Chris Ponting: Decoding the genetics of ME/CFS
Chris Ponting: Image courtesy of Chris Ponting
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As a child back in the 1980s, I remember seeing headlines about so-called ‘Yuppie flu’ - a strange health condition that often affected people in the prime of life, draining them of their energy. You won’t hear that term any more, as it’s now know as myalgic encephalomyelitis or chronic fatigue syndrome. But while things have moved on a lot in terms of recognising this condition - as well as public attitudes to people who live with it - there’s still a lot we need to learn.
ME/CFS is a multi-faceted, fluctuating condition that’s often characterised by extreme tiredness, although there can be other unpleasant symptoms like joint and muscle pains, headaches, problems sleeping, eye pain, problems with concentration or ‘brain fog’ and more.
Although ME/CFS is rare, affecting less than one per cent of the population, that still adds up to quarter of a million people in the UK living with it. Yet we still know very little about what’s going on at a biological level.
One person who’s trying to change this is Professor Chris Ponting at the MRC Human Genetics Unit within the Institute of Genetics and Cancer at the University of Edinburgh. He’s leading a major new research study called DecodeME, searching for genetic variations that may explain why some people are more likely to develop ME/CFS than others. The first thing I wanted to know was what triggers it to start in the first place?
Chris: So the triggers of ME are many, but the principal one is infection. So people with flu or other types of bacterial infection often can later on in their illness be diagnosed with ME. What do we know about it's biology? Well, we know that if you have a second degree relative who has a ME, then you're more likely yourself to have ME and you don't share the same environment. So it does seem that there is a genetic component that contributes, and then there've been studies, which I think have shown reasonably well that aspects such as the mitochondrion contributes to whether you have ME or not. But this is exactly why we as geneticists need to start studying it at greater depth, because there is very little that is actually known about the predisposing factor.
Kat: So it does seem to be that it's something to do with the immune system. And you know, as well as I do that, there are a lot of genes and things like that involved in the immune system. So how do we start to tease out what might be going on?
Chris: It's very hard to know what might be going on when you've got so few leads. So what we're doing at the moment is trying to see whether there's an immune signature. As you know, we have T-cell receptors that are responding to infection, and it may be that we'd be able to show that people diagnosed with ME have a different repertoire of T-cell receptors.
Chris: But if we look from a genetics point of view, objectively looking across the whole genome and find something, of course we don't know ahead of time what that will be, but we are looking at everything. That's the beauty of the genome and genomics is that we're not prejudiced as to what the outcome will be. It may be that we'll find that indeed, because the trigger is immunological, that there is a problem in the immune system. It may be however, that it's nothing to do with the immune system. It's the inability of people to get better after an immune challenge. And so therefore it could be something to do with the brain, for example, or other aspects that we haven't yet even perceived. So that's why I'm excited to look at this new challenge from a genomic perspective.
Kat: So let's dig into what you're actually doing there with the DecodeME study. What exactly is it? Who are you looking for? How many people, and then what are you going to do with them?
Chris: We are looking for upwards of 20,000 people in the UK who have been diagnosed by a health professional with ME. We hope that people can log on to our website after we launch and are able to respond to a variety of questions. So we will have hopefully upwards of 20,000 people with ME, we will send out a saliva sample collection kit to people in their own homes. They will spit in the tube, package it up, send it back to us, via the post, and we will then get going. We will take out the DNA, we will send it to a company securely so that they can then read out, at up to a million places in the genome, where there are common differences in DNA between people, and then from each of those up to a million places, we'll be able to ask the question, are these changes in DNA differences in DNA, they occur more frequently in people, ME versus healthy controls.
Chris: And we have the data for the healthy controls already. So we are therefore going to be saying, are there genetic reasons why some people have a greater likelihood of being diagnosed with ME or not? That will then enable us to say, given that we know this difference and it's genetic and it's inherited, we will then know what are the correct biological experiments to then throw at this problem. And as we've already talked about, we actually don't know what's going wrong. So asking the right question is in fact, the starting point to the next phase, once we have finished doing our genetics experiment, DecodeME.
Kat: So the kind of study that you're doing, it's what we'd call a genome-wide association study and I think it's really important to explain what you're going to find from that. Because quite often we hear about these studies and it's like, scientists are looking for the genes for this or that. And you're not actually from the data from the study, you're not going to necessarily find genes per se. You're going to find variations between people. And so then the first challenge is to figure out are these actually in genes, what genes? And then what do these genes do? That this study isn't immediately going to spit out; These are the genes, this is what's important, this is what's inherited, and this is how this disease works.
Chris: Absolutely right. The genome wide association study will not, as you say, fly a flag, which says gene X. It will say that there is a DNA difference in around a bunch of genes. And we have to figure out which of those genes or more than one gene has the downstream consequence of that DNA change. I'm not just a human geneticist. I'm an experimental genomics researcher. And so we and the field have worked out ways where we can determine what are the downstream changes that occur because of that DNA change. And so now we've got some pretty sophisticated ways in which we can work out the downstream consequences and therefore will enable us to work out, which are the experiments to work on what genes to decide why it is that some people will have ME.
Kat: So what is going to be the longer term benefit of this information, whether it's just the data from the study saying these variations are more or less common, or then finding these downstream genes. What do you do with this data? Is it a way of screening people, a way of finding treatments, what then happens with the results?
Chris: Great question. So obviously, and unfortunately this will not immediately provide treatment for people with ME. This is a journey we will start it, but it won't be the panacea that everyone would wish for the quarter of a million people who are suffering in this country. But we have to take the first steps. Unfortunately, it is also not going to be able to ensure that there is a genetic test to say, yes, you have ME and that is because of your DNA. So it's not relevant to individuals. The findings will be relevant to the population, to the quarter of a million people. And the outcome will be that we will hopefully know where to look for the problems with ME rather than just guesswork, which is what the situation is now guessing what is going wrong with ME?
Chris: So it will shine the light as to which path to follow and down the path it will enable us to come up with what are the molecules that need to be targeted for therapy. And we will engage with the pharmaceutical industry to as quickly as possible develop potential therapies and follow those up with clinical trials. But if I may, our study I believe will have another consequence. It will bring together, because of the need of having so many people in the study, It will bring together thousands of people who have not been connected. It will bring to light to the general community how difficult these people's lives are. It will shine light for health professionals as to the lived experience of these people. And therefore will have a greater benefit perhaps in the short term as to the social recognition of the plight of so many people with such a devastating disease.
Kat: Chris Ponting from the MRC Human Genetics Unit within the Institute of Genetics and Cancer at the University of Edinburgh.
