OMF Directors Interview Transcript

An Interview with OMF’s Directors: Transcript

Dr. Meadows: Hi everyone, and thanks for listening today. I am Dr. Danielle Meadows, OMF VP of Research Programs and Operations, and with me today are each of the Directors of our research centers. So, we have Dr. Ron Davis at Stanford, Dr. Jonas Bergquist at Uppsala, Dr. Wenzhong Xiao leading our Computation team, Dr. David Systrom at Harvard, and Dr.Alain Moreau at Montreal. And hopefully our friend, in Australia, Dr. Chris Armstrong will be able to join us at some point, although time zones are making it a little challenging.

OMF’s collaborative research model really tries to, you know, bring together each of your different areas of expertise, all with the goal of solving such a multi-system complex disease. So, I really want to welcome each of you and thanks for taking the time to be part of the panel discussion today. So this discussion is wrapping up a series of interviews that I’ve done with you all, that’s trying to get at the big picture of things and drawing connections between all of your research.

So this is going to be a little less structured than some of my other interviews with you because I want to focus on your discussion and let you all drive where we go with this. But I’m going to start you out with just a prompt and we’ll go from there. So, as we think about all of your overarching hypotheses of the disease and how they connect together, I’d love for you to each kind of comment on how your theory explains the variability and symptom presentation. Maybe Jonas is one of our directors with clinical experience, you can kind of start us off with that.

Dr. Bergquist: Yeah. Thank you, Danielle. Really good to be with you all today. So, of course, as I think we have discussed a bit during your interviews with some of us, we said that we all come from different angles and we have some different perspectives of things based on our background and what we have been looking at before and so on.

And I think definitely what we see is that, since we’re investigating such a multi-organ complication and disease as ME and also Long COVID, to large extent, I think that we have to join four forces from all these different perspectives. But of course, um, I think what is important is that we actually focus a lot on what are the reported symptoms or the worst reported symptoms from the patient side.

And, uh, there we have a number of things to touch upon. I mean, the neuro, of course, since I’m from the neurological field, I of course want to tell something about that, but I think the neurocognition and problems with neurocognition functions and memory functions and, uh, the brain fog as many patients report on as one of the more severe and also affecting the quality of life so much in patients. I think that’s something we have to look into, of course. But saying that I totally agree that we have to approach this disease with different angles and look into what could be the common, uh, factor behind all these involvements, all these symptoms, and all the different organs. And yeah, I will stop there and get, leave the word for someone else to take over.

Dr. Meadows: Maybe, David, do you wanna comment as our other clinician on the group?

Dr. Systrom: Sure, well, I, I would echo everything Jonas said a second ago. As a putting on my clinician’s hat as suggested for a second, I have been intrigued and increasingly impressed that what we have been able to do as a group over, for me anyway, the last decade or so, is to put ME and subsequently Long COVID on the map as true organic diseases. So, when I first got into this business and on the exercise side, I was seeing lots of patients who were coming to me with classic symptoms: fatigue, post-exertional malaise, non-refreshing sleep, brain fog and orthostatic intolerance, and even shortness of breath as a lung doctor.

But they had defied a classic diagnosis. They had been many, if not all patients, had been through the mill as it were with multiple specialists and subspecialists had literally millions of dollars spent on them, precious healthcare dollars, within ineffectual diagnostic attempts, and at the other end, no effective therapy.

And I think what I, the needle I have witnessed moving over the past decade is that with the help of this group and everything that everyone brings to the table that we now recognize ME as an organic diagnosis. It is not simply in a patient’s head. It is not something that they can simply go to the gym and train their way out of without any help.

And so it’s a real and organic thing. We’ll get into some of the biomarkers that this group has helped discover. It’s different from deconditioning, it’s different from pure psychiatric disease. So it deserves recognition as such. And then the other part of it is, increasingly as a clinician, we have found evidence that some repurposed drugs, FDA approved drugs have begun to help with symptoms. So, um, it’s been very fulfilling over the past decade to witness all of this.

Dr. Meadows: Thanks David. And maybe, you know, in terms of the varying in symptom presentation, I think you’ve talked some about, you know, how you’re seeing different things in the vascular world with preload failure versus, you know, impaired oxygen extraction and those sorts of things and maybe you can just comment briefly on how that’s relating to the difference in symptom presentation.

Dr. Systrom: Sure! Well, I think what you’re speaking to, Danielle, appropriately is that there are very likely subsets of patients within the ME and the Long COVID communities. Not everybody is the same, although there may be a lot of shared pathophysiology and overlap of symptoms.

And I certainly, I don’t think any one of us has the answer about exactly what causes what symptoms in every patient. And it may be different in different patients, but no what I I’ve come at these diseases with a certain area of expertise, which is the invasive cardiopulmonary exercise test.

And what we have found, this would come under the category of organic disease, is incontrovertible evidence of relaxed blood vessels inappropriately. So, on the venous side we call that preload insufficiency, and likely on the arterial side as well, at least in some patients where blood flow is not directed appropriately to the exercising muscle and perhaps other organs. So, that’s all about oxygen delivery and then its final uptake in utilization. And we’re increasingly making some discoveries along those lines.

Dr. Meadows: Very nice. Thank you. Maybe Ron, I think you have obviously a little bit of a unique perspective on the disease. Do you want to comment a little on this area, on, you know, subsets, symptom differences and things like that?

Dr. Davis: Well, we are really trying to figure out a hypothesis that makes some sense. And then to test that hypothesis is sort of where we’ve switched from just measuring things, trying to collect data on the patients. And one thing that seems to be consistent in this is collaboration with Robert Phair and Chris Armstrong has also been a bit involved in this. It’s called the Itaconate shunt, and it’s where it’s a known pathway, fairly recent, where metabolites are taken out of the citric acid cycle, which is where most of your ATP energy is generated and siphons it off so that it’s not available. So that basically decreases your ability to generate energy, and that’s why people feel tired.

This happens with any infection. When you have an infection, you feel tired. That’s because of this activation. And a lot of the patients say, well, it feels like I have an infection. But yes, that makes sense. If the Itaconate shunt is the problem. So potentially the problem is that the Itaconate shunt goes on, because of that early infection. But then does it shut off once the infection is gone? And of course, maybe the infection is not gone and so it stays on. One of the hypotheses that was generated by Robert Phair from modeling is that a JAK-STAT inhibitor should shut it off. And so, in fact, we’ve had two patients that have taken JAK-STAT inhibitors and they’ve gone in complete remission and they’re still in remission.

Unfortunately, a lot of other patients have tried it, and it doesn’t work. So, this has to do with there’s something happening that’s causing it to be stuck, and we have to figure out what that is. And that requires a lot of new approaches. And we’ve a solicited group, a group at University of Utah, and that was with one of your, Advisory Board Members, Olivera, who is at Utah. He’s very familiar because he is attended a lot of these. He’s not, he doesn’t work on ME/CFS, but he’s a smart person. And he can think about complicated things and he thought, well, it’s not with the Itaconate shunt model, it’s something that really can be tested effectively, but it needs a lot of different skills.

And we don’t necessarily have all those skills. So, he has solicited a number of people at Utah to do this. And one of them is a zebrafish. He’s in pharmacology. He uses zebrafish to test drugs. He has a massive zebrafish set up that’s all automated. So if we have a test of this, he can run lots and lots of drugs through.

And natural products, and he has a large collection of drugs. So what we, what he has done is put in the gene that’s essential for launching this Itaconate shunt into zebrafish, and it takes a while to do that because it’s, when it goes in initially, it goes in different places and you have to stabilize it by basically inbreeding, which you do for dogs and everything else, you inbreed them so they’re stable. And that is, it’s pretty stable at the present time. And it’s inducible, so it’s not always on. He can turn it on and turn it off, and when he turns it on, this is all automated, he measures the amount of swimming that the fish do and they swim less. And, if you turn it off, then they swim normal.

So, we now have that pathway in zebrafish turned on. And it’s very similar to human. That gives a capability of screening for drugs, and that’s one of the things they are doing. So, if we can find a good drug that can be, that’s very effective and can be used in humans and doesn’t require a new FDA approval, which will take 10 years it’s already approved or it’s a natural product which doesn’t require approval.

And then we would try it on some patients and see. Now there’s two possibilities, here is that it unlocks that whatever is locked in that pathway if that’s what’s the problem and it will cure people. The other possibility is the fact that it doesn’t unblock the block, but in fact it does shut the pathway down. So it’s a treatment, not a cure. But it could generate, it could help patients have more energy and it maybe even lower some of the brain fog. That’s kind of our style right now is also not to try to do everything ourselves, but when we find an expert that is not, instead of trying to learn that expertise, convince them to work on it.

That was a little hard at the beginning because it was kind of viewed as psychosomatic disease by so many doctors and even researchers and mostly NIH. And so that’s been dispelled, so now it’s a lot easier. What the barrier is for people entering the field is that it is, it’s a complicated disease and you know how you learn about it and how you get a grant. So that’s the barrier at the present time. And, what’s been very fortunate that there’s people that have affected member and their family that have a fair amount of wealth. And they have been very generous at donating money. They donate to OMF, they donate to us, they donate to other people that are working, doing the research.

And that’s been essential! Pretty difficult to get an NIH grant for anything right now. And, ME/CFS is just extra harder. It’s about two times harder. So you have to write an awful lot of grants. We have a grant just turned in, which I think is actually a pretty good grant. And we’ll see how that goes, ‘because we have a lot of preliminary data for it. Anyway, this is a tough field, but we really need to get more people involved in this. And I, I like the idea of focusing on treatments and cures because people have been suffering for so many years. Even a treatment that helps a little would be very worthwhile our efforts. And if you do find that you actually learn something so it’s not just oh, something off the side. Why did that help?

Mr. Meadows: Exactly. Yeah. Why did it help? What did it help in terms of the symptoms? There’s a lot that we can learn from something like that.

Dr. Davis: So, it’s kind of probing the disease. One of the models we have as to why is it so? They’re different in different people, well a lot of diseases are somewhat different as well. So, it’s not, that’s not uncommon, but seems to be more different than most diseases. Some people are affected extremely badly, my son is for example, and we think that it probably is that not all cells are affected. And so it depends on how many cells are affected. It comes from a number of measurements, oxygen consumption, and Robert Phair models all this stuff. And, he’s trained in electrical engineering as well as human physiology, so he’s a perfect person too, because he knows how to model for electrical engineering and he knows the physiology from his physiology training.

So his modeling has been extremely valuable. And, I suggested to him a long time, I think it might be heterogeneous disease, and multiple cells are affected and he’s modeled that and he has come up with that. It must be the case as well. So, it could just be localized somewhere. Hopefully not in, only in the brain, because the brain’s hard to treat, but it doesn’t seem to be. It could be in the muscle and Michelle James scanning, and stuff indicates that it probably is widespread. And not every tissue is involved, but some are involved more than others. So, we’re getting more traction at Stanford as well. Michelle James is totally dedicated to doing this and she’s really, really good. She’s like almost the best in the world at doing some of this stuff. She’s a chemist and she can make probes; that’s the whole secret to the scanning.

Dr. Meadows: Definitely. Yeah. We’re lucky to have her on the Scientific Advisory Board.

Dr. Davis: Yeah, so anybody can do the scanning, but what you can’t do is design probes. And she’s working with us now in the sense of knowing what we do, as well as talking about what she could do next and what probes to make.

Dr. Meadows: Awesome.

Dr. Davis: And then Mike Snyder has gotten involved in it now. And he is gotten, he is very, he’s an incredible he does big data kind of analysis and he has a lot of good people working with him.

Dr. Meadows: Excellent. That’s a lot of great points, Ron. And I want to say quick hello to Chris. Thank you for braving the time change. I know it’s tough getting up this early for you. Right now we’re just kind of starting things off, talking about, how kind of all of your big picture theories can explain some of the difference in symptom presentation that we see.

And quickly before we go onto, uh, you know, Alain, Wenzhong and Chris, who I know you haven’t had a chance to talk about this particular topic, I want to maybe kind of jump off of something Ron said about JAK-STAT, because I know Jonas, you’ve kind of recently published a paper kind of touching on that, so I just want to kind of draw that connection really quick and see if you want to make any comments there.

Jonas Bergquist: Yeah, thanks Danielle. Yeah, so we recently published a paper on our Long COVID, post COVID cohort, and did the transcriptomics, which is sort of a bit unusual for me. I’m more downstream, so I do proteomics, metabolomics, or targeted markers for neurotransmission signaling and so on. But, actually our transcriptome data showed very clear and significant connections to JAK-STAT signaling dysfunction. So what exactly, what Ron is also indicating. I think that is a very interesting target for potential drug treatments in the near future. So, yeah.

Dr. Meadows: Thank you. Alain, I want to turn to you for a second talking about, you know, the varying symptom presentations, because I know you have kind of been driving towards this precision medicine angle of things. So maybe I’ll let you elaborate on that a little bit here.

Dr. Moreau: Yeah. Thank you for the opportunity to further discuss about this. In fact, I think the secret ingredient here is to do our best to keep the focus when we develop tools and, and protocols around post-exertional malaise as a key driver and, and as you know, the cardinal symptom of ME.

And it is very difficult to capture patient when they are in their bad day versus the good day. And that’s why we develop, I think, a very pragmatic approach to especially study more severe people, those that are housebound, that are rarely participating, with the goal that by studying severe patient, we might learn more that can also be challenged and tested in other form of the disease as well.

So that’s why we focus on that. Well, brain is certainly involved in the disease process. We realized that by studying different circulating factors, like SMPDL3B, FGF-21 and more recently haptoglobin. All these factors are connected also to the brain because some of them are expressed in the brain.

They can go there easily and having an exchange between brain and other organs as well. And they are connected to cognitive dysfunction. So, we shouldn’t see the brain as a separate organ and even if it’s a noble organ, very vital for everyone, I think there is a stronger connection about what is circulating and is more like a two-way street. Okay, in such communication. So, what is circulating may influence the brain, and the brain certainly may influence those secreting factors and development. And this is, I think, so far, we have seen, especially through the DOMINOME project, supported by OMF, where we are engaging a very active collaboration with Uppsala, Melbourne, even Harvard with Wenzhong, with the modelization. So, I think this is a strength of this network of OMF Collaborative Centers to work together to attract also as Ron mentioned, new players with different expertise and expertise. And that gave us a unique strength, compared to maybe similar networks. I don’t think there are similar networks but that’s I think make us a bit unique and the fact that we wish, and this is the common goal, to fast track as possible to engage toward a therapeutic solutions, even if some of them are not fully curative. If we can remove some, at least one debilitating symptom, either brain fog or dysautonomia, or at least something else, that would be a great win for the patients as well as caregivers and the rest of the community.

So I think this is where we are, I think in my case after a decade. And, you are seeing recently scientific productivity in terms that we are almost now on a monthly basis having a publication out. But it took us a lot of time and support to arrive at that point. But I think the key ingredient is working together. There is no secret weapon. It is the difference between other very well active, very bright people, but working together between bright people makes a tremendous difference. We are more than the additive effect of each of us. It is a synergy that is unique and again, I think OMF is part of this action as a catalyst here.

Dr. Meadows: Thank you so much for that, Alain. I completely agree. Bringing all of your expertise together is exactly what we’re trying to do. Maybe, Wenzhong let me turn to you for a second. I think you have, you know, obviously with the breadth of analysis that you do, a really interesting perspective here. I mean, you’ve looked at clustering based on symptoms. You’ve done sex difference analysis, looking at duration, severity, so maybe I’ll just kind of open the door to you to kind of just make some comments on subgrouping, severity, all those sorts of questions.

Dr. Xiao: Thank you. First, I’d like to second what Alain mentioned. You know, the strength of, this research network is really everybody can learn from each other and utilize different expertise that different groups, different labs have in this group. My background is computation, so I learned quite a lot from everybody on this call, including the members in the advisory committee. So, one of the research studies that we did recently, which I talked about it last Friday, was this treatment survey, where we looked at the symptom profiles and treatments of more than 5,000 patients of ME/CFS and Long COVID and have to say that was a single handedly organized by patient researcher Martha Eckey and I just want to say, you know, express my highest respect to her initiative and dedication. What we found there was if we only look at the patient symptoms and comorbidities they seem to, as you already mentioned, fall into different subgroups. So, you get one group of patients that have many more symptoms than others.

And they typically have lower functional capacity. And those are probably patients that are more severe, unfortunately. And, then there’s a group that probably are more on the mild end, where they don’t really have as many symptoms that are debilitating. And then in the middle, there’s one group patients that have predominantly POTS related symptoms that David mentioned earlier.

And then there’s another group that apparently is not as much bothered by POTS, but instead bothered by pain and sleep problems and the brain fog. And what we saw was that each group of patients seem to have, you know, different response to the same treatments.

So that indeed along the lines that you mentioned and Alain and others mentioned, give us this hope that potentially we can treat different patients with different symptom profiles differently. So that’s the hope. And also, I’d like to mention that after that publication, actually preprint, went out, you know, I got more than one department heads,

Department of Medicine heads wrote to me and said that a problem they face is that their patients with ME/CFS and Long COVID would bring the paper to them and to their physicians and ask them how to treat these patients. So that actually reflect this issue, that Ron sort of touched, that we don’t really have enough specialists in this country, and perhaps in the world to treat ME/CFS and Long COVID patients.

So, I also just want to show my highest admiration to David and Jonas and other physicians who actually spend their life treating patients. And independent of this related issue would be, you know, how would one actually solve this problem? So in Ron’s symposium, there is this idea that came up that maybe these days with the help of AI and large language models, we can potentially develop some kind of artificial intelligence driven tools to help physicians who are not as familiar with ME/CFS and Long COVID to treat their patients. That might be another issue that we should look into.

Dr. Meadows: Definitely. Thanks, Wenzhong. I think there are a number of things that I want to build off of in that realm. So, maybe let me turn it to Chris first. You can maybe comment if you want to add anything about the difference in symptom presentation. And then I have a couple of questions to go off of some of the things that people have already said. So, Chris, go ahead.

Dr. Armstrong: So yeah, I think we have for a long time been interested in the heterogeneity of the illness and the way that it presents and the way that many factors that people have, that could explain this heterogeneity. Whether it be some of the genetic predisposition whether the triggering factor might have been different, the other comorbidities that they have, and the comorbidities in particular are very interesting to us because through our analysis of the UK Biobank in particular, and even talking to clinicians, the number of comorbidities we found. Just the fact that they had more, not specifically which types, but the number of comorbidities was a strong predictor of having an ME/CFS diagnosis and severity as well.

So, things that you may not think about, but the fact that have like the number of comorbidities was a marker towards defining ME/CFS as a disease, suggests that that comorbidity component to it is a key factor. And that’s what some clinicians would suggest about the disease, that it is the disease of comorbidities. And so that’s something in terms of trying to unravel what that looks like when you’re dealing with a patient population that have other diseases or other pathologies layered on top. And that’s the cohort, that’s the very real cohort that we all work with and try to extract what that ME/CFS component is against the blank canvas of healthy control, you are going to be picking up signals from all those comorbidities mixed in together as well. So, trying to tease that apart, I think has been something that has been a really important goal to try and attempt to start doing. But that’s, I think we’re still quite a while away from being able to really do that effectively. Large efforts like the DecodeME project, but also some of the projects that we’re doing internally, like, the biomarker project, as well as some of the large-scale studies that we’re looking at, even LIFT trial, being able to look at many different patients from this interventions. Thinking in the order of hundreds, really helps to start analyzing data in this way.

But in terms of the heterogeneity of a hypothesis around it, I think the cell type difference that Ron alluded to, the fact that you could have a single mechanism, a single metabolic mechanism or even an immunometabolic mechanism between inflammation and metabolism changes as a mechanism or a pathway.

The fact that that could exist in different cells or different cell types could explain heterogeneity of the illness between people. You could have people who are more likely to have, depending on where those cells are or what they’re meant to be doing, especially if they’re, you know, neurons are in the brain.

But if they’re also potentially ones that are related to muscles versus different types of tissues. I think Long COVID is a really interesting example of this because you have people early on with Long COVID, have a range of different types of damage to different tissues. Some of those get better, so some of them will have, you know, issues in cardiac or lung. And some might have ones, you know, I guess based on the Netherlands papers around muscles. So the idea is that if these people all get defined as this, having this post-acute  sequelae from COVID itself, even though they don’t meet an ME/CFS diagnosis, but they have that initial sequelae. Some of the damage or some of the problems that are occurring within some of those cell types may actually be just representing the problem very early on, and they somehow recover. But perhaps there are some cell types in the body where this happens, and it doesn’t recover and it’s not as obvious. And so that’s something that keeps us up at night because if that’s kind of the case, how do we access all those different cell types and individuals and how do we really understand all this?

And so I guess moving to animal models is a really great way to do that. And so that’s probably an area where that’s going to be unraveled in terms of the cell type story. If you can move a model into an animal. But in terms of what we think around the heterogeneity and what we are trying to, kind of, how we’re trying to approach this is by trying to subtype individuals based on things we already know are separating them and things that may indicate towards the biology. And one of those is treatments, the combination of treatments that actually work in individuals as a way of well subtyping effectively from that, thinking, well, these people are all impacted by this particular drug. What is it about their biology that might have made them susceptible to be improved by this medication, versus those who weren’t improved by this medication or what are we looking at biologically different between those to try and understand the biology central to that.

Dr. Meadows: Awesome. Thanks. Really quickly, I think I want to pause here before we go onto some of the other topics that we’ve touched on. Since you know, we’ve brought a lot of aspects into the conversation already, and I wanna kind of pull up a really quick graphic and maybe let you all react to it, but, it’s kind of building off of some of the summary work, Chris, that you’ve started and has built off of, you know, conversations that we’ve all had in the past. And I wanted to just kind of share this really quickly as, you know, some kind of way to show the different connections between everything that we’re all talking about. So, you know, this is just kind of a graphic, I’ll walk through it really quick and I’ll let you all comment. You know, where we have up in the left corner, some of the triggers and risk factors that can, you know, eventually lead to ME/CFS. And what we have here is this idea that there’s this failure to recover.

And Chris, you kind of alluded to this a little bit you know, whereas somebody who has these triggers as a healthy person might recover from them, but for someone with ME/CFS, it drops somewhere into this kind of web of things that are potentially going on and they’re all interacting with each other and building off of each other. Where, you know, we’re eventually getting to this disease phenotype with all of our hallmark symptoms down at the bottom. But depending on how these all interact together, that’s maybe where you’re getting some of that symptom presentation differences among different people, the different subtypes and things like that. So I just wanted to throw this up as since we’re bringing all these different ideas together and I’ll pause for a second and then take it back down again so we can all see each other’s faces as we talk. But if there are any comments before I do that, happy to let you all jump in here.

Dr. Moreau: If I may, Danielle, we need to eventually do some kind of, not prioritized per se, but to really establish what are the drivers of the primary event that will lead you to develop this chronic condition and some specific symptoms versus the compensatory mechanisms that are. We’ll sometime naturally try to compensate or to response to what is imposed. So, what is a primary event versus a secondary event I’m not saying that the second event are just as trying to compensate critical situation. Sometime by applying the natural response can put you in a vicious circle. And now maybe this is a connection with what our friend Bob Naviaux is often mentioning that you are unable to go out of this vicious circle and you end up with this chronic condition like ME and you are not able to select the right gear to go back to your natural living process. But because we are measuring with our different tools and different expertise, different part of the process, sometime it can be confusing the best of us, and also for the overall community about, okay, what are we looking here? Is, is it the drivers of this and that, or is it a response?

So, so this is, I think a challenge. How can we discriminate between what are really the molecular drivers of the primary events versus the natural or abnormal response? And sometime even pushing on the abnormal response, even if we don’t control the initial driver is okay. At the end of the day is to find the solutions to how can we put the patient back on the right cycle to recover at some point. But it’s still a challenge, I think to address and separate secondary and primary event here in this process. I think we’re getting there a bit slowly than expected, but it’s complex.

Dr. Meadows: Absolutely. I think that’s a great point. I mean, I think, you know, in some cases, some of the analysis that we do, I’m going to take this down for now, but, some of the analysis that we do is important to look at potentially what the primary trigger was, or like you’re saying, secondary events and I think you know, Wenzhong and Ron have both done some work in even like viral reactivation and, you know, maybe that’s considered a secondary event from some kind of trigger that happens and how does that play into things? And I think there are a lot of questions that we can ask in that area. I think that’s a great point. Go ahead, Ron.

Dr. Davis: One very important thing is that if the patients that have been cured, they are totally normal. So, this disease does not appear to cause damage to the body as some diseases might like a heart attack or a stroke. So that makes it even more important to try to find a cure for this because they will be a good chance that they will be normal.

That’s a great point and hopefully can provide some hope as well. It, you know, it is something that we can get back to a healthy state once we find the answers. So yeah.

A lot of patients seem to be depressed because they say, you know, I’ll never get better, and if I do, my body’s so badly damaged, and things of that. No, it’s not damaged, which actually is a little bit of a clue as to what’s going on. It isn’t damaging the body even though it feels awful. So whatever is there that’s causing all that is something that is biologically set to be reversible.

Dr. Meadows: That’s a great point. I want to switch gears a little bit here. So Alain, when you first started talking, you mentioned something about, you know, centering a lot of our thoughts around post-exertional malaise as you know, the kind of the hallmark symptom of ME/CFS. And I just want to, you know, draw some connections here, because I know, David, you have your muscle biopsy study going on, kind of examining PEM , and Chris, I think you also have maybe a PEM study or two mixed in there. So maybe, if any of you want to comment on, you know, that, that idea around focusing on PEM a little bit .I’ll open the floor.

Dr. Systrom: I guess I’ll go ahead. So no, I mean, post-exertional malaise is as almost everybody in this audience, I’m sure knows, is one of the unique features of ME and a majority of patients, I think with Long COVID, to precipitate a crash with what’s viewed maybe in retrospect with undue physical activity, but sometimes cognitive or emotional activity that persists for variable amounts of time is a key feature of the disease and I think probably grail of understanding pathophysiology and treating this disease. So one, one particular angle on this is that the mitochondrion is contributing to post-exertional malaise in some fashion. That might be at rest, meaning no exercise, but our focus is with exercise. And the skeletal muscle is one of the quote “accessible tissue beds” in the body where we can get a small needle under local anesthesia gets a phenomenal amount of anatomic and physiologic information with a biopsy.

So, our particular two-day study funded by OMF thank you very much is looking at the contribution of both baseline mitochondrial dysfunction and the impairment of oxygen uptake during exercise. So, it’s been known forever that genetic forms of mitochondrial disease, their hallmark during exercise, is the inability to take up and use oxygen properly. The machinery doesn’t work. They’re unable to take up and use oxygen. So, this might be a problem at rest without exercise, but it certainly is a problem with exercise. Muscle, skeletal muscle being a high energy tissue bed requiring lots of flux and energy demand and production.

So we are doing baseline muscle biopsy studies. I think we have approximately 40 patients with ME and more recently Long COVID where we have found some abnormalities. This is preliminary. It’s not published, but with the help of a Bob Naviaux, we have found evidence that the mitochondrial number reflected by something called citrate synthase activity is decreased in somewhat unique fashion in ME and Long COVID, and then a subset of patients have what everybody has suspected, and that’s an intrinsic problem with the electron transport chain and its ability to produce ATP. So, mitochondrial number may be down in ME and Long COVID and mitochondrial function may be down. And then additionally, we’re looking to see with provocation. And our provocation is acute exercise, little prolonged exercise, not too egregious but designed to provoke a bit of PEM to see if we can have additional evidence and subsets of patients that the mitochondrial dysfunction contributes to PEM.

Dr. Meadows: All right, Chris, do you want to add anything?

Dr. Armstrong: Yeah, I can. I can add, so from some of our a few of our different studies looking at over several days or immediately after exertion. One of the interesting things I think that pops up is what’s occurring from exertion itself. The reason post-exertional malaise is very important to study, I think, is because there are theories suggesting that it is the basis of ME/CFS.

If you were to understand post-exertional malaise, you would understand ME/CFS. And what’s valuable about it is that you have the pre-exertion state, you have immediately during exertion, immediately after exertion. These are all time points which we can get data from patients, which we can’t in regard to before ME/CFS, before the trigger, before all this sort of stuff.

So, that gives us this window where we could actually see that if PEM itself is a minor echo of the major concept of the entire disease, then that’s an avenue for which we could understand it. And interestingly, some of the very early post exertion, so two minutes after exertion, 30 minutes after exertion, some of this work we’ve done is highlighting some interesting things about the biological differences between ME/CFS and controls. So that’s something that we’re really interested to keep pursuing. And in particular, I think, so thinking about the idea that early in that stress event, you actually do get a lot of changes, which may be the same with the trigger. Maybe a lot of the changes we actually miss because there happened the acute phase of whatever trigger this was that created this long-term infection or long, sorry, long-term sequelae or long-term ME/CFS. And then we have yeah, these other studies looking at changes in markers over several days, and, looking at what that recovery looks like, differences between people who have, you know, the severe symptoms 12 hours after 24, 48 hours, you know, these different peaks. And whether that’s creating any differences, any reason for that difference or whether it just happens to be how they deal with whatever stressful component is being created as part of that exertion itself. And I think the muscle work that David Systrom is doing and also in combination with the Netherlands group is, this is really important research. And especially because muscle itself is so hard to come by within this population, very precious material. So the fact that we’re able to do this sort of work, I think is gonna really lead to a lot of very interesting information for us all.

Dr. Meadows: Awesome. I think, maybe as my last prompt for today, I’m going to throw out maybe a complicated question for you which is you know, I think there are multiple answers to this. So, in each of your opinions, you know, what does treatment look like down the road? Is there going to be some kind of cocktail of things required? Based off of what you think the mechanism is, or you know, some kind of short-term treatment that gets you back to a better baseline state and then some maintenance I’ll kind of, you know, throw out those brief options. But see what you all think of that as what does the future look like for us?

Dr. Davis: I may make one comment about that in terms of the patient that was in Australia that was treated with the JAK-STAT inhibitor it only took three pills and he went in complete remission. So that’s an example. The other individual that went into remission was more complicated, but it also reflects another thing that we have seen is that patients don’t necessarily respond quickly to drugs. And Abilify is a good example. My son took Abilify and it we went up to two milligrams, which, and no symptoms from the drug. So, we said, we’ll just keep him on it for a while, but it wasn’t doing anything. But after, I think it was around four months, he starts, he made an indication that it was helping and it had a profound effect on him. Well, it was one of the most important ones he’s ever had with any of the drug treatments. And going back to Wenzhong, when you do these surveys, it might be important to know how long have you tried it?

This may not be true for less severe patients. It might be because it’s severe, and it might be because of epigenetic changes that have happened that have to get reset. But we also have to be careful about taking a drug for a day and saying, oh, it doesn’t do anything. That may be the wrong answer.

Dr. Wenzhong: Yeah, I agree.

Dr. Davis: Yeah, so if it has a lot of side effects, you may not want to do that, but a lot of these drugs don’t have a lot of side effects, and it might be worth trying it for a while to see. In fact, it eventually has an effect, but that may be true for the cure. It may take a fairly long time of treatment because of this. I don’t know what’s causing that. You would expect Abilify to have an immediate effect.

Dr. Meadows: Yeah, those are great points. Ron. Jonas, did you want to comment on this area too?

Dr. Bergquist: Yeah, definitely. I want to allude back to something that Chris brought up, which I agree with. I mean, in his studies that on patients and their comorbidities and the overrepresentation on certain comorbidities also in the patient cohort, and I mean, that put points in the direction of maybe a increased sensibility or susceptibility to be affected by other things also. But there is a big difference, I think from what is the comorbidities and what is the ME-related symptoms because most of those comorbidities actually can be treated today with really, or rather effective drugs, actually, while we still are struggling to find something that would I mean cure or even support most of the ME patients with medication. So, I still think we, we have to find rather tailored medications for most of the patients initially, at least until we really hit the golden bullet or whatever we call it.

Right? But I also over the years been collecting stories from patients who actually have recovered. They are not that many. And as I think I mentioned before, it’s hard to find them because. Once they have recovered, they don’t want to see you anymore. They go out and live their life again and don’t want to be in connection with maybe with the researcher and so on. But I think it’s been broadly individual, what has been the big change for them. But the time has really been one factor. So it has taken quite a long time, and they’ve been slowly progressing back to recovery. In different ways. And yeah, when I think about some of the patients that I know have recovered to almost normal life, again, it’s fantastic to see that of course. And it’s a big encouragement for all of us to find that solution for everyone. And I think we have many, much things to do, still to find it, but I think we are working together in that direction.

Dr. Meadows: I think that’s a great way to, you know, kind of wrap things up. But we’re really driving towards, I think, that precision medicine idea, trying to find these more individualized treatments based off of what’s happening for, you know, different people depending on all these factors that we’ve talked about.

And, you know, emphasizing that there is hope, there is recovery happening and we’re, we’re trying to get answers from that too. And so I think that’s a really great way to, to wrap up our discussion today. I want to thank each of you for all of the research that you’re doing and for taking the time to talk amongst each other today. So, thank you all.