The OMF’s Severe ME/CFS Big Data Study

Remember the Open Medicine Foundation’s Severe ME/CFS Big Data study? Initiated in 2015, it was one of three unusually large and expensive ME/CFS studies (Intramural Study NIH, CDC’s Multisite Study) begun in the 2010s.

The study, which contained 20 severely ill patients and 10 healthy controls, was predicated on the idea that the disease would shine most brightly on the severely ill. With over 1,000 tests per patient, including state-of-the-art genomics, gene expression, metabolomics, microbiome, cell-free DNA sequencing and quantitation, cytokines, and clinical tests, the Open Medicine Foundation reported in 2018 at the study end that it had produced the biggest data set ever generated in ME/CFS.

The hope was that it would illuminate the core features of ME/CFS but disappeared from view for awhile. Thus far, the study has produced just two papers – a 2021 one, “A Comprehensive Examination of Severely Ill ME/CFS Patients“, that singled out low cortisol and focused on symptoms, and a 2024 study “A Network Medicine Approach to Investigating ME/CFS Pathogenesis in Severely Ill Patients: A Pilot Study“, that illuminated some intriguing pathways.

As we’ll see, though, the short publication list to come out of the Severely Ill Big Data study thus far hardly reflects its potential impact: its story is far from over.

Talk with the Big Data Guy

Given it was a very “big data” study, it made sense to go to the big data guy who’s been making sense of it. Check out the Zoom interview and/or read the blog below, or do both!

Dr. Wengzhong Xiao is the director of the Immunometabolic computational center at the General Hospital at Harvard Medical School, and leads the Computational Genomics group at Stanford Genome Technology Center (note all the computational stuff).

More to our purposes, Dr. Xiao is also a member of the OMF Scientific Advisory Board, is the Co-Director of the OMF-funded Ronald G. Tompkins Harvard ME / CFS Collaboration at the Harvard-Affiliated Hospitals, and is a longtime collaborator of Ron Davis.

In an era of billowing amounts of molecular data from genomics, metabolomics, proteomics, and immunology, finding ways to computationally integrate these enormous data sets is one of the hot areas in medicine right now – and that’s what he does.

The data, you might say, stops with him.

 

Findings

When asked what findings the study produced, Ron Davis stated they “almost found too much”. Many metabolic and immune abnormalities were found, including test results that were orders of magnitude different in the severe ME/CFS patients.

The low morning cortisol finding may seem like yesterday’s news, but Xiao sounded shocked by how significantly it popped out – it looked like a major driver. With Akiko Iwasaki’s similar finding in long COVID (it was the most significant finding there as well), we should see more interest in the HPA axis and the adrenal glands. Plus, Wengzhong stated that the low estrogen findings they found, in combination with the low cortisol finding, put even more attention on the adrenal glands.

The HPA axis – one of the two major stress response systems in the body – was a hot topic early in the history of ME/CFS and faded over time as a topic, but studies still regularly come out on it. Dr. Janet Mullington in an Open Medicine Foundation-funded study, for instance, is in the midst of a rare deep dive on cortisol and sleep in ME/CFS. (Blog coming up.)

Another thing that popped out was the brain-derived neurotrophic factor (BDNF). BDNF is a key neuroplasticity supporter in the central nervous system and here Xiao presented a kind of theme in their work – using other data sets to validate their findings.

An analysis of an NIH long-COVID muscle study suggested similar alterations in BDNF were occurring in the muscles. That’s an intriguing finding because BDNF helps the muscles use fatty acids to produce energy, and fatty acid metabolism seems pretty clearly disturbed in ME/CFS. Could BDNF be a surprise entry in the disturbed fatty acid metabolism sweepstakes?

“Network Medicine” Produces Drug Possibilities

The cortisol and the recent pathways finding highlighted a distinct way the Stanford team works. They’ve put past ME/CFS molecular findings in ME/CFS into a large database they can analyze all at once. If the data indicates that a metabolite might be off, they will look to see if other data indicates that the gene that regulates that metabolite is off as well. If both show up, they will start to look for a drug that might affect both.

Then because ME/CFS is so understudied, they’re also going outside the disease to gather molecular data on better-studied diseases to: a) help them understand what might be going on in ME/CFS; b) uncover diseases that look most like it; and c) determine whether drugs used in these diseases might be helpful in ME/CFS. They call this molecular bootstrapping approach “network medicine”.

The process has worked – they’ve come up with several potential drugs for ME/CFS and are exploring them further.

If I’ve understood it correctly, they’ve also downloaded around 1,000 papers in an attempt to use artificial intelligence to answer questions about ME/CFS and have been exploring that with Efthymios Kalafatis – who used AI to recover from ME/CFS.

Rare Pathogenic Genes…

Decode ME, a joint UK/NIH-funded study that got started in 2021, is the most recent mega-ME/CFS study to get going. (DecodeME says it’s the largest ME/CFS study ever :)). Wengzhong thought this genome-wide association study, or GWAS study, will help determine if common genetic variants created genetic weaknesses that allowed this disease to get started. Note that a 2011 ME/CFS heritability study suggested that genetic weaknesses to these diseases are present.

(DecodeME recently published a study which found that people whose ME/CFS was triggered by an infection had a different pattern of symptoms, that women with ME/CFS tend to have more comorbidities (other conditions), that being female and having ME/CFS for more than 10 years increased one’s risk of having more severe ME/CFS.)

Ron Davis and Wengzhong Xiao and the Stanford group are looking at a very different possibility, though. They are using whole genome and/or exome sequencing (WGS/WES) to determine if very rare genetic variants are contributing to ME/CFS. The GWAS studies, for instance, as big as they are, examine hundreds of thousands to a million of the 3 billion genetic bases, i.e. about one in 3,000. WGS, which is quite a bit more expensive, looks at all of them.

The whole genome sequencing approach highlighted 96 possibly pathogenic mutations in the Severe ME/CFS Big Data project. The central nervous system showed up in spades – suggesting that the buck may end up stopping at the CNS in ME/CFS.

While many of the genes were different in different patients, as a group they were distinguished by their ability to alter neurological functioning. Six potential neurodegenerative disease pathways were identified in the severely ill patients. This paper comes on the heels of a Ron Davis and Michael Jensen paper from Stanford suggesting that antibodies found in multiple sclerosis may be attacking the myelin sheaths of the nerves in ME/CFS.

Interestingly, none of the pathways identified were associated with depression. In fact, the analysis suggested that ME/CFS was about as far away from depression as could be.

Epstein-Barr Virus (EBV) on the Prowl Again

Pathogenic genes associated with the Epstein-Barr virus (EBV), and antigen processing and presentation (how the immune system recognizes invaders), also showed up big time. That’s an encouraging finding at a time when EBV is also showing up in spades in long COVID. It’s yet another finding suggesting that EBV could be a core driver of severity in ME/CFS.

Wengzhong said they’re still trying to figure out what the EBV findings mean and is involved in several studies that will attempt to determine if EBV reactivation in ME/CFS is sparking an inflammatory or autoimmune reaction.

He noted that Rob Phair’s Itaconate Shunt hypothesis proposes that the body shuts down metabolism (energy production) to shut off the inflammatory response to a virus. On the autoimmune side, Health Rising recently reported that Akiko Iwasaki’s Yale group recently produced a long-COVID-like state in mice by transferring IgG antibodies from long-COVID patients into them.

If that was happening with EBV in ME/CFS (or long COVID), that would mean that in its effort to attack EBV, the immune system had misfired and ended up attacking our own tissues. Finding the antigen – the part of the virus the immune system had aimed at – is apparently not a trivial matter. The search, however, is on.

An NIH Interlude

Always the careful researcher, Xiao stated, “I think we have to basically validate this rigorously” with larger studies – a seemingly constant theme in ME/CFS. While we don’t have them or the funding to do them, the good news is that ME/CFS research is not lacking for findings or possibilities – it’s simply lacking in money – and to a large extent that means National Institutes of Health (money).

That brings to mind #MEAction’s Petition to the new NIH Director, Monica Bertagnolli, who has shown interest in both ME/CFS and long COVID – to provide funding for the Roadmap Initiative. The NIH created the Roadmap Initiative to guide it in its ME/CFS research – with the understanding – at least in the patient community – that funding would follow.

The same was true with Nath’s Intramural Study. The Intramural study was designed, then-director Francis Collins said, to provide clear research avenues the NIH would follow up on. So far, though, it’s been business as usual for the NIH regarding ME/CFS. Please help to change that and sign the petition.

• Sign the petition here.

The Severely Ill Patients – Not Different – Just Worse Off!

One train of thought has been that the severely ill are different – that something extra must be going on to make them so ill. The other train of thought is that they’re the same as other ME/CFS – just worse off.

It’s an important question. If the severely ill are in some core biological ways different from the rest of us, they are in a world of hurt given how hard it is to get them into research studies. If, on the other hand, they are similar but worse off, they should be able to benefit from all the other ME/CFS studies (and long-COVID ones as well.)

When I asked Wenzhong about this, he said the study suggested it was door number 2: biologically, the severely ill appear to be the same as other ME/CFS patients but just worse off.

Connective Tissue Breakdown?

One potentially important gene variant (ADAMTSL2 RS 35767802) was found in 45% of the severely affected patients, but – and here was the kicker – it’s not found in the general population in such a high degree. This variant appears to play a role in the degradation of the extracellular matrix and that means connective tissues, which potentially means spinal issues, blood vessel and gut problems, tweaked nerves, and more.

These kinds of amino acid changes can completely disable a protein but since this mutation only affects one amino acid in the protein it’s not clear if that’s happening in ME/CFS. Nevertheless, it was startling to see it pop up in such high amounts in severe patients.

What’s Exciting Wengzhong Right Now

The treatment possibilities popping up from the Severe Big Data study – particularly molecules that modulate the nervous system – most excited Wengzhong now. Those are under wraps as they figure out how to test them and when and how to announce them or publish them. Their concern is patients trying strong drugs before it’s clear they can be safely used in ME/CFS.

Note that the Stanford OMF team recently published a study suggesting that an amino acid combination called LOLA might be helpful. The authors proposed that using the L-ornithine plus L-aspartate (LOLA) supplement regimen “could potentially rescue the metabolic changes observed in ME/CFS patients” (!). LOLA is a supplement combination that is readily available and has been used for decades to reduce ammonia levels in people with liver problems. That’s intriguing given that some researchers believe the liver is involved in ME/CFS.

Wengzhong was also intrigued by the possibility that the neurological pathways found in some neurodegenerative diseases will shed light on what’s happening in ME/CFS – and that was it for our talk! Thanks so much to Wengzhong for taking the time to talk about his and the Open Medicine Foundation’s work.

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