thinking personal perspective: if you want to shoot me up with a little bit of a couple of cells into my cerebral spinal fluid - versus ongoing seizures…(!) I mean, that's just me…
08:33 David Henshall
That's another benefit we think from RNA therapy. So, the molecules that we're able to design last a really long time. So, unlike your typical anti-seizure meds that you know you have to take sometimes several times a day; most of these molecules that we're talking about now might last 2 to 3 months after they've been injected! So, the route to deliver them might be a bit invasive as you say, intrathecal injections but once injected you might not need to have a treatment for 2 to 3 months. The molecule itself survives a really long time in the body. The body can't break it down because it's a sort-of an unnatural molecule and it's big and it's difficult to get its hands on.
09:14 Torie Robinson
So, you say “unnatural”; that might scare a few people
09:17 David Henshall
Ah!
09:17 Torie Robinson
Could you reassure us please?
09:20 David Henshall
So, what I'm saying when I say “unnatural” is that if we design a gene therapy out of say pure RNA, it would be digested immediately. We have enzymes sitting everywhere that break down RNA because viruses use RNA to get their job done. So, we have evolved very good defences against that, if you like, so, naked RNA will be dissolved very, very quickly as soon as it enters the body. So, what we have to do is make little chemical modifications to the RNA so that our natural defences don't detect it or can't break it down. So, when I say an “unnatural” molecule, essentially, we're taking a sort-of a natural molecule, just making a few chemical changes to it so that it evades the body's defence and can survive for a long time.
10:12 Torie Robinson
And so, at the end of say, 3 months (that you spoke of before), so you know, it could have beneficial impacts for that long; what happens to the actual RNA that you've shot into somebody's system?
10:27 David Henshall
So, we think, over time, the sort-of, the artificial molecule begins to break down… that although it lasts a long time eventually it is sort-of removed from the cell or breaks into smaller pieces over time.
10:42 Torie Robinson
And what else would you like to tell us from your book?
10:44 David Henshall
So, the first chapter of the book tells the story of the normal gene pathway from DNA to protein. And then the moment about 30 years ago where a new type of gene was discovered: that gene would eventually get the name “microRNA”. So, it tells us the story of how this gene was discovered, which is a really cool and exciting story because the researchers that were working on the discovery were studying actually how worms develop! And worms are obviously very simple creatures(!); this particular worm has only about a thousand cells in its whole body. We have trillions. So it’s a very simple…
11:21 Torie Robinson (26:19.203)
Wow!
11:21 David Henshall
But because it's so simple you could understand which genes switch on and switch off as the worm developed. And they made this discovery that there was this other type of gene that clearly didn't code for a protein but was really critical for the worm development. So, they made this discovery and then it got largely ignored…because people didn't really grasp what had been discovered.
11:47 Torie Robinson
What a big deal it was, how cool it was.
11:49 David Henshall
A few years later, a second type of this gene was discovered and then the big moment was that, “Oh, that second type of gene is also in humans!”!
12:02 Torie Robinson
Huh!
12:03 David Henshall (27:24.982)
This isn't just an odd gene/oddity of a worm. We have the same gene! And it was identical, the sequence was identical, so we have been separated, you know, our last ancestor that we shared with the worm is sort-of 600 million years ago or something. We have the exact same sequence of this particular gene! So, we have required this gene over the hundreds of millions of years that we have evolved from the last ancestor with this worm. So, that's the opening chapter of the book and it's such a… it's a really cool story. It's cool because it shows that you know, sometimes you don't even know what you're working on and how it might impact science in the future.
12:44 Torie Robinson
And how exciting is that? It's like the unknown, sometimes of the significance of one's discovery, right? That's one of the amazing things about science. Anyway, sorry, next chapter…!
12:55 David Henshall
Yeah, so, chapter 2 is sort-of the explosion of interest in this new type of gene that within a couple of years had been referred to as a microRNA. And the remarkable thing was within a very short period of time (2 or 3 years), scientists around the world had figured out the species that have these microRNA genes, more or less how many genes that we have (there's about 2,000 of these in the human genome). They had figured out the pathway by which they were made, sort-of how they got formed, where they acted, and what they did in the cell. And so, there's this wonderful sort-of explosion of research that generated the core understanding of the whole microRNA world. And it happened within 2 or 3 years.
13:43 Torie Robinson
That's amazing. And which years are we talking about here?
13:45 David Henshall
So, the kind of “explosion moment” was around the year 2000 to 2004. So, it was this sort-of 3 or 4 year period when a lot of the fundamental discoveries were made. I mean, we've continued to make discoveries about microRNAs ever since, but there was this amazing period of time that a lot of the basics were uncovered.
14:11 Torie Robinson
What was the next stage, the next step and the next chapter?
14:14 David Henshall
Yeah, so, during the next couple of chapters, I sort-of explain why microRNAs evolved. So, what is it, what is the important job that they do for the cell that wasn't getting done just by our regular protein coding genes? So, this is sort-of this idea that they work to stabilise gene activity within the brain and within other parts of the body, that they're critical for how we develop (as cells divide, particular microRNA genes switch on and switch off). And essentially, they're critical for every stage of the development of organisms, but also once we finish developing, they help stabilise the genes that are switched on on a day-to-day basis and keep everything working smoothly.
15:03 Torie Robinson
It sounds like they are at least partly responsible for the complexity of us as a species.
15:09 David Henshall
This is exactly right and one of the points I make in the book is about something called the - and this is going to sound a bit nerdy…
15:18 Torie Robinson
Please!
15:20 David Henshall
The “G-value paradox”.
15:22 Torie Robinson
Oooo!
15:23 David Henshall
Well, the G-value paradox is that we share the same number of protein coding genes as that worm did. We both have about 20,000 genes. So, clearly, complexity is not simply a function of the number of genes that we have. So, there must be something else in our genome which is taking these 20,000 genes and creating the rich diversity that we have as humans and also other more complex organisms. And this is one of the key roles that microRNAs do: they can sort-of take this basic set of instructions (our protein coding genes), and they can use them and control them in ways that creates enormous diversity! All of the different cell types, systems that we have, tissues, all the way up to the wondrous complexity of the brain; is partly helped by the presence of these microRNA genes.
16:24 Torie Robinson
Do you talk about the… the not-so-positive aspects of some microRNAs in the book?
16:32 David Henshall
Yes. So, because microRNAs are so critical to normal, healthy cell function, it's not surprising that if levels of microRNAs either increase too much or decrease too much, then things can go wrong. In the book, I focus mostly, I think, around epilepsy and trying to describe a little bit of the research where we've identified some microRNAs where levels are either too high or too low within the brain. So, if levels of a particular microRNA are too high, you can imagine that that may switch off genes that we want on. And if levels of a microRNA are too low, then genes that should be off; start to switch on. So, for sure; we know that changes in microRNA activity in the brain could be contributing to some of the epilepsies. Now, a lot of that research is still at a pre-clinical stage, so, the proof, if you like, is at a pre-clinical stage. So, people have shown, for example, that if you have a knockout, if you remove 1 or 2 of the really important microRNA genes, it can cause an epilepsy.
17:45 Torie Robinson
Okay.
17:45 David Henshall
And if you stop them getting produced in the brain, then… say you stop them being produced in the brain of a mouse; that mouse actually, over a period of weeks, begins to develop seizures.
17:57 Torie Robinson
Huh.
17:59 David Henshall
So, we know that the brain must make a number of microRNAs all the time - because if you prevent them being made in the brain then seizures can develop.
18:10 Torie Robinson
Does that happen sometimes? So, somebody's microRNA can change and they start developing seizures?
18:16 David Henshall
This we don't know. We can see, we can study, for example, animal models of epilepsy, and we can see that there are changes in microRNA levels as epilepsy is developing…
18:27 Torie Robinson
Right.
18:28 David Henshall
…some of them switching on, some of them switching off. So, we think that that's contributing to the development of epilepsy -- but proving that that happens in the person isn't possible at the moment. The proof may be, you know, if we can design a drug against one of these microRNAs and that… if that can interfere with an epilepsy in a human, then of course then that's more evidence. But, at the moment, the evidence is really just coming from what we can do in preclinical models.
18:57 Torie Robinson
Do you talk about what the future may or may not hold in your book?
19:01 David Henshall
Yeah, so the final chapter of the book looks to the future and asks some of the questions, you know, what is next for this field of microRNA research? And I talk a little bit about where I think the possibilities and opportunities lie in the field of epilepsy, but I also take a bit of a step back and say, you know “What are the really big discoveries and what are some of the top scientists around the world that are working on microRNAs?”, you know “What are they doing in the future?”.
19:30 Torie Robinson
And do you touch at all upon, actually, in the book (I don't know if it will be at the end or in the middle, or throughout), but, you know, lots of people are… kind of get a bit, a little bit scared. You talk about things in acronyms that we're not aware of and talk about anything, anything to do with genetics. It's like “Oh my goodness!”, So, is… do you cover anything about the manipulation of this data or people using microRNAs in potentially not-so-positive way?
19:56 David Henshall
So, what I try to do is get across where the science is in relation to, if you like, health or applications in medicine and technology. So, at the moment, there's 1 or 2 drugs that have been developed to target microRNAs: one of them has already gone through a clinical trial (it wasn't for a brain disease, it was for a Hepatitis C, it was a liver infection, but it went through to human testing) and it showed to work. We've also seen the emergence of some blood-type tests. There's a couple of tests, for example: there's a cancer test that's being developed where they measure levels of microRNAs and that can be used as a way to determine that cancer may be present ([a] particular type of cancer) may be present in somebody. Of course, for us, we're excited that the possibility that you might be able to make a measurement of microRNAs in a…maybe in a blood sample that could tell you if you have a risk of developing epilepsy (!),or maybe if your epilepsy is of a particular type or may respond to a particular type of treatment.
21:08 Torie Robinson
That's just amazing, just through getting a bit of bodily fluid, whether it be a bit of spit - or you mentioned tears before - you know; there are so many potentials here. It sounds like this is - and it sounds like your book reflects this - and I can't wait to read it!(!) - reflects that this is an exciting time in this sphere of microRNAs.
21:30 David Henshall
Yeah, one of the reasons I wrote the book when I did was because I felt the field had got to a level of, sort-of, maturity, you know: we'd made these incredible discoveries. We'd learned what this system was important for, how it contributed to all of the functions within the body, and we were starting to see applications in the medicine and sort-of health-technology fields. And in the epilepsy field as well, we'd reached a level of maturity where we understood that these genes really are changing in epilepsy. It's different types of epilepsy. We don't know if it's all epilepsies, but it's certainly many of the epilepsies that we've looked at seem to have some change in the function of these genes. And we're beginning to see the development of potential treatments and diagnostics, but we're not yet getting into the clinic. So, will there be a book 2? I hope. There might be, in the future, a point where we can look at where we were now and look back on that time and think that was just before this moved into the clinic. And now look what we've got.
22:41 Torie Robinson
Gosh, if one doesn’t get David’s book now, then, yeah, I just don’t know…..
But, thank you to David for making learning about genomic history exciting and cool - because THAT is a brilliant skill in itself!
You can find the link to David’s book and other info on his work 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 the channel, share this episode with your friends/colleagues/family members(!) and see you next week!
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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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