“We’re on the job and we intend to provide a resource for the community that will really move things forward”. Ron Tompkins
Times are changing. The Stanford area with its bevy of researchers and doctors (Ron Davis, Robert Phair, Mark Davis, David Kaufman, Bela Chedda, Jose Montoya, Rahim Esfandyapour, Michael Zeineh, Fereshteh Jahanbani and others) seemed like “it” for ME/CFS.
Harvard Symposium on ME/CFS
But look at Boston now! A new hub of ME/CFS research has appeared that’s centered on the Open Medicine Foundation funded ME/CFS Collaborative Research Center at Harvard. I must admit the skeptic in me reared its head a bit when I heard about the new center. I loved the fact that it was at Harvard and that Ron Tompkins was going to be involved, but was this actually going to be a “Center” – a hub around which all sorts of activity flowed?
I should have known better. If Ron Tompkins knows how to do anything, he knows how to build teams. For over a decade he and Ron Davis lead one of the largest continuing grant efforts ever funded by the NIH. Tompkins’s 13-year “Glue” grant on Inflammation and Host Responses to Injury involved 22 academic centers and dozens of researchers over 13 years and turned the field of sepsis and burn injury on its head. For one, it indicated that the cytokine storm that everyone knew had to be happening in these patients never actually occurred.
As good as Tompkins is, it surely wasn’t just Tompkins which prompted the OMF to plunk down $1 million for the new center at Harvard. Harvard is a special place. Harvard and Stanford are the top two medical research universities on the two coasts. (While US News and World Report places Harvard just above Stanford, another assessment places Stanford Medical School, with its greater focus on research, on top.) With both accepting only about 5% of applicants, these universities clearly get the cream of the crop. The potential access to the best and the brightest medical students and the “many special facilities” present at Harvard surely played a role.
The Open Medicine Foundation just hosted the first ever ME/CFS research symposium at the new ME/CFS Collaborative Research Center at Harvard. At the Stanford Symposium last year, Tompkins was visibly excited at the prospect of getting a research center at Harvard. That, he thought, would be a very good thing for ME/CFS. My bet is that Ron Davis has had his eye on this possibility from the beginning.
The list of Tompkins’ and Wengzhong Xiao’s (the other co-leader of the Center) collaborators is already staggeringly large. In addition to the nine MD’s and PhD’s at Massachusetts General (the teaching hospital associated with Harvard), Tompkins pointed to thirteen other founding members of The Harvard ME/CFS Collaboration.
Some – Ron Davis, Maureen Hanson, Tony Komaroff, David Systrom, Wengzong Xiao, Michael VanElzakker, Chris Armstrong – are well known to the ME/CFS community, but others are more or less new names.
Philip Atherton, a busy exercise physiologist in the U.K., most recently examined the effect exercise has on gene expression. Janet Lord is the Director of the Institute of Inflammation and Aging at the University of Birmingham in the U.K. Janet Mullington was so interested in the sleep issues in ME/CFS that she applied for an NIH ME/CFS research center grant; Richard Smith is an internationally known mass spectrometer and proteomics expert; and Donna Felsenstein is an MD who has been seeing ME/CFS patients at Mass General for years.
In short, Tompkins is doing something history has shown he excels in – building strong teams and enrolling others to work on projects. Tompkins has also done video interviews with Llewellyn King, Dr. Allan Gurwitt – a person with ME/CFS, and Rivka Solomon, an advocate. In short, this very experienced researcher has taken the ME/CFS ball and run with it.
Ron Tompkins talk with Llewellyn King ( – https://www.youtube.com/watch?v=3VPFJsNJS88 )
Tompkins went right to the heart of the matter when he reported that the Center would focus on post-exertional malaise and the muscles. Small, scattered research studies have repeatedly suggested problems are present in the muscles (it’s hard to know how they couldn’t be), but we’ve never had an organized effort to find out just what’s going on. Now we’re going to get as good an effort as the funding – it should be noted – will allow.
The good news is that so much is known about how the skeletal muscles work that some of this just requires applying known science to ME/CFS. Tompkins will be looking at the muscles themselves to see if structural or other issues are present.
Plus, one of his most exciting and potentially fruitful projects will involve analysis of the samples David Systrom gathered before, during and after his iCPET exercise tests. Given the invasive nature of Systrom’s exercise testing, Tompkins will surely be testing the most comprehensive set of exercise-associated blood samples ever.
That analysis is going to provide a missing element for Systrom. Systrom’s invasive tests have found that something called preload failure occurs in ME/CFS during exercise. In preload failure the heart fails to fully fill with blood as it starts the pumping process. Through his multi-omic analysis of Systrom’s samples, Tompkins will be providing a molecular ying to Systrom’s cardiovascular yang; that is, he will be using Systrom’s data to attempt to dig into the molecular roots of the exercise issues Systrom found.
If there’s anything we need to know more about, it’s how exercise wreaks the havoc it does in ME/CFS. Unraveling it will, I believe, lead us to the heart of ME/CFS, and it’s great to see Tompkins working with Systrom and placing a major emphasis there.
Then there’s neuroinflammation. It’s becoming pretty clear that neuroinflamnation is present in ME/CFS. Indeed, it would be hard, given all the brain symptoms present, to explain ME/CFS otherwise. One of Tompkins’s big tasks will be to find a way to marry the neuroinflammation present in the brain with the muscle and exercise issues he uncovers. Given Tompkins’s work in sepsis and trauma – two vastly complicated fields – he may be just the man to do it.
It was encouraging to hear Tompkins repeatedly speak of the “many” MD’s and researchers at Harvard, Mass General and elsewhere who know of ME/CFS and are interested in it. He reported that an ME/CFS talk before a crowd of 700 researchers earlier this year received a “very positive” reception. If Tompkins’s experience is representative, all we need to do is provide the opportunity and they will come.
Tompkins’ Closing Remarks
My guess and hope is that many interested doctors/researchers are simply waiting for the opportunity to enter this field. Australia’s EMERGE conference earlier this year, which featured Paul Fisher, a mitochondrial disease expert, is one example. He’s been trying to get into this field for ten years. When he finally got in, he produced some fascinating findings and is continuing his work.
Getting these researchers in, of course, requires more funding and infrastructure and Tompkins – who’s used to big, big projects – has an ambitious vision: at some point he wants to build an ME/CFS Center of Excellence at Harvard that will provide clinical care and be integrated into the ME/CFS research effort, and he’s actively seeking support for that.
It’s a huge goal – a long term goal – but note that Tompkins may already have many of the doctors he needs. Plus, Tompkins has quite a track record – and men/women with track records tend to speak carefully. If Tompkins is publicly stating that he wants to see an ME/CFS Center of Excellence at Harvard, he clearly believes it’s possible and is working towards it.
The interest, Tompkins said, is there. Given enough funding, he could easily double the number of scientists and clinicians working on ME/CFS in the Boston area. He said the new Center provides a tremendous opportunity to make a massive impact on this disease. Hopefully, we will be able to take full advantage of that opportunity.
Ron Davis Reports
As he has in the past, Davis is using everything in his lab he can to get at ME/CFS. This time, he’s turned a tool called a spot genetic sequencer, developed by Peidong Shen, to quickly find mutations in newborns to use in ME/CFS. He’s using the tool to look for mutations in the ID02 genes that form the basis for Robert Phair’s Metabolic Trap hypothesis.
The spot sequencer’s ability to quickly and efficiently look for specific mutations has allowed Davis to dramatically ramp up testing of ME/CFS patients. Thus far, of the almost 70 ME/CFS patients that have been tested, all of them have a mutation in this gene.
Since mutations in this gene are commonly found in healthy populations, they cannot alone be the cause of ME/CFS, but the fact that every patient tested thus far has a mutation in this gene suggests that it MUST in some way be involved in this disease.
The stats are adding up. The probability that the mutation results could be occurring by chance in now in the 1 in billions range. Because they appear to be something that’s necessary for ME/CFS to be present, Davis is viewing these mutations as “a handle” – something he can count on to tell him more about the disease. One obvious question is why these mutations might be more deleterious in people with ME/CFS than in healthy people? What is it in ME/CFS patients’ systems that might make them more vulnerable to problems with IDO2?
The microbiome part of the severe patient study is also revealing something very interesting. Instead of finding something bad in the microbiome, Davis is finding good things that are missing.
One called indole-3-propionate is an important free radical scavenger and an intestinal barrier and nervous system protector. It’s also considered a key potential target for pharmacological interventions to help cardiometabolic diseases. Attempts to find the bacteria that make this substance have thus far failed: either it’s gone, it’s hiding from their search, or it’s decided to stop producing this substance.
Another missing factor, which Davis would prefer to keep unnamed at the moment, is involved with IDO2. Davis said he didn’t target this factor – it just popped out – and the fact that it has must have intrigued them greatly.
High levels of hydroxyproline (in the urine, I believe) present another potentially interesting finding. Hydroxyproline is a major constituent of connective tissues (collagen and elastin). High levels of hydroxyproline could indicate that significant connective tissue breakdown is occurring, possibly as a result of the severe patients’ inactivity or as a part of the disease. The hypermobility and craniocervical instability found, the increased neuromuscular strain, even the potential blood vessel problems (blood vessels are composed of connective tissue) that may be found in ME/CFS suggest, though, that this finding is more likely directly connected to this disease. The degradation of this substance could set the stage for many connective tissue problems.
Hydroxyproline also, interestingly, is found in hypoxic (or low oxygen levels) and plays a role in the metabolic reprogramming that occurs in some cancers.
Stanford Symposium Registration Open
Registration for the OMF sponsored Stanford Symposium on Sept 7 is now open for registration to attend the event in person or to watch it online.
The Grant Man
The 78 year old Davis is putting the rest of the ME/CFS research field to shame with all his NIH grant applications. As the rest of the field seems to tumble into apathy, Davis’s team is pouring grant applications into the NIH. No less than four are going in – which is about equal to what the total ME/CFS grant review panel usually gets, at best.
Davis has had his own horrific experiences with ME/CFS NIH grant applications, but he hasn’t let them stop him. He kept going, had a recent win, and now he’s working harder than ever to get them in. The current applications coming from his team include:
- Relieving an Overworked Nanoneedle – the nanoneedle has been overwhelmed. Diagnostics, drug testing, looking for Waldo (the bad factor) in the blood – it’s just been asked to do too much. It needs to be updated so that it can run many more samples, etc. That’s what Rahim Esfandyapour’s application intends to do.
- Poorly Deformable Red Blood Cells – Ron Davis said the data on the red blood cells is looking better and better. Calling it “really clean”, it’s more and more showing that a substantial difference in red blood cell deformability is present in ME/CFS. This grant application is to create a better device (better camera, automatic image analysis, etc.) to do the analysis. Ron Davis, the Stanford engineers he brought in, and the San Jose State University researchers are all on this application.
- A Better Seahorse? – there’s something about being in Silicon Valley that seems to promote creativity. (Is it the bay breeze? :)) Davis found an instrument locally that is able to measure many more things than the Seahorse. The pilot data on ME/CFS patients from this instrument is showing big differences in the amino acids ME/CFS patients are using and identifying which parts of the citric acid cycle are shutting down. Ron and Mark Davis and Mike Snyder would all love to get their hands on this instrument, and they’re all on the NIH grant application.
- Heavy Metals – Laurel Crosby’s look at heavy metals in the hair found a remarkable thing – high mercury/uranium and low selenium levels in about a third of the severely ill patients. Kyle McNease’s story demonstrates how devastating heavy metal exposures can be. Plus, Lily Chu’s recent study indicated that about 20% of ME/CFS patients reported having had a toxic exposure prior to getting ill. This is an area that clearly needs more study, and that’s what this R21 grant is trying to accomplish.
The Hidden Gem
Whenzhong Xiao, the co-leader of the Harvard Center, leader of statistical effort at Stanford and Harvard, etc. – basically a man of many hats – provided one of the more exciting presentations on one of the lesser known ventures Davis’s team has taken on – the Open Data Center at Stanford (which will be coming to Harvard as well).
Davis explained that the genesis of the idea came from the Genome Project. The push back to the idea at first fierce but within six months the data sharing was so effective that everyone was required to post their data on servers.
Open databases and the open sharing of data in ME/CFS were talked about a lot at one time but thus far, all that talk appeared to been just that – another good idea that hasn’t been acted upon. The Stanford Open Data Center, on the other hand, which Xiao put together, is reality.
Talk about building the infrastructure to attract other researchers to this field. Researchers can log into the database and get real-time data. As soon as an experiment is done – this is prepublication data – Davis’s researchers throw it onto the web. Plus other ME/CFS researchers are free to post their data there.
Other researchers can go into the database, pluck out (anonymized) patients and dive deep into their results. If someone was looking for patients with high IL-10 cytokine levels and low BDNF levels, if I understood the process correctly, it appears they’d be able to find them – and then learn everything else about them – their symptoms, duration of illness, and other test results.
Xiao showed another figure plucked out of the database which showed that high BDNF, cortisol and TNFB levels (red) in combination with low hydroxyproline and hydroxylysine levels (blue) were highly correlated with problems with physical functioning.
Another interesting finding was the higher-than-normal percentage of pathological genetic variants known to affect pain, sleep and cognitive functioning found in patients in both the severe ME/CFS patient study and in the U.K. biobank study. That suggests genes probably do play a significant role in this disease.
- Coming up – Another ME/CFS research hub forming? / The Metabolic Hypothesis is published
Conclusion
Ron Tompkins and the many people he’s already enrolled to participate in the Collaborative ME/CFS Research Center at Harvard, Ron Davis and his team’s four NIH grant applications, Wenzhong Xiao and an impressive data center open to all researchers – these all bear witness to just how active and ambitious the Open Medicine Foundation and its researchers are. We don’t know how this all will turn out but it’s good to see a group acting with such urgency and putting such big plans on the table.
The train finally left the station!
It feels so much like critical mass to get the ME field going further and growing to a really big one has been achieved, thanks to the of hard work of many brave researchers and advocates defying all odds.
I’ve been rarely excited about new announcements, but this is such time. The road is still long and bumpy, but it seems to me a force is created to be reckoned with.
The force of different research centers of excellence collaborating and creating result upon result that entices doctors and researchers in many other fields to look from a safe distance at what is going on in this field that pushes the frontiers of medical knowledge time and again.
The disease that was formerly avoided because it created nothing but confusion and conflict with current medical science now starts to become a source of new insights that so many different fields long for.
Nicely said! The most exciting thing for me about the new Center is the support and interest it’s already received. Tompkins and Xiao’s list of collaborators is impressive and will I’m sure grow.
I remember Suzanne Vernon saying “If we build it they will come”. That strikes home with this new Center. I do believe that we have allies than we think and they will be showing up more and more.
This is all very exciting news. Thanks for a great read. Very promising.
Wow, Dejurgen is right , the train has left the station packing in so much information , and Hope
for us all . Amazing team we love you all … especial thanks to Ron with his strength of purpose and his lovely family . From the U K
While trying to understand some of the things Cort wrote in this very nice writ-up, I looked into:
* IDO2
* hydroxyproline
* indole-3-propionate
And something that seems both interesting and remarkable turned up:
from omf.ngo/2018/10/19/healthrising-the-metabolic-trap-shines-during-the-symposium-on-the-molecular-basis-of-me-cfs-at-stanford/ :
“Then tryptophan levels rise, inhibiting IDO1 even more, resulting in less tryptophan oxidation, causing tryptophan levels to rise even more, and so on.”
Now, as I keep hitting on the oxidative stress nail, I wondered if tryptophan could be oxidized by hydrogen peroxide. And it appears so:
pubs.rsc.org/en/content/articlepdf/2016/ra/c6ra12859a :
titled “Oxidation of Free Tryptophan and Tryptophan Residues in Peptides and Proteins”
But it does get better, from that paper:
“The latter species can react with another Trpmoleculeviaa hydrogen-atom abstraction reaction generatinga Trp hydroperoxide, which could produce either a hexahy-dropyrroloindole or an endoperoxide derivative.”
As that sounds like arcane stuff I had to dig deeper. Hexahydropyrroloindole also contains “indole” in its name. Sometimes similar naming means partly similar functionality (as the praised indole-3-propionate in the blog.
It appears that hexahydropyrroloindole has remarkable properties tlo.mit.edu/technologies/diazene-directed-modular-synthesis-oligocyclotryptamines:
“Hexahydropyrroloindole alkaloids, including oligocyclotryptamines, are structurally complex, naturally occurring chemicals with a wide range of therapeutically relevant properties, including antibacterial, antifugal, anticancer, and analgesic activity.”
Now we ME patients sure could use plenty of molecules that have antibacterial, antifugal, anticancer, and analgesic activity if it actually worked in Vivo! We could use all of these benefits (if they were for real)!
Having much more tryptohan “to play with” according to the metabolic trap theory, plenty more of it would first react with ROS, acting as an anti-oxidant, and then form much more of this promising molecule.
Now tryptohan is also a precursor of seratonin and melatonin en.wikipedia.org/wiki/Melatonin#/media/File:Melatonin_biosynth.jpg
What is important about melatonin? Well, when looking into en.wikipedia.org/wiki/3-Indolepropionic_acid :
“IPA is an even more potent scavenger of hydroxyl radicals than melatonin, the most potent scavenger of hydroxyl radicals that is synthesized by human enzymes.”
Now IPA is superb, but melatonin seems to be the next best thing. And having a “fault” that produces plenty of tryptophan will produce more serotonin and melatonin.
Yet, melatonin is the sleep hormone and we can’t catch sleep well. So if this fault produced plenty more of it, it may be “eaten” by all those radicals, fulfilling its (neuro)protective role.
From en.wikipedia.org/wiki/Melatonin
“Melatonin was first reported as a potent antioxidant and free radical scavenger in 1993.[41] In vitro, melatonin acts as a direct scavenger of oxygen radicals and reactive nitrogen species including OH•, O2−•, and NO•.”
“While it is known that melatonin interacts with the immune system,[51][52] the details of those interactions are unclear. An antiinflammatory effect seems to be the most relevant.”
So shuffling plenty of tryptohan into it may be not such a bad idea in our diseases.
Now I wondered if serotonin would protect against ROS. I did not find it directly on wikipedia so I searched for “serotonine hydrogen peroxide” and I got ncbi.nlm.nih.gov/pmc/articles/PMC4074966/ with title:
“N-Acetyl-Serotonin Protects HepG2 Cells from Oxidative Stress Injury Induced by Hydrogen Peroxide”
That’s not ordinary serotonin unfortunately, but when looking back to en.wikipedia.org/wiki/Melatonin#/media/File:Melatonin_biosynth.jpg it is clear that it is the intermediate chemical between serotonin and melatonin.
So once again having a fault producing far too much tryptohan protects against (hydrogen peroxide induced) oxidative stress.
Unfortunately, now that I finally learned to better appreciate the metabolic trap, there is a slight problem showing up: the trap predicts very high amounts of tryptophan in ME patients but metabolics research so far didn’t find any of it (McGregor) meaustralia.net/wp-content/uploads/2016/07/metabolic-profiling-reveals-anomalous-energy-metabolism-and-oxidative-stress-pathways-in-chronic-fatigue-syndrome-patients.pdf:
Looking at figure 3 and 4 its seems to me that tryptophan in ME patients blood is normal and in their urine quite below normal (so it is not dumped out of the body) if I can interpret these tables well.
If my interpretation is correct then it does not look that this metabolic data supports it.
But wait, that may actually not be entirely true. Suppose the metabolic trap is correct. At least the part that it pushes plenty and plenty more tryptophan into the tryptohan -> ROS scavenging -> hexahydropyrroloindole and the tryptohan -> serotonin -> N-Acetyl-Serotonin -> melatonin pathway and none of those appear to be (too) high in our bodies nor it is shown to be ditched by our bodies then:
If both this excessive production of all these chemical plus non of it being too high in our bodies is confirmed and ALL of them can be consumed by ROS, then ME is very very close to be categorized as a disease with extreme ROS production combined with turning near all of our bodies into a massive anti-oxidant producing machine (leaving few energy for anything else). Both ROS production and anti oxidant production would be in this hypothesis massive and counter each other sufficiently so that they both may hide in plain sight (meaning that, despite the really excessive ROS production, total amount of ROS and ROS induced damage is not blatantly clear to be observed).
Having all 6 patients this IDO2 mutations with a combined 1 in a billion chance may fit in here:
=> Does the IDO2 gene play a role in shifting metabolism away from energy (ATP) production into a strong anti-oxidant producing machine?
=> Does this mechanism shows a sort of hysteresis just like the glutathione and serine mechanism show in regard to oxidative stress? With that I mean that once the defensive mode is switched on it only is switched of at far lower levels of “problems” than at the levels it was switched on. Meaning it only switches off if the body believes all problems are cleaned up really well.
=> Then these IDO2 mutations may be indeed switched “on” by certain problems like a hit and run disease, but having a too strong effect of them due to the mutations, it may switch only off or “leave disease and inhibition mode” at far lower levels of “remaining perceived danger” than with the average person.
In a sense, the above hypothesis would mean our bodies leave inhibition far more reluctantly then those of healthy people. That may be nothing but a rephrasing of the metabolic trap. But shedding light on all those anti-oxidant and anti-bacterial, anti-fugal and anti-cancer effects these IDO2 genes !*COULD*! trigger may tell more what our bodies are trying to do and what they are stuck in.
@dejurgen
This hypothesis is very smart and an incredible epiphany!You did a lot of searching.What is your profession if I may?Also would you please forward this to Ron Davis?It may easily be wrong but there is nothing to lose.I could do it for you if you don’t have a problem.
Hi Steve,
Thx for the kind comment. I am a engineer with a PHd, but now too disabled to work. I can do this but I need plenty of rest and naps in between and I still fail on very basic skills.
I combine experience, previously developed ideas and research results form literature in my writings on HealthRising. I write many of them of varying quality. I believe the ME community will help sort out what may be valuable and what not.
So if you see value in it, please feel free to forward and share. But when forwarding to really good researchers like Ron Davis, please add:
“I do write about many ideas regarding ME that pop into my head. They are of varying quality and all my comments are unfinished and brainstorming like.”
Won’t make researcher believe by mistake I dove in deep. These are still half-lose ideas!
If you’d decide to forward this, please wait a few more days. I’ll add other things and who knows I’ll change my mind upon what I’ve already written :-).
dejurgen
FFS …. please summarise these comments in simplistic terms for us non medics ?♂️?
Hi Matthew,
I can understand these comments are too long and complex for many ME patients. I wouldn’t have been able to read nor understand them a few years ago myself.
If it wouldn’t be too much trouble for Cort, feel free to request an expand / collapse comment button. That can solve the problem of them spamming the blog. I made that suggestion before too ;-).
I do feel they have their value however, and so do some people like Steve. By sharing more technical and in depth knowledge among patients we may help better understanding this disease. By experiencing the disease we sometimes may have a better feel for how the disease could work, providing potentially helpful hints to real researchers.
I am not good in short and clear texts. Cort is. I am still a strongly affected patient and must work within my limits. Summarizing my thoughts is as difficult as coming up with them and that costs plenty of energy to start with. I have ME + FM so I am short on energy!
Here is what a summary of mine would look like, and coming up with this wasn’t that easy for me:
The metabolic trap says our bodies degrade far too few tryptophan through the kyurine pathway. That leaves far too much tryptohan in our blood.
I say having more tryptophan to push into the seratonin and melatonin pathway may be a good thing. These and other chemicals in this pathway eat plenty of ROS and some of chemicals may even fight nasty stuff.
So maybe these genes aren’t broken?
Note also that metabolics research from McGregor didn’t find too much tryptophan in ME patients. So that doesn’t support the metabolic trap.
=> Now let me say:
This summary sucks. It is not clear, not really informative, very incomplete, is far too unsubtle and may give patients who only read this summary bad and untested ideas like supplementing plenty of tryptophan. And after writing 3 of such summaries, I need a rest for much of the day.
=> So please ignore these long comments and request Cort to add a collapse button if they bother you. Absolutely no disrespect meant! As said, I would have disliked them myself in my worse days!
This is difficult stuff – hard to make it easy to understand. I will check on that expand / collapse comment button.
Hehe, civil engineer here too, PhD 😀
I was intenting to write a similar comment, it is indeed a free-abstract thinking process and probably connects dots that aren’t connected.But it makes some sense and it hit something when I read it, we have nothing to lose.I’ll wait a few days, no pressure.
Cheers
Thank you Cort and Dejurgen – it’s very much appreciated ! When you have some energy (Dejurgen) have a look at a guy called Raymond Perrin (Manchester, Northern England) as I believe he too will play A significant role in progressing this condition and he has certainly helped me. ?
Read your whole comment and got a lot out of it. Thank you from a fellow sufferer.
This is some good news. These teams are obviously deeply committed to the work.
Thank you so much, Cort, for always keeping us informed of the efforts on our behalf.
Thanks. It’s always a pleasure and its personally exciting as well to write an article like this. Hopefully there will be many more in the future.
I find this all very interesting. I suffer from CFS for years. Diagnosed with FMD in November 2018. I’ve always said it’s like I have an exercise intolerance. The more I do it the more fatigued I get. I cut sugar, gluten, breads, from my diet. I’m losing weight slowly. It didn’t give me more energy eating healthier? Still exhausted. Still stretching and walking when rested, but find myself pushing through sometimes which is not healthy, but this life is so boring. I miss myself! Hoping research propels forward to answers. Regular GP/PCP have no idea and it’s frustrating when you know something is wrong in your body and feel like no one cares. Truth is…we scare them because of the unknown. I’m still hopeful
Thank’s for this wonderful information about Harvard invest MECFS CLINICAL soon.
Cort can you tell if they take name for be in the patient field research and medical follow ? Where and who contact for given our name?
You can contact me if you need to inform about that if you prefer .
They need us for this clinic.
We need that and need to invest us for this clinic.
Keep hope and participate are the best best things to do.
I don’t know as yet. From what I can tell they’re using Dr. Systrom’s samples in one study but I don’t about the others. For sure they will be needing patients. I imagine we’ll find out more when the website opens.
Thanks Cort, that’s the best news in quite a while.
This is interesting..but I’d be keen to see the different centres use ICC to screen for their biological samples etc to ensure the results are properly meaningful.
Also, and whilst PENE is the defining element of this disease, I for one find the sensitivity/ pain aspects far more disturbing in terms of my QOL than ‘fatigue’ per se.. in fact these other aspects are now frighteningly awful. If one of these teams (using properly ICC-defined cohorts) can understand why people react so adversely to their environments (in all sorts of sensory ways and including allergy type presentations that do not fit regular constructs about allergy or even emerging constructs like MCAS) and develop severe neuro pain presentations in association with these sensitivities then maybe we’d be getting closer to ‘ground zero’ for this hideous illness.
Fwiw I have been keeping abreast of the work Anne Oaklander (also usefully at Mass Gen : https://neuropathycommons.org/experts/anne-louise-oaklander-md-phd) and I can’t help but think her work looking at small fibre poly neuropathies could be apposite.. maybe she should be encouraged to liaise with the team at Harvard given she is already on that patch?
Right. Thanks for mentioning Anne Oaklander. I’m surprised that she’s not on the team. Quite surprised actually as she’s been working with Systrom and appeared at NIH Conference. It’s possible that she just has too much on her plate.
The neuro-pain/sensory sensitivity subset in ME/CFS is IMHO a major subset which will – along with the other subsets – have to be figured out. it’ll be interesting to see what the CDC and their multi-site study comes up with as they’re digging deep into symptom characterization.
Thanks for your incisive reporting on the big news, Cort! Please DO keep us posted about participation in trials and any clinical care waiting list. Us folk in New England are more than ready!
Woo woo! and what a great job Mass ME/CFS has done. 🙂
Thanks Cort, very good news. There seems to be hope on the horizon, goodness knows we all need a dose of that at the moment.
The quick growth of the Center suggests to me that the interest may be there and we just need to get the funding and build the infrastructure. We may be closer to that than we think. Time will te…
I am so happy this is finally happening. I have had ME/CFS since my 1975 and I was diagnosed by Anthony Komaroff in 1995. It took so long bc I live in RI and there is not one doctor who believes CFS exists. I went to many many doctors in RI. Finally picked up the book INSIDE THE LABYRINTH OF THE CHONIC FATIGUE SYMDROME EPIDEMIC by Hillary Johnson. That’s where I found Dr Komaroff’s name. It took me getting volumes of paperwork from all the docs I had seen in RI and a whole lot of phone calls to his research assistant at the time Rich Schacterle. They were not taking any new patients; but finally dr Komaroff agreed to see me. After going up to Boston for many years; it was too much for me to go up there any more. My primary doctor was at B/W too. Heidi Behforouz MD. excellent doctor; she told me quite a few years ago that there was a lot of money donated to open a research center for CFS; glad it’s finally happening. I’m 73 now living in a body that feels like I’m about 90. Pretty much homebound. I have written a 3 page article about my battle with CFS, but it was last updated about 6-7 years ago or longer Cort, you had published it when you first started your journal, not sure if you remember . It’s much too late to help me, but I’m glad for those it will help. Thanks so much Cort for all you do whil having me/ CFS yourself.
I see that you’re in Rhode Island. So am I. I would love to be in touch. Is there a way to exchange contact information outside of this site?
I don’t know; Cort maybe you could help with this
Thanks
Hi.
The huge Boston event Ron Tompkins mentioned (and MCed) actually had 650 in attendance, not 700.
And it was mostly students in the allied medical professions, with some healthcare providers attending too.
It was an exciting event, hosted by MGH Institute of Health Professions, with the Massachusetts ME/CFS & FM Association helping organize it and speaking on the panel.
You can read about it here (below) and watch a video of the entire event too.
https://www.prohealth.com/library/huge-event-held-mass-general-hospital-89607
https://www.prohealth.com/library/huge-event-held-mass-general-hospital-89607
We think that perhaps it is the biggest in-person event ever held for ME. 🙂
Such great news! It seems like our disease may finally be taken seriously in a big way. Thanks for letting us know about it, Cort.
I have had ME/CFS & FMS since childhood. Frustrated w/the lack of support & education from the medical community as a whole. Am encouraged by this Cort, Thank you for providing detailed information about the new Harvard U. Center for ME/CFS research.
Hopefully I will finally see the day when a definitive cause/s & treatment will happen. Am 76 & optimistic.
My experience is that each patient has 25 different problems that all need to be addressed. There are some commonalities of course: poor sleep, hormone depletions, infections and nutritional deficits. But overall, they need to be dealt with very individually. Instead of thinking that CFS/ME/FM are diseases, we need to think of them as syndromes with multiple underlying components. It is a paradigm shift if you really want to get these people well.
In a lengthy comment on top of this blog, I wrote about potential benefits of shuffling more tryptophan into the serotonin – melatonin pathway. Now I’ll look at the other side: shuffling less tryptophan into the kynurenine pathway.
The kynurenine pathway can help produce more ATP. That sounds very attractive for energy depleted patients. But some of the intermediates in that pathway could pose severe problems for ME patients. Please follow by looking at the picture on top of en.wikipedia.org/wiki/Kynurenine_pathway:
Normally, according to Cort’s writing on the metabolic trap, 95% of tryptophan is converted to kynurenine.
* It *seems* that an accumulation of kynurenine is bad en.wikipedia.org/wiki/Kynurenine
“Downregulation of kynurenine-3-monooxygenase (KMO) can be caused by genetic polymorphisms, cytokines, or both.[15][16] KMO deficiency leads to an accumulation of kynurenine and to a shift within the tryptophan metabolic pathway towards kynurenine acid and anthranilic acid.[17] Kynurenine-3-monooxygenase deficiency is associated with disorders of the brain (e.g. schizophrenia, tic disorders) and of the liver.”
Now this conversion step not only requires KMO but also en.wikipedia.org/wiki/Kynurenine_3-monooxygenase NADPH per each conversion of kynurenine. That consumes plenty of NADPH, essential for both the immune system and for recycling glutathion. Glutathion is an major anti-oxidant plenty of us are short on. The reaction “employs one cofactor, FAD.” and that may be short in ME too, not sure about it.
* According to above point, too few KMO or NADPH leads to more kynurenine acid. Too much of it is a mixed bag however en.wikipedia.org/wiki/Kynurenic_acid: “It acts as an antiexcitotoxic and anticonvulsant… …As a result, kynurenic acid has been considered for use in therapy in certain neurobiological disorders. Conversely, increased levels of kynurenic acid have also been linked to certain pathological conditions.”
* Suppressing the KMO step is considered a potential therapy for several nasty diseases that somewhat relate to ME en.wikipedia.org/wiki/Kynurenine_3-monooxygenase:
“Kynurenine 3-monooxygenase is an attractive drug target for several neurodegenerative and neuroinflammatory diseases, especially Huntington’s, Alzheimer’s, and Parkinson’s disease. Administration of potent enzyme inhibitors has demonstrated promising pharmacological results.[3][5] Specifically, genetic elimination of the kynurenine 3-monooxygenase enzyme has been shown to suppress toxicity of the huntingtin protein in yeast[17] and Drosophila[18] models of Huntington’s disease”
The problem with this is that blocking this step leads to too much other nasty byproducts as the kynurenine needs to be converted to something in order to prevent it from piling up:
“Kynurenine 3-monooxygenase deficiency, which can be caused by genetic polymorphisms, cytokines, or both,[19] leads to an accumulation of kynurenine and to a shift within the tryptophan metabolic pathway towards kynurenic acid and anthranilic acid. Recent research suggests that hyperphysiologic concentrations of kynurenine in kynurenine 3-monooxygenase-deficient patients results in a shift towards kynurenic acid production, believed to be related to cognitive deficits in predictive pursuit and visuospatial working memory.[20] Kynurenine-3-monooxygenase deficiency is associated with disorders of the brain (e.g. schizophrenia, tic disorders) and of the liver.”
=> Now there is a way to mimic the benefit of knocking out KMO without having the problems of kynurenine to pile up: simply produce fewer kynurenine by shuffling far more tryptophan into the seratonin – melatonin pathway!
* The following two chemicals in the kynurenine pathway are linked to increased ROS production and protein damage by ROS scinapse.io/papers/2080568925:
“…3-hydroxykynurenine (3HK)… …and 3-hydroxyanthranilic acid (3HAA)… …Both 3HK and 3HAA generated superoxide and hydrogen peroxide in a copper-dependent manner…. …These data support the possibility that 3HK and 3HAA may be cofactors in the oxidative damage of proteins”
* Quinolic acid, another chemical in the kynurenine pathway, has some disadvantages too frontiersin.org/articles/10.3389/fmolb.2019.00003/full:
“Quinolinic acid (QUIN) is an excitotoxic agonist at the NMDA receptor, and has been shown to be elevated in neurodegenerative diseases such as Alzheimer’s Disease and Huntington’s Disease. Thus, inhibitors of enzymes in the kynurenine pathway may be valuable to treat these diseases.”
scinapse.io/papers/2002763309 goes even further, see paper title: “Replication of the neurochemical characteristics of Huntington’s disease by quinolinic acid”
=> While the kynurenine pathway certainly will have it’s needs and advantages, plenty of side effects seem to affect ME patients badly.
=>Producing fewer of it and shuffling more tryptophan into the serotonin – melatonin pathway may both reduce the side effects of the kynurenine pathways and increase the oxidative stress scavenging properties of the serotonin – melatonin pathway.
But these two long comments make having more IDO2 copies sound like a good thing. That doesn’t fit with all 6 severe ill patients having IDO2 abnormalities at a combined 1 in a billion chance. So where is the catch?
I suspect IDO to effect more then only how tryptohan is metabolized. In particular: it seems to affect immune strength too.
https://en.wikipedia.org/wiki/Indoleamine_2,3-dioxygenase
“IDO has been implicated in immune modulation through its ability to limit T-cell function and engage mechanisms of immune tolerance.”
=> This leaves the option that the effect of IDO2 on tryptophan’s fate is protective rather then causing our disease and that the real culprit is the likely strengthening of part of our immune system by having multiple copies of IDO2.
Does this hypothesis, build upon the metabolic trap hypothesis invalidate the metabolic trap hypothesis itself?
No. The IDO2 enzyme may very well create a two position switch like Dr. Robert Phair proposes. Such a switch with different stuck positions is however a form of instability. And many technical systems that are unstable appear to have several modes (frequencies in technology) of triggering instability. The easiest mode (frequency in technology) triggered the instability and can be easily observed. The other(s) are hidden for sight, just as if they don’t exist.
So in the case of the metabolic trap: long before tryptophan levels build up to be soooo high to get stuck in the second position, another vicious circle involving massive production of ROS and anti-oxidants is triggered. That would mask the proposed stuck state proposed by Dr. Robert Phair but it would still be there. It just would be overwhelmed by another stuck state.
Without the immune system jumping in, the state Dr. Robert Phair proposes would kick in. With the immune system jumping in, new complex feedbacks are created that can mess up things.
In my personal case for example (highly speculative):
* a strong infection activates IDO2.
* IDO2 activates both my immune system and the compensating increased anti-oxidant production
* IF I would have IDO2 gene mutations my immune system could be set a lot stronger then normal
* The immune strength in my gut would be strong enough to create gut damage if it lasted long enough
* That would happen with plenty of people as about 40% of healthy people have this IDO2 mutation, yet far fewer get stuck in ME. So I “need” something additional
* I do very bad on fructose, likely having fructose malabsorption.
* Not knowing for a very long time I had fructose intolerance, it probably created a really imbalanced gut microbiome.
=> If a strong infection (elsewhere then the gut) increased my immune strength (potentially higher then with non-IDO2 mutation people) in the gut then having a hidden weakness in the form of fructose intolerance could lower the threshold for a leaky gut a lot. That would spill plenty of both good and bath bacteria in my bloodstream, but the immune system has to remove both as they do not belong there. That would close the vicious circle by activating IDO2…
=> Having an amplification of the strength of the immune system plus some hidden weakness would leave plenty of different “forms / expressions” of our disease.
IDO2 mutations + fructose malabsorption would present different then IDO2 mutations + GSD and that would look different then IDO2 mutations + compex-I deficiencies and…. leaving plenty of room for variation in symptoms from patient to patient.
Thanks again Cort for your wonderful work covering these updates! I greatly appreciate.
When the phrase “the probability that the mutation results could be occurring by chance in now in the 1 in billions range” is expressed, I mean IOD2 has to be involved now…right?
Yes. Ron Davis now believes IDO2 must be involved.
This might be a rookie question because this is definitely over my head, but would a 23&ME test (or ones similar) show if you have the IOD2 gene? Or is that not how it works…
I gave Dr Phair my full gene sequencing from Genos. I don’t think 23 and me does it, but you could ask.
Hi. The huge Boston event Ron Tompkins mentioned (and MCed) actually had 650 in attendance, not 700.
And it was mostly students in the allied medical professions, with some healthcare providers attending too.
It was an exciting event, hosted by MGH Institute of Health Professions, with the Massachusetts ME/CFS & FM Association helping organize it and speaking on the panel.
You can read about it here (below) and watch a video of the entire event too.
https://www.prohealth.com/library/huge-event-held-mass-general-hospital-89607
https://www.mghihp.edu/students-hear-little-known-illness
We think this perhaps was the biggest in-person event ever held for ME.
This Harvard development is not necessarily good news. Instead of trying to solve the entire puzzle of ME/CFS in one go, which involves curing numerous complicated and often interlinked symptoms and which will undoubtedly take many years, we should maybe turn things upside down and just seek to resolve one symptom at a time. For example, there are natural treatments like Mutaflor that have helped with IBS symptoms, or we could look at re-purposing existing drugs that have been around for a long time and proved valuable in treating fatigue, sleep problems, headaches or extreme sensitivity. In this way we wouldn’t find a miracle cure, but the suffering of patients could be greatly alleviated and our quality of life improved significantly. If it’s a choice between finding some relief today or waiting for 10 years to find a 100% solution, I know which one I prefer.
The good news is that Ron Davis is testing drugs that could be repurporsed such as Copaxone in the nanoneedle – hence the need to improve it – so that the testing can be done more quickly. Plus Dr. Klimas is testing two already approved drugs in her GWI and ME/CFS trials. There’s Cortene – the drug was not in use but it had been created. Some of that is going on.
And suramin!
Yes! Let’s not forget Suramin – a trial is starting up. Thanks!
Hi, Cort. I am also in RI. Can you please connect me with Arlene and Katherine? Would like to compare notes. We’ve been neglected in this neck of the woods for a very long time.
Done!
At the 2016 OMF symposium I told Dr Xiao about the failure of “Big Data-think”
I explained that in 35 years, all this testing and technology failed to discover what researchers could have found out just by asking.
“Mold at Ground Zero for CFS”
Naturally, this will piss you people off.
Tough. Doesn’t change it.
I have no doubt that mold is part of the picture for some. One interesting question though is how that’s going to show in the research. My guess is that it may not show up as high mold concentrations in the blood but is going to be more like MCS – a hypersensitivity to mold sparked no doubt by a mold exposure – and I don’t know how that’s going to show up in the tests. It’s going to be interesting.
What is more interesting than the mold phenomenon itself is the behavior of “researchers”
Toxic mold was at the very core of why the CDC was called for help, and was a major part of what baffled them into creating the CFS syndrome.
Yet even after being told about “Mold at Ground Zero for CFS”, they do not respond.
This drops them below the rock bottom minimum standards for ethical “researcher” conduct.
would be useful if those who investigated the US diplomats with like symptoms to cfs/me got on board as well.
think their list of difference are not different, only under-reported.
one that seemed to be a true difference was that the affected diplomats to Cuba did not have decreased executive functioning brain lesions.
https://www.google.ca/amp/s/www.nytimes.com/2019/07/23/science/cuba-diplomats-health.amp.html
I love these blogs, Cort Thank you. They give me hope progress is actually happening. I wish someone so talented would come to the UK and build a center of Excellence to revitalise biomedical research here too. The UK Government finally acknowledged a lack of biomedical research in Spring and #says# it welcomes “all good funding proposals”. With the NICE review underway hopefully PACE gate can be buried and we can get back on the right track.
You know Cara you certainly have the pieces there – a good research community – and progress as you noted is being made. Who knows what will happen? I imagine that some researchers over there are just itching for something like that to happen.
Just a small thing: Just signed up. If I could pay via PayPal, I would donate monthly. ??