Mary Anne Fletcher (1937-2023) – In Memoriam
I only met Mary Anne a few times, but they were vivid. I remember – years ago – watching with a little awe as she boldly and vociferously called for NIH-funded treatment trials for ME/CFS.
She clearly had a very full life. She was active in civil rights during the 1950s and 60s, and during the campaign for the Equal Rights Amendment in the 1980s, during which she wrote a column for the National Organization for Women in Florida under the nom de plume Donna Quixote.
She loved animals – particularly dogs and horses and was clearly competitive – raising champion Samoyed and Norwich Terriers, competing in endurance equestrian events before turning to competitive carriage driving which she pursued into her 80s (!).
A leader to the core, she is survived by her two partners, Janet M. Canterbury, Ph.D. and Nancy Klimas, MD, her daughters, and numerous grandchildren and godchildren.
She’s the kind of person I would have loved to have known better. Thank you Mary Anne for your 40-years of dedication to people with ME/CFS, Gulf War Illness, and similar diseases.
Research Highlights from the Institute for Neuro-Immune Medicine at Nova Southeastern University Conference
Nancy Klimas, the leader of the Institute – which focuses on complex diseases like chronic fatigue syndrome (ME/CFS), Gulf War Illness, and long COVID – started the day off.
Nancy Klimas noted that you can’t talk about ME/CFS or long COVID as autonomic or metabolic or immune diseases. All of them are present. These complex diseases are diseases of homeostasis; i.e. they affect multiple systems which, in turn, affect each other. That’s why they went to supercomputers to study them.
A (The?) Key Need for the ME/CFS Field
Nancy reiterated again the need to get an ME/CFS group in there with long-COVID patients in the NIH RECOVER Initiative, stating that it “can only move us if the trials allow an ME/CFS comparator group“, and asking them to at least “allow, if not require, an ME/CFS comparator group in the trials that are being planned. It is so, so very important”.
Note that right now, the RECOVER project won’t even “allow” an ME/CFS group in the RECOVER project. Advocates are pushing for RECOVER to simply “allow” an ME/CFS group in there. Could RECOVER be so uncaring and heartless to not even allow ME/CFS in there? Reportedly, some progress has been made, but time will tell.
The opposite is also true. ME/CFS researchers need to incorporate long-COVID patients into their studies, and she’s in the midst of a big one – funded by the CDC – that is. That’s “big” as in 750 people, but it’s STILL missing a big chunk of long-COVID patients (!). Nancy talked about her problems finding long-COVID participants at the IACFS/ME last year and apparently, the problem persists. The ME/CFS patients were eager – they knew her and were ready to participate but not so much the long-COVID patients. She needs at least 150 more long-COVID patients to complete was is looking like a fantastic study.
Long Awaited ME/CFS Clinical Trial – About to Begin…
Then it was onto the next delayed study! I’ve begun to think of the ME/CFS clinical trial as: “The study that’s always about ready to begin”. Three years ago, then COVID happened. I thought I heard last it was ready to go, but apparently now it really is ready to go. (“We’re about to launch this really cool study”).
Nobody in the ME/CFS field has brought this much data – millions of data points generated by measuring everything they could (gene expression, immune functioning, immune cells, neuropeptides, cytokines) 9 times before, during, and after a ride on the bike to exhaustion (or at least near it) – to a clinical trial.
This clinical trial is not backed by a hunch, a case report, or some doctor’s good ideas but by supercomputer findings. You only use a supercomputer when less than supercomputers won’t do (i.e. unless you have massive amounts of data) – and that’s what Nancy brought to this trial (and the similar Gulf War Illness trial).
All that data, plus a wide variety of treatment possibilities, were fed into a supercomputer, which was then asked – using chaos theory (no preconceived notions here) – what combination of treatments could turn this mess around. (I’m sure I’m greatly simplifying things.)
- Please see the Memorium to Mary Anne Fletcher – longtime ME/CFS researcher and partner of Nancy Klimas in the blog.
- Mary Anne Nancy Klimas noted that you can’t talk about ME/CFS or long COVID as autonomic or metabolic or immune diseases. All of them are present. These complex diseases are diseases of homeostasis; i.e. they affect multiple systems which, in turn, affect each other. That’s why they went to supercomputers to study them.
- She emphasized the need to get an ME/CFS group into the RECOVER Initiative for long-COVID patients, stating that this massive $1.15 billion effort “can only move us if the trials allow an ME/CFS comparator group”, and asking them to at least “allow, if not require, an ME/CFS comparator group in the trials that are being planned. It is so, so very important”.
- Her long-awaited and long-delayed ME/CFS clinical trial – I’ve begun to think of it as the trial that’s always about to begin – is actually about to begin.
- Nobody in the ME/CFS field has brought this much data – millions of data points generated by measuring everything they could (gene expression, immune functioning, immune cells, neuropeptides, cytokines) 9 times before, during, and after a ride on the bike to exhaustion (or at least near it) – to a clinical trial.
- It took a supercomputer to come up with the treatment regimen – staggered doses of etanercept to tackle neuroinflammation and mifepristone to reset the HPA access.
- A Phase I trial in GWI using the same treatment regimen “moved the needle in the right direction” and “made some real headway” and a modified Phase II trial is either underway or is on the books.
- The nice thing about these trials is that they’re potentially self-correcting; you give the patients the drugs, test the heck out of them, feed the data back into the computer, and let it self-correct. The potential for understanding this and other illnesses seems immense.
- Nancy Klimas has also put in an application to become one of the 3 NIH-funded research centers. Her approach is creative and novel and I, for one, hope she wins out.
- Moving onto mast cells, Nancy said they were “chronically leaky” in ME/CFS and noted that “serious headway” can be made in ME/CFS by quieting them down.
- Reduced blood perfusion to the brain makes it difficult to concentrate and produces brain fog, but “treatable points” are available and she pointed to luteolin, a mast cell stabilizer, that helps some people with ME/CFS. Much work in being done in this area.
- Travis Craddock asked why, with all the evidence of EBV reactivation in ME/CFS, the Rituximab study, which was designed to knock EBV-infected B-cells, didn’t work.
- First, he noted that the Institute’s genetic studies suggest that problems with the mucous membranes that protect the body from viruses may leave people with ME/CFS more open to viral invasions.
- His model showed that so long as other EBV reservoirs in the body are present, knocking the virus out only in the B-cells, allows the virus to remain in the body and soon reinfect the B-cells.
- His modeling efforts showed that combining Rituximab with an antiviral was much more efficacious. While the virus did persist, it was knocked down for long periods of time.
- Better EBV drugs may be on the horizon. An old drug called spironolactone led one University of Utah researcher to uncover a target that could stop EBV very early in its reactivation cycle. Plus, University of Ohio State researchers are attempting to recruit drug manufacturers to knock out a destructive EBV enzyme that’s been found in ME/CFS.
(One would have hoped the NIH – understanding the rigor (aren’t they all about rigor?), the depth, and the possibilities that this approach might present for other diseases might have funded this trial – but no – so far as I know, the ME/CFS Special Emphasis Panel (SEP) that rewards ME/CFS grants still refuses to fund any clinical trials. (C’mon guys – loosen up!) If I remember correctly, Nancy and colleagues raised the money for the trial on their own.
Nancy calls it their “moonshot” study and stated she was “really, really excited by it”. The Department of Defense (DOD) funded the Gulf War Illness trial using the same drugs. The DOD appears to be a tad less conservative and a tad more focused on getting patients better than the NIH.
First, the drug combo was tested in mice (yes, GWI has mouse models – thanks to DOD), and the mice responded as the model suggested. A Phase I trial in GWI “moved the needle in the right direction” and “made some real headway” (but apparently did not return the patients to “homeostasis”) and a modified Phase II trial is either underway or is on the books.
I wasn’t surprised to hear the first effort wasn’t a total success. I would have been surprised if it was, actually. So long as the models are good – and they should be getting better all the time – and Nancy can continue to get funded, this approach should be self-correcting. You give the patients the drugs, test the heck out of them, feed the data back into the computer, and let it self-correct. The potential for understanding this and other illnesses seems immense.
Note that Nancy’s using repurposed drugs that are readily available. If this thing works, there should be no problem getting them.
An NIH-Funded ME/CFS Research Center at INIM?
It was GWI funding that allowed her to create the infrastructure she was then able to bring to bear on ME/CFS and produce this clinical trial. Now she’s applying to be one of the NIH-funded ME/CFS research centers, and I hope she gets it.
So far as research center grants go – these do not appear to be not great grants. One research effort I spoke is not going to apply because they felt the administrative requirements were just too much. David Systrom apparently backed off during the last round for the same reason.
Maureen Hanson’s group, in particular, though, has really made hay with these grants – putting out interesting finding after finding, and Ian Lipkin has produced some major papers. Nancy’s group – 16 faculty members and 60 members in all – is now huge (by ME/CFS standards). If any group can productively handle the administrative load, one would think hers could.
She’s doing “moonshot” work that’s creative and novel, though – too novel for the NIH? We shall see. I would hope that the NIH would look at what she’s doing – see that she’s zeroed in on finding data-driven treatments – something they know this disease needs – and gives it to her.
The NIH’s refusal to fund clinical trials through the ME/CFS SEP, after all, is because they don’t feel the field is “ready”. They’re being careful – they’ve seen fields that moved too quickly set back for considerable periods, but Nancy comes loaded with data. That seems different.
Nasty, Nasty Mast Cells
Referencing Theoharides, who did a sabbatical at their lab and came to stay, Nancy was onto mast cells, which she said were “chronically leaking a lot of nasty toxic mediators into the bloodstream” (now there’s a vivid image) in ME/CFS. These mast cells are apparently everywhere in the body. An activation here, and activation there and pretty soon you could have something like ME/CFS. Every day in the clinic, she said, they “can make serious headway” when they quiet down mast cells in ME/CFS and long COVID. (A mast cell blog is coming up).
Next, she was onto the problems with blood perfusion to the brain. The brain is a finely-tuned machine that quickly delivers oxygen and glucose to areas in need. If you’re doing math, for instance, it will shunt blood to the part of the brain that does calculations. Except not so much in ME/CFS, where studies have shown that stressing one part of the brain does not necessarily lead to increased blood flows to it. No wonder brain fog is prevalent.
She stated, though, that treatable points in the brain that calm down the mast cells exist. Glutathione – the major antioxidant in the body – has trouble getting through to the brain, but luteolin, a mast cell stabilizer, can. A lot of work outside of ME/CFS is being done to find ways to deliver antioxidants and other anti-inflammatories to the brain.
The Epstein-Barr Virus (EBV) Conundrum or How to REALLY Knock EBV Down
Travis Craddock – the head of the modeling department – noted that despite the fact that EBV and herpesvirus reactivation appears to be present, antiviral drugs have limited effects. Craddock questioned if that’s due to the antiviral’s inability to completely wipe out the viral population, and then noted that EBV infects and hangs out in B-cells. The Rituximab trial tried to wipe out the B-cells in hopes of removing the virus. The first, small trial showed efficacy, but the larger study failed (miserably).
The question that nagged at them was: why? We have EBV reactivation and we know that EBV loves to hang out in B-cells – so why would a trial that removed those B-cells fail? Craddock proposed it just didn’t go far enough. Recent studies have found EBV in T and NK cells and epithelial cells. HHV-6 can get into NK, dendritic, epithelial cells, and the salivary glands. Given that – why would we expect a drug aimed at just one of those cells to work?
Mucous-Deficient ME/CFS Patients Give Viruses a Leg Up?
The other big question is why people with ME/CFS don’t recover from a virus that’s found in 95% of the population. Asking what is different about them, Craddock pointed to an INIM genetic study (unpublished) which found alterations in the genes that produce salivary and nasal mucous; i.e. the protective layer that pathogens and chemicals must surmount to get into the body, and which harbor pathogens as well. Craddock suggested that inadequate mucous layers might result in low-grade inflammation in these herpesvirus-laden epithelial cells that causes them to release herpesviruses into the body – jumpstarting the reactivation process.
The Model Builder at Work
The obvious next thing for Craddock to do – because that’s what he does – was build a model. Together with a Boston researcher, he built a mathematical model that took into account the saliva, the damaged mucous layer, the herpesviruses, B- and T-cells, and simulated the systems involved. Then they altered the parameters of the model many times.
The difference in their model was that they started out with an EBV infection in both the epithelial and the B-cells. The model showed the infection spiking and spreading and then settling down – with a reservoir established in both the epithelial and B-cells.
Next, they added several Rituximab doses a year. Sure enough, the virus dropped to nothing in the B-cells but then bounced back as the EBV emerged from the epithelial cells and reinfected the B-cells. It didn’t take too much time for the virus to return to its full strength.
Then, they changed the effectiveness of the antiviral from 100% to 99% down to 85% in the model. Only when the antiviral was nearly completely effective (99%-100%) did EBV get knocked down for long. The dose of antiviral needed to achieve that degree of effectiveness, however, would leave it toxic to humans. With the antivirals we have, knocking down EBV for good looked like an impossible task.
But then, they asked, what if you add a B-cell suppressor like Rituximab to the mix? Adding a timed B-cell treatment to an antiviral basically flatlined the virus – it was no longer able to reactivate. Craddock stated the model – which they are continuing to improve – suggested the approach could theoretically produce a long-term reduction – not a forever reduction, but a long-term reduction of viral load.
These are the kinds of novel approaches we will need. Prusty said it well – we are going to need a set of targeted treatments that match the complexity of the disease. No one silver bullet will do – but a couple might.
Better EBV Drugs on the Horizon?
The remarkable spironolactone saga demonstrates that better EBV drugs might not be that far in the future. In an attempt to knock out EBV in its earliest stages of reactivation, Sankar Swaminathan MD, an infectious disease researcher at the University of Utah, uncovered an old mineralocorticoid drug called spironolactone that was able to do that – but was too toxic to be used regularly. That drug, however, lead him to uncover a key aspect of early EBV reactivation, which he is now trying to target with drugs. Success could lead to a new, more effective generation of EBV-specific drugs.
Plus the Ariza-Williams team at Ohio State University published a paper alerting drug-makers to the potential that tamping down the EBV dUTPase enzyme may hold in treating herpesvirus infections.
Lastly, I was told that a potentially better EBV drug, that was developed but failed to get much interest, was looking more hopeful with the emergence of herpesvirus reactivation in long COVID. Time will tell, but suddenly the potential for a better herpesvirus drug seems greater than ever.
Watch a video of the conference – which also included some talks on healthy homes, getting better sleep, and nutrition here.
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