The Roadmap initiative is about charting a new path for ME/CFS at the NIH.
The Metabolism webinar is part of the ME/CFS Research Roadmap effort. The effort was put together by Dr. Koroshetz and Vicky Whittemore as a way to advance chronic fatigue syndrome (ME/CFS) research at the NIH. The Roadmap effort was conceived pre-COVID, then was derailed for several years by the COVID-19 pandemic, and took life again about a year ago. Because this is an NIH-created and produced effort it has a unique cachet at the NIH and it’s hoped that it will, as other Roadmaps have done in the past, boost interest in and funding for ME/CFS.
It’s a big effort. The Metabolism webinar is just one of 8 webinars that will go to form a report to the NINDS leadership and NIH for setting research priorities for chronic fatigue syndrome research.
Because these Roadmap lectures are designed to flesh out the way forward, they will all at some point focus on not what’s happening but what they believe should be happening, and why the researchers believe the NIH should invest more in ME/CFS.
The Metabolism Webinar
Dr. Shuzhao Li Ph.D. – associate professor investigator at the Jackson Laboratory. Dr. Li is a leading expert in the field of metabolomics for precision medicine, i
mmunometabolomics, and multi-omics modeling of the immune system.
After Chris Wikman told his ME/CFS story, Dr. Shuzhao Li led off with a fascinating and helpful talk on metabolomics. In the last ME/CFS NIH conference, the metabolomic speaker talked very little about ME/CFS but a lot about how far the metabolomics needed to go. He actually seemed apologetic about the state of the field.
Five years later, Li was excited – not apologetic. Li talked about the major steps forward the metabolomic and immunology fields have taken recently. Highlighting the inconsistencies in the immune results we’ve seen in ME/CFS for decades, Li encouragingly said there is an answer for that and that it’s not surprising – given the relative newness of the field – that we’re getting inconsistent results. Making sense of it – if I got it right – requires bigger studies that look at more factors. Once that happens, things start making sense.
He talked about a vaccination study done outside of ME/CFS which looked at virtually everything (cytokines, metabolites, cells, genes) over various time points. Once they did that, they could start to see how the different factors interacted. A gene network, for instance, was linked to a metabolite network. They could even see how a change on day 3 in metabolites showed up in changes to an immune gene network several days later, and they made special note of the gut microbiome’s effect on the immune system.
One of his post-docs (Minghao) ended up dedicating most of two years to working on the massive ME/CFS dataset that Derya Unutmaz and his group at the NIH-funded Jackson lab had produced.
The study had 78 patients who’d had ME/CFS for over 10 years (n=78), 75 patients for less than 4 years, and 96 healthy controls – in other words, it was a nice, big, meaty NIH study – the kind we want more of.
Duration Matters
The first takeaway was that the cell populations – the immune cells found in each cohort – were different – and the people with longer-duration ME/CFS had the most unusual sets of immune cells. The same pattern prevailed with the metabolomics assays – the longer-duration ME/CFS patients had more unusual lipid findings than the shorter-duration ME/CFS patients and the healthy controls.
Not surprisingly, duration mattered – the longer the patients had been ill, the more lipid abnormalities and toxins they found.
Lipids showed up big time. That was a nice finding – as several of Hanson’s and Lipkin’s NIH-funded studies have also emphasized abnormalities in the lipids or fats that surround our cells. Even better, the Li study appears to have plucked out many of the same fats – the carnitines, ceramides, cholesterols, and sphingolipids that the other studies found. Since everything that happens in a cell is triggered by a receptor on the surface of the cell, lipid problems could cause a lot of mischief.
The really surprising finding for Li, though, was the high number of xenobiotics; i.e. toxins found in the ME/CFS patients – particularly the longer-term patients.
When they assessed the patients a year later, they found just what we would want them to find – consistent results. With this study, then, we appear to have consistency not just between the patients in this study (all from the Bateman Horne Center) but consistency between the different cohorts and different laboratories in the Hanson and Lipkin studies.
Li then used three different methods – multi-omics factorial analysis or latent factorial analysis, multiscale modeling, and tests to assess the impacts metabolites and individual immune cells have on each other.
The multi-omics factorial analysis again showed that the data from the two visits were consistent with each other and they found a quite changed ecosystem in the ME/CFS patients. Some lipids (lysophospholipids) in the ME/CFS patients, for instance, were associated with dramatic changes in their CD4 T-cells but didn’t have an impact on the healthy controls.
The bottom line – the immune, metabolomic, and clinical data were all correlated, and that was good news. The goal is to be able to form a story, and it’s data like that that can form a story. The other interesting news is that that the immune-metabolite connection involved a lot of metabolites derived from the gut – suggesting, as other studies have, that the gut may play a major role.
Li didn’t say much about where the high levels of toxins (xenobiotics) came from or the role they may play. He called them the “exposome” which refers to the “environmental exposures that an individual encounters throughout life”.
Room For Improvement
In a surprise finding, more xenobiotics or toxins were found in the ME/CFS patients.
While the study provided some intriguing findings – we’ll learn more about them in the paper – it’s also clear that the metabolomics field still has a ways to go to achieve its potential. The 1,000 metabolites they sampled, for instance, only captured a part of the potential metabolome data. Given how important metabolomics has been to ME/CFS, further advances in the field will only bring more insights. Li also stated that the “systems immunology field” which assesses how the immune system interacts with other systems needs more work.
We’ll know much more about this very complex study when the paper or papers come out. It presented some nice validation of other study findings – indicating that our researchers are on the right track – but not enough clarity regarding what’s causing what. We’re not at the point yet where researchers can point to a critical pathway or metabolite and state this should be treated in a clinical trial.
The Future of Personalized Treatment?
While the metabolomics field is not yet mature, Derya Unutmaz of Jackson Labs made it clear that when it came to treatments, he thought it was the future. He believes these metabolomics analyses will lend themselves to personalized treatments. Note that a study found that some metabolite changes came first and resulted in immune dysfunction. If primary metabolite alterations can be identified, then they should be assessed in a blood test. If the blood test is positive, then ways could be found to alter the metabolite levels through diet or drugs.
Unutmaz thought the metabolite-immune connection was particularly fruitful given the high numbers of metabolites found in ME/CFS that were associated with the gut microbiome – which lends itself to manipulation. That was interesting given that, if memory serves, the LIINC group’s findings focused on a gut coronavirus reservoir. Could the same be true with ME/CFS and Epstein-Barr, or another virus?
Jessica Maya Ph.D. – Cornell University – Maureen Hanson’s Lab – Immunometabolism
Metabolism plays a key role in our immune response. To activate and help fight off an invader, our immune cells must rev up their engines dramatically. When they’re not activated, they rely on aerobic energy production to keep their engines purring, but when activated, they switch and rely on glycolysis (anaerobic energy production) to get moving.
As with the immune studies, the metabolic studies (which often assess immune cells) have been inconsistent as well. Why? Again we saw a reason that we’ve been hearing about for decades – small sample sizes – but a different one showed up this time – throwing all the immune cells found in the blood together and then assessing them as a whole..
Instead of throwing all the peripheral blood monocular cells (PBMCs – monocytes, NK cells, T cells, B cells, dendritic cells) together in one batch (as is usually done) and analyzing them as a whole, Maya separated out the 2 kinds of T cells and NK cells and analyzed them that way.
Jessica Maya found exhausted T-cells. T-cell exhaustion has been found in both ME/CFS and long COVID.
She found that the T cells were stuck in a hypometabolic state – they couldn’t rev up their engines enough to get going – and were in a state of exhaustion: i.e.; they weren’t able to proliferate properly, they had trouble killing infected cells, and they died off more quickly than normal. That’s not a good finding for one of the key virus-fighting immune cells in the body, but it makes sense with what we know about ME/CFS.
Liisa Selin’s recent paper on T cells in both ME/CFS and long COVID stated that both disorders appear to be characterized by dysfunctional CD8 T-cells with severe deficiencies in their abilities to produce IFNγ and TNFα.
Maya reported that other studies suggest that other immune cells (neutrophils, monocytes) may also be exhausted. and she reported a possible reason – the altered fatty acid/lipid profiles that Li found in the first presentation. Since fatty acids are important for energy production, the altered lipid profiles found in past studies could help explain why.
In the end, she brought us back to the promise of the single-cell analyses and outlined the many, many different analyses, as well as other techniques, that could help understand the metabolism of immune cells in ME/CFS.
Dr. Jiabao Xu, PhD – Collaborator with Karl Morten – A Biomarker in the Making? Raman Spectroscopy
Jiabao Xu’s focus is on using Raman spectroscopy to deciper ME/CFS, long COVID and chronic Lyme diseases, as well as inflammatory autoimmune diseases.
The Raman spectroscopy findings suggesting that a biomarker might be in sight made big waves in the ME/CFS world and it was good to see Jiabao Xu talk about them and what’s needed to move forward.
Once again, we were back to… single cell tests. No more throwing a bunch of immune cells into a pot (or test tube) – and hoping that something pops out. The focus now is on testing each immune cell by itself.
Raman spectroscopy demonstrates the remarkable steps that have been made in the medical field. Xu started off by saying, “as we all know every molecule in our body is constantly vibrating”. That was news to me, but it turns out that Raman spectroscopy measures the “vibrations” in a sample by bouncing light off it and assessing the wavelengths found. By doing that, it can tell what kind of molecule is present. (So simple! (lol).)
Raman spectroscopy is special because it doesn’t disturb the cells; is very sensitive; and because it can handle water, it can assess cells in their natural environments. It can also assess cells at the “subcellular” level. When used with machine learning (artificial intelligence), it does very well at diagnosing diseases.
Raman spectroscopy was first used in ME/CFS on a small scale: it assessed the PBMCs in just 12 patients and 12 controls but was successful. The next study was larger (n=89) and included multiple sclerosis (MS) patients. This time, it used both PBMCs and single-cell testing and was able to differentiate ME/CFS from MS and healthy controls (90% accuracy) and mild, moderate, and severe ME/CFS patients from each other (84% accuracy) – something that has rarely, if ever, been done in a diagnostic study. Accuracy, sensitivity (91%), and specificity (93%) were all particularly high for the ME/CFS group. And there you have it – a potential biomarker for ME/CFS that could be done with a couple of droplets of blood and can be used with frozen blood as well.
That was best accomplished by using single-cell assessments. When they turned the Raman spectroscopy onto a metabolic analysis which suggested that tryptophan metabolism, in particular, was dysregulated in ME/CFS – possibly resulting in inflammation, the production of neurotoxic compounds, and lower serotonin levels in the brain.
THE GIST
- The ME/CFS Research Roadmap effort was put together by Dr. Koroshetz and Vicky Whittemore as a way to advance chronic fatigue syndrome (ME/CFS) research at the NIH. The Metabolism webinar is just one of 8 webinars that will go to form a report to the NINDS leadership and NIH for setting research priorities for MECFS, and hopefully increase funding.
- Dr. Shuzhao Li Ph.D. of the Jackson Labs talked of a large NIH-funded project which – as other studies have – found evidence of problems with the lipids that surround our cells, plus – in a surprise – he found higher than normal levels of xenobiotics, or toxins. The lipid issue could affect everything from cell viability to energy production to very basic cellular operations. The longer a person had had ME/CFS, the more lipid abnormalities and toxins they had.
- While this study did not identify a specific cause, Derya Unutmaz of Jackson Labs metabolomics analyses will lend themselves to personalized treatments, first via a blood test, and then via diet/drugs to alter the metabolite levels. He noted that many of the altered metabolites in this study came from the gut.
- Jessica Maya of Maureen Hanson’s Cornell lab found that ME/CFS patients’ T cells were stuck in a hypometabolic state – they couldn’t rev up their engines enough to get going – and were in a state of exhaustion: i.e.; they weren’t able to proliferate properly, they had trouble killing infected cells, and they died off more quickly than normal.
- Maya reported that other studies suggest that other immune cells (neutrophils, monocytes) may also be exhausted, and that the altered fatty acid/lipid profiles that Li found in the first presentation could be the reason.
- Wenzhong Xiao, the co-director of the Open Medicine Foundation’s Ronald G. Tompkins Harvard ME/CFS Collaboration, asked why the metabolomic results have not been as consistent as we want and why we do not yet have a metabolic signature. Aside from the routine answers – small sample sizes, non-standardized sampling, etc. – he suggested that we have to look deeper – at the tissues.
- He reported that the muscles of intensive care unit patients still sometimes cannot produce energy even 2 years after they’ve left the ICU. Modeling results suggested – surprise, surprise – that oxaloacetate, a supplement now being explored in ME/CFS, would help.
- Now they’re employing a similar approach at the Open Medicine Foundation-funded Harvard Collaborative ME/CFS Center. With their muscle biopsy studies, they hope to find similar ways to get ME/CFS patients’ muscles going again.
Morten’s group plans next to continue to focus on single-cell assessments and include long COVID and chronic Lyme syndrome in their next efforts to validate their approach. (She noted how often he heard ME/CFS being discussed in a recent Lyme conference – a good sign – and how after a chronic Lyme patient was cured, they got the same old Lyme symptoms after coming down with the coronavirus.) They also want to look more deeply at the metabolism, and metabolic and energetic pathways of the immune cells involved in ME/CFS.
Wengzhong Xiao – Down to the Tissues. Do the Muscles Have it?
Wenzhong Xiao wears many hats, including the co-director of the Open Medicine Foundation’s Ronald G. Tompkins Harvard ME/CFS Collaboration, Director of the Immuno-Metabolic Computational Center at Mass General, leader of the Computational Genomics Group – Stanford Genome Center; Director of the Open Medicine Foundation-Supported Computational Research Center for Complex Diseases.
Xiao started with the 2016 Naviaux metabolomics paper that really got things going concerning metabolomics in ME/CFS. The paper proposed that ME/CFS patients were in a state of hypometabolism; i.e. they were unable to generate normal amounts of energy at the molecular level.
Noting that the results have not been as consistent as we want, and that we do not yet have a metabolic signature, he addressed some reasons why. Different platforms (NMR vs mass spec) assess different metabolites. Metabolomics is also very sensitive to things like diet, activity levels, drugs, sleep status, the quality of the assays used, etc.
He recommended that ME/CFS researchers use the same standard operating procedures when it comes to sample collection, sample processing, assays, and patient and healthy controls selection. (We’ve seen these types of recommendations again and again, and it’s this kind of standardization that makes the RECOVER studies into long COVID potentially so valuable.)
Next Xiao asked how testing for metabolites in the plasma could tell us what’s causing ME/CFS. He noted that when Naviaux compared the metabolites in the cerebral spinal fluid with those in the plasma, he found few correlates; i.e. the metabolite analysis of the blood didn’t tell him much about what’s happening in the brain. For instance, nothing was found in the blood that could inform us about the status of dopamine in the cerebral spinal fluid.
The takeaway – one that we’re increasingly seeing in ME/CFS and long COVID – is to examine the tissues, and that’s what David Systrom and Xiao are doing with their muscle biopsy study.
The goal is to find the “bottlenecks” that are shutting down or impairing the metabolic pathways. When they did this using muscle biopsies in ICU patients, they found that even 2 years after being in the ICU, their muscles were still unable to generate much ATP.
When they employed modeling to find a way to get their muscles working again, what did they come up with but oxaloacetate (!). This was years before oxaloacetate showed up on the scene in ME/CFS. (Dr. David Kaufman chanced on it, as I remember, after looking at metabolomic studies in ME/CFS.)
Now that they’re employing a similar approach at the Open Medicine Foundation-funded Harvard Collaborative ME/CFS Center. With their muscle biopsy studies, they hope to find similar ways to get ME/CFS patients’ muscles going again. Speaking of muscle studies – we are suddenly awash in ME/CFS muscle studies!
The Open Medicine Foundation is leading the way with two muscle studies – one of which is employing a 2-day exercise test. Plus, Paul Hwang and Avindra Nath at the NIH are continuing to extend the muscle cell findings that sparked Hwang’s exciting WASF3 paper, and Rob Wust and his Solve M.E. Ramsay award will be examining ME/CFS muscles after exercise as well. Plus, we’ve recently had some muscle findings that Klaus Wirth believes tell us something fundamental about this disease.
The muscles are finally starting to get their due.
Conclusion
While we still lack a specific target – a metabolite or group of metabolites that researchers agree are the cause or a cause of ME/CFS – it was heartening to see the lipids pop up once again and to see the metabolomic, lab, and clinical results jive. It was also good to see a gut emphasis as the gut is one of the more easily manipulated organs. On that note, Derya Unutmaz held out metabolites as the future of personalized treatments. We’re certainly not there yet, but innovative doctors will take results like these and test them out – as David Kaufman is doing with oxaloacetate – and a blog on lipid replacement therapy is coming up.
The increased levels of xenobiotics (toxins) were new, and one wonders what they signify. The T-cell exhaustion finding, on the other hand, helps to validate past findings and may be a prelude to future findings … could all the immune cells in ME/CFS be exhausted? Finally, the increased emphasis on digging deep into the muscles is nothing but encouraging, and one hopes that Wengzhong can duplicate his ICU findings and find a way to get ME/CFS patients’ muscles moving again.
Lots of interesting info there that my brain will have to come back to!
As always, thanks for pulling out the best info from these events, Cort.
On another topic, I’ve been wondering if there’s any news on when Avi Nath’s monster NIH paper will get published? I think he was hoping it would be 2023.
I was thinking 2023 too! This seems to be par for the course – things take longer than expected. There should be one major paper and a bunch of smaller ones.
Nothing to add, Cort, but just once again thank you . Thank you for always bringing us the latest in research. Where would we all find out anything that is going on except what you so brilliantly report on .
Thank you, Cort. Thank you.
A little birdie told me the main/big Nath study is coming out tomorrow. So buckle up!
Ha! What a nice tweet! May it be so 🙂
I have it on very good authority. The study is 100% coming out tomorrow in Nature Communications and the press embargo is being lifted tomorrow morning so we should see the first news articles about the study being published tomorrow morning along with the study itself. You should be able to find the study here starting tomorrow morning EST:
https://www.nature.com/ncomms/articles
https://www.nature.com/articles/s41467-024-45107-3?utm_source=miragenews&utm_medium=miragenews&utm_campaign=news
https://www.eurekalert.org/news-releases/1034817
Brian Vastag comment: https://sciencemastodon.com/@brianvastag/111942702404360244
Study is out. Along with what looks like the first two of what will probably be dozens or even hundreds of articles…
NYT: https://archive.is/8Kh63
STAT: https://www.statnews.com/2024/02/21/nih-study-myalgic-encephalomyelitis-chronic-fatigue-syndrome-news/
Study in Nature Communication: https://www.nature.com/articles/s41467-024-45107-3
https://www.nature.com/articles/s41467-024-45107-3
https://www.nytimes.com/2024/02/21/health/chronic-fatigue-syndrome-long-covid.html
Thx Adam
I am not at all impressed with this study. Moreover, it is a strictly selected group of patients. Not representative for most of us.
Very disappointing study. No POTS for example. And 4 patients were cured spontaneously. Very strange. In conclusion it is suggested that deconditioning is an important factor.
This study does confirm previously found abnormalities. And reports that it is somatic. That’s positive.
@Gijs – Completely agree. After 7 years and $8 million you would hope they would have found more, included a much larger and more diverse severity cohort than 17 (of which 23% fully recovered afterwards!!!), screened for/discussed overlapping conditions like mast cell, etc. etc.
But overall I do think it is a step in the right direction. I hope the NIH’s Research Roadmap initiative that Cort is writing about above can help pave the way towards hundred of millions and soon billions of dollars in much needed (and long overdue) research funding from the NIH for ME/CFS and related conditions.
No way! 😮waiting with baited breath!
Thank you for summarizing the talks, Cort. I listened to them but had a hard time understanding most of it. It is exciting that the researchers are finding anomalies and potential targets, but it seems like it will be many more years before we have actual treatments available. Thanks again for all that you do for our community.
They were very hard to understand and I did not understand much of them. At least with the metabolomic studies I’m coming to the conclusion that it will be a while before they point to “x” factor that is causing ME/CFS or long COVID. There always seems to be a long list of other studies that need to be done to nail that down.
We are in an exciting period with long COVID so I could be wrong on that. On the other hand, I think they will provide plenty of “meat” for doctors and patients who see something and want to experiment. In that I am quite hopeful and I think this is the way that science generally goes. It takes longer to explain or truly understand the disease than to find way to treat it.
The Li study pointed to lipids – again! That was very encouraging to me, yet Li said he could not speak to cause… Researchers are very precise – all they know is that the lipid abnormalities are showing up – whether they are the cause or a secondary factor or whatever they can’t tell. Doctors on the other hand are exploring lipid replacement therapy and a blog is coming up on that.
Long COVID has already opened up a lot of possibilities (nicotine patch, methylene blue, guanfacine, monoclonal antibodies, antiviral combinations) and I expect it will open up many more. While it’s not happening in ME/CFS yet, long COVID trials are, for instance, starting to look at some pretty heavy duty immune drugs.
About those two kinds of T-cells being found to be exhausted, I wonder if that ties in with low-dose naltrexate therapy, which (as I understand it) gets rid of the malfunctioning T-cells so that they can regenerate in a more healthy form? Any persapectives on this, Cort?
I haven’t heard that but if clearing out malfunctioning cells (apoptosis or other means) is an important. Our bodies need to take out the trash. Those toxins that one study found – I wonder if it’s due to poor trash collection (?). Intuitively it makes sense to me that too many toxins would result in a brain-fogged state.
And exposure to toxic mold also seems to be prevalent in the ME population — this inability to “take out the trash” like in mold exposure makes sense (to a layperson like me anyway!)
The intracranial hypertension finding really stuck with me. I had a picture of all this gunky fluid getting stuck up in our brains (lol)
That too!
My blood work showed low red blood cells and high acidic. Doctor had no good explanation. I have fibromyalgia, IBS, Migraines, narcolepsy, etc. I have been researching and trying to find help. Tried low dose naltrexone and gave me the worst joint pain. Sensitive to medication. I’m sure there won’t be no good treatment in my time and I’m 44.
Please don’t think that! I feel confident that that will happen 🙂
Oh, and I also have a probably somewhat dumb question. but I want to ask: what exactly is “a metabolite”? I understand “metabolism” (I think) but how is a metabolite different from other measurable elements that might be compared with and contrasted to a metabolite?
That is not a dumb question at all and I have really struggled with this. So far as I can tell a metabolite is something that shows up when molecules or compounds are broken down. Our bodies have to break down molecules and compounds into usable elements in order to survive.
Here’s what the AI CoPilot says metabolites do
Provide fuel for cells and organs.
Build and maintain structures like proteins, DNA, and membranes.
Signaling and regulating cellular processes like enzyme activity, hormone levels, and gene expression.
Defending against pathogens, toxins, and stress
Essentially everything! Which shows what a huge field metabolomics is. Metabolomic studies then can show where this metabolic breakdown process gets broken or stopped. Since each disease has or should have a distinct metabolomic signature they’ve been very helpful with biomarkers and diagnosis. We do not, however, have a metabolomic biomarker for ME/CFS.
I don’t know how they are differentiated from other elements except that we know they are byproducts of metabolism and can search for them (?)
Apparently we still don’t either know much about many metabolites or haven’t figured a way to analyze them.
I’m interested in hearing from those who have tried oxaloacetate. Any improvements in your baseline?
So this is really a chicken/egg question in my mind. Does the metabolite/metabolic abnormalities cause immune cells to be abnormal and fail their usual tasks or does a pathogen and/or active immune cells and/or the cell danger signals turn on some sort of metabolic abnormality? The CDR theory certainly postulates that cells go into “abnormal” metabolic states on purpose to get into a fight mode that’s supposed to end when the threat is removed. Changing ideas here, that it’s not say “smoldering” pathogens triggering ongoing abnormalities but some sort of metabolic abnormality from elsewhere that lead to an insufficient immune system is new for me. How then would the whole system have been triggered from a virus say? Say EBV and COVID somehow interrupt (not on purpose) cellular respiration is a whole other can of worms. I feel like lots of us have tried to address this by fixing the energy abnormalities but it never helps?
The mention of the problem with the breakdown of the cell wall lipids..if I remember correctly plasmologen was a major one? Has anyone tried to supplement that? It can be found via diet with mussels, scallops, krill and also to lesser degree pork, chicken and beef.
I take oxaloacetate. It seems to slightly increase my crashing threshold and I recover more quickly when I do crash. I used to take a higher dose but I lowered it since it’s so expensive.
When Dr. David Kaufman started selling oxalaocetate, I purchased it, but was perplexed when no change was observed. There was no response at all – no symptom change, no GI distress, no achiness, NOTHING.
I’m also interested in this, especially since it would cost about $1000/month to use it in the amount that the studies indicated made the most difference (1000mg, 3 times a day). Really hoping the price comes down soon.
i know someone verry severe where it did nothing sadly enough. maybe searching on the toolbar of 25% ME fb group. just a suggestion.
I’m interested too.
I haven’t tried oxaloacetate, but I have seen a marked improvement with NMN, another Nad+ precursor👍
A study recently came out showing that too much NAD may cause cardiovascular disease.https://www.webmd.com/heart-disease/news/20240220/excess-vitamin-b3-linked-increased-risk-of-heart-disease
I tried taking a low dose of oxaloacetate and it made me feel so ill, like the potential to seriously lower my baseline. No idea why. Stopped taking within a week and it took a couple more weeks to return to previous baseline.
The NIH intramural study will publish their findings in Nature Communications this Wednesday February 21st. Brian Vastag posted comments on Mastodon. He apparently read a draft. As per Dr Walitt, additional papers will follow.
do you maybe have a link to it? tomorrow? I am not from US and verry verry severelly ill. thanks!!!
Thanks as always Cort. But…. Not convinced by any of this research.
You are a real skeptic : )
I haven’t yet found the time to answer to you from our discussion from last week. But I have here an answer to an answer that Gijs raised back there, and I thought that you might be interested as well.
I hope I can come back to what you said soon.
Thanks for the link to this article, Gijs. I didn’t know it yet. It seems that these researchers are from Eastern Europe and Russia mainly. This is great because they are good in herpes research.
One of my professional health supporters with parents from that region made me aware that the Russians seem to have a treatment against HHV-2 and the debilitating herpes genitalis it causes. Since smoldering HHV-6b reactivation has just the same outer form with its “characteristic persistent remitting and relapsing nature of the ME/CFS syndrome in many individuals”
https://www.brunel.ac.uk/research/projects/reactivation-of-herpesviruses-in-chronic-fatigue-syndrome
this could be one path to the development of drugs.
Regarding your question: I have very little understanding of EBV I have to admit. So I can only talk about the HHV-6b hypothesis in ME/CFS.
To me, what Bhupesh Prusty theorises about these questions sounds the most interesting and most promising.
https://www.youtube.com/watch?v=0dI7uaTni5g
The main reason is that he has not only an interest in his molecules but he is extremely well infomerd also of the clinical presentation of ME/CFS. Especially, he understands that there is (in some patients) in the beginning a mild level of illness and that at that stage it is quite normal that people go back to being cured when they pace and rest for a couple of months.
Clinically, the mild level is described best here: https://www.youtube.com/watch?v=EUIdbbwcnAE
And very importantly the doctors from this institute even present a diagnostic procedure for the mild form.
I think that this is something extremely important to know because at that level patients do not fit the Canadian Consensus Criteria or other diagnostic apporaches when at the same time the ailments they present with already have that specific mark of ME/CFS.
I had this slow entry into the disease myself and when I got worse and my symptoms had progressed into a smoldering, “mild” form of frontal lobe brain inflammation which looked like this: https://www.tagesanzeiger.ch/andrea-salvisberg-hirnhautentzuendung-und-spitzensport-973838521004
and only then found out that I had ME/CFS I was extremely angry that no one could have told me that I needed to pace and rest. But I am losing track of your question…
Since for many patients the trigger isn’t a viral infection I wouldn’t focus too much on those for the onset of the disease. It seems that different paths lead into a mild or directly into a moderate form of ME/CFS.
Since I believe that smoldering (the full blown meningoencephalitis often ends with the death of the patients) HHV-6b reactivation and brain inflammation ( https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912523/ ) is the pathomechanism of ME/CFS and not only plays an important role I would theorize that many different events can bring a change to the immune system and has the effect that it is not capable anymore of controlling smoldering HHV-6b inflammation.
On the rest of the processes I have to read up first. For example it is known that HHV-6b is “lymphotropic”. I think that means that it likes to replicate in cells of the immune system… Just yesterday I posted an article that showed that HHV-6b reactivation is facilitated by a lack of T-cells.
Thanks again for your question! I think I want to focus on bringing forth more arguments that episodic, smoldering HHV-6b reactivation is the best scientifically substantiated explanation that is available right now and that we should have therefore the most money going into researching this question.
When my health allows I hope I can do more about that.
Last but not least: I have written about this before, but maybe you are not aware. The reason why I am 100% convinced of the smoldering HHV-6b reactivation hypothesis in ME/CFS is because when I realised I had possibly some form of herpes encephalitis I suspected that I might have Mollaret meningitis, a not lethal, self-ending form of HHV-1 brain inflammation. Thus I pressed my Ear Nose Throat doctor to prescribe me aciclovir on speck – and it worked and stopped the inflammation process immediately. After tapering off after two weeks I didn’t even have PEM anymore when I severly violated the energy limits that I had had for more than two months during the episode. Plus, I have talked to one doctor who prescribes herself aciclovir herself and goes on working and experiences just the same symptoms and drug effect that I had. (Aciclovir has good activity against HHV-6 in vivo)
I was pretty angry at first that my family doctor denied me aciclovir when I had the next episode about four months later after a period of experiencing more distress than normal. However, given that it is pretty toxic and I was able to learn to rest and pace well and haven’t provoked a relapse within 13 months now and are recovering slowly but gradually I am glad!
Thank you Cort! Your blog posts really help putting studies into their concepts. How different research projects relate to one another, and the way it has travelled to reach where it is. Your long experiece with this is outstanding and you, and what you are doing, matters!
Absolutely! Cort & Cort’s work — this is just an immense gift to all of us!
This sounds great. Especially the work of Maureen Hanson sounds interesting to me. As always I would like to suggest that everyone has a look beyond the first ideas of what could go wrong here in the immune system and includes the theory of HHV6B reactivation!
Here is a quote from a study from 2018 that looked at T-cell problems and HHV6 reactivation in the immunosuppresses (Aids and organ transplantation):
Basically the paper by leading HHV6 researchers into the typical meningoenchephalitis that it causes in the immunosuppressed say that the reason for these dangerous outbreaks of HHV6b is the lack of T-cells.
“The T-cell response is considered critical for control of HHV-6B infection since reactivation commonly occurs in cases of T-cell lymphopenia.”
https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2018.01454/full
Thanks for providing these reports, and I really appreciate “The Gist” for helping to get a general overview of the longer blog on days I just can’t get through it. I have one curiosity about the findings on the T cells – how do we relate that to the subset of us with ME/CFS who (almost) never seem to get colds, flu, and other typical bugs that go around?
In my case, I am hardly able to go out and I always mask up and have visitors do so. So, maybe we aren’t as exposed to communal contagions as most folks are?
The only “flu” I get is when I overexert and have PEM as a result . . .
I appreciate that thought, but thankfully, I’m able to get out a couple times a week as long as I’m not on my feet for any long periods. I come in contact with a variety of strangers and friends on my errands. I’ve never masked anywhere except when forced to by one store and the Drs office. (Masks increase my HR.) I’m also very bad when it comes to using hand sanitizer. Something in my immune system changed after I had the mononucleosis which started the whole ME/CFS thing. I’m certainly not bragging very grateful for what I do have left. I just wish I could make sense of it. But then, don’t we all? Lol
This must be the third or fourth time I’ve heard of a test for mecfs that works around 80% or 90% of the time, if these tests aren’t good enough to work as a biomarker alone I wonder if having the patients do some combination of 2 or more different types of these promising tests could get them near 100%
I don’t know if exhausted T Cells of this type are something any other disease has dealt with, maybe an infusion of healthy T Cells would work? Wonder if that’s possible and where they would come from
At the end of this article is a discussion about what can be done and what is in the research pipeline about the problem of exhausted T-cells.
https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2018.01454/full
And yes, HHV-6b meningoencephalitis in the immunosuppressed (organ transplantation, Aids) is understood to develop when there is a lack of T-cells.
Personalised medicine has been talked about since the start of this century or thereabouts. I haven’t actually seen any progress to deliver personalised medicine to the patient or to actually use. Seems like a idea that won’t ever get off the textbooks and into the real world.
Actually, patiens with chronic conditions have devoloped it themselves! It is called Wellness Recovery Action Plan and can be learned here:
https://copelandcenter.com/
It was first developed for people with chronic challenges to their mental health because in the field of psychiatry doctors can’t offer much that is effective.
However, I have used the Wellness Recovery Action Plan-approach to manage ME/CFS with great success because it can be adapted to every health challenge that one faces.
Sometimes answers to complex problems have simple answers. I am the director of Birth Defect Research for Children, a nonprofit organization that sponsors the National Birth Defect Registry. The registry was designed through collaboration with seven prominent scientists. The concept behind the registry is that the majority the causes of non-heritable birth defects have been identified by the “alert practitioner”; that is, a doctor or researcher started to see a clustering of certain birth defects and looking for similar exposures or conditions in the prenatal histories. In 1990, we began the National Birth Defect Registry which operates like the alert practitioner on a grand scale. Today, we have 119 pages of data on 6550 children who have both structural and functional birth defects (immune, neurological and endocrine problems). In each exposure category, we have an area where conditions that are not currently on the questionnaire can be added. This is where we started finding reports of 531 cases of ME/CFS recorded. 435 of these cases are in the children of veterans who served in Vietnam and/or the Gulf War. Studies have shown that these veterans carry a body burden of toxins like dioxin which can have an impact on the thyroid and developing immune system. Maybe we need to look further back into the histories of people with ME/CFS to see what their prenatal histories might include.
Are you publishing a paper on this? I think you should! Maybe get together with an epigenetics scientist for this. How prenatal environmental influences and stress influence children is a topic of epigenetics. Is it excluded that veterans’ doctors are better informed about the existence of birth defect registry than average doctors? (which would lead to an overrepresentation in data? Even in that case, it would not change the significance of association of gulf war history of parents with ME/CFS in their children though.)
What I mean is that though it could very well be veterans’ bodies still carry toxins at the time of conceiving a child, it might not only be about that but also that epigenetic changes caused in the parents’ cells by environmental factors even long before a baby is conceived can be passed on to children via the egg cells and sperm (like in the famous epigenetics experiment where mice conceived from the sperm of mice trained to fear cherry blossom fragrance were afraid of it too, even if raised in separation). As far as I know, transgenerational effects following exposure to environmental factors have by now been well established by epigenetic research. But I’m probably not telling you anything new here 🙂 Epigenetic changes (meaning kind of the up- and downregulation or on- and offswitching of DNA genes via various systems surrounding the DNA) need not be permanent.
Hi JR, It is wonderful to read that you are so knowledgeable in this area. Actually, the veterans’ cases only represent about a third of our total registry cases. Each category of exposures or birth defects has an ongoing control group. What is fascinating about the registry data is that different exposures often create different patterns of birth defects. Please visit http://www.birthdefects to read more about this.
One interesting way we can look at our data is by looking at the top 20 related conditions associated with a specific condition. This is what we have for the ME/CFS cases:
Top 20 Related Conditions
Joint Pain 330
Muscle Pain/Weakness 313
Frequent Headaches 311
Depression 294
Allergies 259
Mood Swings 246
Heat/Cold Sensitivity 218
Chronic Stomach Problems 218
Anxiety Disorder 214
Sleep Disorder 212
Anger 202
Frequent Upper Respiratory Infections 197
Frequent Ear Infections 183
Math 178
Memory Problems 173
Light Sensitivity 171
Menstrual Problems 169
Drug Reaction 166
Arthritis 153
Reflux 152
(02-21-2024 3:24 PM)
Hi Betty, you’ve got a really cool job if I may say so 🙂 About the epigenetics, I am no expert, just retained some interesting facts from a popular science book about the topic. Another one of them is that I think there are life phases where the organism is particularly vulnerable to epigenetic changes, like the prenatal phase and adolescence too, if I remember correctly.
I got interested in this also because I am part of a ME/CFS subgroup with no obvious infectious but gradual onset, where (though I carry EBV and there is familial predisposition for ME/CFS too) high chronic stress seems to be the most obvious onset (co?)-factor in my case; and stress is also a known epigenetic mediator.
I would not be surprised if there is an epigenetic component to onset of ME/CFS too, simply because such a disease onset model (genetic predisposition that gets “activated” via epigenetic changes) exists for many other diseases today (for example here are links discussing it for diabetes https://www.dzd-ev.de/en/press/press-releases/press-releases-archive/press-releases-2020/epigenetic-changes-precede-onset-of-diabetes/index.html and other autoimmune diseases https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-019-0632-2), or there’s long been a “vulnerability-stress”-model for onset of bipolar disorder.
I think you’ve got something very interesting here, namely a clearly defined non-infectious onset ME/CFS cohort, involving even control groups (though non-infectious onset might possibly not exclude viruses being involved in the background I think). You might reach out to epigenetics researchers already working on ME/CFS to ask their opinion on it and if there is any interest in publishing a case report paper making the ME/CFS findings of the birth defect registry known or working with that group of patients.
Anyway, I am posting here some links I’ve saved on ME/CFS epigenetic research:
https://www.meresearch.org.uk/resetting-me-cfs-with-epigenetics-part-1/ (by Cort) , https://www.meresearch.org.uk/resetting-me-cfs-with-epigenetics-part-2/ https://www.medrxiv.org/content/10.1101/2022.02.24.22270912v1.full.pdf
https://www.biorxiv.org/content/10.1101/2021.12.20.473375v1 ,
plus a few links on how viruses affect cells via epigenetic mechanisms: https://www.news-medical.net/news/20200825/Advances-in-Virus-Epigenetics.aspx
https://www.meresearch.org.uk/research/activated-hervs-and-immune-response/
(Prusty’s HHV6 paper is also an example of that, as microRNAs are an epigenetic mechanism: https://www.uni-wuerzburg.de/en/news-and-events/news/detail/news/herpesviruses-awaken/ )
Haha, and if one really wanted to dive into the data, one could probably look whether there are other diseases that practically never happen together with ME/CFS – the little we know about ME/CFS, we might then maybe at least learn what it is not 😀
Nath study out! Just had a first, skim read. Not sure what to make of it.
They conclude that post-infectious ME/CFS is centrally mediated (brain/CNS). But go on to speculate that this may be caused by immune system factors.
So…… I guess you could treat the brain-mediated things, or preferably treat the immune-related things that lead to the brain mediated fatigue….I think 🤔
82 years old. Contracted traumatic fibromyalgia & chronic fatigue syndrome post fireman’s carry in 1964 while performing a fireman’s carry to extract a soldier from an airplane crash with extreme JP4 fuel raging like an inferno. I weighed 125 and the man I picked up was large approximately 200-220 pounds and was savable. I was able to get him around my neck and carried him 150 feet. His weight shifted as I off-loaded him and what I simultaneously experienced took me down as well. Subsequently these multiple injuries required surgeries. I was never able to hold a full time job of any sort due to incredible debilitation weakness. Thus not sufficient quarters to qualify for SS disability. Treated for unknown etiology. Dx with both in 2005 by Rheumatologist within the VHA system. My life has been exceedingly challenging as a result. 3 weeks ago I was informed about the breakthrough as a consequence of the bewilderment as to what is Long Covid. I would believe that the professionals that are studying these maladies would appreciate my medical records as a very long term patient. I am 100% open. Reason. I care about all human beings. I very seriously hope that what I have lived with since 1964 can be avoided with breakthrough understandings.
Very interesting and informative . Thank you.
However, in my need to help myself as there are no other alternatives , do supplements actually help? If our multitude of damaged physical processes aren’t synthesizing properly, do supplements actually help? Can I actually stimulate dopamine and serotonin production with supplements?