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S01-E05: Unlocking the Secrets Behind Peripheral Nerve Injury and Research Update

• Dr Biswajit Podder • Season 1 • Episode 5

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In this episode, we will embark on an intellectual journey with the eminent Dr Guillem Mòdol Caballero from University College London as he navigates the world of neuroscience and sheds light on his pioneering work in peripheral nerve injuries and gene therapy. Peripheral nerve injury refers to damage or dysfunction of the nerves that lie outside the brain and spinal cord, which are part of the peripheral nervous system. This system is responsible for transmitting information between the brain and spinal cord and the rest of the body. Peripheral nerve injuries can result from a variety of causes, including trauma, surgery, compression, and certain medical conditions.

The impact of a peripheral nerve injury can range from mild and temporary to severe and long-lasting, affecting sensation, movement, and organ or gland function depending on the nerves involved. Symptoms may include numbness, pain, weakness, or paralysis in the affected area.

Our conversation peels back the layers of genetic mutations and their profound effects at the protein level, revealing the potential of gene therapy to alter the course of devastating neurodegenerative diseases. Dr. Model's insights not only underscore the importance of understanding these conditions from a molecular standpoint but also spark a beacon of hope for those affected by such relentless ailments.

If you have any questions, suggestions, or feedback, please contact at scipodchat@gmail.com

Disclaimer: This podcast is for informational purposes only, and SciPodChat is not intended to replace professional advice. Please note that the views, information, or opinions expressed during SciPodChat are solely those of the individuals involved, not any professional organization in which they are involved.

We Talk Science

Speaker 1:

Hello Science Labr. This is Cyberture, a podcast where we explain science puzzles in a way everybody understands. I'm your host, dr Vishwajit Puddar, a scientist with more than 12 years of research experience in cancer disease. This podcast is brought to you by STEM Dradoo. The goal of STEM Dradoo is to make learning fun and interesting for kids. The games and exercise on STEM Dradoo are fun and help kids learn math and science at the same time. If you are enjoying our podcast, please consider leaving us a review. Wherever you listen to Cyberture, your support means everything to us and helps our goal to bring you more quality content.

Speaker 1:

As we begin today's episode, I hope you will find it as interesting, as educational as the previous episodes. Welcome to our podcast. In this episode, we are excited to have Dr Gilliam Model, a neuroscientist who is working at the University College London. Dr Model, who earned his PhD at the University of Autonomia de Barcelona, has been exploring innovative treatments for nerve disease. His current focus is on how to repair damaged nerves and turn this scientific discovery into real-world treatments at the UCL. Without further ado, let's dive into this episode and let's learn about peripheral nerve injury. Hi Gilliam, welcome to Cyberture. How are you? Hi Vishu.

Speaker 2:

It is a pleasure being here. Thank you for inviting me, and I'm excited to talk a bit about neuroscience and nerve injuries, and also nerve regeneration.

Speaker 1:

It's my pleasure, man. Thank you so much for coming. Can you tell about your motivation working in neuroscience, why you are motivated to start in neuroscience as you did?

Speaker 2:

in.

Speaker 1:

PhD in neuroscience. Can you tell me more?

Speaker 2:

Yeah, exactly, I'd say that it's a live motivation, as many of us scientists, since we grow up, we see our loved ones with some neurodegenerative diseases or cancer or other diseases. I think that if you're a curious person and you like investigating things, knowing more about things, I used to grow up in this kind of environment. I really wanted to help. I really wanted to know more about this kind of diseases. That was definitely one of my motivations, right.

Speaker 1:

Yeah, very exciting. You did your PhD in neuroscience. You told me that you work on neuroscience, but can you tell me a bit specifically what topic was there and what you did? Can you explain to our audience?

Speaker 2:

In my PhD right.

Speaker 1:

Yes.

Speaker 2:

Okay, sure. So basically, in my PhD I did research on ALS Amiotrophic Lateral Sclerosis. This is a disease that is also related to the peripheral nervous system.

Speaker 1:

For the audience, I think it's going to be easy to understand now, because a very famous scientist named Stephen Hawking oh yeah, actually I had another day one episode of motor neuron disease and Dr Dwey was there and she also mentioned about motor neuron disease.

Speaker 2:

Exactly so. It's a great example because you can see how hard these diseases are, and the genetic disease that Dr Stephen Hawking had was actually rare, because he got a motor neuron disease Exactly, which is rare.

Speaker 2:

Yes, which is rare, and at the same time, normally the prognosis and the survival for the people that has this disease. It's about two or three years and he could live for many more, even though in this condition where you lose the ability to move yourself, so it's really tough. So, basically, what I did in my PhD was trying to find new treatments for these diseases.

Speaker 1:

Okay, how did you try so? You work in the laboratory. So can you explain briefly what exactly you did and what was your approach? Scientific approach.

Speaker 2:

Exactly so we tried something that is quite new and exciting, that is called gene therapy.

Speaker 1:

Oh yeah.

Speaker 2:

And basically we know that in ALS there are some mutations.

Speaker 1:

Okay, I will stop in here. Can you explain a bit about gene therapy. What is actually gene therapy Exactly?

Speaker 2:

So when we talk about genes, we know this is our DNA, every cell of our body. We are all made of DNA. Dna is the basis of life.

Speaker 2:

And this DNA in order to end up producing a functional protein, it is transcribed in something that is called RNA, which is a middle stage between the DNA and the protein, and the thing is that sometimes in these diseases, you have these mutations in these genes and what happens is that in the end, you have a malfunctioning protein, and this can really harm the cell. In this case, it really harms the motor neurons, the neurons from the nervous system that are essential for our movement.

Speaker 1:

Right.

Speaker 2:

So that produces, in the end, the death of these cells, and what we wanted to try was to, since one of these genes was causing the malfunctioning of this protein. It was basically trying to have this functional protein again. Right, it's a very specific thing, but, like modifying and increasing the expression of this normal functioning protein, we could have again these in the cells, and some of the results were actually very exciting.

Speaker 1:

So if you talk about the gene therapy, so basically you are telling that you modify a gene and Well, it's more like in our case you can actually modify genes in what is?

Speaker 2:

So, basically, there's a lot of different ways of modifying and editing a gene, and one of them, the most famous one, is called.

Speaker 2:

CRISPR exactly, and with this one you can actually edit and modify a gene. So let's say this gene has a mutation, so some changes in the gene that produce this abran protein. If you modify the gene, you delete this mutation and therefore you have a normal function in protein again, right? In our case it was more like this disease has a mutation, but we are not so interested in the mutation itself. We are more interested in what happens after the mutation.

Speaker 1:

You mean the protein level yes, exactly.

Speaker 2:

So we know that a very famous mutation that it's in one of the important genes in the in the motoneurons, it causes the downregulation of another gene, right? So another very important gene that is called a no-rebulant one. And basically what we were trying to do is increase again the levels of expression of this, of this protein, because it was downregulated in another very scientific term. But basically we wanted to restore some sort of normality in the in the motoneurons and with the gene therapy we were able to direct this viruses, because you use viruses as a vehicle to inject again this, this, the DNA, and with that we were directly affecting again the motoneurons and therefore having a normal functional expression of this protein again right.

Speaker 1:

So, as you're mentioning about some tools that you were using virus, so what model exactly did you use? Did you use animal model or cellular model?

Speaker 2:

Exactly, yeah, we were. We were using two models in what we call an in vitro that it was basically a cellular model some motoneurons, as well as an ex vivo model using some spinal cord motoneuron cultures, and also an in vivo model, which is basically mice that have this very important mutation in ALS.

Speaker 1:

Okay, right, thank you. So today we will discuss mostly about peripheral nerve injury, right. Exactly so for my audience, can you explain what is peripheral nerve?

Speaker 2:

injuries. Definitely so if we start from the, from the very basics of the nervous system. Just imagine yourself as your nervous system is some sort of squid, so imagine that the head of the squid is like your brain so basically controls everything right. And then you have the body, which would be sort of your spinal spinal cord, very essential for your motoneurons, and then all the different arms would be your nerves, right, meaning your nerves are very essential for everything because they transmit all the information from the, from the brain exactly yeah.

Speaker 2:

So communication is essential and your nerves get everywhere in your body and they control everything. All your senses, they this is exactly what allows you to move. So nerves are essential and a very essential part for your in your nervous system right exactly. So, yeah, getting a bit more into this.

Speaker 2:

So imagine that something that has happened to a lot of people, even some of us, which is you cut your finger you have a cut in your, in your finger, and sometimes this can go a little bit deeper, and what happens is that you lose the sensation in the tip of your finger yeah, it happens why? Why does that happen? Because you have affected and you have cut an nerve. And when you cut a nerve, what happens after? And more distally in another scientific term that we use you lose the ability to feel anything right like there's a disruption in the communication exactly.

Speaker 1:

There's a disruption oh okay, I see, yeah, it happens sometimes as a deep cut so I found that like some part of my body. It's like there's no sense at all, okay definitely so.

Speaker 2:

What happens in an in a nerve injury is that obviously there's a lot of different types of nerve injury, but if we account for the main ones, which and the harshest ones we are called transactions, where the where the nerve is completely cut, in those ones you lose the ability to feel or to move what has been cut, distally of this, of this nerve cut.

Speaker 2:

So the main goal of this regenerative process is for the nerves to again regenerate distally and so you can regain your function, functionality in this case, for instance, the feeling, the sensation of feeling touch in your fingers right so actually like, as you mentioned, that, whenever that injury in the nerves.

Speaker 1:

So so what is the chance to regain the sensation.

Speaker 2:

Nerve injuries are often incomplete and even though that nerves have the incredible ability to regenerate which is important to say that this is something that we don't have in the central nervous system we have a brain injury or if we have a spinal cord injury, you are most likely never going to regain the, the the function of the part of the brain or the spinal cord that you have injured whereas if you have an injury in your nerve.

Speaker 2:

Nerves have the ability to regenerate and this is because the axons with it, which is one part of the neurons that go beyond the cell body and reach, as again inside of the nerves, any part of the body, these are cut and they can regenerate. So you will, they can't, they can't, okay, they can't okay, they can yes, so you will be able to feel again.

Speaker 2:

The problem is is that this regenerative process doesn't happen, or doesn't succeed 100%. So it happens. Yes, you can have again. For instance, if you have this cut, you will feel again, but it's never going to be the same as it was before, all right. So just imagine yourself something a bit harder than this, which would be, for instance, injuring a nerve in your leg. Depending on how big has been the cut, or how much do you need of this nerve to be regenerated, depending on that, the regenerative process is going to take a long time and it's never going to be complete.

Speaker 1:

Right, okay, so thank you so much for explaining what is peripheral nerve injury. So obviously, the next question is what's the reason why people get peripheral nerve injury? Exactly, so are there any specific reasons like genetic factors, environmental or any kind of mechanical injury. So why could it happen?

Speaker 2:

Yes, so, starting with the numbers, we know that the incidents of peripheral nerve injuries are between 13 and 23 per 100,000 cases and just to give you another number that is going to be important to see how often do these injuries happen, there's 20 million people in the US that have had a very important peripheral nerve injury. So it's really we are talking about big, big numbers.

Speaker 1:

One of the things that is very important. What does mean it? It means like serious peripheral nerve injury, serious knee injuries.

Speaker 2:

Let's imagine and we are not talking now about cuts in your fingers- which is something that can happen, but it's never going to be a bad injury.

Speaker 2:

Let's imagine you have a car accident. In cars accident, it's very easy to get a trauma and very easy and it happens. For 3% of all traumas not even not only car accidents you get a nerve injury and then the problem is that these nerve injuries, as I was saying, they are not complete and then the regenerative process is very slow and you can also get something that is called neuropathic pain, which is a kind of pain where you don't really have a stimuli, something like, for instance, I'm pinching you with a needle. That's a painful stimuli and your body recognizes this as a painful stimuli, whereas with neuropathic pain it means that there's no stimuli there, there's nothing there that is actually acting, but the nerve detects, the actions detect, there's something wrong. This is really huge disability for these patients and they require lots of treatments. So patients require rehabilitation, require loads of medication.

Speaker 1:

Yeah, probably I will go in that direction later. What they need? But so my question was like what was the major cause. So, as I understand, trauma. We're talking about trauma, yes, and is there any reason for like genetic factors, like existential family history?

Speaker 2:

No, not really, not really In most of the cases. We are talking about accidents. We are talking about, as I was saying, car accidents or any kind of accident at work. It's mostly that there's no genetic, mostly any other environmental.

Speaker 1:

How about autoimmune disease? Like a driver takes on autoimmune disease.

Speaker 2:

No, no, no, there are similar situations as, for example, it's called neuropathy.

Speaker 2:

Exactly now, for instance, we will be talking about neuropathies, where nerves can be injured, but we're talking about quite a different process in this case, because there's no traumatic effect on it. But, for example, diabetes can lead to neuropathies, and again, this is a defect in the nerves, where actions can also lose the contact with their targets, as, for instance, the skin or the muscle, and therefore you can get what we were saying before neuropathic pain, and yes, this is another kind of injury that also affects your nerves.

Speaker 1:

Okay, so we're not talking about today about Exactly yes. So let's say, someone gets these peripheral nerve injuries.

Speaker 2:

So how it impacts in their daily life, like the lifestyle, yes, again, it depends on how big was the nerve injury, but in most of the cases it's not only, not only it promotes a huge disability for the patient, but these patients need a lot of care, they need a lot of medication to control the pain, they need a lot of rehabilitation, and this is something that actually completely changes the life of the patient. So this is a very we're talking about very serious kind of injuries.

Speaker 1:

Okay, so how about the treatment part of the diagram currently to treat peripheral nerve injury patients?

Speaker 2:

Yes, visho, this is another very important thing, because there are no treatments for nerve injuries At all. There are no treatments at all, no treatments focused only on what happens in the regenerative process. So I'm going to explain it myself right now. What normally happens is that you have a nerve injury and, depending on how big has been the cut, what the surgeon tries is to take a little piece of nerve from any other place in your body and make some kind of graft, so you have again a nerve between the two parts where the cut has been. So then again, you have some nerve it and then the surgeon sutures the nerve again.

Speaker 2:

What happens is that this is not like a very effective treatment because, yes, you have another piece of nerve there, but the actions won't know how to go through it, how to get again to the same place where they were targeting before, as in talking, again in muscles or skin. They are not going to know this why. That's actually something that it's worth doing research on. There are a lot of people trying to understand how the actions find their way across the injury and back to their targets, but we know that normally after an injury they do not find. Most of the times they do not find the right path, but they do end up in the same place.

Speaker 1:

So you are working on a favorable nerve injury currently.

Speaker 2:

Can you?

Speaker 1:

tell me about what you do in your research currently?

Speaker 2:

Yes, definitely so. In my lab, lead by Professor Alisson Lloyd, we do research, as I was saying, on nerve regeneration, but we focus on the complex multicellular processes. So we are talking about, we are trying to understand the biology, the cellular biology and molecular biology underlying this process of the nerves regenerating.

Speaker 1:

Can I explain what is regeneration? We are using the term, probably most of my audience will not know what is regeneration.

Speaker 2:

So there are two concepts here. One is injury, the other one is regeneration, Starting with injury. There is obviously no regeneration if there hasn't been an injury. If there has been an injury. What happens is that, as I was saying before, in the central nervous system there is no way a neuron will be able to proliferate, first of all because neurons are what is called post-methodic cells.

Speaker 2:

That means that they do not proliferate again in the adult and after that also, they are not going to, let's say, extend their actions, or let's call it, in a way, processes, because actions are just a part of the neurons that is used for these cells to reach really distant targets. So regeneration is the process where, in this case, these neurons extend again their actions across this injury site back to their targets. In this case it would be mostly either the muscle or the skin. There is a main cellular type that is essential in this regenerative process, and these cells are called Schwann cells. Now, schwann cells might what is Schwann cell?

Speaker 2:

Exactly that's the main question. These cells might not be familiar for the audience, but they are essential. They're from body right.

Speaker 1:

Exactly they are from body.

Speaker 2:

And if you think about nerves, most of the people will think about some white, very long thing. If they have seen maybe they have been in some kind of museums about science they will think oh yes, it's some kind of very whitey thing, some kind of like a filament, something that goes everywhere in your body. And why the nerves are white? It's basically because of the Schwann cells. Schwann cells produce a protein that is called myelin, and myelin is essential for the neurotransmissions, for the electric impulses of the neurons.

Speaker 2:

So, for instance, when we think about moving our hand, yeah this is a very fast thing you think about it and immediately you are able to move your hand. Why does it happen?

Speaker 2:

Because this Sign up exactly this electric impulse, it's going to take a place in milliseconds, yeah, really, really, really fast. And this is mostly thanks to the Schwann cells, because the Schwann cells are wrapping these actions, this, as we were saying, these processors of the neurons, and taking care of them. They are some. There's a really Interesting communication between actions and Schwann cells. This communication, obviously, again, is essential for the nerves to be healthy and to be transmitting these signals back and forth From the peripheral nervous system to the central nervous system.

Speaker 1:

Right. So, as I mentioned, you are using Schwann cells. So how do you get that cells? So do you use, uh, human Schwann cells or from any kind of animal model?

Speaker 2:

Indeed um. Again, as most of scientists, we do use in vitro and in vivo cultures Sorry, I mean and in vivo models. In vitro it's mainly uh, schwann cells from rat. We do Some kind of preparations and we and we extract the Schwann cells and we culture the Schwann cells from rat.

Speaker 1:

You mean that in the, in the laboratory? Yes you give food to survive, exactly.

Speaker 2:

Exactly we do. We do give, we have the cells in, uh, something that is called incubator. We keep them house of cells. Exactly like a house of cells indeed it's. It's a really nice nice, nice term to use. Yeah, that's where. And we feed them With something that we called media.

Speaker 1:

Which is a lot of me a lot of nutrients.

Speaker 2:

Exactly yeah it's actually some something that you could. You could easily Easily it, because it's it's basically, it's like it's like food for your cells.

Speaker 1:

It's Carbon and all. Actually, shall I money? I see it all. Micronitrients and micronitrients. Yeah, indeed, food for cells.

Speaker 2:

Exactly food for cells. Um, so, yeah, so your cells are happy, your cells grow, and then you can test different things with your, with your cells in this case, in this case with the Schwann cells. And then our in vivo model uh, we do use mice and uh, we do use uh sciatic nerve, uh, transaction model, which is mainly an injury on the, on their sciatic Nerve, which is, uh, the one that we have Behind our back that goes Into your, into your leg. It's probably this is something that some of the audience will be familiar with.

Speaker 1:

Yeah, exactly yeah, especially sports person. Yeah, or uh, gym fanatic.

Speaker 2:

Exactly, exactly, because it easily Causes you pain, what is called a sciatic. Oh, I have pain in the back. I don't know what it is, and the doctor tells you it's the sciatic. Sciatic nerve, it's uh, yeah, right, yeah, yeah.

Speaker 1:

Okay, thank you. So I got the idea. What model are you using the lab? So what is your goal to To investigate? Probably you would not be comfortable to speak everything, just I want to know. So what like goal, what you want to try to find out.

Speaker 2:

So, um, as we were discussing before, um, there's no, literally there's no treatment for these injuries besides, as as we were saying before, the graft and the surgery to repair your nerve and uh Treatments to ease, um, uh, the the pain from this, from this from these injuries and inflammation.

Speaker 2:

There's no particular treatment for uh the nerve injuries. So our main goal is now that we have a better understanding in our lab, um and we know uh that the Schwann cells are essential in this regenerative process, as well as Many other types of cells, but the Schwann cells have a central role in this. We want to um Try and try to get a treatment that direct to these cells, so these cells can help Uh Make a A better regeneration for the nerves and I also a faster regeneration for the nerve. Both those things Right. So the main goal is to find new treatments targeting these cells.

Speaker 1:

Okay, thanks, okay, good. So my next question is um. Do you see that like in next, um several years, that will be a treatment for Uh, particularly in our vineyard patients. So how do you see as a researcher, how do you see that line we will have?

Speaker 2:

treatment. I'm confident that there will be some new treatments for nerve injuries, um, because, as as as I was saying before, um, I think that these last 10, 15 years there's been a lot of discoveries in this field, a lot of better understanding of what happens during nerve regeneration, and I'm and I'm confident that there's going to be some improvements, I'm some possible new treatments, um, so um.

Speaker 2:

Yeah basically, basically, we need to bring this all of um, you know, discoveries that we've made, into the clinical path. But again, obviously, uh, this is something that takes time. Yeah definitely, unfortunately, but this is the way that we have to, that we have to follow, but I'm confident that in the next years Um, if we're able to, to continue this, this work, there's definitely going to be new treatments Okay.

Speaker 1:

At least there is a hope.

Speaker 2:

There's hope, definitely.

Speaker 1:

Okay, cool, Um. So my next question is you are what you mentioned about the problem of an arm injury. You explain your model and then you explain what is it goal in the laboratory. So my next question is what kind of challenges do you face in this research? So would you think that if I have these tools so we could do more? So what kind of challenges do you face?

Speaker 2:

This is a very complex Uh, even though that initially you might think, oh well, but the nerves do regenerate, right? So then it's just, you know, improving a little bit this regeneration. No, this process is very complex, right. This process is involves a lot of different cell types and it takes place in a very fine and defined way, such as we need first some cells In the injury area, then we need Other cells to follow them, and then we need the axons to follow them. So that's a very complex thing and it's not easy to find, you know uh, sometimes, techniques that are you know uh, or that can show us a really and uh, very defined result for some experiments that we are, that we are doing because of this complexity.

Speaker 1:

Right, so the variability of the of the uh injury right, you mean that, like um, to study shown cells and prepare an arm injury. So basically, the environment is very complex because, uh, those cells also interacting with other cells, probably exactly, and it makes more complicated.

Speaker 2:

Indeed. Am I right?

Speaker 1:

Yes, Okay, so that's why you think, if there's a better tool to handle this situation could be better for an accelerated research.

Speaker 2:

Yes, there's definitely a lot of new tools that scientists would use a lot, especially these last few years. As it's been explained in many different journals, we are in what is called the transcriptomics era. There's a lot of different transcriptomics tools, such as what is called RNA sequencing and tools like this, and this is obviously something that we could use more Right, definitely, and it would definitely help. So there is. We know that every year, science advances and we know that, and we definitely see that some of these tools can be applied and it can help our research to be faster and better.

Speaker 1:

Okay, good, thank you. Do you have any comments to our audience? You do not say about prefrontal nerve injury, just open mic to you, just you can tell whatever you like.

Speaker 2:

What I would say is maybe I'll I'm going to be repeating myself once again, but I think that it's very important and I hope the audience will will will see this way that, first of all, because how important it is the nervous system it is obviously controls it controls everything, but, like, as I was saying, this ability to regenerate, to regenerate for the prefrontal nervous system.

Speaker 2:

This is super interesting because imagine that in a, let's say I'm obviously talking hypothetically in a 10 year time, you completely understand this regenerative process. Maybe then you can bring it to the central nervous system and then somehow, because of the knowledge that you have acquired right, be able to regenerate injuries in your in your brain, or injuries in your spinal cord. This would be super exciting. Yeah, this would really change a lot.

Speaker 1:

The life of patients like struggling Exactly, exactly.

Speaker 2:

Exactly Talking about the, the, the, the, the clinics, talking about how much patients suffer, because this is something that, after your injury, you're going to be probably experience this kind of pain, as it was, as we were saying before, for a really long time, or your whole life. This is a huge disability, so imagine being able to to uncover this whole mechanism. It's going to be super important.

Speaker 1:

Okay, great Thank you. To finish this episode with a note that we need better treatment for peripheral nerve injury. Thank you, William, for the insightful conversation.

Speaker 2:

Thank you so much, Vishu.

Speaker 1:

Yeah, to our listeners. Thank you for joining me on Cybertjet. We talk science and let's know science together. Until next time, stay curious, stay inspired, stay tuned for more exciting conversation right here on your favorite Cybertjet. Thank you, bye, bye.