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“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 ME/CFS Symposium

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 KingDr. 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.

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