+100%-

Day two of the Conference – not all of which is covered here, started off with a physicians’ panel, then NIH Director Francis Collins showed up (covered later) just before the Intramural study presented some results, then it was onto Ian Lipkin, Dr. Oh, Bhupesh Prusty and Ron Davis.

Physicians Panel

The ME/CFS experts on the panel spent 10 minutes on a topic of their choosing. Dr Montoya reported that some of his long term patients with herpes viral infections were doing quite well on antivirals. Dr. Levine covered mast cell activation in 10 minutes – a valiant effort! I didn’t cover it but if you’re interested check a blog which includes a longer presentation at the 2018 Dysautonomia Conference.

2018 Dysautonomia International Conference I: Small Fiber Neuropathy, POTS, MCAS and Vagus Nerve Stimulation

Dr. Bateman – Orthostatic Intolerance

“Orthostatic intolerance is the low-hanging fruit. It is diagnosable and treatable, and we have a lot of literature about how to deal with it.” Dr. Bateman

Dr. Bateman spent her ten minutes on orthostatic intolerance – the inability to stand or stay standing without symptoms flaring up.

She, like others have, warned how quickly bed rest can cause orthostatic intolerance and had some clever ideas about how to exercise as safely as possible.

She has added pyridostigmine bromide (Mestinon) to her bag of tricks for fighting orthostatic intolerance (OI). Mestinon is another helpful drug which has been hiding out in plain sight for decades.  Brought to the attention of the ME/CFS community by David Systrom, it provides another option for dealing with OI and energy issues.

Mestinon

Mestinon completely cleared up one person’s POTS. (Not everyone has such a dramatic result.)

Check out a superb overview on Medscape by Miriam Tucker which goes over Dr. Bateman’s talk and David Systrom’s findings on exercise intolerance in ME/CFS. In it ,Tucker reported that the rationale for using Mestinon is to enhance norepinephrine release at the postganglionic synapse, thereby improving the constriction of the veins at the site of exercising muscles. It appears Systrom believes that impaired blood flow from the muscles is reducing blood flow to the heart. Increasing blood flow from the muscles improves blood flow to the heart, and ultimately better flow of oxygen to the muscles. One excellent Mestinon ME/CFS responder was able to exercise for the first time in decades.

Rowe reported to Medscape that Mestinon can be “transformative for some patients… even if they have not responded to fludrocortisonemidodrine, or beta-blockers”, and Dr. Bateman stated that Mestinon has “been an interesting and very effective intervention” and relayed the case of one responder.

Dr. Bateman also uses midrodrine, low dose propanolol, compression stockings, hydration and others in OI. Check out her video below.

Dr. Levine gave an outline of mast cell activation syndrome (MCAS) – a thankless task – in 10 minutes. Dr. Montoya reported that increased herpesvirus activation is found in his severely ill patient cohort (just the opposite of what Ron Davis found in his cohort) and that extended (as in over a year) antiviral herpes treatments do return some patients to health. Then, Dr. Peterson reported on the role of precision medicine in ME/CFS.

Dr. Peterson’s Precision Medicine Hopes

Dr. Peterson’s talk, which focused on the ever evolving world of diagnostics, was fascinating. He rattled off several cases of obscure diagnoses (Powassan virus, overt (and correctable) cytokine abnormalities, and others) enabled by technical advances in medicine. I was in contact with one person who Dr. Peterson diagnosed with uranium poisoning. Peterson is using tools like Genecept and the Precision Medicine Test for Pathogens to get ever more precise diagnoses.

Plus, Peterson provided some more hope when he reported that a heart disease drug (of all things) called spironolactone may provide a new class of drugs to fight herpesviruses.

He and the Simmaron Foundation are also mining his database of patients to learn what works best in which patients, and the Simmaron Research Foundation is doing a deep dig into the effects of Ampligen. Results from that study were presented at the Young/Early Career Investigators’ workshop and will be presented on this site soon.

NIH Intramural Study Scores Some Early Hits

The fact that the Intramural study was able to deliver so little at a conference that was intended to show its results off suggests that everything is taking longer than expected. That seems to be a theme with the NIH and ME/CFS.

The good news is the intramural study is starting to do some preliminary analyses, and they are finding some things. Using – what else – the Seahorse, they’re finding increased (not decreased) mitochondrial respiration in the ME/CFS patients tested so far. This isn’t as far-fetched as it sounds. A Stanford study found that immune cells from ME/CFS patients had double the rate of energy production compared to cells of healthy controls. The study findings suggested increased glycolysis was the culprit. Increased folding of mitochondrial membranes called “cristae” (which results in increased membrane surface area) suggested that the mitochondria, even though they were pumping away, were under energy stress.

The author of that study suggested that immune activation could be driving the high energy production in the cells.  Note, though, that these cells are being measured outside the bloodstream. Ron Davis’s tests suggest that something in the blood is tamping down the energy production of immune cells.

The Stanford Paradox: Elevated Energy Production Found in Chronic Fatigue Syndrome (ME/CFS)

mitochondria exercise ME/CFS

Exercise causes a drop in oxygen consumption (energy production) in about half of ME/CFS patients.

Where the intramural study really shines is in its use of a maximal exercise stressor to really shake things up. Much less data on this is available, but Walitt did show that the bout of exercise caused mitochondrial oxygen consumption to increase in the healthy controls but decrease in half of the ME/CFS patients (in blue) tested thus far.

The NIH is doing something else that hasn’t been done before – flow cytometry on cerebral spinal fluid from lumbar punctures and the blood at the same time.  Walitt then highlighted another strength of the intramural study – the huge database of findings that NINDS has for other diseases that can be matched with ME/CFS – giving us, hopefully, some idea of what diseases ME/CFS is most closely allied with.

Among other things, flow cytometry allows researchers to minutely characterize the types of cells found in a sample. Finding elevated numbers of cells that get activated when a pathogen is present, or are indicative of an autoimmune process, gives researchers an idea of what’s going on. Finding low levels of cells could suggest a hole in our immune defense.

The NIH’s plan is to start off with a coarser filter and then dig down further to better characterize any anomalies they find.

B-cells NIH flow cytometry

The very low purple levels on the right side of each diagram indicate a “bottoming out’ of B-cells in the spinal fluid of the ME/CFS patients.

The NIH found no difference, thus far, between CD4/CD8 ratios or NK cell frequency in ME/CFS and healthy controls, but check out what happened when they examined B-cell frequency: normal in the blood but very low – so low that Walitt called it a “bottoming out” – in the spinal fluid. This was particularly unusual, as it looked like every other disease in Walitt’s chart demonstrated increased B-cell frequencies. Another B-cell was similarly low in the cerebral spinal fluid (right diagram). This is another piece of evidence suggesting that the immune system in the brain may be a key player in ME/CFS.

The study protocol has been – as Nath suggested it would – shifting. (It’s now on its 11th amendment.) It appears that the NIH is now inviting participants who washed out after the first study to come back and do more testing (rTMS, fMRI, EEG, muscle and skin biopsies). These studies are now going to be included in the first week for all participants. One wonders if the NIH is finding these tests to be particularly discriminative.

A Colorado doctor who has a patient in the study got up and called the study an “unbelievable opportunity” and asked them to increase the number of participants.

This trial is taking time but is off to a good start with some positive preliminary findings. It needs more study participants! They would particularly love to have ME/CFS patients who have a healthy family member who can participate.  Find out how to participate in this study here. 

Ian Lipkin’s Possibilities

Lipkin first presented a map showing an impressive array of collaborators stretching from coast to coast. He’s all about rigor – and highlighted that fact on his slide. One gets the sense that Lipkin is not going to get ahead of the science – and he pointed out an important theme – large-scale studies, done correctly, start to add up.

ME/CFS is, of course, full of small studies with interesting results that have done little to spark the imagination of other researchers. Large-scale studies done well that come up with consistent results is another animal entirely – and the NIH funded research centers, with their large studies, are helping with that.

The three projects underway in the Lipkin lab demonstrate just how important these centers are. No other institution has the cash to fund, on an ongoing basis, three large projects like those underway at Lipkin’s center. For instance, the full genome analysis of the microbiome, underway at Lipkin’s NIH center, contains 195 cases and controls.

gut bacteria ME/CFS

Lipkin finds consistent upregulation of harmful bacterial species and downregulation of helpful bacterial species in ME/CFS.

Lipkin’s now got two big microbiome studies under his belt. (The other one, funded by the Hitchens Foundation, has 100 cases and controls.) The good news is that these fantastically complex studies have come up with some similar results. Two bacteria associated with inflammation and gut permeability are upregulated in ME/CFS, while butyrate-producing bacteria which tend to dampen inflammation are reduced in ME/CFS.

Lipkin has found dramatically different gut bacteria in ME/CFS patients with IBS.  Next, he noted that butyrate species were also reduced in this group and that two studies have found increased numbers of Clostridium species. The Clostridium bacterial group contains some notably pathogenic species.

The fact that Lipkin also found harmful bacteria in the saliva of people with ME/CFS associated with oral and gut issues made one wonder if any part of the microbiome is not “off” in ME/CFS.

His search for a virus – which he had great hopes for – has been for naught, however. A more detailed search for herpesviruses in white blood cells, saliva and even in fecal material has found nothing statistically significant in ME/CFS. Ron Davis, with his severe ME/CFS group, and the SMCI, with a previous study, have reported similar results.

That presents the odd paradox of knowing that some patients benefit from antivirals, without any evidence, thus far, that viruses are present. Lipkin did hedge his results a bit by saying that, at the time and in the compartment they’ve sampled in, they’ve been able to find nothing that would jump out at them. He also said that he believes a herpesvirus trial in patients with the right test results makes sense “biologically”.

Lipkin next presented evidence suggesting that the metabolomics field is not yet on sturdy legs. An apparently dramatic change in the databases researchers rely on over just a few years made it “very difficult” to compare the results of his recent NIH study and his last one – which was published just last year (!). That probably didn’t put a happy face on a researcher focused on rigor and reproducibility, but the good news is that, after finessing the data to account for the changes, a similar set of metabolites popped out that have shown up in his studies and in past ME/CFS metabolomic studies.

plasmalogens

Low plasmalogen levels – an early but intriguing finding from Lipkin.

A fascinating but early result involves plasmalogens – lipids that play important roles in the structure of cell membranes in the heart and brain. They’ve shown up in both of Lipkin’s metabolomic studies and are reduced in the brains of Alzheimer’s, Parkinson’s, multiple sclerosis and – this preliminary findings suggests – ME/CFS.  They’re degraded by a compound called cytochrome C that is released by the mitochondria when they are under stress – including the oxidative stress that is common in ME/CFS.

The plasmalogen finding, if it holds up, could provide a nice link between mitochondrial issues, the oxidative stress found in the brain and elsewhere, the issues of premature aging, and the nervous system problems in ME/CFS.

Lipkin’s pilot epigenetics study was notable for what he did with it – he added a transcriptomic analysis his study.

Transcriptomic analyses give “a broad account of which cellular processes are active and which are dormant.” Lipkin was able to tie those two analyses together in a nice package to show that genes associated with iron uptake, not only did not appear to be turned off, but the transcriptomic analysis indicated that they were less active in real time.  The differences were modest, but Lipkin noted that modest differences can add up if they show up repeatedly in a pathway – which may be happening in ME/CFS.

If they are, they could have quite an effect. Lipkin stated that, based on their “very early” data, they would “predict” lesions would be present at four parts of the iron intake pathway into the cell, which plays a role in two potentially very important aspects of ME/CFS: oxidative phosphorylation (ATP production) and oxidative stress.

All in all, Lipkin’s talk presented some fascinating possibilities. It’s still early days – we don’t know if these results will be relevant to ME/CFS – but they certainly showcased the way these large and complex ‘omics studies may be able to provide some answers.

Coming back to the pathogen issue, Lipkin reported on a “serochip” he’s developed in collaboration with Roche, which allows him to use antibodies to detect previously undetected infections. The chip, in his work with ticks, for instance, allowed him to detect several new tick-borne infections.

lipkin acute flaccid myelitis

Virus studies were uninformative, but a new antibody approach worked.

He then referenced acute flaccid myelitis, a rare (1:2,000,00) but devastating neurological disease, which in its onset – a mild viral infection involving enteroviruses – has some similarities to ME/CFS.  (Avindra Nath is also right in the thick of the hunt for the cause of the disease.) Identifying the pathogen producing the lesions in large sections of these childrens’ spinal cords has been torturous. Enteroviruses are highly suspected, but even Lipkin’s very sensitive techniques, done in the cerebral spinal fluid, have often proved fruitless.

A Serochip specifically designed to assess the disease, though, produced positive results in 87% of the children with the disease and not in other neurological disease. Lipkin, then, is on his way to possibly solving the greatest question in acute flaccid myelitis – is an enterovirus causing the disease? Lipkin’s results suggest yes, and can even point to the two enteroviruses likely to be the culprits.

His results suggest – as has been suspected in ME/CFS – that acute flaccid myelitis is a hit and run phenomenon: the pathogen strikes, sets a damaging process in motion, and then disappears. Lipkin’s success here suggests that if a putative trigger can be identified, then a specialized antibody panel can be produced to identify it.  His next phase is to complete the fungal and other work (nobody to my knowledge has assessed fungi in ME/CFS yet) and then use a serological approach to dig deeper.

Lipkin’s talk, then, presented a nice blend of hard results – consistencies found in the microbiome and metabolomic studies – and intriguing possibilities which we’ll have to wait to see if they pan out.

Lipkin’s talk was another reminder of how good it is to have this researcher, with his wide array of sophisticated technologies, working on ME/CFS.

Dr. Oh – The Strain of Getting Gut Results

MAIT Oh NIH conference

Are highly cytotoxic T-cells in the gut causing problems in ME/CFS?

Then it was on to Dr. Oh, who immediately shored up Lipkin’s gut findings with one of her own, indicating that butyrate bacteria are indeed reduced in ME/CFS. When she tried to add butyrate bacteria to ME/CFS cultures, they failed to thrive, suggesting that something in the teeming gut ecosystems of ME/CFS patients was knocking them out.

The question, of course, is what is turning up the heat (inflammation) in ME/CFS patients’ guts? The answer might be those MAIT T-cells Unutmaz referred to earlier – and the bad bacteria activating them.

A search for bacterial triggers found so many different bacterial species that the sheer variety of them, Dr. Oh said, blew her mind.  Then it got even more complicated. MAIT cells are known to be activated by antigens that are generated from a precursor of the riboflavin (Vitamin B2) biosynthesis pathway, but Oh reported that: (a) not all bacterial species that activate MAIT cells produce riboflavin; and (b) some that do produce riboflavin do not activate MAIT cells.

The fact that the reduced ratio of bacterioides/firmicutes bacteria found in ME/CFS is also found in other diseases such as inflammatory bowel disease and type 2 diabetes suggests it may be having negative effects.

When Oh said that it’s not actually “this easy”, I had to laugh as it didn’t seem easy at all, but then it did get a lot harder. Lipkin and Oh are looking at actual bacterial species – a big jump up in clarity for ME/CFS  – but species, it turns out, can only take you so far. The real juice, Oh suggested, lies in the strains found within the species. How different can strains within a species be? Broccoli, cauliflower, brussel sprouts and cabbage are all strains of the same species. There are benign E. coli strains and deadly ones.

Precision gut therapeutics

Precision gut therapeutics

So, the question becomes, which strains of bacteria best activate MAIT cells, and they are looking to find out. So far, they’ve found a huge difference in MAIT cell activation across different strains of a bacterial species.

The goal in the end is precision microbiome therapeutics that seeks to return the microbiome to a healthy, non-inflammatory state. Antibiotics – long the preferred therapeutic modality – are too crude. Precision replacements, including probiotic transplants and even engineered probiotics are the wave of the future.

In response to a question about diet, Oh noted that they will include diet in their analyses. In fact everything – immune findings, gut findings, diet, etc. is all going into the big data mix. Diet does have an effect on the microbiome, and it may play a role in the therapeutic approach to ME/CFS. (It’s hard to believe that it could play a significant role in triggering it.)  Oh noted that,  as with our genes, we’re born with our own unique bacterial makeup, which diet can then affect to some extent.

Oh said it’s entirely possible that researchers will be able to create a specialized fecal transplant, which, through a single or a few bacterial species, addresses the gut issues in ME/CFS. When that might occur, she would not say…

Still, the Unumatz/Oh team has gone beyond the exploration phase; i.e., they have a pathway. They have a T-cell their research indicates may be a major player, they’re determining which bacterial species and even strains may be triggering the production of that T-cell, and if they can identify those, they’ll have a shot at turning MAIT cells down. If they are right, reducing the immune activation that so many people believe is driving this illness, may be the key.

Bhupesh Prusty’s Big Idea

“There is clearly something in the (ME/CFS) patient’s serum” Prusty

While exploring his big idea, Prusty came to the same conclusion as Ron Davis and Fluge and Mella: something in ME/CFS patients’ serum is affecting the ability of their cells to produce energy.

What an intriguing character Bhupesh Prusty is. Speaking just minutes after Ian Lipkin reported that he could find no evidence that herpesviruses are playing a role in ME/CFS, this young German researcher from the University of Wurtzburg suggested that HHV-6 infections are alive and well in ME/CFS and are putting a hammer to cellular energy production.  The title of his talk “Pathogenic Alterations of Mitochondrial Dynamics: A Working Model for ME/CFS” said it all.

Funded by the SMCI’s Ramsay Awards to study ME/CFS (as well as the HHV-6 Foundation), he was one of the few researchers from outside the U.S. to present. The NIH must have thought he was doing something right to get him over here.

Over the past year or so, it’s become pretty clear that something is up with the energy production of our immune cells. Could it be a pathogen? In what was one of the more provocative talks of the conference, Prusty made it clear he thought so. The association between pathogens and ME/CFS is clear: from the Dubbo studies on, the data is very clear – whether it’s EBV or another herpesvirus, or giardia or Coxsackie or another pathogen, any serious infection is typically going to leave a subset of people in a long lasting ME/CFS-like state.

The big question dogging this field, of course, is how that happens. Prusty will present on HHV-6A data, but he believes that that pathogen, and herpesviruses in general, present the tip of the iceberg. He believes his model will also fit other pathogens.

Prusty mitochondria shape

Not necessarily like the textbooks show at all…In their elongated state, the mitochondria play an important role in immunity.

Prusty, like Naviaux, believes the mitochondria are much more than the energy producers of our cells – they also play a key role in the cell’s antiviral response.

Prusty’s data indicates that HHV-6A – the more pathogenic of the HHV-6’s – prevents the mitochondria from combining together to form the elongated forms that participate in antiviral defense.

Prusty found a miRNA in charge of breaking the mitochondria up. HHV-6A not only promotes the expression of this miRNA, but produces a bit of RNA (sncRNA-U14) which also prevents the mitochondria from joining together to knock out viruses. Plus, viral reactivation causes ATP levels to drop.

Suspect RNA herpesviruses

Suspect RNA is found throughout the herpesvirus family.

Prusty then showed that the piece of RNA he believes is jamming up the works of the mitochondria is found throughout the herpesvirus family.  He called it a “potentially universal” approach pathogens take to affect the mitochondria.

But what about HHV-6A? Lipkin just reported that he was unable to find any evidence that HHV-6 is playing a significant role in ME/CFS. Prusty looked and looked and looked. The blood and serum were a wash. The PBMC’s were a bit better, but when he looked, there wasn’t that much there there – even when the virus was present – the loads were low.

See the green (elongated mitochondria) disappear and the dip in the graph to the right as mitochondria surface area declines as the mitochondria begin to break up.

Was another beautiful hypothesis about to bite the dust? Prusty then looked for evidence that his mystery RNA was present in blood clot cells and found it – in about 40% of patients and in none of the controls.

Then some serendipity struck. Fluge and Mella had just published a paper, and Ron Davis had suggested that something in ME/CFS patients’ serum was interfering with ATP production – causing what Prusty called a “senescence” – something similar, one would think, to the hypometabolism proposed by Naviaux.

Serum mitochondria

The mitochondria are in green. Again, adding ME/CFS patients’ serum (right hand pictures) into healthy cells causes the mitochondria to break up and decline.

When Prusty added ME/CFS patients’ serum to his culture, the mitochondria began to break up. Adding supernatant from an HHV-6 reactivation caused the same process to occur.

It was great to see Ron Davis’s and Fluge/Mella’s serum findings replicated over in Germany in a completely different cohort. While only one study showing these findings has been published, the fact that serum from ME/CFS patients from the U.S., Norway and Germany appears to be producing the same results is good news indeed.

Referring to a graph which I couldn’t make sense of, Prusty reported that removing ME/CFS patients’ serum from the cells produced a startling transformation – the mitochondria began to come together, reproduce their elongated forms and appeared healthy again.

Prusty is attempting to isolate that mysterious, mitochondrial-inhibiting factor in a very interesting place – the exosomes that Maureen Hanson is examining in her NIH research center. Exosomes – small vesicles that kind of burp free from the cells from time to time – are a different form of cellular communication. By releasing their contents or otherwise communicating with other cells, they’re able to alter cellular function. If something in ME/CFS patients’ serum is causing problems, it could be an exosome. Alternatively, high levels of oxidative stress, small RNA’s or cytokines or other proteins could be the issue.

Prusty’s serum work set the stage nicely for Ron Davis’s presentation.

Ron Davis – Always Pushing Forward

Davis started his talk acknowledging that the title “Estabilishing New Mechanistic and Diagnostic Paradigms for ME/CFS” was a bit optimistic, but intentionally so because we always need to push forward.

He couldn’t be more correct. Our actions always align with the future we hold in front of us. If that future is one of resignation, of little change and progress, then our moods, our thoughts and our actions will correlate with that and things will probably go on as they have.

The big data study

Big data indeed.

Resignation provides its own kind of juice. There’s a kind of righteous comfort in knowing that things will never change, that things are preordained to go the way they have.  It gives you a sense of control, but it also takes you off the hook for trying to change things, and there’s ultimately no cheese down that tunnel.

If, on the other hand, we hold a future in front of us of this disease being validated and worked on, of sick people becoming well, then our thoughts, feelings and actions will correlate with that future and we will be freed up to move and take the actions that will ultimately bring those things about. I have no idea when those things will occur, but I do know that that’s a far more exciting and fulfilling future to live into. It even brings a sense of worthwhileness to the suffering.

The Gist

Orthostatiic intolerance is common, is often not diagnosed and often can be treated

Some of Dr. Montoya’s patients on longterm herpesvirus antivirals have responded well

Precision medicine is helping Dr Peterson uncover diagnoses that would have been missed before

Early results from the Intramural study suggest mitochondrial abnormalities and low B-cell frequencies in the spinal fluid are present

Three large gut studies have all found reductions of butyrate gut bacteria – suggesting that a pro-inflammatory gut ecosystem is present in ME/CFS. Two studies have found in increases in possibly pathogenic Clostridium spp

Both Ian Lipkin in his “normal” ME/CFS group and Ron Davis in his smaller severely ill ME/CFS group have failed to find any evidence of unusual viral activity. Lipkin did, however, note that specialized antibody panels prove fruitful in the quest to identify viral triggers in ME/CFS

The metabolomics findings continue to show good consistency across the studies.

Ian Lipkin’s early finding of increased plasmalogens could link oxidative stress, mitochondrial problems and neurodegenerative issues together.

Ian Lipkin’s very early epigenetics/transcriptomics results predict problems with cellular iron absorption and ultimately mitochondrial issues are present

Oh is searching for specific strains of bacteria that are triggering high levels of MAIT cells that Dervya Unutmaz believes may be causing major problems in ME/CFS.

Oh held out hope for a precision fecal transplant which returned the gut ecosystems of ME/CFS patients to normal.

Prusty, a young German research, finds that a small bit of HHV-6A RNA is able to stop the mitochondria from joining together to participate in antiviral defense.  This RNA is found throughout the herpesvirus family.

in a rather stunning addition to the plasma findings from Ron Davis and Oystein Fluge, Prusty found that both the serum from ME/CFS patients and the serum associated with HHV-6 reactivation, caused the mitochondria to disassociate, thus turning off their antiviral defense.

Ron Davis is finding, as Jose Montoya did before him in less severely ill patients, that cytokine levels are correlated with severity in his severely ill cohort.

Assessing the validity of the Metabolic Trap hypothesis has hit a snag as neither filtering cells, changing the media, or improving the instrument used has resulted in results that can be trusted. Next, the group will assess the trap in individual dendritic cells.

The nanoneedle continues to be able to distinguish ME/CFS patients from healthy controls with an astonishing specificity and the results will soon be published in a distinguished journal.

Plasma exchange experiments continue to indicate that something in ME/CFS patients plasma is causing their cells to behave strangely when placed under (salt) stress. in a possible major breakthrough early testing suggest that exosomes – small vesicle cells emit which communicate with other cells – may be responsible. Both Maureen Hanson and Prusty ( and probably Ron Davis :)) are examining exosomes in ME/CFS.

Early hair analysis results highlight increased mercury and uranium (!) levels associated with decreased selenium levels. The sample size is small, however.

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Davis’s first stab at fulfilling a future of a healthy son and ME/CFS community was to collect as much molecular data as possible from people in whom this disease shines brightest – the very severely ill (20 severely ill patients and their 15 families).  If Davis had let the past define his project, this project never would have happened. New ways of collecting data from bedbound patients had to be devised, and then to make the data available to outside researchers, he had to poke a hole in Stanford’s firewall – something that had never been done before. It took a long time, but the firewall was breached and the data is now available to researchers outside Stanford.

The point is, the future that Davis is living into – beating this disease as quickly as possible – requires collaboration and sharing data as broadly as possible. Given that future, Davis was able to find a way for Stanford to do something it had never done before – letting outsiders inside its gates.

It was good to see that cytokine levels do correlate with illness severity in Davis’s small but very severely ill ME/CFS group, as we’ve seen in Montoya’s much larger and less ill group. (Several times, Davis made clear that he believes his severely ill group is probably more severely ill than others; i.e. than Dr. Montoya’s!) This field appears to be developing a new way of looking at cytokines – which, after all the variable cytokine results, appears to work for ME/CFS. While introducing a new way of looking at the immune system bumps up against barriers, it seems it will be necessary in this category-defying illness.

The search for viruses, bacteria and parasites is not over, but it appears to be mostly over and nothing of consequence has shown up.  An in-depth genomic analysis (provided for free by Illuminex) is still being assessed, but it did indicate that all 20 of the severely ill patients had damaging mutations in their IDO2 gene. Because those mutations are common, they would not have shown up in an automated search, but there was something different in the ME/CFS patients – many of them were homozygous; i.e. both alleles of their genes carried the mutation, rather than just one.

Davis described Robert Phair’s Metabolic Trap hypothesis, how high tryptophan levels can knock out the IDO1 enzyme, which in turn knocks out the serotonin pathway. There is a backup – the IDO2 enzyme – which converts the problem substance, tryptophan, to kyneurinine – thereby dropping tryptophan levels to the point at which IDO1 and the serotonin pathway are functioning again.  Phair’s modeling work suggests that even a heterozygous mutation could so impair IDO2’s ability to drop tryptophan levels that the pathway could remain broken.

The thing about this trap is that, if it exists in ME/CFS (or other chronic illnesses), it would be very hard to get out of. In fact, Davis suggested that metabolic traps could explain why illnesses tend to be chronic and so difficult to get out of. Once you have one, you tend to have one for life.  Phair and Davis have, in fact, uncovered another possible metabolic trap involving tyrosine.

The tryptophan trap model proposes that tryptophan (trp) will be increased, the kynurenine/trp ratio will be decreased, and the flux through that pathway will be impaired. The trap seemed set – the results of the first six patients accorded with it, but further testing revealed too much variability, indicating that the testing couldn’t be trusted. They went back, changed the media to boost the signal, switched to a better mass spectometer – and still got results that were all over the map. They filtered cells out to concentrate on the dendritic cells believed to have the trap – and are still getting too much variability.  It may be, though, that the trap is present in only a subset of dendritic cells  – so the next step is to examine isolated dendritic cells.

But this is how science goes! No one ever said it would be easy, and Davis has alluded numerous times to how hard it is and how complex the body is. Bumps in the road are expected.

Davis asserted that the Metabolic Trap hypothesis makes sense – it suggests, as Cortene’s hypothesis does (in a different manner) that serotonin problems are mucking things up in the brain. If it is present, the metabolic trap should affect the gut, brainstem and immune system.

Nanoneedle

Meanwhile, on a brighter note, the nanoneedle continues to demonstrate an amazing specificity in ME/CFS. A quick look at the chart indicates a huge separation between the ME/CFS patients (in red) and the healthy controls (in blue). Statistically, the odds that such a thing could be happening by chance is now in the 1 in a billion range.  We should see the results soon in the official journal of the National Academy of Sciences – “The Proceedings of the National Academy of Sciences of the United States of America”, a distinguished journal indeed.

Plus, the fascinating plasma issue is holding true.  Adding ME/CFS plasma to healthy cells causes the impedance levels to wildly increase, while adding healthy plasma to ME/CFS cells causes them to react normally. Something in the blood appears to be taking a two-by-four to our cells. Studies indicate that it’s not a metabolite – our metabolism is not producing some metabolic breakdown component that is disturbing our cells. Nor does it appear to be a cytokine, but in what may be a very lucky break, Davis was able to recreate the problem with an exosome. Davis wouldn’t commit to it being an exosome, but right now that’s what it looks like. That would be a great break and good news, given that both Maureen Hanson and Prusty are examining exosomes.

We know the nanoneedle indicates something dramatically different happens to ME/CFS patients’ cells when they’re stressed with saline, but we still don’t know what – a question that clearly has to be answered. Davis suggested the increased impedance signal may reflect a mitochondrial breakdown, and that would surely make sense, given what we’ve learned. Two drugs – both coming from Bob Naviaux – that are able to obliterate that signal (Copaxone and an SS-peptide) point to that.

Then came a preliminary but really weird finding – elevated levels of mercury (not so weird) and high levels of uranium (really weird) associated with low selenium levels in the hair analyses of a significant subset of patients. Both the mercury and uranium issues derive from low selenium levels. Selenium, interestingly, also plays a role in the conversion of T4 to T3 in the thyroid. (Chris Kressler recommends getting your selenium levels tested and, in general, using dietary methods (not selenium supplementation) to safely increase selenium levels in hypothyroidism.)

A Common Theme?

A lot of the work was preliminary but it was fascinating to see the potential overlaps emerge: the intramural studies’ early mitochondrial findings, Lipkin’s possible plasmalogen and epigenetic iron findings, the mitochondrial breakdowns that Prusty induced using ME/CFS plasma or HHV-6A reactivation, and Ron Davis’s nanoneedle and plasma exchange results pointed to a general theme – mitochondrial issues and problems with oxygen delivery/utilization – which come to think of it, showed up on Day 1 with David Systrom’s, Maureen Hanson’s and Betsy Keller’s presentations. Plus, a new possible culprit has emerged – exosomes – which Maureen Hanson and Prusty are looking into now.

Check out the first day of the conference 

Accelerating ME/CFS? The NIH Conference Day I: Exhausted Systems, Inflammation and Weirdness

 

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