Visible At Last? Are Long COVID and ME/CFS Tissue Diseases? The PolyBio 2026 Symposium Pt I

The 2026 PolyBio Spring Symposium – Pt I

One way to gauge the health of a field is by the number of conferences/symposia it supports. From the looks of things, the long COVID and ME/CFS fields are moving up.

• • • The International ME/CFS conference – May 7-8
    • Invest in ME 15th International Biomedical Research into ME Colloquium – May 27-29
    • PolyBio Spring Symposium – May 29-30
    • 14th Annual Dysautonomia International Conference – July 9-12
    • ISLC-PAIS Conference – Aug 26-29
    • 4th Canadian Symposium on Long COVID – Oct. 15–16, 2026
    • 4th Long COVID International Conference in Nice, France –  Nov. 12–13, 2026

Usually, with conferences/symposiums, I hunt and peck and focus on a few presentations. The 6th PolyBio symposium, however, was so interesting and brought up so many issues that I ended up covering more than usual. It’ll be covered in two rather long blogs.

At this point, we have to ask: where, really, would we be without PolyBio? Founded by a person with ME/CFS (Amy Proal) and a researcher with a longstanding interest in ME/CFS (Michael VanElzakker), PolyBio has funded over 50 high-quality, innovative research projects over the past 6 years.

PolyBio received a grand total of $24,211 contributions in the year (2020) it was incorporated. Two years later, it received almost $18 million in contributions. Over time, it’s received about $50 million in private funding, including massive support from the Balvi Filanthropic Fund established by Ethereum co-founder Vitalik Buterin.

Why has PolyBio grown so quickly from such humble beginnings? It’s provided a blend of rigor, creativity and urgency that’s found an audience. Focused entirely on pathophysiology, it’s an antidote to a rather stodgy, do-it-by-the-book RECOVER project. (On a plus note, note that RECOVER has funded over 60 outside investigator research studies. While they account for only about 3% of RECOVER’s budget, they will surely deliver significant results. A future blog will dig into RECOVER’s long COVID (and ME/CFS – yes, there is at least one:)) grants.

The Long COVID Cure Initiative (LCCI)

PolyBio took its biggest step yet with the Long COVID Cure Initiative, launched in March of this year, courtesy of a $10 million donation from Todd Park and Steve Pagliuca, each of whom has family members affected by long COVID. The significance of this effort dwarfs any study finding.

If you want to make a difference, you look around, see what’s missing, and fill it. That’s what PolyBio did with The Long COVID Cure Initiative (LCCI).

The LCCI is designed to turn the long COVID cure space from a bucking bronco that is going nowhere fast into a smooth, steady quarterhorse that produces results efficiently and quickly. It’s not magic, and no, PolyBio hasn’t found a cure. It’s actually very simple; it’s what a good decent business would do as a matter of course. The problem is that the long COVID field comprises hundreds of businesses, each operating in its own way.

The LCC builds an infrastructure to accurately assess the effectiveness of a treatment. I hate to keep picking on the NIH’s RECOVER project, but I would have thought their first order of business would have been creating something like the LCCI.  PolyBio believes the Long COVID Cure Initiative will cut 15 years off what would have otherwise been an interminable, chaotic search for effective treatments; i.e., it’s designed to play a transformative role in the long COVID field.

It’s no surprise it’s missing. This is, after all, a new field.  At some point, it was going to pull itself up by its bootstraps and get organized.  For all the long COVID field has produced – and it’s produced a lot – the treatment space is chaos exemplified. Six years later, there is still no standard diagnostic criteria, no telling who’s in what study, and no standardized procedures. The result is a field that can produce possible biomarkers but has a lot of trouble validating them. (Cue ME/CFS for the past 40 years.)

So PolyBio, steeped in the urgency that long COVID, with its lack of validated and effective treatments, has produced, stepped in. It partnered with a crack UCSF team that’s been honing its techniques in HIV for years.  One of the leaders, Stephen Deeks, said the UCSF team (LIINC) is looking at the same pathways in long COVID that brought so much success with HIV.

The LCCI’s four-point plan

• 

  Once the VIPER project hits its target, we WILL have a biomarker

  The Foundation – the VIPER (Validating and Investigating Promising Existing biomarkers) Project – it all starts with diagnostics; without diagnostic tests that identify the biological drivers behind the subsets we all know are there, we may be pretty much lost when it comes to clinical trials. (On that thought, it’ll be interesting to see if the big long COVID clinical trials produce. Hopefully, they are big enough to pluck out subsets)

• The $8 million VIPER program – is the beating heart of the Long COVID Care Initiative. Built on the UCSF HIV biomarker program, it will test all possible biomarkers in an organized way. Its first project is a large, 150-person study in which everyone will undergo a gut biopsy, and many will also undergo an endoscopy. Just six months ago, the LCCI was a very good, very underfunded idea. Now thanks to Park and Pagliuci it’s the real deal
• Commercializing Diagnostics: The second step shows just how comprehensive PolyBio’s plan is. Apparently, many potential biomarkers die on the vine because commercializing them and getting them into labs requires a completely different skill set. PolyBio is bringing that skill set in to ensure that when good biomarker(s) are found, they can quickly make it through the regulatory process, withstand intellectual property challenges, and secure strategic partners who can fund the production of a commercial diagnostic test.
• Mobilize Smarter Clinical Trials – Once you have a biomarker, you have to use it to test drugs/treatments in smart” clinical trials focused on the appropriate patient set. To facilitate that happening as quickly as possible, PolyBio is creating “a national, diagnostics-guided, clinical trials network purpose-built for Long COVID” (!). PolyBio will also, and this is potentially very important given the many generic drugs out there that drug companies no longer have an interest in, fund clinical trials of generic drugs. Generic drugs are probably the quickest and easiest way to get affordable treatments into long COVID patients’ hands, but they are hardly ever tested.
• Train Doctors – Even with that, there are still hordes of busy, often overworked doctors, who will not be able to catch up with the long COVID field. To that end, Polybio and Mt. Sinai will embed clinical trial findings into core CME courses to ensure that doctors can quickly recognize and access promising treatments for their patients.
• Check out the entire plan here.

Looking at this initiative, I don’t think it’s any surprise that PolyBio was able to find two individuals to provide massive support for it.

Yet Another Big Bold Project

So, we have another big, bold initiative popping up! We can put the LCCI next to the $10 million or so SequenceME, the OMF’s $2-3 million partially funded Bioquest Project, and several million-dollar, 1,000-person Amatica ME/CFS and long COVID gene expression project, PrecisionLife’s mechanistic work, and Germany’s truly magnificent commitment to spend $500 million on post-infectious diseases over the next ten years.

An Aside – The Funders

We can thank PolyBio for providing the vision and Todd Park and Steve Pagliuca for funding it. It’s worth looking at the individuals whose support may make a difference for millions, if not hundreds of millions of people with long COVID. What a legacy to leave, and would that there were more of them.

Todd Park (net worth @$1.4 billion) graduated magna cum laude and Phi Beta Kappa from Harvard College. An entrepreneur, he co-founded Athenahealth, Castlight Health, and Devoted Health. He also helped launch Healthpoint Services, which is focused on delivering affordable clean water, medications, diagnostics, and telehealth to rural villages in India.

Park also serves on the boards of New America and The Public Health Company, both of which focus on public‑interest policy. Park, then, is well aware of the needs and has the know-how to build transformative infrastructures in the medical field. In short, he’s perfect for this initiative.

Steve Pagliuca (net worth @4 billion) on the other hand, is a private equity investor, co-chairman of Bain Capital, and former co-owner of the Boston Celtics. He has a long history as a philanthropist via his involvement with the Celtics Shamrock Foundation (youth development), the Massachusetts Society for the Prevention of Cruelty to Children (MSPCC), and the Harvard Life Lab which supports medical entrepreneurship, and has strong ties to Duke University and Harvard.

With his deep biotech experience (via Bain Capital’s life‑science investments), and his own infrastructure‑building expertise, he, like Park, is a perfect match for this project. Both know a good thing when they see it – and PolyBio produced a very good thing.

Another Aside – A Good Gilded Age?

We are currently living in a new Gilded Age. In fact, recent reports indicate that a smaller tier of Americans own a greater share of America’s wealth (the top 1% own about 1/3rd of the U.S.’s wealth; the top 10% own about 70% of America’s wealth) than ever before. The concentration of wealth in the US far surpasses that of the “Gilded Age”.

The fact that much of this wealth is untaxed has, yes, disadvantages for the rest of us who have to foot the bills, but also contains immense opportunities. The upper tier has money to spend – sometimes lots of money – and how better to spend than supporting medical research?

Historically, some wealthy individuals in the US, many of them ruthless competitors, have ended up making a significant difference.  After rapaciously consolidating the oil industry (and ruining many of his competitors), John D. Rockefeller Jr. essentially spent the rest of his life and fortune building a remarkable college and university system across the US. At a time when racism was rampant in the US, and many blacks in the southern states still could not vote, Rockefeller provided large, systematic, and long-term support for southern Black colleges – most of which still exist.

Rockefeller also founded the first biomedical research institute in the United States (1901), which has since produced 26 Nobel Prize winners and 26 Lasker Award winners.  Its focus on peer‑reviewed, project‑based, university‑centered grants became the blueprint for the NIH’s system.

Andrew Carnegie violently smashed protests and crushed unions, and imposed 12 hour workdays as he cornered steel mining, refining, and transportation. After he retired, though, Carnegie gave away 90% of his wealth and built 2,500 libraries and  Universities across the U.S. Carnegie’s early life was filled with poverty and hardship, and though he was the epitome of a hard-driving, callous businessman, by the end of his life, he was described as being “deeply contented and fulfilled”. European visitors were astounded to see the libraries in even medium-sized towns in the US, which surpassed those found in Europe.

The SpaceX, Anthropic, and OpenAI IPOs are projected to produce somewhere around 16,000 new millionaires, at least 20 billionaires, and 1 trillionaire. Let’s hope some of them give back as Park and Pagliuci have.  These fields are ripe for progress. All they need is the funding.

Onto the Symposium

Into the Tissues We Go

Several symposium presentations suggested that to really get at these diseases, we’re going to need to go deeper and deeper into the tissues. This question has been discussed for decades in ME/CFS, but the field has never had the means to do so.  Thanks in large part to PolyBio, long COVID researchers are going to the tissues, and the findings are raising eyebrows. First, though, some microclot findings.

Into the Gut We Go

Take I: Gut Sealing Study

Peter Moschovis of Harvard presented early results from an attempt to seal the gut lining in 107 patients using a drug called larazotide in a Phase 2a randomized, double-blinded trial. Larazotide is a synthetic peptide that prevents tight junctions in the gut from opening, thereby preventing the spilling of gut contents into the blood. The idea is that leaky gut linings are allowing the spike protein or the coronavirus to spill into the bloodstream.

An earlier study in children with multisystem inflammatory syndrome (caused by the coronavirus) found that larazotide helped clear the spike protein from the blood, reduce inflammation, and improve gut symptoms. An interim analysis suggested that the drug may improve sleep, fatigue, daily-life impact, GI symptoms, and cardiovascular symptoms. With data collection wrapping up, hopefully we’ll get the full results in the not-too-distant future.

Note that the problem is not necessarily that the spike protein is found in the gut lining, but that it’s escaping into the bloodstream, where it may be causing inflammation, autonomic instability, and even blood vessel damage.

Thankfully, larazotide appears to be well tolerated, only affects the gut, and can produce mostly mild gut side-effects. Given these findings, one wonders why, given the CDC study finding that exercise exacerbates leaky gut in ME/CFS, increases symptoms, and produces post-exertional malaise, a drug like larazotide, which seals the gut lining, hasn’t been trialed in ME/CFS.

Gut Healing Take II

Speaking of the gut, Dominque Salmon reported that not only did a small pilot trial of maraviroc plus pravastatin reduce severe GI symptoms  (stomach cramps, diarrhea, and bloating) by at least 30% in 13 of 19 Long COVID patients but that it also shrank their microclots. When the treatment was paused, their symptoms returned, and when it was resumed, symptom reduction recurred. Spike protein levels declined in 5 of the 7 patients who had the spike protein. Whole blood serotonin levels also increased.

Dr. Bruce Patterson pioneered the maraviroc-pravastatin approach in long COVID about five years ago but he was focused on the blood vessels.. Patterson was targeting monocytes that he believed were attaching to the endothelial lining of the blood vessels. Patterson’s early theses: that classical monocytes are activated, that the endothelial lining is under attack, that platelet activation is happening, and that microclots are present, have all been validated by subsequent research groups. Patterson used these drugs to prevent monocytes from attacking blood vessels and to stabilize endothelial cells.

This group targeted the gut, but because the blood vessels are so abundant, the basic idea is the same.  The idea is that monocytes in the gut produce inflammatory factors that increase gas levels and sensitize the nerves, causing cramping, bloating, and reduced gut motility.  The maraviroc/pravastatin combo may prevent monocytes from attaching to blood vessels, reducing inflammation, increasing blood flow, improving oxygen levels, and supporting blood vessel health.

Salmon’s was a small study, but a multicenter randomized trial is in the planning /fundraising stages. HealthBio – another company formed by Patterson –  began a 252-person maraviroc/atorvastatin long COVID trial in September of last year. Its completion date was April, 2026.

Into the Lymph Tissues we go

In Long COVID, B cells in the lymph nodes appear to be producing faulty antibody responses against SARS-CoV-2 — a defect that is invisible in routine blood tests but may explain why the virus is not fully cleared.

In “Adaptive Immune Responses to Long COVID Lymphoid Tissue,” Michela Locci went straight to the lymph nodes to examine how the B-cells found there are doing. She used an ultrasound‑guided fine needle aspirates (FNA) – developed apparently by her – to draw them out.

Why examine B-cells in lymph tissue instead of blood? Because the lymph nodes (and spleen and MALT) are essentially B‑cell factories and training grounds. These sites are where the B‑cells encounter a pathogen, activate themselves, and produce enormous numbers of clones to hunt the pathogen down.

Locci found a strange thing: the B-cells in the lymph nodes of long COVID patients reacted very differently to the SARS-CoV-2 virus than the B-cells from the recovered patients.

Locci believes the aberrant germinal-center and altered B-cell activity she found is impacting the a) B-cells’ ability to clear the virus, allow for herpesvirus reactivation, and c) promote the survival of autoreactive (autoimmune B-cell clones) that are feeding autoimmunity. This is probably happening in ME/CFS as well.

It’s a pretty darn impressive finding, and it took – a central theme of this conference – digging deep into the tissues. The B-cells found in the blood – which researchers usually study – turn out to be something of an anomaly. Only 2-5% of B-cells are present in the blood at one time, and they’re usually in a naïve or immature state. The rest are present in the lymph nodes, spleen, etc., but it’s apparently only in the lymph nodes that they proliferate, mutate, and become memory or plasma (killing) cells. It’s only the lymph nodes, then, that action is occurring, and that’s why Locci went to them.

PolyBio was jazzed enough by this finding that it and the Wallace Research Fund are now incorporating the ME/CFS field’s absolute favorite virus – the Epstein-Barr virus – into the study, which, by the way, infects and loves to rest in B-cells. (EBV lies low in the very cell designed to kill it). Three presentations in this conference indicated that EBV reactivation is occurring.

Into the Arteries We Go

“Since 2020, we have been publishing work showing that even mild or asymptomatic COVID infections can have serious cardiovascular consequences, even in previously fit and healthy individuals,”  David Putrino, 2025

We’re going to hear more about serious cardiovascular issues in the future – and it’s not pleasant. Infections in the gut are one thing, but the heart and blood vessels and cardiovascular system – that’s striking closer to home. Several studies have found that a coronavirus infection increases the risk of cardiovascular events.

Giannerelli’s assessment of plaque samples from 140 participants found that having a coronavirus infection played a bigger role in plaque gene expression dysregulation than smoking, hypertension, and dyslipidemia (ouch!). It appears that the arterial plaques found in people with long COVID are locked into an inflammatory state.

Once again, a clearance problem showed up. Macrophages appear unable to clear the dead and dying cells associated with these plaques, likely leading to increased inflammation, impaired tissue repair, mitochondrial dysfunction, and yet another vicious circle. Unfortunately, macrophages are the body’s key defense against atherosclerosis.

Time will tell what the full paper shows, but it should be noted that this finding likely applies primarily to people who already had evidence of atherosclerosis before their coronavirus infection. It fits, though, with the ton of cardiovascular, blood vessel, and autonomic nervous system findings that have shown up in these diseases.

Even two years after the initial infection, Giannerelli found coronavirus RNA was still present in some of the plaques, indicating that the immune system had been unable to get at them and clear them.

The good news about this finding is that atherosclerosis, if it is present, and the cardiovascular system have, of course, gotten a ton of study over the years. Agents that tamp down inflammation, restore macrophages’ ability to remove dead cells, and improve lipid levels in these cells are all potential treatments, should these findings be validated.

Into the Eyes We Go

Sean Miller’s retinal findings fit nicely with VanElzakker’s brainstem findings (see below). Because the eye is part of the central nervous system and is easily accessible via non-invasive means, it provides a useful way to assess what’s going on in the central nervous system.

Miller’s Yale study was small (n=15) but comprehensive, using three methods (autopsies, live-patient retinal imaging plus ERG, and organoid models) to assess central nervous system activity in the retinas. Increased microglial activity (neuroinflammation), astrogliosis (increased astrocyte levels), and increased activity in neurodegenerative, antimicrobial, and protein-aggregation pathways were observed.

The brain fog and other symptoms have told us that something pretty dramatic is happening in the brain, but the big question this study raised was whether long COVID is associated with an increased risk of Alzheimer’s or other dementias.

Studies have shown that acute exposure to the spike protein can result in accumulations of the amyloid proteins associated with Alzheimer’s. One idea is that the body is actually producing these misfolded proteins to protect itself from a coronavirus or perhaps other infection.

In this case, the Yale group was able to reverse the amyloid buildup in the retina using an NRP1 inhibitor (which is not currently available). Pretorius has also found amyloid products in the microclots in the blood, and  Baraniuk found them in a 2010 ME/CFS study. The problem is that these misfolded proteins are difficult for the body to break down.

While the convergence between Miller’s retinal amyloid, Pretorius’s fibrin amyloid microclots, and VanElzakker’s possible tau findings in the CNS  (see below) presents a compelling narrative, the studies themselves are far too small to provide confidence that long COVID patients may be at risk for dementia.

A systematic review that covered 940,000 post-COVID survivors and 6.7 million controls (!) did find that 12 months post-infection, long COVID patients showed an 84% increased risk of dementia. The very high heterogeneity, though, suggested that the patients studied, the control groups, and the effectiveness of the long COVID diagnosis probably varied widely, casting doubt on the findings.

Increased new onset dementia in COVID-19 patients over 50 appeared to be driven primarily by respiratory and vascular (blood vessel) problems, not by the dementia associated with Alzheimers. In his substack, Eric Topol reported a 50% increased risk of dementia after three years, but only in COVID-19 patients who had been hospitalized. A UK Biobank study came to a similar conclusion. Older COVID-19 patients who had been hospitalized or had a history of high blood pressure had higher markers associated with β-amyloid pathology (and Alzheimer’s) as well as more subtle cognitive deficits after three years.

Into the Spine We Go

Finally, someone – Mario Murakami from Harvard, of all places – is taking on craniocervical instability not in ME/CFS but in long COVID. Murakami is a postdoc, specializing in neuroanatomy and brain imaging. One of his first projects at Harvard is assessing neuroinflammation in conditions like Long-COVID using PET-MR and magnetic resonance spectroscopy (MRS)

His pilot brain-imaging study found that long COVID patients with craniocervical instability(CCI) have impaired cerebrospinal fluid flow –  something that could explain the brain fog and fatigue found. Impaired CSF-blood flow is probably no surprise to anyone who knows anything about CCI in ME/CFS, but it needs to be published in the scientific literature to be taken seriously. The fact that this study is coming from Harvard is a substantial bonus.

The very small pilot brain imaging study (n=8) found that CCI compression near the fourth ventricle and the cerebral aqueduct disrupted cerebrospinal fluid flow and glymphatic waste clearance.

Murakami chose these regions because they’re in a kind of hydraulic junction at the transition between CSF flowing up in the brain’s ventricular system and CSF flowing below the brain in the brainstem, cerebellum, and upper spinal cord.

Thankfully, Murakami did not find a dramatic blockage; instead, he found blunted pulse flows. (The CSF flows in pulses). The craniocervical junction is so tight, though, that a bit of inflammation, muscle weakness, etc. could effect it.

While a blunted CSF pulse flow does not automatically cause problems, it could prevent toxic metabolites from exiting the brain, potentially leading to brain fog, fatigue, and autonomic dysfunction.  Although Murakami did not state so, everything from orthostatic intolerance, nausea, sensory sensitivity, sleep disturbance, cognitive slowing, and “sickness behavior” could result.

This study was too small (n=8) to be representative of what happens in CCI.  Now that he has his pilot data, though, Murakami hopes to expand the study to include more ME/CFS, Long COVID, and chronic Lyme patients. Let’s hope he can get the CCI ball rolling.

Into the Brainstem We Go

That brings us to VanElzakker’s brainstem presentation. A neurologist with a longstanding interest in ME/CFS, Michael VanElzakker, proposed the vagus nerve hypothesis of ME/CFS many years ago, suggesting that small infections near the vagus nerve might have major effects.

(You might or might not wonder why VanElzakker spells his name VanElzakker instead of Van Elzakker? I wondered that for many years so I looked it up. It turns out that when many Dutch people emigrated, the clerks in the immigration offices – being the blunt instruments they were – simply merged Van and Elzakker (which refers to alder trees – nice!) into VanElzakker. So now we know! 🙂

Years ago, VanElzakker pointed out that most brain scans scan from the top down and are not good at assessing the brainstem.

VanElzakker aimed his MRI/PET scan towards the bottom of the brains of long COVID patients, and found signals that suggest that inflammation was particularly high in the nucleus of the solitary tract, right where the vagus nerve enters the brainstem.

Since this region regulates sensory and gut-brain signaling, the autonomic nervous system, “sickness behavior” (whoa!), pain, and more, the potential for mischief in these diseases is high. Everything from fatigue, nausea, dysautonomia, sensory sensitivity, pain, sleep disruption, and “sickness behavior” could result.

Additionally, disruptions to blood vessels and the blood-brain barrier in the brainstem suggest that vascular problems in the body extend to the brain as well.

VanElzakker also found 4-fold higher p-tau217 levels in long COVID patients than in healthy controls or ME/CFS patients. Elevated p-tau217 levels are associated with an increased risk of Alzheimer’s. Because they could also be caused by a number of other things (neuronal stress, blood-brain leakage, blood vessel injury, we can’t say that long COVID patients are at a higher risk for Alzheimer’s, but it’s definitely something to keep an eye on.

This finding could point to a wide variety of treatment options, which include anti-inflammatories, vagus nerve stimulation, breathing practices, blood vessel therapies, and more.

There are some cautions. As most brain imaging studies are, this study was small (23 Long COVID and 14 COVID-recovered controls), and the TSPO signal used does pick up inflammation, but cannot tell us what cells it’s coming from (microglia, astrocytes, macrophages, the blood vessels).

Hopefully, with this data in hand, we’ll get a larger PET-MRI/blood-biomarker study that tracks things like symptoms, autonomic nervous system activity, sensory processing (pain, touch, etc.), cerebral blood flow, cognition, and p-tau217 and amyloid/tau levels.

Conclusion

We’re getting lots of interesting findings from the blood but its possible that direct examinations of the tissues are the way to go.

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Keeping on top of major opportunities and themes in long COVID, ME/CFS, and fibromyalgia is a major goal, and in this part of the Symposium, two immediately stood out.  One – a potentially transformative project – the Long COVID Cure Initiative has begun. Two – these diseases may have been “invisible” to the naked eye, but once you peer into the tissues themselves, lots of oroblems are showing up, and in lots of places.

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