Geoff’s Narration
The GIST
This is the next in a series of blogs on potentially groundbreaking ME/CFS, long-COVID, and/or fibromyalgia studies that are underway. This isn’t a series that I thought, “Why don’t I do a series on X?” This is a series that demanded to be done.
Sequence ME and Long COVID is another project designed to take ME/CFS and long COVID to the next level.
The big ME/CFS projects have been few and far between. The $8 million 2013 PACE Trial (approximately $12 million today) still beats everyone regarding cost, but its shady trial redesign and mediocre results (even after the project had been tweaked) probably laid the groundwork for the virtual disappearance of the biopsychosocial field in ME/CFS.
The Open Medicine Foundation’s 2015 Big Data Severe Patient study probed severe patients using over 1,000 tests. While it provided few published studies, it did give OMF researchers plenty of leads. Finally, the NIH’s 2016 Intramural ME/CFS project got hijacked by the pandemic, and undermined itself in the public with its “effort preference” interpretation, but despite its small size, still provided plenty of intriguing findings (norepinephrine, immune, metabolic, gender findings) for researchers. In fact, its ability to do so much with such small sample sizes by itself argued that the ME/CFS field was ripe for study.
It took about ten years, but big ambitious studies have begun popping up again. It appears that researchers feel more confident in their ability to take and fund big studies that take on big questions.
Our series began with ME/CFS’s biggest study ever – the DecodeME study, continued with PrecisionLife’s ambitious attempt to identify the mechanisms driving ME/CFS and long COVID, moved on to Amatica’s 1,000-person gene expression study, and recently featured Open Medicine Foundation’s 1,000-person, multi-dimensional, multi-year, multi-phase biomarker project. All that in the past 6 months or so.
Along the way, we also examined Liz Worthey and Camille Birch’s small, but deep, deep dive into whole-genome sequencing, and the unhide project to build a massive ME/CFS patient database.
The GIST
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Sequence ME and Long COVID is another project that’s designed to take ME/CFS and long COVID to the next level.
As far as I can tell, the ME/CFS field has had three massive studies: the ill-fated PACE project, the Open Medicine Foundation’s “Severe ME/CFS Big Data project, and the NIH’s truncated Intramural Project led by Avindra Nath. All these began in the mid-2010s.
- Over the past 6 months or so, a sea change appears to have occurred. Health Rising has reported on 4 massive projects. There was the DecodeME study, PrecisionLife’s ambitious effort to understand the mechanisms behind ME/CFS, the Amatica 1,000-person gene expression study, and the Open Medicine Foundation’s 1,000-person BioQuest project to find molecular biomarkers for ME/CFS.
- We also had Liz Worthey’s and Camille Birch’s deep, deep dive into the whole genome of ME/CFS patients and the unhide project that aims to build a huge complex, chronic disease database.
- Now comes one of the most ambitious projects in ME/CFS history: the $20 million (gulp) Sequence ME & Long Covid project. Action for ME, the Schmidt Initiative for Long COVID, and the Complex Disorders Alliance (CODA) announced the launch of project.
- Action for ME states that the projected $20 million study (!), is not only the biggest genetic study in ME/CFS, but will be the largest “long-read” whole genome study of any disease.
- In contrast to the DecodeME project that looked for common genetic variants, this project will scan the entire genomes of 18,000 ME/CFS and long-COVID patients for hidden genetic variants that are driving these illnesses.
- Liz Worthey and Camille Birches recent whole genome study suggested that up to 40% of ME/CFS patients may have a clear genetic cause for their illness. The GWAS study the DecodeME project has done won’t find them – but this study will.
- This study will employ a “long-read” approach that allows the researchers to scan longer bits of genetic data which are likely producing damage in diseases like ME/CFS and long COVID.
- The study begins ahead of the 8-ball in four ways. First, one of the co-leaders, Action for ME, also successfully co-led the big Decode ME project. Second, it has already secured all the ME/CFS samples it needs.
- With the University of Edinburgh (Chris Ponting), Oxford Nanopore Technologies, and the European Bioinformatics Institute, EMBL-EBI (Ewan Birney) joining together to seek funding for the study, the study rests on a strong research foundation.
- Finally, Action for ME is hiring a professional with experience in “securing significant funding or investment at the six or seven-figure level” to support the project.
- Their first task will be securing about $8 million (@ 6 million pounds) to analyze the 9,000 ME/CFS samples. Not only will people with severe and very severe ME/CFS be assessed first, but ME/CFS will be assessed first as well.
- DecodeME was just the start. The Sequence ME/CFS and long-COVID study is the logical next step for Chris Ponting and his group. It has the potential to uncover the precise drivers of these illnesses like never before.
- This is the kind of big, ambitious project that the ME/CFS field, in particular, needs. Action for ME and DecodeME proved they could successfully take on big projects like DecodeME. Now it’s time for the next step – Sequence ME and Long COVID.
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Huge Whole Genome ME/CFS and Long COVID Study
Action for ME, the Schmidt Initiative for Long COVID, and the Complex Disorders Alliance (CODA) announced the launch of Sequence ME & Long Covid project.
One of the most ambitious projects of all, the Sequence ME & Long COVID study plans to study the whole genome of 18,000 ME/CFS and long-COVID patients. Whoa, I thought. Is that really the whole genome (all 6 billion base pairs)?
Yes, it is. We’re definitely in new territory with this study. The DecodeME GWAS study (genome-wide association study), which assessed common genetic variants, examined perhaps 500,000 variants. As Chris Ponting, the leader of DecodeME, stated, it’s the logical next step for DecodeME. DecodeME, after all, has all the genetic data – it’s just waiting to be analysed.
“The SequenceME study represents a unique opportunity to build on DecodeME’s foundation and use world-class technology to address one of the most challenging medical puzzles of our time.” Chris Ponting
Action for ME states that the projected $20 million study (!), is not only the biggest genetic study in ME/CFS, but will be the largest “long-read” whole genome study of any disease.
Now, we’re talking! Let’s set some records.
A Crucial Project
Identifying variants associated with ME and Long Covid will reveal their biomolecular mechanisms, and existing drugs can be identified that target the actions of these genes, leading rapidly to effective treatments. Action for ME
Why do we want this study to be done? First, not only did the smaller DecodeME GWAS (not WGS – GWAS) study find common gene variants that contribute to the risk of getting ME/CFS, but those variants made sense with what we know about this disease. Note that when PrecisionLife analyzed genetic data from DecodeME and others using a different approach, it came up with similar findings, suggesting that DecodeME’s analyses, and indeed, the field as a whole, are on the right track.
If DecodeME could get those results using common genetic variants, what could Ponting, Sanghera, and Birney learn from exploring the entire genome? In their small whole genome study, Liz Worthey and Camille Birch found what they believe are significant drivers of the illness in 30-40% of patients. The fact that their results also pointed to the same general themes that have shown up in Decode ME, PrecisionLife, and the ME/CFS field at large, suggests again that the field is on the right track(s).
Their study was notable, though, in how many ways they found it was possible to produce the same biological outcome. Mitochondrial inhibition or metabolic problems that lead to fatigue, pain, etc., were induced in different ways in different patients. They believe whole-genome studies are crucial to getting at the specific drivers of these illnesses in a significant number of patients.
Looonnnngggg Read Study
What answers are buried deep in our genome? Sequence ME and Long COVID aims to find out.
The Sequence ME and Long COVID whole-genome sequencing study may differ from theirs. Their analysis involved a labor-intensive chromosome-by-chromosome analysis. Sequence ME and Long COVID, on the other hand, is a “long-read” WGS study; i.e., instead of chopping the DNA up into 100-300 base pairs, this study will assess genetic sequences 1,000 to 10,000 base pairs long.
Sequence ME and Long COVID is going “long read” because the kinds of problems found in ME/CFS and long COVID (energy metabolism, immune sensing, autonomic control, and neurocircuitry) may be caused by larger-scale structural changes, repeats, and complex haplotypes (multiple genes) that short-read analyses may not be able to pick up. Interestingly, long reads are also more apt to come up with new classes of genetic risk that have not been seen before.
The project will focus on finding major genetic variants that have the potential to produce dramatic changes; i.e. genes that affect the functioning of proteins (the big workers in our cells), genes that regulate the expression of other genes, and large structural changes that impair gene functioning or gene expression.
Once they’ve identified genetic areas of concern, they’ll look at existing drugs that target the specific genes or biological pathways that have been disturbed.
Say, for instance, they find that loss-of-function or missense variants in a mitochondrial gene called NDUFS7 in some ME/CFS and long-COVID patients with particularly high levels of exercise intolerance and post-exertional malaise (PEM). Damage to this gene – which affects complex 1 in the mitochondria – would fit prior research findings. It would also point to targeted interventions (e.g., mitochondrial protectants, NAD+ boosters, complex I‑supporting strategies) in this group.
Similarly, finding rare missense variants in STAT1 genes in a subset of ME/CFS/long-COVID patients would result in immune dysregulation, increased interferon activity, and JAK/STAT activation. Each of these have already popped up in ME/CFS/long-COVID studies. This would call for testing JAK/STAT inhibitors in this group of patients.
Likewise, finding a rare regulatory variant in the ADRA2A (alpha‑2A adrenergic receptor) gene would make sense for people with dysautonomia/POTS. Because this gene affects sympathetic nervous system activity and norepinephrine release, it could help produce the increased heart rates and other autonomic problems in POTS (possibly including hyperadrenergic POTS). This finding would not, at this time, open the door to new drugs, but it would point to drugs like clonidine or guanfacine for those who are not currently taking them.
Funding
Twenty million dollars is a big chunk of change. If successful, this will be the most expensive ME/CFS/long-COVID project to date. Together, the Schmidt Initiative and the Complex Disorders Alliance have started the project off with $250,000 in funding.
Only $19,250,000 to go. 🙂 That’s a lot of money, but this project has a lot going for it.
(1) Proven Success in Big Projects – The co-leader of the project, Action for ME, also co-led the DecodeME project, which must have seemed out of reach when it was initiated. DecodeME, though, was able to raise almost unprecedented funding (@$4,200,000) for an ME/CFS project by securing two large Medical Research Council and NIH grants.
DecodeME has turned out to be the foundational project we hoped for. Since it opened its databank to outside researchers in 2024-25, at least four studies have used its data, and doubtless many more are in the process of doing so.
(2) ME/CFS Samples Secured – The SequenceME project starts off with the same magic juice that the Open Medicine Foundation’s BioQuest biomarker project has – it already has all the ME/CFS samples, all 9,000 of them, from, who else – DecodeME.
(3) Strong Research Foundation – Action for ME, the University of Edinburgh (Chris Ponting), Oxford Nanopore Technologies, and the European Bioinformatics Institute, EMBL-EBI (Ewan Birney) have “joined together to seek funding for the study”. The inclusion of Ponting, Oxford Nanopore Technologies, and EMBL-EBI lends considerable cachet to the project.
“DecodeME created the world’s largest ME/CFS study, and we are proud to take the next step with SequenceME. Using Oxford Nanopore’s any-length read sequencing technology, this project will uncover genetic insights that could transform patient care and open the door to personalised medicine for those living with ME.” Dr Gordon Sanghera, CEO and cofounder of Oxford Nanopore Technologies
If you build it, will they come? They did for DecodeME. Action for ME believes they will for Sequence ME/CFS and long COVID as well.
We all know Ponting – he’s a senior genomics researcher and leader of DecodeME. EMBL-EBI is a major center for bioinformatics and large-scale genomic data analysis. Ewan Birney at EMBL-EBI is a leader in the genomics/bioinformatics field. Birney played a major role in ENCODE, the 400+ researcher follow-up to the Human Genome Project, which began in 2003, aimed at identifying all the functional elements of the human genome. He’s won several awards in bioinformatics.
For its part, about 20 years ago, Oxford Nanopore was spun off from Oxford University, has over 1,000 employees, and has developed novel DNA/RNA sequencing technology.
This project is clearly in good hands. 🙂
(3) Professional Fundraising – Sequence ME is hiring a full-time Partnerships and Business Development Manager to drive the work. They’re looking for a proven professional who has demonstrated “experience securing significant funding or investment at the six or seven-figure level from strategic partners, philanthropic funders, or major donors “. A Management Group and a Scientific Advisory Board will also be established.
Their first task will be securing about $8 million (@ 6 million pounds) to analyze the 9,000 ME/CFS samples. Not only will people with severe and very severe ME/CFS be assessed first, but ME/CFS will be assessed first as well.
This is the kind of big, ambitious project that the ME/CFS field, in particular, needs. Action for ME and DecodeME proved they could successfully take on big projects like DecodeME. Now it’s time for the next step – Sequence ME and Long COVID.
- Find out more about the project and how you can support it here.
I do so hope they get funding but I’m also afraid of no one stepping up for it. The german national decade seems to involve a sequencing project as well that is already funded so that might tide us over. I do have more trust in Pontings and co because of their former experience though.
Hudson Alpha in Huntsville, AL got an Amazon Web Services Imagine Grant for a smaller project. Has anyone from this project asked Jeff Bezos yet?
Steven and Alexandra Cohen have funded tons of Lyme research, and more recently psychedelic research. Would they fund this, too?
I’ve sent my sample off to sequencing.com because of this series. Look forward to the results and maybe something useful in them.
About ”the virtual disappearance of the biopsychosocial field in ME/CFS”: It has definitely not disappeared in the Nordic countries. Maybe it’s not specifically focussing on ME/CFS, but rather on a wider field, but they are definitely including ME/CFS and LC into “persistent physical symptoms” or “functional somatic symptoms”. It’s not big in terms of research budgets, but they have a large influence on the thinking in the health care system through their courses and conferences.
I would like to know if I am able to join this group that is having their DNA submitted to be tested. I have had ME/CFS, FM, TMJ for over 33 years and it has defined and heavily restricted my life immensley. I live in Australia.
Really exciting to see a project of this scale. Looking at the entire genome instead of just common variants feels like a big step forward, especially for such complex conditions. Hopefully this leads to more personalized treatments and clearer answers for patients in the future.
snow rider
Thank you for sharing this insightful post about the Whole Genome ME and Long COVID Project. As someone who has grappled with chronic fatigue syndrome, I deeply appreciate the efforts to uncover precise drivers of these illnesses. It can feel isolating navigating healthcare systems that often overlook our experiences. Your discussion on how genomic sequencing could illuminate underlying causes resonates with me; I recently read some related material on block blast free about personalized medicine that highlights just how crucial this research is for us all. It’s encouraging to see a project like this aiming for real change!
Yes, indeed! 🙂