Dr Adam Walker

Dr. Adam Walker is a neuroscientist studying motor neuron disease (MND). He became interested in MND during his undergraduate degree when he learned about a gene linked to the disease. He now focuses on studying a protein called TDP43, which is involved in MND. He collaborates with researchers around the world and aims to understand why this protein misbehaves and causes the degeneration of nerves. The research community is working together to share knowledge and move the research forward. While sharing failures is less common, there is a push for more open communication. TDP43 is normally found in the nucleus of cells but moves to the wrong part in people with MND, leading to the accumulation of clumps and nerve degeneration. The exact cause of this behavior is still unknown. So I've been promising you Brainiacs and today we have a real Brainiac. So this is Dr. Adam Walker. So Adam is the Ross Maclean Fellow, Bill Guest Fight MND Mid-Career Research Fellow, Head of Neurodegeneration Pathology Laboratory and Group Leader at Clem Jones Centre for Ageing Dementia Research and also the Queensland Brain Institute, the Queensland University. That's a big brain you've got Adam. Thank you Jane. I'm not sure that my brain is any bigger than anyone else's but I appreciate that. Well you should know. I mean you study brains. Good morning and thank you so much for being with us. Adam, we like to start off with the person first, not just what you do. So tell us who you are, where you live and what you enjoy doing outside of studying brains. I am a Tasmanian, so I grew up in a small town in the north-west of Tasmania, a very beautiful location near the beach. And I have moved around the country and the world mostly following my career. So I've lived in Hobart for my undergrad, I did a PhD in Melbourne and then I moved to the US and lived in Philadelphia for four years to do post-doc research. Then I was in Sydney for a few years and now I'm in Brisbane at the Queensland Brain Institute. I like hiking and I like reading sci-fi novels, they're kind of my two hobbies outside the lab, although sci-fi novels I guess is related to what I do in my work as well. Yeah it is really, isn't it? So hiking, big mountains or just... Not too big. Good, yeah. Small and medium is usually what I aim for. So Adam, I feel really sorry for Adam because when we attended the very first MND Research Collective meeting, they buddied us up. So there was Jane, who's just Jane, lived experience, not a brainiac, and Adam got me. I still feel sorry for Adam. I think that was a fortunate pairing. I was meant to be paired with you, Jane. Well here we are today. So Adam, what got you interested in this research? So I've always been interested in biology and that's how I ended up working on motor neuron disease. So I don't have a personal lived experience with the disease myself, but I came to research motor neuron disease from the scientific intellectual side of it. So when I was doing my undergraduate degree, it was in biochemistry, and I did... One of my first sort of small research projects was to look at a gene called SOD1, which is one of the mutated genes that's linked with motor neuron disease, and that was the first time that I learned about what motor neuron disease was. And I became fascinated by how one tiny little change in someone's DNA could cause them to develop this devastating disease. To me, that didn't seem right, and it was fascinating, and I could see that there was something there that needed to be done. So that was my introduction to motor neuron disease, and then I decided to do my PhD in neuroscience, and this seems like a great problem to tackle. So I've been working on it ever since then for 15 plus years now. Well, it's a big nut to crack, isn't it? It is. Absolutely. I think when I started in the research area, we knew some things about the disease, but the amount of knowledge that we've gained since I've been working on it, not just from me, of course, from around the world in all the research that's been going on is just amazing. We know so much more now about the causes of this disease, and I can see that we're getting closer to having better treatments based on that building knowledge. And is that mainly for genetic or for sporadic or for both? I think for both. So certainly, we know a lot more about the genetics now than we did 10 or 15 years ago, and that has informed our understanding of the disease in general, so a lot more knowledge about the sporadic forms of disease as well now. So when I was doing my PhD, the protein TDP43 was discovered. That was back in 2006, so that was discovered by a lab in Philadelphia, which is where I ended up going to work. So the reason that I moved to Philadelphia to do research was to work in the lab of Professor Virginia Lee, who discovered TDP43 as being involved in motor neurone disease. So TDP43 is now known as the main pathological protein that's involved in almost all cases of motor neurone disease, although probably not those with broad-bust mutation. And so this protein is the focus of all of the research that's going on in my lab now, trying to understand why this protein, TDP43, misbehaves in disease and why this pathology forms. So 15, 20 years ago, we didn't know this protein was at all involved in motor neurone disease, and now there are hundreds if not thousands of researchers around the world studying this one protein, trying to work out how it's involved in disease and why dysfunction of this protein is linked with the development of MND. So two questions. Do you all collaborate? We do. The people you're researching around the world? Absolutely, and I think we're doing that more now and in better ways than we used to. Of course, the internet allows us to access all of the research that's going on around the world immediately as soon as it's published. So everyone has access now to the research as soon as it comes out online. And there's a lot more emphasis on making better use of resources and working together to do that. So in Australia, of course, we have the MND Research Collective, which you were at the meeting a few months ago where we met, and as part of that we are talking a lot more amongst ourselves as researchers within Australia and New Zealand now, but definitely around the world more so now as well. So a few months ago, we had the first international conference on TDP-43 function and dysfunction in disease, which sounds like a very niche area, and it is a very niche area, but we had about 200 or so researchers gather in Italy from all around the world from labs that focus primarily on understanding this one protein and how it's involved in motor neurone disease. And I think that was a great example of international sharing of knowledge and collaboration and us all being more connected as scientists and making sure that we're sharing what we learn and using that to move the research forward faster. That's so good. Are failures also shared? Less so, I have to say. In scientific research, it's harder to share failure because when things don't work, it's not as sort of sexy in the scientific sense that it's harder to get people excited about things that didn't work. But we are trying to do that more. In my lab, we've published one or two studies that were negative. We tried a drug that we thought would do something that didn't do anything, but we still put it out there to try and make sure that people didn't repeat those failures because the worst thing that you can have happen in scientific research is that everyone does the same thing, finds it didn't work, and then other people do the exact same experiment again. We try to share that, but it is harder than sharing positive results. I understand that, but it would save some labs a hell of a lot of time. Absolutely. I think we're discussing that more. Even if the science isn't necessarily published, then I think there are more conversations between labs about what works, what doesn't work, sharing ideas and thoughts and small snippets of data that may not be big enough to put out there as a big story, but sharing ideas and thoughts and things that are working or not working. Okay. Now, because we know that I'm not a brainiac, the protein, are we all born with it or is it like a glitch in the system that it appears? Yeah. So this protein that we study is called TDP43. That stands for Tardigna Binding Protein 43. That's a random name that was given to it when it was first described more than 20 years ago. It was discovered as being involved in binding to DNA within the nucleus of cells, and at that point, it wasn't known that it was linked with MND at all. But this protein, we now know that it's normally found associated in the part of the cell that has the DNA in the nucleus, and it's in every single cell in the body. So it's in your liver, it's in your little finger, it's in your brain, it's in your spinal cord. It's in every single cell. But in nerves, in particular, in the brain and the spinal cord, we know that in people with motor neuron disease, that this protein, TDP43, it's normally in the nucleus with the DNA in those cells. But in people with motor neuron disease, it moves away from the DNA and accumulates out in other parts of the nerve where it shouldn't normally be found. And so we know that that process of the protein moving to the wrong part of the nerve is linked with stimulating the degeneration of that nerve, but we don't really know what causes that initial movement of the protein, and we don't really know what causes the function of that protein to change early on in disease and cause the neurons to die. So that's kind of what we're trying to work out. One thing that we do know that happens in the way that TDP43 was first discovered is that when it moves away from where it should be in the nucleus of the nerves out into other parts of the cell, it clumps together and forms these really big inclusions, we call them, that you can see down a microscope. So if you have a slice of a part of the brain or spinal cord from someone who has passed away from motor neuron disease, you can see this protein in these really big clumps when you look down the microscope, and that's really characteristic of the pathology of what we see in MND. Okay. So we don't know where it comes from or why it comes from, but we know that it's there. We know it's there, definitely. We don't know why it misbehaves. It's in everyone. And for some reason, in some people, it does the wrong thing, and then that causes the nerves to start to degenerate and for MND to develop. Sorry. It's very interesting, and I'm just thinking, how the hell does this thing happen? Now, how are you studying this, and are you using a lot of AI in your lab? We're not using a lot of AI yet, although I can see that that could be something that would be useful for our research. So my lab is a biochemistry cell biology lab, so about half of our work is cell biology where we grow cells or neurons in a dish, in an incubator, and we give them DNA or drugs and then extract out their proteins and look at how that has affected pathology development. And the other half of my lab is more focused on testing drugs or gene therapies in model systems. So we use genetically modified mice that develop a disease which is similar to human motor neuron disease, and we test drugs and other therapies to see whether it can change the development of the disease phenotype or to change the pathology, this TDP43 pathology that develops in the brain and the spinal cord in these mice in the same way that develops in people with MND. So that's what we do. We don't use a lot of AI yet, but I think it's definitely a big advance for science. One way that we use that a tiny little bit is that AI has been used, for example, to determine the structure of proteins, and so it allows us now to predict how proteins will change in their structure and function. I have no doubt in the next few years that that will really progress a lot to mean that some of the work that we do in our experiments will be either a lot faster or we may not need to do them biologically anymore. We may be able to use predictions or AI systems to do experiments, but it's hard to predict how that will happen, but it will get to that point, no doubt. So this is a big question. Do you feel hopeful that we will... That is a big question, yes. I do feel hopeful. I definitely feel hopeful. I can see that the science has progressed so far in the last 10 or 15 years, and we know so much more that we should be able now to use that knowledge to design better therapies for MND. I think we're getting to the point where that's starting to happen. So clinical trials with small molecules that target known genetic causes of disease are the approval of the first SOD1 targeting antisense oligonucleotide drugs, small molecule drugs, specifically for people with a genetic mutation in the SOD1 gene. So these kinds of therapies have developed because we have built up such a basic understanding of how the disease works, and I think that, of course, there's so much more that we still need to know about how the disease starts, but we have some there now that allows us to hypothesize a bit more clearly about what drugs could work in MND. Of course, there have been dozens or hundreds of clinical trials for different drugs for MND over the last decades, and almost all of them failed, as you know. And one reason for that is that maybe in the past, the clinical trials were not big enough or not designed in such a way to allow an effect to be seen, but it could also be that we didn't understand the disease enough, and so some of those drugs, we didn't really know how they would work, but we thought, oh, maybe they would, so we'll give it a go. But now, we know more, so the drugs that will be tested from now and moving into the future will be better targeted because we know more about the biology and we can predict what those drugs could or should do to have a benefit in people with MND in a more sort of targeted manner. And these are existing drugs? So, some existing drugs, there's a lot of research going on about repurposing drugs that have been tested for other purposes that could be used in disease, and that's a really promising sort of way to move forward because it means that you can progress things a lot more quickly if you have a drug that's already gone into a person and you know that it's not toxic, at least to start with. It may not have worked in the disease that it was tested in, but if you know the biology about what that drug should do and that makes sense to test in MND, then that's a really great way to move forward. But also in designing new drugs, so the technologies that we have now to design new drugs has progressed as well that we can design drugs differently than has been done in the past, so not just small molecules that are extracted from wherever in nature or designed in the laboratory, but drugs that target DNA or RNA in cells in a really targeted manner, things like that have really progressed now that we can predict more what these drugs should be able to do within cells or within nerves and to use that knowledge to design better drugs. So, there are so many different ways that can be used now. In addition to drugs as well, we have advancement in gene therapy approaches, so harnessing viruses for good rather than evil, so using viruses to correct the problems that happen in the nerves in motor neurone disease, I think is a really promising way to move forward as well. It's being used really successfully, for example, in spinal muscular atrophy, which is a motor neurone disease of childhood, which has some similarities to adult motor neurone disease. So, I think the successes in other diseases in gene therapies, it's really positive as well for how that could be harnessed for motor neurone disease treatment too. Wow. I've just got to let the dog out, hang on one second. No worries. You're really annoying when you do this. I'll let that out. Okay, that's the benefit of not being loud. I'll let that do it anyway. She's standing there going, ah, ah, ah. Oh no. Dude, I'm doing a podcast. Okay, so I'd better get back to it. So, do you think that eventually these drugs will be or therapies will be targeted to each individual person with MND because everyone presents so differently? Everyone is really different and I think that inevitably we will see treatments for MND which are combinations of different things. I think it's probably not realistic to expect that one drug will correct the disease and prove to be the one cure for MND. Ultimately, it's going to be a combination of things that people will be prescribed and will take and those drugs or therapies may change over the disease course. So, there may be drugs that are good to take early in disease and drugs that are better to take later in disease and that may be possible to predict how that change needs to occur over disease progression. But in addition to that combination of different therapies and different drugs, I think it is inevitable that there needs to be more personalization of therapies. So, at least in the 10% or so of MND cases that have an inherited component where we know genes that have mutations that are linked with causing the disease, for those people with those mutations, there will need to be drugs that are specifically designed to target those. For people with sporadic disease who primarily have this TDP-43 pathology, there may be different drugs that target that pathology in different ways that may be more beneficial for some people over others depending on onset of symptoms, for example, or the rate of progression. I think at this point, it's still hard to predict how that is going to play out, but I think inevitably there will be personalization of therapies. It's not going to be one approach fits all. So, we're going to have to tighten up the diagnosis then too, aren't we? Absolutely. So many people are diagnosed later down the track and it takes a long time to diagnose motor neurone disease from what I'm hearing from people and I know with our personal story. So, yeah, what can be done about that? Yeah, I think that is a problem, the diagnosis of motor neurone disease. It's always been a problem and it's often ruling out other things rather than having a positive test. But there is a lot of work going on in that space as well around biomarkers. So, trying to find ways that we can test people to differentiate whether they have MND or something else or nothing. How is that done, through blood? Yeah, so through blood or through testing the CSF, the fluid from around the spinal cord, which can be taken up by a lumbar puncture or other sort of methods to measure activity of muscle or the brain using scanning technologies. So, in the sort of blood testing space, there needs to be a lot more done in MND, although that is happening. But there have been a lot of progress in other neurodegenerative diseases like Alzheimer's and Parkinson's, for example, which have tests now which are becoming a lot more specific to identify people who have those diseases specifically. So, I can see that that is something that we all develop promoting neurodegenerative disease and it's actively being researched as well by lots of different labs around the world as well as different pharmaceutical companies too. So, I think if we have, it probably again will be similar to the drug situation where it won't just be one single test. We might have a few different tests that combined can give you a positive indication of whether someone has MND or not and which type of MND as well. So, we can test people who have inherited disease and look at their DNA to see whether they have the mutation, but being able to have a test that can look at the rate of progression in a bit more of a specific way rather than just tracking symptoms would be really beneficial as well when we get to the point of having these multiple drugs, these multiple therapies and working out how is the biology of the person with the disease progressing over time and how can we work out which drugs would be better at different stages of disease. I think that combining as we get more and more drugs with these tests that specifically will tell us what's going on in the nerves and in the brain and in the body of people with MND, how we can marry those up together will be really important. Well, yeah. Yes, because currently it's just a long process of ruling out everything else. So, something like that would be quite extraordinary. Absolutely. And it's an issue that fusses many people that it takes so long and then by the time they're diagnosed, in many cases, it's too late to really do anything. Yeah, by the time the symptoms show. Oh, absolutely. Yeah, we definitely know that certainly for the drugs that are available, if you start them earlier, then it's better. So, the earlier we can have diagnosis, the better. Absolutely. Which drugs are you talking about? So, Rilazole, which has been around for a while. Yeah, around forever and ever and ever and ever. Yeah. Yep. But there have been new approvals in the US recently for new drugs that will no doubt at some point come to Australia as well. They're still being sort of progressed in terms of the final testing in people with MND. But there are so many drugs going through the clinical pipeline now that inevitably some of them will be positive, although we've had a lot of failures in the past. There are more drugs that are looking positive that will come out soon. And so, being able to give those drugs to people as soon as possible is definitely what we want to be aiming towards. And to do that, we need better tests. It's not enough just to get a better drug. You need to have better diagnosis as well. Hmm. Sorry, my brain. You've given me too much information. Is the Walker Lab named after you? I prefer not to call it the Walker Lab, honestly. But inevitably, people just use the last name of the lab heads. So yes, that's where the name comes from. But I mean, I guess it's kind of appropriate for a lab that studies motor neurone disease as well. A lab head. So you're a lab head. Yeah. Yeah. That's what I am. A group leader is the term that we use at the QBI. So I know that you're extremely proud of the people who work with you. So tell us a little bit about them. I am very proud of the people that work with me. It's a big team effort doing science. And yeah, I couldn't do what I do without all the people that work with me. So in my lab at the moment, we have four postdoctoral fellows and a couple of research assistants and students as well who are on different stages of their research journey from undergrads up until PhD students who are almost finished with their degree. And we work together in a collaborative way, I think. And we try to have an open system where everyone can raise ideas and ask questions. And my motto is there's no stupid question when you're in research because you never know where a good idea is going to come from. So I encourage everyone in my lab to ask questions and to come up with ideas and to do the best research in science that they can. We've been successful in my lab in developing projects and in people developing their careers. So Bex Stangel, for example, was the inaugural early career research fellow from SiteMND. And so her research has really progressed over the last five years or so. Bex and I started at the Queensland Brain Institute together on the first day. We walked into the lab, which was empty. And Bex really helped to set the lab up and to order all of the bits of equipment and reagents and things that we needed to do the research. And since that first day in 2018, where it was just the two of us, we now have 12 or 13 people working together in my lab. It's been great to see the growth of the lab and to see everyone gaining in knowledge and confidence and learning all of the techniques and coming up with new research findings, which are really accelerating now as well. You don't just study MND though, do you? So we study the protein TDP43, which is involved in both motor neurone disease and also in the form of dementia called frontotemporal dementia, which is not as well known as Alzheimer's, for example, but it's an important form of dementia, which is more common in younger onset forms of dementia. And rather than affecting memory, it more affects behavior, language, kind of signs and mood in people. So the link between these two diseases, motor neurone disease and frontotemporal dementia is this protein TDP43, which is found in the pathology in almost all people with motor neurone disease, primarily in the spinal cord and in the motor cortex in the brain. But it's also found in about 50% of people with frontotemporal dementia, the difference being that the TDP43 pathology accumulates in different parts of the brain in people with frontotemporal dementia. So the same protein doing similar things at different parts of the central nervous system leading to the development of different symptoms and different forms of disease. And that's something that we're looking at as well, isn't it? What are the differences between different forms of this pathology and trying to work out why it forms differently in different people, which leads to different types of disease? That's a tricky one. It is. Yeah, it's scientifically fascinating, but also really important to understand why is everyone different? That's a question. When these diseases strike, why is it not the same? What are the determinants of whether someone develops motor neurone disease versus frontotemporal dementia even though they have a similar dysfunction in this protein? And how can we use that knowledge to make sure that we're designing therapies that will help people with different forms of disease? I think that's really important. Is it the same protein involved in Parkinson's or not? Yeah. So all of these neurodegenerative diseases like Alzheimer's, Parkinson's, Huntington's, motor neurone disease, they all have a lot of similarities that they have this pathology of different proteins that form within the brain or the spinal cord. So the primary protein that's involved in these different diseases is usually different, but this protein that we look at in motor neurone disease, CB43, it can be found in pathology in a minority of cases of people who have Alzheimer's or Parkinson's and other diseases as well. So in those cases, it's probably a secondary sort of effect that's happening, that the disease starts and then later on, for some reason, there's also this additional CB43 protein dysfunction. But in motor neurone disease and some of frontotemporal dementia, it's the primary driver of disease. So I think there's more recognition that there's a lot of overlap between these different neurodegenerative diseases now in terms of what's going on in the brain. So that could mean, for example, that drugs that we develop for motor neurone disease, they may be beneficial for a subset of people who have Alzheimer's or Parkinson's as well if they also have this CB43 pathology. So that could be one way in the future that approaches to drug delivery to people is even more personalized that if we're able to work out who out of all of the people who have Alzheimer's disease also has this pathology that's similar to what we see in motor neurone disease, who are those people and could they benefit from drugs that were initially designed for people with motor neurone disease? I think that'll be important to look at too. Well, it's just so big, isn't it? I mean, it's really big. It's huge. It kind of feels like the more you know, the less you know. Because we now know more about what we need to learn about. We can see where the holes are more. So do you think that the research that you're doing at the moment with the protein and the drugs, that would be to assist people's quality of life whilst they have MND? Yes, that's right. Ideally, of course, what we want to do is to prevent MND. We want no one to ever develop it. But given that we don't know what causes it to start with, I think the most realistic option at this point is to develop drugs that can slow down the disease and hopefully improve quality of life. And then hopefully at some point, if the drugs and the tests develop to that point, we can identify people before they get the disease and stop it from even starting. That would be ideal. I think that the drugs that exist, they slow down motor neurone disease in some people, in some cases, if it all goes well, but don't necessarily improve the quality of life for people with this disease. But that's what we want. We want a drug that makes people feel better or to feel some improvement. God loves the real result. It progresses maybe by three, sorry, elongates life by maybe about three months, but the quality of that life may not be terrific. So, yeah. It's true. And a person with MND may not, from taking the drug, may not feel the benefits themselves. So it's only if you look at a population of people that you can see that those who took the drug have a longer extension of life than those who didn't. But on an individual level, a person taking the drug may not notice an effect necessarily. So we want drugs that make people feel a benefit of either stopping the disease or improving their symptoms. You've given me so much hope today, Adam. I mean, I knew you were smart, but you're smarter than I thought you were. Thank you, Jane. It's a pleasure, Adam. Are you going to Wollongong to the seminar? I am going to Wollongong, yes. I'll be watching online. Yeah, the agenda looks amazing. It does, yeah. There's so much stuff. Yeah, I'm really looking forward to it. Yeah, a whole lot of brainiacs in a room there. Saturday night will be a big night. We'll be talking about our proteins and our genes. You will. Now, you've given me so much time today. I'm extremely grateful. Oh, you're welcome. Thank you. Is there anything you want to say to us before we go? I would just like to repeat, based on your question, is there hope? Yes, there is hope. We know so much more about the disease. I think that the researchers who are working in this space are really excited about the advances we've made. And the technology and the new ways that we have to do experiments has just made things progress so much faster in the lab. Now, what we need is just to take that and progress it even faster into therapies for people with MND. And we are aware of that. I think that we're not just in the lab doing our little experiments on the bench without thinking about what it means. We do think about what the ultimate goal is, which is to help people with disease. So that's what we're working towards. Absolutely. Okay, good. We need that. Good. Thank you, Jane. Hi, very much. Yeah, this was great. Lovely to speak with you. Thank you. And I think this podcast was probably your idea when we were sitting there together at the back row when you got stuck with me. You said a podcast is a good idea. Did I? I don't know about that. I think that was your good idea, Jane. Whatever. We'll share it. Okay, we can share it. Yeah, fantastic. Thanks, Jane. Okay, you're an absolute joy and we will be in touch. Thank you, Adam, so very much. Okay, cheers. Bye.