Genetics Podcast 072
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[00:00:00] Patrick Short: Hi everyone. And welcome to the genetics podcast. I'm here today with Sonya Choudry, Chris Ponting and Andy Deveraux cook. And we're going to talk today about myalgic and Cephalonia myelitis also abbreviated as M E and also known to many of you as chronic fatigue syndrome and may affects an estimated quarter of a million people in the UK and about 17 million people around the world.

It's a chronic and fluctuating neurological condition that affects many body's systems most commonly it's the nervous and immune systems. And if you know someone who's affected by ME or if you yourself are you'll know that people with ME have very different experiences, but often experienced episodic, debilitating pain, fatigue, and a range of other symptoms.

So our three guests that we have today have been working in this area for a long time to try to understand the role that genetics plays in at me and also working in the area more broadly. And it's a very understudied area relative to the scale of its impact on people. So I'm excited to get into it today.

So Sonya, Chris, Andy, welcome. And thanks so much for being here. 

[00:00:59] Andy: Thanks for having us. 

[00:01:00] Patrick Short: Great, Andy, I'd love to just kick off with you. You've been living with me for about 40 years. I understand. And I'd love to just start with your experience because from my perspective, the individual experiences is really key to unlocking what the research priorities ought to be.

So those who haven't experienced it, maybe you could just give everyone a sense of what ME CFS is like and your personal story. 

[00:01:20] Andy: Yeah, absolutely. I mean, as you touched on just now, many people have different experiences of it and that I believe is reflected in, in the differing severity levels that do exist. So there's many people out there with it who are able to continue working all be it with great difficulty and going from that end to the incredibly severe end where they're confined to bed, they'd struggle with daylight, even artificial light, struggled to eat. So I'm towards the, the severe end I've I've had to give up work. I'm very fortunate to be supported by a long suffering wife. And for me, I always struggle in explaining how it is for me. I fall back on many, I think good, but possibly bad analogies. My latest one is the, my body is a like a car, which has got a far too small fuel tank and has also got the handbrake on at least partly.

So the fuel tank is obviously meant to represent the kind of energy levels that I have. And the best way to describe that is that rather than, so us patients struggle with the fatigue part, part of chronic fatigue syndrome as is often used to name it. The fatigue, that people, healthy people, normal people, your average person feels after they've done a task after they've gone for a run, even just a day's work that doesn't really give them an idea of what I, as a patient feel.

I feel more a lack, a deep lack of energy. I just do not have the energy in the first place. And that's different to motivation because I'm here kind of spending what energy I do have speaking to you and your listeners. So is very, definitely not a lack of motivation. So that small fuel tank, that's what I'm feeling.

I wish I had that enormous fuel time. Let me go miles. I just don't have that. And then the handbrake that's stuck on everything is just feels just much harder. And that may be just me perception because of the small fuel tank. But it means that in attempting to do things now, this is just an analogy, not a description of the actual biological processes.

It feels like that friction is building up, you know, the heat levels building up to, to the detriment of the car. And if I do too much. Then I exceed whatever safety limit we have and then everything starts falling apart. Not quite literally. I've got everything still connected, but you know, that's when we call it post exertional relays, which is when, when an individual patient has gone over their own individual level through exertion, whether that's physical exertion, mental exertion social. So talking on a podcast is quite a challenge for many people and all of the symptoms kind of get ramped up and even new ones can be introduced. And then it's essentially all stopped until the system cools down again. If ever. And going back to the severity levels for the very severe people, they can only travel a small distance. If at all, before everything overheats, it means that they got to come to a stop. 

[00:04:25] Patrick Short: And what is your experience been like in the last 40 years from when you first started being affected? How long did it take to get a diagnosis or recognition from the healthcare system? And what has the support been like from the healthcare system that you've gotten and how's that evolved over the last 40 years.

[00:04:42] Andy: Well, my story is that I, as best I can identify, I came down with ME, with following a case of measles, which would appear to be quite an unusual trigger. Many other people have more recognizable, viral starts, and other people have non viral triggers as best we can identify I've also had a fluctuating course. So during my childhood things were challenging were difficult for me, but I got through the end of primary school, secondary school, and I got to college. By the end of college that was when the system was really overheating. So I kind of came crashing. But recovered enough to, to get recovered enough, actually to get working full-time. But from my early twenties, it was a decline from that, that point. And it meant, I just struggled through, because you know, the, the whole narrative was around fatigue, chronic fatigue.

That was how I viewed it, even though it was far more, more than that. So the whole narrative is you just got to put more. Try and get fitter, just exert yourself more, which in hindsight was absolutely the worst thing to do. So I just kept going, I'd go to the doctors with vague descriptions of what, what was going on.

They were my best descriptions, but they didn't really get, identify what I was suffering. So I didn't get, um, an actual diagnosis until my mid thirties, you know, and that was because things were really, really getting hard and I was trying to find answers. Did things change once I got diagnosis, not at all. In terms of the support from the medical system, no change.

They sent me along to a clinic who declared that I was to high-functioning for them to be able to help. That didn't help me. So I kept carrying on as best I could in full-time employment, full-time became too much or a part-time, part-time became too much. I stopped working. So after a period of time, kind of trying to recover as best I can and really finding out what my limit was.

I then started to become aware of the online patient community, joining in with that, which then led me eventually to get involved in setting up a patient, uh, forum. I say patient forum, where we very much encourage researchers and carers as well. You know, who anybody interested in the topic to come along and engage with us there.

And just through kind of sticking my nose into things. I eventually ended up with me on board this project. 

[00:07:09] Patrick Short: Great. I think that's the perfect segue and it's important to have people like you who have lived experience involved in the very beginning, right? Otherwise you end up with these maddening research projects where they assume they've got everything figured out exactly what people want and spend two years planning and then unveil the plans and people it's actually supposed to help say, ah, why didn't you think about asking us about this first?

Sonya, maybe we could just come to you quickly and love to hear about how you came to lead action for ME. And one of the biggest challenges that you all are focused on today, and maybe from Andy's great introduction there. Talk about the challenge from your perspective. 

[00:07:44] Sonya: So I came to action for ME because I wanted a CEO role.

I'm not ashamed to say that it gave me a great stepping stone from a very senior role I had in Barnardos into leading an organization, an organization that was facing a range of challenges, including financial. They gave me an opportunity to make my mark, but I went into my first interview, not really sure whether this was right for me.

I previously worked predominantly children and families as well as adults and health, etc.. But I went to my first interview and I heard stories from the team. I did a kind of speed networking ran the team, got to meet the team. And I heard people talking about the work they were doing with people with ME the inequity that existed, the neglect that existed.

And I came away from that first interview desperate for this job. It really talked on my passion and the challenge of trying to turn this awful situation around. A year after I joined the charity and obviously was very lucky to get the role. A year After I joined the charity, my youngest son got a chest infection, then just turned 11 and never recovered and was subsequently diagnosed with ME.

So whilst I was passionate and have thrown everything into the role prior to that, there is now both a personal and professional sort of tug on me and I've really find it very difficult to walk away, at least until we've done the completed, the decode ME study, the challenges are very much as, and Andy identified issues with diagnosis of paucity of appropriate support and care for individuals.

The inequalities that exist. The people with ME are so profound, I've worked in frontline child protection and very dire situations and understand the impact that various things can have on individuals that I wasn't prepared for the fact that the most severely neglected people with ME are often the most severely or poorly served.

Should I say? And the lack of recognition, the lack of understanding that people are faced is appalling.It's a horrible thing to say that people with ME are often invisible, but that is the case. And children and adults with ME have told us repeatedly that isolation is a major issue. So I think all of those things feed into the challenges that we face.

There is loss, potential children missing from school. Adults are missing from employment. People arn't paying into the economy, has a worldwide impact with over 250,000 people in the UK and 30 plus million worldwide. So I think there's a huge challenge ahead of us, but we are seeing things. Starting to change.

There was a new guideline, the nice guideline that came out last week. So the guidelines for doctors, the challenge now is to ensure that they are implemented well. We've also been funded aside from the Decode MEstudy action for ME has been funded to lead in partnership with people with ME and clinicians and carers a priority setting partnership using the tried and tested methodology developed by the James Lind Alliance. And we will in sort of March time, March, April time, next year, have the top 10 research priorities as identified by people with ME carers and clinicians. And as you said, that is the key to unlocking research priorities, but what really now needs to follow is the funding for more decode ME studies both programs to deliver against those top 10 priorities. And we sincerely hope that this will follow. 

[00:11:32] Patrick Short: Wonderful, Chris, I'm wondering if you could introduce yourself as well as the Decode Emmy study. And maybe then we could start to dig into one of the challenges that you highlighted Sonya which is understanding the biological basis of ME CFS itself and this diagnosis challenge, I think, along with it.

So, Chris, I'd love to hear how you came into this space and started thinking about it and, and the origins of the study. 

[00:11:54] Chris: Thank you. So I'm a geneticist. I work at university of Edinburgh and I usually, at least in my career, I usually think about abstract things like evolution and what genes do and their function and in what cells etc., I didn't think in my career ever that I would try and make a contribution to helping the patient experience.

And for many years, I talked to a friend of mine. Simon who has ME and I thought I'm not going to be able to help him what is clearly a devastating disease. But then there were some proposals to go forward, to do a genetic study, in ME and I thought I'd help with those if I could, they didn't succeed.

I think for one reason, um, that once they didn't have the patient and public voice within the, and so when an organization that I'm part of and at the time was led by Stephen Holgate. When that organizations met with a patient advisory group and the, and the funders, and then came up with a plan together to prioritize genetics.

I thought, well, here is something I can help with. The Emmy field has been so fragmented, but it's been fabulous to see over the last few years, how it's beginning to come together with the patient voice, leading the way and telling us what we should be doing as researchers. And it's just been, eye-opening what the scientific value of the patient, the person with ME their experience is.

Because they are clearly the expert, but not just the expert in their own experience, but often the experts scientifically as, as Andy is because it's their world, they have lived in it. They've explored it. They've understood it far better than I have over the few years that I've been involved with. 

[00:13:50] Patrick Short: Thank you. That's a great overview. And Andy, maybe we could, you know, I'd love to hear from you. And then Sonya Chris, feel free to add anything on top of this. What is our current understanding of the biological basis of ME. So when somebody is diagnosed with ME and starts experiencing it. What are the reasons why they got to that state in the first place?

We've talked a little bit about triggers, like viral infections. What else do we know about the complex factors that ultimately result in this, this change of state from not having ME to ME Andy maybe you can start with, with your view on it and, and Sonya, Chris, you can add anything on top of that, that Andy doesn't cover. 

[00:14:25] Andy: . Well, unfortunately I have to say from my point of view, we don't know really anything with any certainty, even the trigger for somebodies ME like I say, our . Best guesses at the moment, asking the person who is suffering those symptoms that we're currently calling ME did you notice something before it.

[00:14:47] Patrick Short: Well, and what do people typically say? Is there anything that comes up for you? 

[00:14:51] Andy: Yeah, it's definitely the case that when you ask the member of the patient community, typically they will, they be able to say, well, you know, at this time point, surely before all of my symptoms started, I had about, of whatever it might be an infection viral or otherwise. Some people won't be able to do that. Some people say, well, yeah, you know, I, I had infections before, but you know, nothing that really lasted, but just gradually over time, these symptoms snuck up on me. So from a patient point of view, that it's about as certain as we get. The whats and why of how will that progresses into ME.

Obviously we do do have and we're obviously seeing with COVID post viral fatigue, post viral symptoms that can last for quite some time. So there's obviously a mechanism for that, but then most people get over posts, viral symptoms, fatigue, whatever it might be given time for people with ME it doesn't.

So why it sticks again? We don't know. Really it's that lack that really Sonya and Chris touched on and why Decode projects like Decode ME are so important, we need to start probing and investigating those basics. There's loads of theories floating around about, unfortunately that they're just those they're theories studies into those theories that are, have been too small.

It's no fault the investigators, I don't think. It's the fault of not having enough money to, to properly investigate them. The investigators no doubt with love larger studies. They just don't have the money. 

[00:16:26] Patrick Short: Sonya Chris, anything to add on top of that, maybe you could talk through the plan with Dakota, Emmy, and I know you're going to enroll participants on a scale of 20,000 people.

Be great to hear how, how you're planning to tackle some of these, some of these questions, Sonya, maybe we could start with you. 

[00:16:40] Sonya: So I think the first thing to say is to add to what Andy said is that people with ME often tell us that they've tried things and that things work and their doctor has prescribed something for that patient voice hasn't come through.

And that's where something like the priority setting partnership is critical. As Chris mentioned earlier on we've had over 27,000 people sign up for updates and indicate that they would like to participate in the study if they're eligible. And that just shows the level of desperation that people have.

The commitment that people have to the science, to seeing studies that are well put together that should produce a high quality of scientific rigor that has the level of power that is needed to start to give us findings that we can utilize eventually to develop. And to also see a replication study so that we can gradually build up that power.

One of the things that we have done again, as Chris mentioned, is to add in an additional 5,000 people. So we'll be looking at 25,000 people with this additional five having been diagnosed with Emmy following COVID. And that is a real sort of development. I think we're starting to see some researchers, some studies talking about looking at other post viral illnesses as well as long COVID, but what we're not seeing yet in terms of funding and commitment, is that the money going into long COVID being leveraged for other post viral illnesses like ME and we really need to see that happen. 

[00:18:22] Patrick Short: Is your view that these are two sides, potentially two sides of the same coin or, or are there important differences? Um, if we took the average or the group of patients that develop long COVID or post viral fatigue, as Andy mentioned, Many people go on to recover from that, but others are diagnosed with, something like ME CFS that lasts for, for far longer, are you all developing a sense of different groups within the larger population or, or these all subtypes of, of, a, of a very high level and more common set of post-viral fatigues of which ME CFS might be one case, Long COVID might be another. I'm curious to hear what the current thinking is although I know there's a lot that's TBD. 

[00:19:06] Sonya: I think it's fair to say scientifically. We don't know. There's so much, we don't know about ME and other post spiral post-infectious illnesses. What I can say is that we are seeing a range of different subsets. We have people experiencing respiratory only difficulties following COVID, that's very different from the cohort of people that we're seeing with ME like symptoms as an organization action from is starting to see we're already seeing a massive increase actually in the number of people who want to utilize our information support and advocacy services, because they suspect they have ME following COVID long COVID or have been diagnosed with ME as well as long COVID in fact so much. So we've had to shut our advocacy service waiting lists at six months, which is shameful. It's really shameful. So we just don't know. And that's why we really need. High quality science and funding to enable that, to ensure that we are able to understand this spectrum of illnesses or different illnesses.

I think the other thing to add is that had we put money into ME research 30, 40 years ago. It's a very reasonable question to ask whether we'd be in this position with long COVID today, 

[00:20:21] Chris: As a scientist, I think we have a blank slate. We just don't know. And we should ask ourselves why we, we don't know. And that's what Sonya said, because there's just been a vacuum, a vacuum of funding, a vacuum of, of leadership or a fragmentation of views and imperfect studies that have gone on for far too long.

Let's hope that with this blank slate, we can start to write down what we we know. And with genetics, we should be able with sufficient power to see what is going wrong with some people with ME and I very much hope that others maybe even with us, we'll see what is going wrong with people with long COVID and through modern genetic approaches we can ask a really interesting question. Are these similar, are they different? Are they overlapping? Are they distinct and overlapping same or different? We just don't know yet, but it, these are exactly the right questions. What causes it? Are they the same? Are they different? Now we have to say that this is just one part of the process, but we need to know through genetics, what is going wrong so that later people can develop treatments and therapies and drugs. That is what is needed. This is why we have 27,000 people waiting to contribute to this project. And they shouldn't have been waiting for so long, over many years when virtually no funding was availbale. And they're still waiting because I'm not talking about decode. I mean, I'm talking more generally, they're still waiting because there is still no fund for ME CFS.

And yet there is a substantial amount for long COVID. You have to ask yourself, why is that? And is this, I mean, we know more about ME than we do about long COVID from a biomolecular point of view and that's almost nothing. So why is it that there's so much money going to long COVID? 

[00:22:15] Patrick Short: Yes. And I think these arguments have also been made on an even larger scale. For example, cancer has had an enormous amount of funding and obviously it's an enormous priority, but if you zoom out and look at all the areas where we spend research funding, you find that there's a lot of opportunities for improvement, just in terms of where, where are we potentially under investing and need to spend more?

I, you know, I would hesitate to say we're over investing anywhere. It's probably just areas where we're under investing that we need to improve. Chris. One thing I wanted to ask you. Whether there had been any smaller scale genome-wide association studies in ME previously. I certainly don't think there's any anywhere close to the scale that you all are, are planning to do, but I'm wondering if there were any, you know, well, well conducted smaller scale studies that have given you a hint of what you might expect from a genetics perspective as to what's going on, or is it really the first study of its kind.

[00:23:08] Chris: So thank you for this question. The, the nearest and best is one or 2000 people who have been recruited. Serendipitously through the UK biobank project, essentially. And even then they haven't gone through the more rigorous processes of working out, whether they, they do have ME for example. So there isn't such a study of the size that is required to find that a good likelihood of finding the genetics.

And again, I need to ask the question, well, why not? This is a disease that affects many women. It affects many people, probably affect a lot of people equally across the socioeconomic scale, but so many marginalized people have ME. And, um, people without voices. And I think that is the answer to the question.

I said, why is it that those little funding it is because it is not apart from the people with me. There are very few advocates for it that are speaking up and deciding to dedicate years and careers to try and answering some of these questions. 

[00:24:14] Patrick Short: I think that's such a good point. And hopefully the work you all are doing can be a domino that starts to tip others. Right. And can catalyze in particular, some of the large funding agencies here in the UK and elsewhere around the world to start investing more in this area. I wonder if we could just give everyone a, an overview of genetic studies in general, Chris, maybe you can, for those who aren't as familiar with what you might expect to find, and you alluded to this earlier around development of therapies as well, but maybe you can just give an overview on the scale that these kinds of studies need to be at.

The typical findings of a complex disease association study like this might be, and then what the longer term impacts are, like I said, you alluded to it a little bit earlier, but how do these studies ultimately translate into development, uh, treatments and therapies, and what does the five to 10 year, uh, potential arc on this look like?

[00:25:06] Chris: So this is science, so we don't actually know the results of our research, but what we hope to see is around about five different places in our genome, in our DNA that we can point to and go something in there has gone wrong. And what was different in people with their me, and from then we can see what other genes that are in those regions and go ah right. That makes sense. And okay. That story telling, but we make up stories, they're called hypothesis in science, and then we follow them, see if they're true or false. So that's the next step beyond that? If we eventually, as we shall, Im sure. Find out what are the molecular problems that people have with ME then there ought to be an army of people just waiting to deploy all of their skills in pharma and spin-outs to, to try and work out what are the best drug targets that can be pursued. But what you alluded to in your question was that this is a very long process. And genetics is trying to speed it up because when you find something in genetics, then it is more likely to run all the way through to therapy and work twice as likely than other types of research.

And that's why we do genetics. It's not just because we want to find out, you know, what's gone wrong to solve it. It is that by solving that problem, we hope that in the future we'll help to solve people's life problems. Their disease. 

[00:26:37] Patrick Short: We're running up against time here. So I'd love to just close out with the same question to each of you. And I'll, I'll give you a moment to think about it. Whoever wants to be brave and go first. But I think the overarching theme of this conversation has honestly been one of, a little bit of a frustration of how little has been done over the last 30, 40 years. And what a journey we still have ahead of us.

Obviously there's a Ray of hope in here. And you all are doing something and have a rally to quite a community around you. So I'd love if you could just take a moment to think if you're able to be successful with what you set out to do, how does the world look different for someone with ME CFS and in 10 years time, or let's go even further out actually to 20 years time.

So science has its opportunity to manifest over the long arc. So if you all are able to be successful here with Decode ME, and can tip this domino towards greater funding and the industry greater understanding within the healthcare system and amongst the general population. How does the world look different in 20 years than it looks today?

[00:27:36] Chris: So I think for me, the near term is interesting as well. I hope that by pursuing projects like Decode ME, that people can speak up about their illness. And be understood better too, not just by us in the general public, but by people in the healthcare profession, by GPS, by people, in hospitals, et cetera, that I hope happens sooner with that I think will come the longer term impact that with the greater recognition of the severe impact is one of the worst diseases in terms of quality of life.

That will be a recognition that far more needs to be done across healthcare, across research, across societal needs and not all of those should happen now. Not let alone 10 or 20 years. But in research we should see a shift, I think soon, and we should see the first biomolecular findings within the few years, but those will take time from 10 to 20 years to translate themselves into a drug based therapy.

[00:28:41] Patrick Short: So I knew what are your thoughts? 

[00:28:43] Sonya: So I agree with Chris with, we need things to change now, but if we go for a 10 year trajectory, I would hope that if we are still having to live with ME and it's not eradicated. That people are treated with dignity, with respect, with understanding that they're listened to, they receive the diagnosis, the support, the care that they need.

At a point they need it at the earliest possible point. That they need it. And I actually, for once disagree with Chris quite strongly, that it shouldn't take 10 or 20 years for us to get to personalized individualized treatments. We have seen what can happen when a community of scientists, when a government, when a whole world comes together to, to deal with an awful, awful situation. Like we've all lived with, with the pandemic when money can be put in, when scientists get inspired and interested when pharmaceutical companies sit up and say, we've got a part to play, we shouldn't have to wait 10 or 20 years for treatments to follow the genetics that should happen. Now, 

[00:29:55] Andy: just that what I hope for, from, from Decode ME, both in the short term and obviously the longer term.

Is that people with ME will feel believed that when they say that they feel ill, ill does not, does not even come close, that they feel desperately ill, that they cannot do the normal things that everybody else seemingly can or that if they can, then it, it takes such a toll on them that they believed that they are supported to live the best life that they can, you know, so while we're waiting for treatments that will, will have a major impact on, on the wellbeing of patients, no matter whether that's 10 years, 20 years or sooner, if Sonya has her way, that patients can live the best life that they can possibly can give them the limits that the illness has of them, because until very recently, there's been such disbelief, such suspicion of patients that you could set it in against a different comparison. And you start to question whether it's, whether it's getting close to hate against a particular segment of society. And other areas of thought society seem to have such a problem with, with the fact that you might just be that we're actually not putting it on, but we're actually out there we're desperate to live and we disparate to achieve things.

So I hope that the patient population now can see Decode ME is starting to take the very first steps to making a bigger difference. Both biologically, hopefully finding out what those mechanisms might be. But also showing that the patients are listened to as they are through Chris and Sonyas efforts to include us in this process and that we can make a difference when we're listened to. And that, that is the positive difference that there is a light at the end of the tunnel. 

[00:31:50] Patrick Short: And I think it's a good opportunity to call out the study website, which is decodeme.org.uk If you have ME you should visit. Even if you don't, I'd encourage you to share it out because chances are, you know, multiple people, whether you know it or not, who are effected by it.

So the, put this in the show notes as well, but the URL is decode me.org.uk. Sonya, Andy, Chris. Thank you. I really enjoyed this and appreciate you taking the time also, just like to say, thank you everyone for sticking around to listen to this. As always, please share the podcast with a friend. If you liked the episode, take a time to leave a review on your favorite podcast player so you can help other people find us.

And thanks again, and we'll see you next time. .