Eric Schadt, the study’s senior author, is not your average researcher, and Phillip Comella, the lead author, has personal experience with mysterious diseases and difficult diagnoses.
A biomathematician and bioengineer, Schadt has been at the forefront of biocomputational technologies for years. Schadt’s goal has always been to get at the biological underpinnings of disease. He’s a systems guy. Our genes, after all, they don’t work in isolation – they work in systems. Schadt believe that many potential therapies failed because they didn’t take into account the systems the gene was participating in.
Not content merely to highlight particular genes, Schadt was one of the first to use genetic data to construct “predictive networks” that targeted aberrant biological pathways that were causing. Once he did that, he circled back to use these pathway analyses to target the genes that were actually making a difference.
Schadt has pioneered the development of biomathematical approaches that identify systemic problems that are causing disease.
In 2011, Schadt founded the new Icahn Institute for Genomics and Multiscale Biology at the Mount Sinai School of Medicine in New York. It was about then that Schadt first showed up in ME/CFS. As MEpedia reported in 2011 and 2013, Dr. Schadt spoke about “applying his cutting-edge expertise to Chronic Fatigue Syndrome” in two ME/CFS conferences.
Phillip Comella, for his part, is a graduate student who spent years under the illusion he had one disease only to come to realize he had something entirely different. Only after convincing his skeptical doctor to do the correct tests did he get an accurate diagnosis. Check out his, at times, hilarious and, at times, horrifying story of medical misdiagnosis in “Science Gets Personal“.
In 2021, Schadt and Comella published a complex study suggesting that ME/CFS, long COVID and other fatiguing diseases share a “common molecular etiology”. Schadt’s predilection for going beneath the surface and uncovering systemic processes that have gone awry was in full display in this study. As in his other studies, he and Comella then circled back to uncover possible “master regulatory genes” which could potentially be tweaked one way or another to return people with ME/CFS to health.
The Study
“A Molecular network approach reveals shared cellular and molecular signatures between chronic fatigue syndrome and other fatiguing illnesses” is a big, little study. It didn’t contain many participants (n=30; 15-ME/CFS, 15 healthy controls), but it subjected the data it got to a number of complex analyses – including some that had never been done before. It’s perhaps no surprise given all the work done that this 30-person study ended up with no less than 17 co-authors.
They drew whole blood before, and then 24, 48 and 72 hours after “moderate cardiopulmonary test (CPET)”. The CPET testing protocol was different from the maximal CPET tests done by Workwell and others.
It involved reaching 70% of age-predicted maximal heart rate and then maintaining it for up to 25 minutes. Some think that while a maximal exercise rate is not reached, that this protocol is actually more difficult for patients, as it’s twice as long and likely requires patients to be in their anaerobic zone for longer than a maximal exercise test. Lactate was measured every five minutes.
Several classes of immune cells (B cells, granulocytes, monocytes, natural killer (NK) cells, T cells) were filtered out the blood. The gene expression in those immune cells and the whole blood was then assessed.
They found no differences in gene expression due to the exercise stressor but acknowledged that this may be due to the sample size. (I believe that Nancy Klimas has found differences in gene expression, but she measured it at multiple points during exercise.)
The study suggested that a high viral load might be paired with malfunctioning immune cells.
Next came what they called a “comprehensive RNA-seq data analysis pipeline” of the whole blood and the immune cells. The first part of that involved putting the blood through a “viral/clonal detection pipeline” which suggested, interestingly enough, that people with ME/CFS may have had a higher viral load.
Next, they looked at T and B cell clonality. When these immune cells get triggered by a pathogen or foreign object, they produce massive numbers of clones. The researchers found a sharp divide between the ME/CFS patients and the healthy controls (p<0.0001) with the ME/CFS patients producing a less diverse array of clones. That suggested that their T-cells may not be responding appropriately to danger signs. That was an interesting finding given that the pipeline test suggested the ME/CFS patients had a higher viral load – which seemingly should have triggered, one might think, a more diverse array of clones.
Next, they went beyond the pure gene expression results and used something called differential expression and machine learning to identify “gene expression features”. First, this approach picked out suspect genes, and then assessed the “directionality” those genes displayed.
They found “molecular differences” between the ME/CFS patients and controls such that alterations in the B and T-cell, granulocyte and NK cell signatures were able to pretty effectively distinguish ME/CFS patients from the healthy controls. That might fit the last two results: could the higher viral load have impaired immune cell functioning, leading to the production of a less diverse array of clones?
Next came Schadt’s forte – putting things into a “biologically relevant context”. First, they looked for “coherent subnetworks of co-regulated genes (modules of genes) for each of the 6 cell types”; i.e.; they were looking for teams of genes that work together to perform biological functions in the immune cells.
They identified 119 co-expression modules (clusters of genes with similar functions) which spanned 6 “co-expression networks” across the ME/CFS immune cells. Finding genes that were expressing themselves similarly across multiple immune cells was potentially big news.
The study suggested that similar core immune elements might be in play in both ME/CFS and long COVID.
One of the most daunting aspects of ME/CFS has been its possibly high degree of heterogeneity. If it may be a disease composed of very different subsets, disentangling and understanding each subset is potentially a long and arduous process. The road to healing in a disease characterized by core processes gone wrong, on the other hand, should be much shorter. This finding suggested ME/CFS was more a disease of common immune problems gone wrong.
That the ME/CFS signatures were “enriched” in about half of the modules/networks identified appeared to suggest that the researchers were on the right track.
Link to COVID-19, Lyme disease and others
Next, they took the top five genetic modules with enriched ME/CFS signatures and compared them with those found in a wide number of inflammatory and autoimmune diseases. They included Multisystem Inflammatory Syndrome in Children (MIS-C), Kawasaki Disease (KD), Macrophage Activation Syndrome (MAS), Neonatal Onset multisystem inflammatory (NOMID), Lyme disease, active Influenza (IAV), active COVID-19, early recovery stage after COVID-19, Mixed Connective Tissue Disease (MCTD), Sjögren’s Syndrome (SJS), Systemic Lupus Erythematosus (SLE), Systemic Sclerosis (SSC), Undifferentiated Connective Tissue Disease (UCTD), Primary Antiphospholipid Syndrome (PAPS) and Rheumatoid Arthritis (RA).
Similar disease signatures to ME/CFS showed up for diseases like MIS-C, Lyme disease, and COVID-19 but not for autoimmune diseases. The authors stated “our data further suggests a shared molecular etiology (between) CFS, COVID-19, and Chronic Lyme Disease”.
That’s, of course, a potentially very helpful result as it suggests that breakthroughs in those diseases might translate to ME/CFS. The COVID-19 similarity was particularly nice to see given the attention and enormous amount of funding being given to it.
Next, they dug into the molecular pathways found in the genetic modules (groups of co-occurring genes) that were most associated with ME/CFS. The module most strongly associated with CFS (NKM4) was also, interestingly, highly enriched with a “recovering COVID-19” signature. The authors suggested that that “molecular link … may help explain why so many recovered COVID-19 patients seem to experience CFS-like symptoms.”
Four of the top 5 CFS-enriched modules were also enriched for another mysterious ailment which has not given up its mysteries easily – chronic Lyme disease. Given the recent dramatic burst in NIH funding for Lyme that was good news as well.
Genes that could be driving the possible immune dysfunction in ME/CFS were identified.
Next, the Mount Sinai team went after “regulatory relationships” in an attempt to uncover the master regulators, or key drivers (KDs), or hub genes, for each of the top ME/CFS modules. Key driver genes are just like they sound; they’re key genes that affect the expression of many other genes.
That analysis uncovered 904 possible key driver genes. Of those, they highlighted 11 potential key driver genes (MXD1, STX3, DYSF, LYN, MLL2, NCOA2, PTPRE, REPS2, RP11–701P16.2, TECPR2, and TUBB1), which they expected would be able to alter the functioning of at least 3 of the 5 top ME/CFS modules.
When they assessed whether these genes were likely to be functionally significant (i.e. likely to be affecting a person’s biology), the answer was an encouraging “yes”. That suggested they may have indeed found some genes that are “master regulators of vital biological processes associated with CFS”.
None of these genes had popped up in ME/CFS studies before, but given how different this analysis was, that might not be surprising. They have, however, been implicated in a number of immunological disorders. While they haven’t shown up in ME/CFS before, the authors reported that they had been shown to be key drivers in other immunological diseases.
At the end of the paper, they also provided a link to an interactive website containing the signatures, modules, KDs, and Bayesian network found in the study.
The Gist
- Eric Schadt, a pioneering biomathematician, oversaw the study. Throughout his career Schadt has focused on getting beyond genetic and gene expression results to uncover the systemic problems that are causing disease.
- The study assessed immune cells in blood drawn before and after an exercise stressor. After finding evidence of increased viral load, reduced clonal diversity and altered immune functioning, this very complex study uncovered “teams of genes” with similar gene expression (if I got that right) across the immune cells. That suggested that core immune processes had been altered across the board in ME/CFS.
- That was encouraging as it suggested that instead of being a collection of different diseases ME/CFS has core immune processes that could be targeted.
- Further analysis suggested that similar immune problems may also be occurring in long COVID, Lyme and other diseases but not in autoimmune diseases.
- Key driver or master regulatory genes which appeared to be driving the immune dysfunction in ME/CFS were also identified. Some of these genes also appear to be key drivers in other immune diseases.
- The study was successful enough that planning for a bigger study is underway. ME/CFS, however, is currently missing an animal model or cell line which would allow these researchers to test their findings and develop a therapeutic target.
- The authors, though, are are currently engaged in Long-COVID studies and hoped that the interest and new funding for long COVID will help them move forward more quickly.
Comella Interview
I asked the lead author of the study, Phillip Comella, “… if anything like this has done in ME/CFS before?”
There have been other co-expression based studies in ME/CFS but to our knowledge this is the first study to integrate Bayesian networks to inform the mechanistic insights driving the co-expression modules.
Our study takes a network-based approach to discover teams of genes, or modules, that are dysregulated in disease and identifies team leaders, or key drivers, of those groups of genes.
We were able to show that the gene modules enriched from our unique CFS disease signature (genes that best distinguish CFS and controls) pipeline were also enriched for other unique CFS study disease signatures.
This is interesting because the disease signature algorithms can be highly picky with what they choose as the absolute best distinguishing genes for disease and control, making exact signature replication difficult particularly for under researched diseases.
The network-module approach shows that although these signatures are unique, they appear to work with a similar group of genes. These teams of genes are also enriched for other post-infection fatiguing illnesses, suggesting that although these illnesses are unique, there is perhaps a thread of biological dysregulation tying them together.
What would it take for results like these to be turned into therapeutic targets? What kind of studies would be needed to get to that point?
Our team has been working on a Bayesian Network perturbation tool to predict the key driver’s therapeutic potential, but validating these finding can be tricky. ME/CFS does not currently have a model organism to help us study the disease mechanisms. Identifying an in vivo model organism or an in vitro cell line for ME/CFS would help us to test the therapeutic potential of altering the key driver genes our in silico pipelines have highlighted.
Our study suggests that a few of these fatiguing illnesses may share a common thread, which makes us hopeful that the recent interest with long COVID along with the increased NIH funding will help fuel findings that may make their way over to CFS.
Are there any follow-up studies planned?
Yes, we are currently planning the next study to build off of these findings and are hopeful that a larger study will yield deeper insights.
Are you participating in any long-COVID studies?
Yes, our team is actively collaborating with long COVID / post-covid syndrome researchers.
Conclusion
This study was notable in a couple of ways. For one, it was overseen by a pioneering researcher. It used a kind of analysis (Bayesian network analysis) that had not been done before in ME/CFS. For another, it was simply successful. After finding evidence of increased viral load, reduced clonal diversity and altered immune functioning, the researchers went on to uncover “teams of genes” with similar gene expression (if I got that right). That suggested that core immune processes had been altered across the board in ME/CFS.
Further analysis suggested that similar immune problems may also be occurring in long COVID, Lyme and other diseases but not in autoimmune diseases. Key driver or master regulatory genes which appeared to be driving the immune dysfunction in ME/CFS were identified. Some of these genes also appear to be key drivers in other immune diseases.
Planning for a bigger study is underway. Using the results to develop a therapeutic target, though, would require testing them in an animal model or cell line – something that ME/CFS does not yet have. The authors hoped, though, that the interest in long COVID would help them move forward more quickly – and they are currently engaged in Long-COVID studies.
WOW! Fascinating ! I haven’t been keeping up with all the articles in full, but just scanning them as my illness ( yet officially given a label ) has wiped me out after 4 or 5 long years of struggling. I’m so FATIGUED !!!! I’m in such pain all over and all the other over 100 symptoms in all my body systems. I am a HUGE fan of System Thinking and getting to the “what lies underneath all this and let’s dig it up” approach! TRUE ! Everything works in a WHOLE SYSTEM no matter what you apply to it. So anything can be figured out using a WHOLE SYSTEM approach given time and minds that think this way. YAY !!!! I look forward to more of the upcoming studies done in this manner! SOS time for me!
Me too. I was so glad to see Schadt taking a systems approach. After recognizing that studying genes in isolation was not producing many results, he got onto this early on and was apparently very successful with this when he lead a lab at MERCK.
I was just given this article. I am on my 5th week of a cfs episode. Although my brain cant comprehend a lot with the fatigue, I think this article is helpful. I see my cardiologist next week and will share with her. I have not been sick nor have had COVID. I have no clue why my symptoms, that usually last a day to a week, have hung on this long.
Dear Cort, thank you as ever for your exceptional hard work. What would we do without you? Thank you. I wonder, however, in your interview was there ever a mention of the type of immune diseases that all this resembled. You write: “Some of these genes also appear to be key drivers in other immune diseases.” Did they mention any specific names of diseases. Thank you
Yes. Are you ready? All sorts of diseases. Bear in mind that many diseases have probably not been assessed for key driver genes. This is the first time it’s happened in ME/CFS. I don’t think it’s happened in long COVID. I feel confident that it hasn’t happened for fibromyalgia. Here they are quite – an assortment:
Familial hemophagocytic lymphohistiocytosis 5 (FHL5) [43], chronic myeloid leukemia [44], Dysferlinopathy and inflammatory myopathy [45], Lupus [46], B cell lymphoma [47] as well as immunological aspects of Kabuki syndrome [48], Kaposi’s sarcoma-associated herpesvirus [49], modulator of macrophage activation and inflammatory diseases [50], prostate cancer [51], spastic paraparesis [52], and abnormal platelet physiology [53].
Hi Cort,
I have been diagnosed with fibromyalgia 12 yrs back after 4 yrs of struggling with the symptoms. My 14 yr old daughter got diagnosed with M.E/PoTs 2 yrs back. Our symptoms are IDENTICAL.
I didn’t even know I had PoTs until my daughter got sick. That’s because I went to a rheumatologist.
So what do I make of this study .
We both got sick after a virus attack.
If this finding sticks it’s good news! Both POTS and ME/CFS have shown up big time in Long COVID. If its true that core immune abnormalities are present across all these diseases that is excellent news. Keep your eyes on long COVID, POTS, ME/CFS and FM research and hopefully the findings will merge together. The kicker in all this is $1.15 billion in Long COVID funding. No one expected that much money to show up.
One thing that struck me is the dividing line between immune diseases and autoimmune diseases. Couldn’t Eric Schadt do systems driver comparisons between the two?
The NP at Stanford’s Chronic Fatigue Clinic remarked that a huge percentage of people under their care have Ehlers-Danlos Syndrome and people who have EDS also suffer from a high level of fatigue. Somewhere around 80-90% have ME/CFS like symptoms. Many also have small fiber neuropathy which is very fibromyalgia like. Then add on another large percent who also have some kind of autonomic dysfunction (POTS or NMH)–like ME/CFS.
Of course having EDS and ME/CFS I wonder if there really is a dividing line between a vector (Covid, Lyme’s, HHV-6, Epstein-Barr etc.) and a supposedly genetic onset. Maybe hEDS is partially autoimmune or perhaps is fertile ground for an infectious ‘vector.’ That ‘vector’ could also be a toxic mold or perhaps some abhorrent man made chemical (thank you Betty. And thank you Issie for that article which had a long list of genetic SNPs linked to ME/CFS that you posted a little while ago).
One thing is for certain, a systems approach is definitely the way to go. Hope you all registered in the ME/CFS database. Like Mary, I’m SO ready to find something that is really helpful!
Hello, Nancy B, I, too, have wondered about whether there is a crossover connection between genetics and specific diseases to bring about CFS symptoms. In my own family of my mother and her 4 daughters, all 5 of us had at one time Mononucleosis. I used to think it was having Mono 47 years ago that started all this, but in comparing notes with one of my sisters, and suspecting that we always dealt with fatigue-type symptoms even prior to Mono, I wondered if it was perhaps a genetic immune defect that could allow 5 family members to all come down with Mono in the first place due to an immune problem.
There does seem to be genetic connections. My sister and I were in a ME/CFS genetic family study. They looked at our genes and also the function of our Mitrochondria. My sister and I both have ME/FMS, FMS and orthostatic issues and I have EDS. We had some common genetic alleles. They could check the function of these to see if we were affected by them and to what degree. I was affected more than my sister, especially with my mitochondria. So there does seem to be genetic components here. We have generations in our family with these issues. And that was true of the families in this study.
There can also be issues with virus here, as that seems at play with many of us. Whether there is latent virus or it created sickness type behavior and our body still thinking its there, remains to be determined.
There is also Chronic Lyme disease, They feel this could cause immune response and activation, when it may not still be there. (I also deal with this.) However, some just can’t eliminate Lyme from their system and it lays in a dormant state and can reactivate. Lyme is not a virus, but a pathogen. Same with fungus and mold in the body. And if we have trouble with being able to detox or eliminate pathogens, we can cycle up and down in our illness. The immune system can also stay in an “On” position and then start to fight and attack self.
Then there is the possible Mitrochondria issues and inability to have proper energy. That can fluctuate. I was in the lowest 20% of function compared to all in the study. (I was really tired that day as I had traveled to get there and was having a bad POTS day.)
So having a full function approach is absolutely needed. We are all different, with different genes and different make ups. Our bodies function differently and genetics can determine if we are predisposed to issues in pathways. Its a fascinating study, but really deep and requires a lot of study. There will not be a one pill for the masses. It will be an individual journey. But we are finding some common things that are wonky and that is not just in families, it seems to be in others with ME/CFS too. So finding those common things gives us a place to focus and a way to tweak and help the masses. Then the rest will need to be further refined on an individual basis.
Science is advancing. YAYYYYYY!!!!
This is fascinating! Thanks for covering it. Two questions:
1) Given that a significant percentage (if not a clear majority) of us have autoimmunity, why are they not including autoimmune ME/CFS patients?
2) Why are they not also looking at cancer related fatigue?
Thank you!
Two interesting articles related to ME/CFS. First researchers in Sweden noticed that Covid long haulers can/have developed POTS like symptoms.
https://www.medpagetoday.com/infectiousdisease/covid19/91566?xid=nl_covidupdate_2021-03-11&eun=g1240599d0r&utm_source=Sailthru&utm_medium=email&utm_campaign=DailyUpdate_031121&utm_term=NL_Gen_Int_Daily_News_Update_active
The second article is from All of Us, the NIH’s project of following one million citizens (with measurements, genetic sequencing, tests etc.) to discover the underpinnings of disease, which has found a correlation between mast cells and IBS. No surprise histamine is involved but the findings tie in MCAS and IBS in certain locations of the digestive track and how those associations may have begun.
https://www.sciencedaily.com/releases/2021/01/210117132238.htm
So why am I bringing up these two topics? They are part of the cluster of symptoms in the Fibro, ME/CFS, EDS realm—and now Covid realm. There has to be some kind of connection—but exactly what?
There are connections @Nancy B. Much of the immune system is in the gut. And one of the best ways to stabilize an over histamine response is to get the histamine receptors to work properly. That includes getting the T cells to work in proper intensity. There are 2 types of T cells and histamine plays a role in how they work and when they work and when they turn off. (To note: One of the mast cell stabilizers works at the gut level to tame down mast cell over response (GastroCrom). That can also potentially help with IBS issues.) But, trying to get the body to turn on and turn off the proper receptors at the proper time is a big part of over response or under response. Histamine plays a big role in immune response. It is needed and needs to be able to work. But not over work.
Over response of mast cells with COVID is an acute situation and it needs to not let get too far out of hand. But it is the body trying to help fight things that goes to extremes. We have some threads on the Healthrising forum that Bayard started with us talking about this. I can think of two different threads and Dejurgen and I have a thread too (that we need to update). But Dejurgen and I have both written a lot about this as a connection and compensation. But needing to be kept in check and getting the three (3) different histamine receptors working properly.
The autonomic nervous system comes into play with helping with blood flow and oxygen delivery. Things such as increase in norepinephrine. (Though very uncomfortable with POTS and causes some rather severe tachycardia. ) But appears to be a compensation and helps to get blood and needed oxygen to the heart and brain. It speeds up the heart to increase pumping. Moving the legs can assist the heart with this and then the heart isn’t having to do all the work. (I sit with my legs on an exercise ball and gently wiggle, bounce and move my legs to assist my heart with this. It has improved my POTS and helps keep my heart calmer.) It will also aid in the constricting and vasodilating of the veins. With COVID, there are blood clot issues. And with us POTS people there is blood flow issues. I happen to also have too thick blood and the type POTS I have I need to vasodilate my veins. I also use enzymes to thin my blood instead of blood thinning drugs.
So as mentioned before, we need to know our WHYS. And then we can work on what to do about it. We are not all the same. I can’t treat my POTS the same as the majority, because my presentation and whys are different. Trying to treat all POTS people the same, will not work.
So this does seem to have science we can work out and get the WHYS. THEN, we can get our “purple bandaids”. ?
Issie, you are a powerhouse of information and introspection! You are great at using your body as a laboratory to pick up where medical research has stopped. As for different approaches for different bodies, those experiments are so helpful. My worst and longest cases of CFS/ME have come after vaccines in the past 2 years (Shingrix, Fluzone Quadrivalent, and Moderna for COVID). Since the 2019 one, I’ve dealt with an annoying irregular heartbeat for which my cardiologist could only prescribe beta-blockers that made me even more fatigued. Only about a month ago, after the COVID vaccine worsened the arrhythmia, did I decide to try adding a magnesium/calcium combination vitamin, and 5 days later, the arrhythmia improved by about 90%. Now, I haven’t noticed it. It makes me wonder, and be hopeful, that if our biochemical systems have a genetic misfire, then maybe something as simple as a supplement will mend a broken link.
hi issie, you mentioned that you and your family were looked at in a genetic me study that also looked at your mitochondria, could you tell me a little bit more about that? I am very severe and there are many cases in my family. THANK YOU
christoph.stroeck@stroeck.at or on twitter also.
@christoph, join the Healthrising Forum. You can look up Dejurgen or my name and pull up lots of things we have written. He is the more technical part of our partnership. If you want the deep science, he is your guy. I’m more of the Summary person. We have researched together into 2 years now. We are in the process of trying to compile what we have discovered and plan to do a series of blogs on Healthrising. Its being written. You can imagine what an undertaking that is. We have combined several decades of what we have discovered on our own and then we got together for 2 years and that accelerated greatly since. And we both are dealing with pretty severe ME/CFS and other issues that seem to go along with it all. But we feel we are finding significant connections and our own experiments that are helping us both to feel we are climbing our way out of this pit. We are finding some much desired “Purple Bandaids”? We will try to show what we feel is happening and what we try to do to tweak that. Its a work in progress, and we are neither well. But any improvement is worth talking about. We hope we can offer HOPE to others. And we also hope other researchers and scientist will look deeper into what we have found and carry on with research and finding us all better bandaids. We may not can “fix” it, but we sure can cover over the boo-boo and give us better quality of life. And isn’t that what its all about…… quality of life.
There are genes that can be looked into that are connected to ME/CFS and other connected things. See the article that I posted by Debbie Moon of Genetic Lifehacks, recently.
Genetics is probably the wave of the future for medicine. Since we are all individual, that may be the best way to address our issues. Finding WHYs with science and then finding ways to address that. And pathways are definitely needed to look into for these dysfunctions.
There are ways to determine if one is predisposed to certain illness with genetics. For example Ehlers Danlos. There are so many different types of it. And only one type (and more common type) that can’t be tested with genetics……Yet!
Its a deep study. But there are and have been certain genes that we may have that epigenetics has triggered to either turn on or turn off. There may be ways to affect their functions even if that is the case. But note, that just because someone has the genes that predispose you to a certain “illness/dysfunction ” doesn’t mean you will for sure get it. It means you inherited that predisposition from your parents. You could get one from each side that makes it more likely. But there may need to be a trigger to cause its dysfunction. And there are also assistor genes that may cause the pathways to work properly, even if this particular gene predisposed you to dysfunction. So its not a given, that you have or will have issues, even if wonky genes. But it can give you clues, if your “symptoms” fit.
@ Issie,
I guess it was my fault for not explaining why I thought the second link was so interesting–and just expecting others to make the connection.
Pardon me for digressing and this is more for others than for you;
IBS (and probably MCAS is similar) often begins with a gastrointestinal infection. What this study has shown is that mast cells remember the original infection linked with the offending food. When that food is eaten again in those with IBS, even if there is no offending virus or bacteria, the mast cells don’t recognize this. They continue to react degranulating all their chemical ‘armaments’ each time the original food is consumed–hence all those horrible symptoms.
Not only that, but this researcher has determined that the area of the intestine where the offender was first encountered by the mast cells, in IBS, will be the area that reacts.
I used to think that IBS affected the entire gut, but evidently this is not necessarily so. It could be a small area or the entire intestine.
Mast cell triggers implicated in IBS are not only histamines, but there are other chemical switches. Therefore, if researchers can find the ‘switch’ which is broken in IBS, then it might not be necessary to continually take anti-histamines or avoid certain foods.
So, a lot of purple bandaid potential here!
Now regarding the group discussions, I can read them but I am not able to log on. I’ve asked Cort about this, but so far no help… Sorry Cort, I don’t even know how you manage to turn out all these well researched blogs–never mind dealing with my little issue. The status quo is fine with me. Anyway, I need to spend less time in front of the computer and more time attempting to do housework…
Give this guy more money!
This all makes me so hopeful- thank you Cort!
I loved Phillip Comella’s story and I loved this study. Is uplifting to have innovative investigators doing great things to shine a light on this misunderstood illness. Sometimes research resonates and this did for me. I have long recognized that my body doesn’t seem to “see” viruses. I really struggle to get rid of them. Every time I get one I go backwards and inflammation flares up for weeks or months. Ps. I hope that Phillip has since found a better doctor, a non-psycho boss and a nicer girlfriend!
Yes. I also never seem to adequately fight any infection I go back and forth for weeks feeling better and worse and then return to my long standing chronic state is swollen glands in back of neck; inflammation and cfs. This is story for over 40 yrs since viral infection in high school. Also have type 1 diabetes and mcas. Tough life but I keep fighting to get to root causes
No studies have been done yet, but in several countries there is evidence that in some people with long COVID, symptoms are drastically reduced with the vaccine. We will see if this is long lasting.
https://www.redaccionmedica.com/secciones/sanidad-hoy/covid-persistente-vacuna-reduce-sintomas-9112
So how do POTS and autonomic dysfuction and autoimmunity fits in these immune findings? Also Nancy B mentioned it.
Just wondering how much of a connection there is to CFS/ME and allergies for those of you who write in. Where I live, the springtime is lush and beautiful right now but filled with so much pollen that people who move here are often seen rubbing their eyes and heard saying, “but I never had allergies before.” When I was a school counselor, I recall reading an article about how allergies affected children in a way that mimicked ADHD and ADD, which was likely due to the exhaustion, brain fog and discomfort, not to mention the effects of their allergy medications. Now that we are in the thick of pollen season where I live, my CFS has gone into overdrive. It’s an effort to breathe, yet it’s not asthma. I know some of you have been diagnosed with MCAS, and I wonder, how many of you have been allergy sufferers?
Until I addressed severe MCAS, my POTS didn’t get better. I no longer use antihistamines. But reset my receptors and find using things such as a combo bee product and also things that somewhat trick my body to think histamine has been released, to turn on the H2 receptors. (Nettle tea is good for this.) Also diet is extremely important. Timing is important for when you use supplements too. And less is more. Dejurgen and I open capsules. We have tiny microspoons and we carefully measure tiny amounts, and that is enough.
I have had the same problem. We live in Florida with beautiful live oaks behind our house. The oak pollen season has been early and awful and I have felt worse since it started.
Unfortunately, as soon as our spring is over, we will go right into the hot, humid mold season and that will last well into mid-October when the ragweed starts to bloom.
These are the kinds of questions I will like to see answered in a patient survey.
Hi LAC, I’ve had various issues with breathing – how does yours manifest itself, what happens?
Hi, Tracey Anne, My breathing symptom basically feels like my lungs are made of lead, but not every day unless I’m in the thick of a CFS reaction such as to a vaccine (or during pollen season). My breaths are short just getting out of bed in the morning, yet doing exercise can sometimes make that symptom vanish while I’m doing the exercise. In this last week during the heavy-pollen North Florida springtime, it just feels like it takes more energy to breathe. Oxygen levels, though, are very good, and unlike asthma symptoms I had years ago when working in a “sick” building, my lungs/bronchial tubes do not feel congested at all. This is not an issue while sleeping, though many years ago when I was more prone to viruses, I used to get a strange breathing symptom that was a lot like apnea. Essentially, breathing became a voluntary rather than involuntary function, and the instant I dozed off to sleep my breathing would stop until I woke seconds later to voluntarily breathe. I only mention this years later because I assume there’s some connection between virus, allergens and lung function, or at least energy levels affecting breathing. Like many who write in to this site, we seem to have “quirks” in our systems that medical tests don’t address. Are these similar to your own issues?
That’s very interesting, LAC. I have two main issues with breathing – more recently (6/7 years or so) I developed asthma – no wheezing, my lower airways clamp shut particularly in response to mould, hot humid or cold damp weather etc.
A second breathing symptom I’ve had since 2007 is in reaction to fructose, especially corn/maize. Say, if I ate some tortilla chips about 20 mins later I would almost keel over, becoming very slow, vague, apathetic, depressed and seemingly similar to you I would definitely have to consciously breath in and out, in and out – repeatedly. One night I suddenly woke up, sat upright in bed and took the biggest, longest breath I’ve ever taken. I believe I had stopped breathing for long enough, that my sympathetic nervous system kicked in and woke me up.
I had mentioned this to doctors over the years but they don’t understand. In fairness to them, when it occurred, I would just go and lie down (and lie motionless for hours – not asleep, like I was heavily sedated) and not go and see a doctor because it was usually no help, a waste of time, energy and money and demoralising.
I’ve often wondered about a connection with the brain/brain stem. In Cort’s previous blog about Long Covid and ME/CFS he writes the brainstem ‘regulates very basic functions – like breathing, heart rate, blood pressure, digestion, alertness, sleep/wake – a lot of which has gone wrong in chronic fatigue syndrome (ME/CFS).’ For me, I don’t think this second issue is specifically lung induced, I think the fault lies back up the line to the messaging systems.
(I think you mentioned you were a school counselor – so was I, for a couple of years, one morning a week, as a placement when I trained)
Thank you Cort, I found this study fascinating and really does seem to make a lot of sense, especially the connection to Long Covid and to Chronic Lyme Disease.
I have felt for a while that it is highly likely that all the research into Long Covid is highly likely to yield results for us, at least the group who got ill after an initial virus but hopefully for all ME/CFS patients whose bodies have had some sort of insult that progressed into ME/CFS. I really hope that follow up studies confirm some of the findings and then relate these to TREATMENTS for that is what is really needed.
The other week on one of the BBC programmes which I think was Horizon on what have been learned about Covid a doctor/researcher said how they were studying the effects etc of Long Covid and how when they found treatments the worked, these could be offered to ME patients who he thought had been abysmally let down by the NHS. It was the most encouraging thing I had heard here in the UK for the 21 years I have had the illness.
Pam
That’s great news – thanks for passing that on. I think long COVID is such a big thing – and ME/CFS is so emmeshed in it by now – that the NHS will listen when good treatments are found.
Finally ME/CFS is getting into the flow of things…
Hi Cort, Thank you for all your effort. I think an interview with a small research group that is starting the 2nd phase testing on a large scale in Belgium, might be interesting. let me know if you like to talk to them. It is promising and has given me hope when I was done with this life. they were the first to talk about long post-Covid danger.
Cort, i have heard some say that the covid money is already “earmarked” for certain centers (and limited researchers). And that researchers who were hopeful to put in for $$ would not succeed, as they said no immediate money available—despite all the hype.
Cort, do you have any info on the grant process for the funding for covid? That might help those researcher groups who are (were) hopeful for funding for covid research?
Lastly, if there is less variety in the ‘clones’ being pumped out, could this mean that the cfs/me body is doing this on purpose, and targetting a specific thing (pathogen?) so that is why clones are less diverse???
“Lastly, if there is less variety in the ‘clones’ being pumped out, could this mean that the cfs/me body is doing this on purpose, and targetting a specific thing (pathogen?) so that is why clones are less diverse???”
I would suspect that that might be part of a more “dual” immune system functioning.
With that, I mean an immune system that is most of the time asleep on the job and from time to time awakes with a vengance in bursts (that is, the trained / antibody immune system). Then, during this asleep phase few new variants / clones would be created. When (this trained part of) the immune system awakes with a vengance, the few pre-existing or the first few variants / clones produced might be replicated very rapidely due to the immune system being really turned up strong, triggering a very strong multiplication of “what is”.
Issie and I have seen a sort of “immune system duality” several times before. One of them is her having been diagnosed with very poor ability to form immunoglobines yet at the same time have tettanus antibodies long in her blood long after how long the effects of a vaccination are expected to last.
That duality could also interfere with how strong our bodies react against some vaccinations.
Cort;
THIS IS AWESOME!
Fascinating, and so exciting! If I had the energy right now, I’d jump up & down in jubilation! Verification of higher viral load, identifying possible mastery regulatory genes that could be tweaked (This is AMAZING to hear!), and the fact that the difference of the blood samples between the Controls & the Diseased became recognizable (Do we see a Blood Test that could diagnose ME/CFS here?) are certainly factors from this study worth celebrating & pursuing!!! I realize that Ron Davis has centered in on a gene expression that could identify patients w/ ME/CFS, but the cost & ease of conducting such a test in the Medical Office has not been established. The more people trying to find a way- the better!
Love reading this blog! Thanks for your tireless( no pun intended!) devotion to keeping us informed on cutting edge research. Always gives me a ray of Hope. Truly a blessing!
Linda
Amazing work as always, Cort! Thank you! The study is fascinating in the ties it makes… one thing, it is too bad that they didn’t also consider Chronic Inflammatory Response Syndrome (CIRS) in the mix.
Over the years, I came to the conclusion myself that my immune system had become highly reactive – at times dangerously so. More recently I came to picture my trigger happy immune system, as a deranged military dictator. I called them General Immune.
For me, that experience of my hyper reactive immune system fits with the idea that ‘key driver or master regulatory genes which appeared to be driving the immune dysfunction in ME/CFS were also identified.’
I haven’t actually been diagnosed with anything, apart from asthma. I’m also doing much better following and implementing my own intuition and research. However I believe General Immune is still alive, hasn’t retired or been fired, so I think it would be interesting to see if abnormalities could still be found in me, sometime in the future?
Super piece Cort.
Thanks Deborah! Appreciate it. Hope you and Llewelyn are doing well.
I had Lyme disease years ago, born on a farm and worked in the woods for 30 years. Now 74 I had COVID last year and am a long hauler, fatigue, brain fog etc. After my second vaccination these symptoms came back with a vengeance. I started taking Teasel root extract for the Lyme and had impressive positive results. I believe these two conditions are linked!
I agree! Three post-infectious diseases: ME/CFS, Lyme Disease and long COVID.
Good luck!