Reprinted with the kind permission of Cort Johnson and Health Rising
By Cort Johnson
It’s great the NIH is doing telebriefings a couple of times a year to inform the chronic fatigue syndrome (ME/CFS) community of their progress. The calls can be more or less interesting. This one was definitely on the more interesting side.
NIH Intramural Study Proceeding on Pace
Good for the NIH for regularly communicating with the ME/CFS community. This was a particularly good call…
Nath reported that the NIH’s intramural study is proceeding on course. The interest in participation in the week-long study has been strong with the group receiving hundreds of inquiries. Eighty people (40 ME/CFS, 40 healthy controls) will go through the study. Thus far 26 people have participated (11 patients, 15 healthy controls).
The pace seems to have picked up a bit. In July Nath reported 10 participants had come through; four months later we’re up to 26, which is about one participant a week. Of the 11 patients, Nath stated that 6 were “adjudicated”, which apparently means passed through to the next phase of the study. (The study is in two parts – a week-long screening stay – followed by another week or so long stay.)
I asked whether the study was proceeding on the timeline and if we would hear anything before it’s over. Nath reported that the study is proceeding as expected – someone is at the hospital being tested every day.
Because patients actually stay at the hospital for two one-week stays, the overall timeline is hard to discern. If everything works perfectly, the 40 patients, given the two week-long stays and the one hospital bed available, would take, if I have it right, 80 weeks. Penciling in a round of one-week stays for the healthy controls brings the total study time to somewhere around 120 weeks.
Of course, nothing works perfectly; several ME/CFS patients didn’t make it to the second round of studies (one became pregnant) and Nath noted that participants have to postpone their stays for one reason or another, etc. Unless I have my numbers wrong, building in some more time would make this approximately a 2 1/2 to 3-year study that’s due to wrap up sometime in 2020. Papers would probably begin flowing in 2021.
Three to four years is actually a typical timeline for a big NIH study and this one is vastly more complicated than most. It’s a great study but it’s also a long time in the life of an ME/CFS patient.
“A Foundational Requisite” Being Established for ME/CFS
Common Data Elements (CDEs) are kind of like a secret weapon the NIH is about to unleash on the ME/CFS research field. Decidedly unsexy but hopefully quite powerful, CDEs could greatly increase the efficiency of ME/CFS research – thus making the limited dollars available for research count for more. The idea is that once CDEs are used, researchers will be able to analyze data across multiple studies, turning them, in effect, into one big study.
Zaher Nahle, the Solve ME/CFS Initiative’s (SMCI) chief scientific officer and a member of the CDE Working Group for ME/CFS, called the ME/CFS CDE project “an important and ambitious” one. He wrote:
“The participation of dozens of disease and community experts as volunteers underscores its importance and anticipated value.”
SMCI states that:
“CDEs are becoming a foundational requisite in biomedical research in any field, and this is especially true for a disease where confusion regarding case definition, inclusion criteria, and study design continue to exist.”
CDEs do what they do by establishing standardized ways to characterize a disease. The 2011 CDE established for multiple sclerosis, for instance, is a massive set of documents containing over 100 recommended data elements which describe everything from how to provide a diagnosis, to how to assess cognitive functioning, to how to do brain scans.
A set of core CDEs, which present essential information that should be present in each study, and supplemental CDEs are provided. A rationale and grade are provided for each CDE. For instance, the multiple sclerosis CDE states that the Berg Balance Scale is a supplemental, but “recommended”, test in MS.
The Common Data Element Working Group for ME/CFS has eleven specialized subgroups/panels covering data elements associated with fatigue, sleep, post-exertional malaise (PEM), autonomic testing, imaging, neuroendocrine test and biomakers and others.
The ME/CFS CDC project was initiated by The National Institute of Neurological Diseases and Disorders and Stroke (NINDS). NINDS appears to have taken a lead role in producing CDEs in the medical research community, and has created 19 thus far. The CDC is collaborating on the study.
The project began in January of this year. The first round of ME/CFS CDEs will be published this month for public comment with the final publication, if my notes are right, early next year.
Derya Unutmaz’s Big Findings
Derya Unutmaz’s story is pretty well known, but it’s still inspiring. Why? Because as everyone knows, if we need anything in this field, it’s new, younger, enthusiastic researchers to jump on board. The whole point of the NIH research center project and the intramural NIH project is not really to solve ME/CFS – they won’t be able to do that by themselves (unless we get lucky!) – but to stimulate this field.
Despite all the advocacy, the growth in donations for research foundations like the Open Medicine Foundation and all the interesting findings, the numbers indicate that where the rubber really meets the road – in the number of grant applications for ME/CFS – this field is still stuck in the mud. The NIH, for those who don’t know, is where the money really is in medical research. Private donations can get us only so far. They’re really great at supporting creative research, but success there almost inevitably ends up in an application for a big, fat NIH grant.
The NIH may be VERY slow. It may lack some creativity (at times). It’s been an incredibly frustrating place for ME/CFS patients to watch over the years, but it’s also where most of the money for medical research is ($31 billion/year). Chronic fatigue syndrome (ME/CFS) simply MUST crack the NIH. Hopefully, the NIH Research Centers project will itself result in a surge of grant applications over the next year.
Back to Unutmaz. Unutmaz, who was really the star of the show on the call, about five years ago got a shout out from Suzanne Vernon (then at the SMCI).
She sent him just 20 ME/CFS samples and the rest, as they say, is history. Unutmaz parlayed his initial findings into a nice, big ROI NIH grant that’s going to fund one of the biggest immunological studies (over 200 patients) ever. Plus, Unutmaz, working out of a major lab, is going to be running one of the three NIH ME/CFS Research Centers. What’s not to like about that?
Unutmaz was inspiring on the call – not because he was a good cheerleader but because he’s obviously smart, competent and enthusiastic about studying this disease. We’re clearly in good hands with Unutmaz.
Check out Unutmaz’s resume and you’ll see studies drenched in T-cells. His 100-plus publications feature just about every aspect of T-cells one can imagine. The fact that it took him just 20 ME/CFS samples to detect “profound” differences in ME/CFS patients was exciting in a number of ways.
For one, in response to a great question during the Q&A period, Unutmaz revealed that the most provocative findings found were in the T-cells, and that the findings have proved to be highly reproducible – something we’ve rarely seen outside of NK cells (cousins, it should be pointed out, to T-cells) – in the immune field in ME/CFS
With the role they play in the humoral branch of the immune system – T-cells are master regulators – any type of T-cell finding could be highly significant. Throw in the preliminary T-cell findings by Mark Davis of Stanford and the energy issues Maureen Hanson is finding in them, and all of the sudden T-cells are becoming a hot topic in ME/CFS.
For those who don’t remember, Mark Davis has found some antigens – immune triggers – that ME/CFS patients appear to be responding to. Another T-cell specialist, Davis reported that T-cells “go clonal”; i.e. start producing replicas of themselves in vast numbers when they meet up with an antigen – a protein nipped off a pathogen or toxin by an immune presenting cell.
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The T-cells produced during this process are like honing missiles – they’re designed for one purpose and one purpose only – to search out and destroy anything that presents with that antigenic signature. High numbers of clonally produced T-cells are a sure sign of significant immune activation.
Davis recently found high rates of cytotoxic T-cell clonal expansion in ME/CFS. If his findings hold up, those T-cells should definitively indicate that either an autoimmune process or some sort of foreign antigen (i.e. an infection or toxin) is setting those T-cells in ME/CFS on edge. The most intriguing part, though, is Davis’ ability to search back and determine what’s triggering those T-cells. The Open Medicine Foundation (OMF) recently reported it was funding more of Mark Davis’ potentially ground-breaking work. Plus, Ron Davis is reportedly working with Mark Davis to submit an NIH grant supporting his work.
Because T-cells have hardly been explored in ME/CFS, they’re kind of unknown territory: who knows what surprises might be lurking in them.
Gut Connection – That the T-cell abnormalities Unutmaz is finding are associated with the gut probably made Mady Hornig and Ian Lipkin – champions of the role that the gut may play in ME/CFS – smile. It turns out that the problematic T-cells Unutmaz is finding regulate gut functioning. Either something in the guts of ME/CFS patients is messing with the regulatory T-cells or the gut T-cells are simply sitting down on their job. Either way, Unutmaz’ findings appear to put an enhanced focus on the gut in ME/CFS.
The gut is a terribly complex place, but with more and more research focusing on it and new methods being developed to understand it, a central problem in the gut might not be a bad thing at all to find in ME/CFS. Unutmaz echoed that hope when he stated that much is known about the cells he’s finding problems in and many treatments are under development to deal with them. That’s very good news for a disease that’s seemed particularly good at featuring issues with cells about which not much is known.
Unutmaz said he’ll be following up his T-cell study with a deep and rigorous probe of the gut bacteria in ME/CFS. He won’t just determine which bacteria are there – he’ll actually stress ME/CFS patients to see how their gut bacteria react. His studies will generate a lot of data; the challenge with them, as with all “omics” studies, will be to separate the wheat from the chaff.
To deal with that, he’ll be using a topological networks approach developed by Peter Robinson, a rare disease specialist. Robinson developed something called the Human Phenotype Ontology (HPO), which Jackson Labs states has become an international computational standard for studying human disease. Unutmaz stated that he also wanted to use the central data center embedded in the NIH’s ME/CFS research centers project to include data from the research centers in his project.
Unutmaz is also working with Precisely to develop an app to collect clinical data worldwide on ME/CFS patients. We’ve heard of projects like this before, but this may be the first one that has the funding to come to fruition.
So here we are – five years after an immunologist new to this field received 20 samples from the SMCI in the mail – leading an NIH ME/CFS research center. This is the kind of pattern we want to see duplicated again and again. New investigators coming in, bringing their talents and insights to this field and being rewarded for doing so.
Unutmaz shone during the call, but so did the ME/CFS patients and caregivers during the Q & A period who displayed a depth of knowledge that few other patient groups can probably muster. Denise Lopez-Majano asked why not a research definition now? Koroshetz didn’t to my mind really have an answer to that question, but did report that the research consortium will be asked to characterize ME/CFS patients in all their different phases, including duration of illness.
Koroshetz did point out the need to be flexible – an important stance to take in a disease that is so heterogeneous and about which so little is known. Everybody seems to agree that this disease is astoundingly heterogeneous. Vicky Whittemore rather dramatically remarked on that fact during the last NIH call:
“many of the investigators are coming at this…. from very different directions, which I think is going to all come together to show us that it is heterogeneous disease with potentially many different mechanisms that all lead to very similar symptoms that we’ve been calling ME/CFS but likely have different underlying causes.”
Unutmaz noted that he plans to follow the patients in his study – all short duration patients – over several years to see if their immune systems “turn” as is suspected. Much like Ron Davis, Unutmaz emphasized we’re in the exploratory phase of understanding this disease.
Koroshetz seemed to be genuinely touched when Lopez-Majano reported she had two young sons who’d been sick for 12 years. Koroshetz has been refreshingly honest about the needs of this disease. He’s stated that the disease needs many, many more investigators and much more funding. He acknowledged that the three Research Centers are simply a beginning – an attempt to jump-start the field.
The Centers grant almost doubled NIH research funding for ME/CFS – an unusual outcome in any disease – but the Research Centers are asked to do a lot with little and the disease is still dramatically underfunded. Koroshetz has written blogs on ME/CFS, and even talked up the little NIH program in his talk to top officials at the NIH Advisory Committee. He was blunt about the needs at that meeting:
“Myalgic Encephalomyelitis and Chronic Fatigue Syndrome is an area that’s really been completely under-investigated across the country, and Francis [Collins] was really courageous and went out there and said that NIH is gonna change that.” Koroshetz called ME/CFS a “pathological condition” and stated that “people are completely disabled for decades because of this terrible fatigue and inability to exercise”
Koroshetz, in fact, stated that he believes the field probably needs 20 research centers and 10-20 times its current funding. That was something of a jaw-dropper coming from the head of a large institute at the NIH.
Ian Lipkin clearly agrees. He warned the NIH (and by implication the patient community) not to expect too much, stating that while the funding for the centers was “helpful”, it was nowhere near “adequate
It’s definitely a start, though.
Is Chronic Fatigue Syndrome (ME/CFS) an Autonomic Neuropathy?
I’ve lost my notes, but as I remember, a doctor with ME/CFS asserted that ME/CFS is an autonomic neuropathy and then questioned whether all the money going to molecular studies were going to be much help.
Dr. Koroshetz, a neurologist, immediately agreed with her that ME/CFS could very well be an autonomic neuropathy. Last summer, Dr. Koroshetz accepted Lauren Stiles’ invitation to attend Dysautonomia International’s one-day conference. It’s become pretty clear that postural orthostatic tachycardia syndrome (POTS) – a main focus of Dysautonomia International – is at least, in part, an autonomic neuropathy caused by an autoimmune reaction, and the group is funding further studies to that end. Stiles expected Koroshetz to stay a few hours. The NINDS director so enjoyed his stay that he ended up staying most of the day.
I thought the idea was brilliant – it encapsulated so much – and wondered why it hasn’t seriously been brought up before. I was immediately brought back to Dr. Pocinki’s description of an autonomic nervous system flopping around under stress, and Staci Stevens’ belief that the ANS had lost its setpoint in ME/CFS. Then there was Dr. Wyller’s recent bizarre finding that Clonidine, a sympathetic nervous system inhibitor, actually made many of his adolescent patients worse…something strange is clearly going on in the autonomic nervous systems of people with ME/CFS.
I don’t know if autonomic neuropathies can explain everything in ME/CFS, but they may explain a lot. Autonomic neuropathies involve damage to the autonomic nerves in the body, interrupting the stream of messages to the brain. They’re most often found in diabetes, but the Mayo clinic reports that infections (hmmm…) can also cause them.
Common signs of an autonomic neuropathy include dizziness and fainting, urinary problems, digestive problems including bloating and constipation (IBS), problems with temperature regulation, sexual difficulties, and, get this – exercise intolerance – because of the failure of the heart to beat fast enough to maintain exercise. Many of these symptoms are found in ME/CFS and I’ll bet they are the tip of the iceberg. The heterogeneity in ME/CFS could conceivably be the result of different autonomic nerves being affected in different patients.
We know that small nerve fiber problems occur in POTS, which is commonly found in ME/CFS. What we don’t know is how common they are in ME/CFS.Nor do we know the status of other autonomic nerves in this disease…
If there’s one thing that was missed in the ME/CFS research center grant winners, it was a group focused on the autonomic nervous system. Dr. Unutmaz, however, begged to disagree about the relevance of molecular studies to a possible autonomic neuropathy. It it’s there, he believes, they’ll find evidence of it. The connections between the immune system and the autonomic nervous system – a major regulator of the immune system – are, after all, bountiful.
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About the Author:
Cort Johnson has had ME/CFS for over 30 years. The founder of Phoenix Rising and Health Rising, Cort has contributed hundreds of blogs on myalgic encephalomyelitis, chronic fatigue syndrome, fibromyalgia and their allied disorders over the past 10 years. Find more of Cort’s and other bloggers’ work at Health Rising