A Critical Look at the NIH’s Accelerating Research Conference

This chronic fatigue syndrome (ME/CFS) conference was different. Besides the normal goal of bringing researchers together to share their latest results, it had an ulterior motive – getting NIH researchers involved and highlighting the work of the new NIH-funded ME/CFS research centers.


The conference room never filled up.

I wasn’t able to get a full picture of the conference. After getting sidelined by a lingering cold halfway across the U.S., I watched the conference from a hotel room in Kansas City. But what I could see suggested the conference didn’t achieve either of its two goals.

While the upper part of the room was fuller, the lower part of the room near the stage never came close to filling up. Many of the questions put to the presenters came from patients, advocates and people with an agenda – not from NIH researchers newly interested in the field.

Plus, perhaps not surprisingly, given how long everything takes with ME/CFS at the NIH, we got precious little from NIH-funded research centers or from the intramural study, and the most interesting talks came from outside researchers.

As a showcase of what the new NIH approach is doing for ME/CFS, then, the conference appeared to be six months or so too early. The NIH, it should be noted, plans these things far in advance, and must have thought things would be further along by now.

This is not to slam the conference organizers. It was a worthy effort and an NIH ME/CFS conference is better than no NIH ME/CFS conference but the failure of the conference to pack the hall with NIH researchers was a pretty stark reminder that, once again, the half measures the NIH is taking on ME/CFS are not going to do it for this field. We have, after all, had NIH conferences, and some small NIH-funded ME/CFS research centers before.  If the NIH going to fulfill on NIH Director Francis Collins’s promise to get serious about this disease, it must do more.

A Good Start

The conference presenters did a very smart thing – they started off with Cindy Bateman! Her sober, clear and impactful presentation was just what the doctor ordered for any skeptics in the audience.

The highlight of Dr. Bateman’s talk for me was her case report of a formerly active and now severely ill person with ME/CFS who is: a) getting excellent medical help; b) has the full support of her husband; c) has the ability to try everything; and d) is still severely ill. The patient – who is getting the best of the best – dramatically represented the limits of our current knowledge of ME/CFS.

It was a perfect way to present how dire the need is.

Metabolomics Session Disappoints

It was not surprising to see metabolomics – the hottest field in ME/CFS research – take pride of place during the first session of the conference. The surprise was how flat the session fell.

Bob Naviaux’s attempt to cram perhaps a decade of thought into a 30 minute presentation contained some of his most intriguing insights (Dauer, the mitochondria-illness connection), but it included almost nothing on ME/CFS and did little to advance the conference goal – accelerating research on ME/CFS.

Similarly, Oliver Fiehn – a metabolomics pioneer – was an impressive presence but spent almost all his time trying apparently to convince the audience that the metabolomics field was: a) legitimate; and b) ironing out its apparently still significant problems. His last second summation of his recent metabolomics results in ME/CFS – which he seemed almost apologetic for – did not seem likely to embolden NIH researchers to enter the field. It’s unfortunate we didn’t get a good overview of this important field at this conference.

Jonas Bergquist – on the other hand – whom the Open Medicine Foundation recently awarded funding for a Swedish ME/CFS Research Center gave a well organized and clear presentation. His talk titled, “The Biochemistry to Support the Evidence of Neuroinflammatory Involvement in ME/CFS”, wasn’t on metabolomics, but it was on ME/CFS.

The presentation focused first on his past proteomic work which he updated with some new proteomic work data. It was good to see Bergquist find alterations in proteins that fit with what we would expect – neuroinflammation, lots of cell damage and an upregulation in proteins designed to repair that damage. Getting results from different compartments of the body which highlight the same thing – in this case inflammation – is a good thing.

Bergquist’s inclusion of multiple sclerosis in his latest study paid off with ME/CFS falling somewhere between healthy controls and MS patients. The fact that he found many more protein differences in the cerebral spinal fluid than in the plasma suggests that the neuroinflammation – as Jarred Younger and Nancy Klimas believe – may indeed be the key.

Bergquist’s results – which are preliminary – will hopefully inform the Ian Lipkin / Simmaron Research Foundation new cerebral spinal fluid study – which now includes metabolomics. Those results of the Lipkin study are not available yet as the journal reviewers passed the study back to Lipkin asking him to get more healthy controls.  Given the latest neuroinflammation findings, the first metabolomics study of the CSF in ME/CFS should be fascinating.

Bergquist has also found evidence of thyroid dysregulation in ME/CFS and has validated Carmen Scheibenbogen’s autoantibody results in ME/CFS. Given his results, it was easy to see why the OMF granted him that new ME/CFS research center. Let’s hope those studies will be published soon.

Immunology Session

Jose Montoya’s “Different Reality”

Jose Montoya of Stanford has a gift with words and always gives an interesting presentation. This time, he gave an excellent presentation that highlighted his current work and demonstrated the wide variety of research projects he has underway.  Montoya contextualized his research quite well – asserting that the normal rules of inflammation do not apply in ME/CFS, that different kinds of inflammation are present, and that NIH researchers shouldn’t be tied to old ideas! His assertion that “a different immune reality” exists in ME/CFS – which he called a “chronic incapacitating inflammatory disorder” – hopefully perked up some ears.

Working with Mark Davis and others, he’s been digging away at the impressive database of samples he’s gathered (200 patients/ 400 controls) with Ian Lipkin, Mark Davis, Ron Davis and others at Stanford.


Mast cell activation – a SIMPLIFIED model.

Montoya’s big cytokine study suggested that cytokine levels do matter in ME/CFS but only (with two important exceptions) if they are correlated with severity.

TGF-B, which has now been found upregulated in five of eight studies is one notable exception, and Montoya asserted that we should now just put a pin in that finding and recognize that it plays an important role in ME/CFS. Besides other things, TGF-B appears to be upregulated in mold exposure and mast cells, and plays a role in Ritchie Shoemaker’s conception of mold-induced illnesses.

Montoya also reported that 10 of the 17 cytokines highlighted in the cytokine study play a role in mast cell activation. His “simplified model of mast cell activation” made one wonder, though, if that finding is a benefit or a curse.

cytokine network hubs Montoya

The hubs of the cytokine networks have shifted from one side to the other in healthy controls (left) compared to the people with ME/CFS (right).

Montoya’s finding that cytokine levels are highly correlated with severity appears to have caused him to dig more deeply and he’s now assessing cytokine networks – something Dr. Klimas has long been a proponent of. His overview of cytokine network findings underscored how dramatically different the networks of healthy people and people with ME/CFS are. Each network circled around different central hubs – suggesting that the immune systems of people with ME/CFS had dramatically changed. Gone were the neuroprotective factors found in the healthy controls – replaced by a pro-inflammatory network found in people with severe ME/CFS.

In another move that seemed reminiscent of Dr. Klimas, Montoya also discussed doing an “in silica” modeling of cytokine networks with the idea of trying to determine how to shift a network back to normality.  He has also found evidence of, if I have it right, a genetic alteration in a HLA gene in ME/CFS which has been associated with a series of autoimmune diseases, and is working with Ron Davis on that.  (Davis recently created a better and more efficient way to assess these highly variable and complex genes involved in our immune response to pathogens.)

Montoya now also has funding for and is getting samples from the severely ill in his studies. All in all it was a good presentation with lots of food for thought for the NIH.

Mark Davis’s Search

Ron Davis got a rare major grant for ME/CFS to fund Mark Davis’s work on T-cell clonal expansion – a project which we learned originated in a hallway conversation between Montoya and one of Mark Davis’s students. That study was (and is) being funded by the OMF, and is the subject of the big NIH grant.

Talking about his T-cell work, Mark Davis started off by saying that ME/CFS more and more looks like an autoimmune disease. It was a complicated presentation full of twists and turns which showed that the deeper you look into the immune system, the more surprises it holds, and the less you can trust traditional thinking. Davis, for instance, found massive clonal expansion of T-cells in a multiple sclerosis model. That indicated that the cytotoxic T-cells had encountered something and were pumping out clones which then went to work obliterating the myelin on MS patients’ nerve cells.

When Davis tried to make the situation worse by adding more cytotoxic T-cells to the mix, the disease got better instead of worse (!). That made it more important than ever to find out what those cytotoxic T-cells were going after. Davis’s student developed an algorithm to do that, which – in a reflection of how difficult (and important) a feat that was – wound up getting published in the Nature journal.

clonal expansion

Clonal expansion IS present in ME/CFS but why????

Davis next found that T-cells in celiac disease were responding to the disease – but not the kinds of T-cells he expected. Apparently, the T-cells are capable of mounting a range of responses in autoimmunity – some of which were a surprise. He found the same in other autoimmune diseases.  In another huge surprise, he found that the cytotoxic T-cells he was sure were attacking the gut membranes were not attacking them at all. The upshot for me, if I got all this right, is that the T-cell repertoire is much more complex than we suspected – perhaps good news for ME/CFS – which has this irritating tendency not to fit traditional boundaries and consistently fall through the cracks.

Which it proceeded to do once again as Davis was able to find evidence of T-cell clonal expansion in every ME/CFS subject tested thus far, but has failed to find a good reason why.  Pathogens don’t seem right now to be the answer. To make matters worse, it appears the significance of the T-cell clonal expansion found in ME/CFS may be in doubt as Ron Davis the next day reported that a similar level of T-cell expansion was also found in healthy controls.

Next steps for Mark Davis.

Davis, is, however, studying a new cohort and is going to broaden his search significantly. Something is causing the T-cell clonal expansion in ME/CFS and if Mark Davis can find out what that is – and it’s something clearly pathogenic – that could be very helpful.

Derya Unutmaz and the Unconventional T-cells in ME/CFS

Next came the first report from an NIH-funded ME/CFS research center. The fact that Unutmaz was able to gather his data so quickly was a bit of a surprise, but he did have an ace in the hole – the Bateman Horne Center – which needed to get so many ME/CFS samples (200) that it ended up creating a new ME/CFS outreach program in Salt Lake City.

Suzanne Vernon, the BHC’s research director, has warned about a welcome new need – the need to get enough ME/CFS patients to fulfill our field’s need as it ramps up.  The good news is that the BHC showed that it can be done and has provided a template on how to do that.  The very, very nice, secondary outcome of the ability to do that is that a lot more doctors in Salt Lake City now know about ME/CFS (:))


Th17 – a big player in autoimmunity and inflammation.

Unutmaz, another T-cell researcher said he was shocked, just shocked, to find significant differences in a first, rather coarse look at T-cells in ME/CFS. Upon probing more deeply, he found some of the differences disappeared when age was taken into account but others did not.

All in all, the finding suggested that the T-cells in ME/CFS may be aging more rapidly than normal – through exhaustion – which perhaps will surprise no one.  (A similar finding has shown up in HIV, plus the Lipkin/Hornig cytokine study suggested the same. Plus, the CDC’s telomere findings in ME/CFS suggest the same, as do some fibromyalgia findings.)

Unutmaz was keen to check out Th17 T-cells – key players in autoimmunity and inflammation that are highly regulated by the gut – in ME/CFS – but when he did, he got a surprise. (No!!!!) He found high levels of Th17 cells but low levels of the cytokine (IL-17) they produce.

That suggested either exhaustion or a malfunction.  Something in the gut, probably, is triggering a massive Th17 cell expansion but the cells (perhaps quite fortunately) are having trouble getting activated. Some of the data from the EMERGE conference and from the next presentation may explain why. The immune cells, like so much else in ME/CFS itself, do okay at baseline but stress them out a bit and they punk out.

Clearly enthused by this finding, Unutmaz next turned to unusual T-cells that could be part of the problem. These MAIT T-cells are associated with the gut lining. We should hear about more of these tomorrow when Dr. Oh, his partner and gut specialist, talks about the gut and ME/CFS next.

For now, MAIT cells apparently lurk in the gut lining as a kind of last line of defense against the bad bacteria getting into our blood stream. Once activated, they turn monocytes into macrophages, which then gobble up the bacterially infected cells.

Unutmaz’s findings suggest that the MAIT T-cells have been repeatedly activated in ME/CFS and evidence the same activated/burned out pattern just described. He and Oh are trying – just as Mark Davis is – to determine what bad actor has turned them on. If they can find out what that bacteria is – and remove it – they may be able to tamp down the immune activation that just about everybody believes is present in ME/CFS…

Maureen Hanson … er … Alexandra Mandarano – Immune Cell Exhaustion Explained?

Maureen Hanson then turned the microphone over to her student, Alexandra Mandarano, who appeared to explain just how those T-cells may be getting exhausted.

This project – done in collaboration with the Simmaron Research Foundation – found that ME/CFS patients’ cytotoxic (CD 8) T-cells were able to generate normal amounts of energy at rest but pooped out when activated. Since they’re activated in order to knock out infected cells, having lethargic cytotoxic T-cells could help explain why the colds that often trigger ME/CFS tend to be so severe.

We’ve long known that T-cells’ cousins, NK cells, are horrible at killing infected cells in ME/CFS, and a Griffith study, if I remember correctly, suggested that cytotoxic T-cells might have the same problem. Now we appear to know one reason why – they just can’t generate enough energy to get off their duffs and wipe out the invaders.

An overview of a fascinating presentation from the EMERGE conference will provide more information on this subject but, for now, it’s good to see energy production problems showing up in the immune cells as well.

Provocation Studies

As time has gone on, creative researchers have used different provocations to stress the systems of ME/CFS patients in new and different ways. Whether it’s Ron Davis and his nanoneedle, Maureen Hanson and the Seahorse, the Japanese and their cognitive tests, Peter Rowe and his tilt table testing, the Griffith group and their NK cells or even, come to think of it, Lenny Jason and his group of infectious mononucleosis students, researchers are provoking ME/CFS patients’ systems in different ways and coming to the same conclusion – that when you stress an ME/CFS patient’s system, it tends to fail.

The exercise tests that Workwell, Betsy Keller, David Systrom and others use provide perhaps the greatest stressor of all – and not surprisingly, bring a welcome clarity to the field. Staci Stevens of the Workwell Foundation – the creator of the two-day exercise protocol used in ME/CFS – has maintained for years that the exercise studies do for ME/CFS what virtually no other kind of study can – elucidate in clear and stark terms the central problem in ME/CFS – the inability to tolerate exertion.

Dr. Klimas on Computing a Pathway Out of ME/CFS

Dr. Klimas’s computational work in ME/CFS is well known.  Collecting millions of data points during exercise, she’s literally observing post-exertional malaise come to life. First, exercise kicks off a burst of inflammation, which in turn triggers oxidative stress and causes the autonomic nervous and hormonal systems and others to go bonkers. She, Gordon Broderick and Travis Craddock have used a computational model of what has gone wrong in ME/CFS to identify drugs they hope will shove our systems back into health.

Dr. Klimas’s fascinating work will be covered in a separate blog.

David Systrom’s Trail Into ME/CFS

“Pathophysiology and treatment of exertional intolerance in ME/CFS: insights from cardiopulmonary exercise testing”

I think of David Systrom as a hopeful harbinger of the future – not just because of his exciting results – but because of how he came to this field. Systrom was not enticed into it. Instead, he came to it through his study of exercise intolerant individuals – many of whom, he later found out, had ME/CFS.

A pulmonologist working out of Harvard University’s main hospital, he brings two things we vitally need: credibility and contacts.  He’s working, for instance, with Anne Oaklander – another Harvard researcher – who uncovered the small fiber neuropathy present in fibromyalgia.

Systrom’s invasive cardiopulmonary exercise test (iCEPT) is like the CPET tests we know, love and occasionally hate – on steroids.  Using a catheter, these fantastically expensive tests provide much more information.

Systrom is finding relatively normal VO2 max in ME/CFS – not a surprise for a first day exercise test – but his invasive tests are revealing problems during that first exercise test that ordinary CPET tests cannot. Two major abnormalities are showing up: both the filling pressure of the heart and the systemic oxygen uptake are uniformly low during upright exercise in ME/CFS.

TRAIL Systrome

Systrom propose that the TRAIL pathway provoked by pathogens could be present in ME/CFS.

They suggest the heart is not getting the blood it needs, and the mitochondria are not getting the oxygen they need to produce the energy we need during exercise.

Systrom cited the story of a former competitive cyclist who had undergone a $1,000,000 workup – not that difficult a thing to do, he said, in the hospital he works in – to no avail. His testing revealed the problem – his heart wasn’t pumping the blood it needed to his muscles and even when the blood got there, the oxygen in it wasn’t being transformed into energy.

Systrom also brings the gift of a big data set – something this field has missed for years.  Of the 200-plus patients he worked up in one data set, 72% met the criteria for ME/CFS. The man has basically been studying ME/CFS for years. POTS was next on the list (27%), followed by fibromyalgia and mast cell activation syndrome (MCAS) (20%).

This breakdown seems to fits perfectly with the degree of exercise intolerance found in these diseases – present in POTS and FM – but not nearly to the degree found in ME/CFS.

Systrom has identified five different subsets which appear to differ depending on their issues with oxygen extraction and blood vessel problems. The high blood flow group, for instance, has pretty good blood flows but is not using up their oxygen.

Etanercept chronic fatigue syndrome

Dr. Klimas’s drug of choice – Etanercept – knocks down the same immune pathway Systrom’s preliminary results suggest exercise is upregulating in ME/CFS.

Most of this group had ME/CFS and forty percent of them also have small fiber neuropathy (SFN) – a remarkably similar percentage to the amount of SFN found in both POTS and fibromyalgia.

Unfortunately, the amount of small fiber neuropathy present did not correlate with the exercise findings.  Systrom, however, believes that small nerve fiber functioning rather than nerve fiber density may be a better measure.

Systrom next surely opened some eyes when he proposed – citing a conversation with another researcher – a new potential immune pathway for ME/CFS called TRAIL. TRAIL involves an uber pro-inflammatory cytokine, TNF-a, that’s often provoked in response to a viral infection. Systrom’s early testing suggests that exercise may be temporarily upregulating that pathway in ME/CFS patients.

A temporary upregulation fits with Nancy Klimas’s model of a massive upregulation of inflammation occurring early in exercise in ME/CFS, which then dysregulates other systems. In fact, Etanercept, the drug Klimas has chosen to tamp down the inflammation in GWI and ME/CFS, is a TNF-a inhibitor (:))

Systrom ended a fascinating presentation with the news that we can expect a treatment study out – something rare in ME/CFS – which shows that pyridostigmine bromide (Mestinon) – at rather increased doses, as I remember, was effective in increasing both VO2 max and, most interestingly, oxygen extraction in the muscles (!).

Mestinon, an old drug, increases the availability of the parasympathetic nervous system neurotransmitter, acteylcholine. Dr. Jay Goldstein recommended it in ME/CFS decades ago but it’s hardly been used in ME/CFS until Systrom came upon the scene.

Check out the story, though, of a person with a longtime case of ME/CFS who is now able to exercise after getting Mestinon (from Systrom).

A Mestinon Miracle: Vagus Nerve Stimulating Drug Helps Long Time ME/CFS Patient Exercise

Systrom is also starting to do muscle biopsies and is incorporating the Seahorse and mitochondrial studies into his work.  He has found positive acetylcholine autoantibody results (using the Mayo tests – he has not used the new German tests yet).  Also, it’s important to note that all Systrom’s results disappear when the patient is tested while supine. He also noted that the results he’s finding in ME/CFS are not found in deconditioning.

Systrom’s first presentation at an ME/CFS conference was for me the highlight of the conference – not only because he brings such exciting results but because he’s clearly now immersed in this field. His first pure ME/CFS project is being funded through a grant from the Solve ME/CFS Intiative (SMCI).

Systrom has taken exercise testing to a new and exciting level in ME/CFS, but as Dr. Keller, the next presenter, will show, the non-invasive CPET studies are still providing plenty of juice.

Betsy Keller

Dr. Keller also, thankfully, has a large dataset of patients (approx. 200) to draw on. Her presentation made it clear that the more patients undergo this testing, the more different kinds of problems are showing up.

She added data on two more twists to exercise issues showing up in ME/CFS.

Chronotropic incompetence (CI) refers to the inability to increase one’s heart rate appropriately during exercise. That issue was first identified in ME/CFS by Workwell researchers in 2016, and updated by them in a new study “Chronotropic Intolerance: An Overlooked Determinant of Symptoms and Activity Limitation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome?” this year.  Dr. Keller showed that the CI in ME/CFS gets worse on Day 2 of an exercise test.

Keller also showed that using age-predicted heart rates in ME/CFS studies ends up in ME/CFS patients working much harder than their “age-predicted heart rates” would predict.  This means that sub-maximal exercise tests which rely on these heart rates aren’t sub-maximal at all. If Keller is right, (and I have this right) people with ME/CFS in these studies are exerting near maximal exertion over extended periods of time. This is a big issue in the exercise physiologist subfield in ME/CFS.

ventilation ME/CFS

Ventilation – yet another exercise issue in ME/CFS.

Keller also added ventilation – the ability to push oxygen in and out of the lungs during exercise – to the list of exercise abnormalities found in ME/CFS.

She presented the case of an ME/CFS patient who was able to dredge up only 22% of her expected ventilation during exercise. Not only was she not delivering oxygen to her muscles, she was not removing CO2 from them either. Keller also found that this person’s blood pressure actually dropped (instead of increasing) during the second exercise test (!).  It was no wonder she couldn’t exercise!

Keller believes that autonomic dysfunction ties together all these findings.

Then she dropped a stunner. Referencing a 1989 Montague study, she showed that the exercise problems in ME/CFS have been hiding in plain sight for thirty years.

The team of exercise physiologists at Workwell have repeated ad nauseum that the NIH has never needed sophisticated technology to uncover the key issue in ME/CFS and this was proof. It’s possible that the technology needed to solve ME/CFS simply wasn’t present in1989 but the technology needed to demonstrate that ME/CFS was a serious disease affecting energy production and exercise was there.

Thirty long years later, it feels like the pioneering work of Staci Stevens, Christopher Snell, Mark VanNess at Workwell, Betsy Keller at Ithaca University and others, is finally starting to come to fruition.  David Systrom’s invasive exercise tests and Nancy Klimas’s immense data gathering efforts during exercise are providing important insights.  The NIH’s decision to make an exercise stressor a key component of its intramural study means the NIH has finally got it about exercise and ME/CFS.

It’s been a long time coming, though. Over a generation of patients have had their lives immeasurably blunted as the NIH has sat, and is still, for the most part, sitting on its hands – pretending as if this disease was an afterthought.  It has hardly begun to make up for that neglect.

Watch the two-day conference here:

Day 1 – https://videocast.nih.gov/summary.asp?live=31636&bhcp=1

Day 2 – https://videocast.nih.gov/summary.asp?Live=31640&bhcp=1

Check out the second day of the conference 

The NIH ME/CFS Conference II: Lipkin’s Possibilities, Prusty’s Big Idea, Oh’s Search and Ron Davis on ALWAYS Moving Forward

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