3rd Annual Community Symposium on the Molecular Basis of ME/CFS at Stanford University, sponsored by OMF, 7th Sept 2019

Isn't it SS-31?

 

Ron Tompkins introduced the new website of the Harvard ME/CFS collaboration (online since yesterday):
http://endmecfs.mgh.harvard.edu/

 

There are other posts saying SS31. I didn’t stay up late enough to hear this one but there’s a bit more detail on this tweet so I included it.

I googled SS19 + heart failure but got nothing.

 

Is there a link to Maureen Hansons talk?

 

Apologize for the confusion, I did of course mean available as in offered to patients with ME-diagnosis outside a trial.

 

Hillary Johnson‏ @oslersweb 9h9 hours ago


Ron Davis: SS-19, an experimental drug that repairs mitochondria, designed for people with congestive heart failure, turned ME blood into control blood. OMF working with inventor.

http://novelconjugates.com/product/tyrosol-ss19carbamate/

Moderator note: The rest of this post detailing molecular structures and following posts with research papers have been moved to this thread:
Treatment of mitochondria with antioxidants SS-19 and SS-31

 

Here’s my short summary/impression of the 2019 OMF Symposium. Please be mindful that this is based on the livestream, so there might be some errors or some parts missing.

Moreau finds something in the plasma

I think the most interesting finding came from the Canadian researcher Alain Moreau who said he put normal cells in ME/CFS plasma and found a strong rise in bio-impedance. He said: “There is something very specific in the plasma of the patients, exactly as doctor Davis has shown recently with similar technology.” There were subgroups with very some different responses. I think the findings are preliminary, but it seems that there’s yet another research team that has found ‘something in the blood’.

Negative findings for red blood cell deformability

Another important finding, but a rather disappointing one, came from Juan Santiago, professor of engineering at Stanford, who has been looking at red blood cell mechanics. After a long and impressive talk about the details of the testing device he has made, Santiago said: “what I’m going to show you may not be what you want to hear, but I want to say it honestly.” There was no significant difference between ME/CFS patients and controls in red blood cell deformability. He said that they’ve succeeded in making a new system that can measure red blood cell mechanical properties at high-throughput, which is corroborated by other, more standard measurements and is applicable to a variety of diseases. But given the data they have on ME/CFS, he said: “it is unlikely that this can be a marker in itself.” They did want to delve deeper into their results because there was a surprisingly large heterogeneity, not just in ME/CFS patients but also in the healthy controls. So figuring out what causes that heterogeneity might give some interesting insights or perhaps a way to clean up the data.

Revamping the ME/CFS centre at Stanford

There weren’t any other stunning findings revealed during the symposium, but there was some exciting news with regards to the ME/CFS research collaborative centres. The conference started off with some really good news. Ron Davis announced plans to revamp and renew the ME/CFS centre at Stanford with the support of Robert Harrington, Chair of Medicine at Stanford Univerity who recorded a video for the symposium. Ronald Tompkins talked about the new ME/CFS centre at Harvard affiliated hospitals, which now has an informational website (http://endmecfs.mgh.harvard.edu/). When Moreau joked that he has a new baby (by which he meant the new Canadian ME/CFS research collaborative), Tompkins retorted that his ‘baby’ is now 3 months old. Jonas Bergquist, who is leading the new ME/CFS research collaborative research centra in Uppsala, Sweden, said he had recently started a collaboration with the prestigious Karolinska institute to look at trace elements (copper, zink, etc.) and to do a PET microglia imaging study.

Lumper-splitter discussion

The keynote address by Maureen Hanson was quite interesting as she openly talked about her view on the illness. She said she is a ‘lumper’, meaning she thinks there is a main cause for most ME/CFS patients. She added an interesting analogy to explain what she meant: If you get hit by a car you can break your leg, your arm or have a concussion. That may look like different subgroups, but they all got hit by the car. During the conference, several researchers came forward with their view on this issue and openly declared whether they are a’ lumper’or ‘splitter’. While Robert Phair and Ronald Davis said they were like, Hanson lumpers, Mike Syder said he’s a splitter. He said that this has become the standard approach in complex diseases; whether it’s autism, diabetes, cancer or neurological diseases, all are now viewed as multifactorial. He said he himself was an example of the success of the splitting approach as a patient with type II diabetes who doesn’t respond to normal therapy but for whom another treatment does work. Ron Tompkins then weighed in, saying "my general view of this disease is compatible with both lumping and splitting." He explained that there may indeed be a common underlying cause but that it's important to look more closely at heterogeneity to come up with successful treatments.

Research findings

Onto the research findings. Hanson talked about abnormalities in CD4 and CD8 T-cells which she reported previously. She said there was no difference in the amount of extracellular vesicles between patients and controls but that the former did have more of the small ones. She said that the findings on cytokines are conflicting in ME/CFS but that it may not be their level count but their pattern of activity and communication that is abnormal in ME/CFS, something that she saw in the extracellular vesicles.

Moreau talked about his non-taxing stress test to induce PEM. When persons were used as their own control he saw a decrease in REM-sleep in the patients, but not the controls after the stress test. He’s also studying brain fog and found a large change in thrombospondin (TSP) in some ME/CFS subgroups, a molecule that is involved in vasoconstriction and could point to reduced brain flow to the brain. These are all preliminary findings though.

Fluge talked about the negative rituximab results and the Cyclo ME trial, which tested cyclosphosphamide, another chemotherapeutic drug that seemed to work in their cancer patients with comorbid ME/CFS. He said they have done a phase II trial of cyclophosphamide that looks promising, but because it’s not randomized and relies on subjective outcomes, it can’t say much about efficacy yet. He hoped to do a randomized controlled trial of cyclophosphamide with objective outcomes and emphasised that these trials have all sorts of useful spinoffs because a lot of data is collected on patients.

Tompkins said that he wanted to look at muscle biopsies, an area in which he has a lot of expertise from studying physical trauma. From Bergquist’s talk I remembered he said they are finding high titers of antibodies to muscarinic and (inaudible: cholinergic?) receptors in approximately 70% of their Swedish patient sample. Santiago reported the negative findings on red blood cell deformability.

Snyder’s talk wasn’t about ME/CFS but it gave some interesting insight into the potential of wearables. Snyder has been testing these devices for quite a while (during the talk he was wearing three watches and a ring, all collecting biological data). One of the things he discovered was that during airplane flights his oxygen saturation (spO2) dropped and that this correlated with fatigue. One time his spO2 dropped more than usual and that’s how he discovered he was sick and had Lyme disease. He also said there was a connection with increased heart rate and CRP (which indicates infection), suggesting that these relatively cheap devices might indicate when someone is getting sick. Snyder thought that these wearables could be used to collect big data on ME/CFS patients, even the most severe ones.

Robert Phair talked about his metabolic trap hypothesis. He explained that each of the four IDO2 mutations is not more common in the ME/CFS than in controls – there is not a statistically significant difference there. But according to the theory, each of these can increase susceptibility to ME/CFS. So what matters is what percentage of persons has none of these four IDO2 mutations. In healthy controls, this is around 10%, in ME/CFS patients 1,4%.

In his talk, Ron Davis highlighted two metabolites that were significantly different in severe ME/CFS patients compared to controls: very low indolepropionate (involved in neuroprotection, made by a clostridium in the gut) and high hydroxyproline (which could indicate collagen degradation). Davis also said they are identifying drugs that stop the abnormal impedance signal picked up by the nanoneedle. Examples are Capoxone (an MS-drug) and something called SS-31 (wich repairs mitochondria). Earlier during the day, Moreau said that he had also found a drug (thymoquinone) that normalizes the bioimpedance they are measuring. But he admitted that they have no idea yet what they are measuring, so it needs further study.

Closing remarks: "now we've got a scientific community"

During the closing panel discussion, Robert Phair said that the OMF, by holding these regular symposiums, has created a ME/CFS research community. He said, “that there's always been a patient community and now we've got a scientific community."

Earlier during the day, Maureen Hanson emphasized that this scientific community needs more funding to grow. She said that the NIH is only funding 14-16% of ME/CFS study proposals, meaning that some proposals get a good, very good or even excellent quality rating, but don’t get funded. According to Hanson people don’t realize the seriousness of ME/CFS and that they should start to worry about it. It’ not a rare illness and we don’t know how someone gets it. Few patients recover from it and there is no FDA-approved drug to treat it. Hanson noted that the recent NANDS report has some very good suggestions to build the field, but that it doesn’t have set-aside funding. “I would like to challenge this working group”, she said, “to come up with new initiatives involving set-aside funds for ME/CFS, next year when they report again.” Let’s hope they do.

 

I thought that Dr. Hanson’s talk was absolutely brilliant - one of the best that I have ever heard. Just wanted to point out that, as she said, the low percentage of NIH proposals that are funded is across the board - not just for ME/CFS grants. In fact, ME/CFS proposals are funded at a slightly higher rate than most right now. As she said, the only way around that is set-aside funding like the RFAs that we currently have for the Centers.

If Congress grants that funding, it is likely to be a large amount, but that is going to take time and lots of push from the community. Internally, NIH really hates set-aside funding for a particular disease - any disease. It really prefers proposals coming into a particular NIH Institute, being evaluated, and the best being funded.

Just because they hate it doesn’t mean that set-asides can’t happen. The likeliest area would be funds for new ME/CFS investigators. I would love to see that happen quickly, then push for Congress to allocate serious funding as the research community grows. They are not wrong when they emphasize building the research community.

I was also thrilled about the new Stanford Clinic. One of my concerns has been that research is being done largely on people who have spent years trying medications, which could alter what the researchers are looking at. The new clinic could both provide excellent care and be a source of new PWME who have not been extensively treated.

About the research at the conference, I had my usual opinion. 1) It is so great to see good scientists working together on this difficult problem; and 2) we sure have a long way to go.

 

Same as our MRC say in UK. Unfortunately as much as they hate it, set aside funding is only alternative to years of slow mo for an already neglected disease, stigmatised & at such a low base we can’t suddenly get up to a fitting level without extraordinary measures. I actually hate being left as a “dead on a bed” statistic , after drs f**** me up, a bit more I think.

 

My general statement about NIH and the research community is “They broke in; they need to fix it.” It’s time for unusual urgency.

 

I was only able to follow the symposium on Twitter and this is how it looked from there. How did it look to those who saw more of it than me?


Overall, I was disappointed by the lack of progress (hey, what's new: this is ME/CFS). In particular, there has been no progress on either the metabolic trap or red blood cell deformability:


Metabolic trap. The early "promising findings" proved to be false positives. Technical issues have prevented further progress, but they are on the case. The latest genetic figures show "broken" IDO 2 genes for 90% of healthy controls with European ancestry versus 99% % for similar ME/CFS. That doesn't look too convincing to me, because it means that almost everybody is at risk. And suggest the gene isn't very important from an evolutionary standpoint.




Red blood cell deformability. Data shows no difference between patients and controls. It also shows much greater variation within patients and controls than they had expected. That makes it pretty unlikely they are going to find a biomarker here.

Though the group will continue to try new approaches to studying this.


Thanks to Cort for treating both graphics

No report from Mark Davis's group either, so presumably not much progress on the T cell clonal expansion either.


On the positive side, Oystein Fluge reported they had submitted a paper on the results of the cyclophosphamide trial. as he wouldn't give details its presumably a positive result (though so too was rituximab, initially).


Ron Davis reported a mitochondrial drug SS31 that normalised Nanoneedle results. All good, though we still don't know if the Nanoneedle findings are specific to ME/CFS, or what on earth is happening biologically to explain the Nanoneedle findings. I remain very excited by the Nanoneedle, just wish progress was faster.

As @Michiel Tack pointed out, Alain Moreau reported that plasma affects bioimpedance, in line with the nanoneedle plasma swap results.


Certainly, compared with two years ago, when everything was bright and rosy, things don't look quite so cheerful. I felt at the time there was too much hype – because science is slow — but I guess that's understandable from a new fundraising organisation, and from a new high-calibre research team who are getting promising results.


That said, I am impressed by the thoroughness of the Stanford team: they really follow up on things and share negative findings as well as positive ones. I think this is incredibly important & shows that we are getting researchers with the right approach on our case.


I would still like a breakthrough . We still have no real idea of what's gone wrong in this illness.

 

That was already known to be a false positive.

Personally I hope they focus 100% on the something in the blood. A cure seems still too far away, but a diagnostic test seems within reach. A diagnostic test will do wonders for accelerating research and convincing the public that this is a real disease that needs to be taken seriously.

 

I can guarantee that there is zero correlation.

 

I was impressed with Alain Moreau's presentation. I missed most of the others but he left me with a feeling of optimism.
I agree @strategist something in the blood needs big focus.

 

How can you possibly guarantee that?

 

From my own personal experience with ME for almost 30 years.

 

Of which nobody knows what influence it had.

 

Can anyone tell me if the metabolic trap is still a viable hypothesis or is it gone out the window?

 

This has to be said and I'm glad it was. The psychosocial school of thought is a pathetic excuse of a research effort and does not amount to a scientific community, it is a failed ideology that has produced nothing but confusion and suffering and is still wasting everyone's time eating paste at the back of the class. This also applies to the early efforts that preceded the psychosocial hijacking, it was a very weak attempt that included far too many people wholly uninterested in figuring it out and an unhealthy number of deniers who impaired the process.

Harsh, but as fair as it is accurate. This year marks the true beginning of research efforts in ME, the point at which the early steps have been done and can be ramped up. It's sad that research institutions like the NIH can't even follow in these footsteps, let alone lead, but things can finally get serious momentum.