The Solve ME/CFS Initiative’s Ramsay Awards are small grants (@$50K – only in the medical field is 50K small) but potentially mighty grants. They are designed to give researchers the funding to produce pilot data needed to get really big grants – the NIH and other grants, worth millions.
The 2016 Ramsay Award winners achieved this in spades. By the end of this year, my calculations suggested that the SMCI’s $250K investment in the 2016 Ramsay Awards may have brought in something like $5 million in new ME/CFS funding with more, hopefully, to come. Plus, they introduced several new researchers to the field.
That’s a pretty good bang for the SMCI’S buck.
The 2018 Ramsay Award Winners
Recently, the 2018 Ramsay Award winners were announced. They continue the SMCI’s focus on understanding the energy production and immune issues in ME/CFS. Plus, this year they also include two new twists: taking advantage of a hot area in drug development, the Solve ME/CFS Initiative is funding a hunt for a drug target in ME/CFS, and is funding a mast cell researcher.
The Hunt for A Drug (Target)
From his beginnings with Dr. Peterson, Vincent Lombardi, PhD, has been involved in the ME/CFS field for decades. His touchstone ME/CFS moment came when a dying patient of Dr. Peterson’s, whom Lombardi knew well, asked him on his deathbed to carry on the fight.
Lombardi’s been involved in several important ME/CFS moments. His data demonstrated that the RNase L finding was a chimera and then indicated that XMRV was indeed a contaminant. After the Mikovits era, Lombardi saved the Nevada Center for Biomedical Research’s (then the Whittemore-Peterson Institute) bacon when an NIH group came to the lab ready to jerk the Center’s grants. Impressed with Lombardi, the grants stayed and the NVCBR’s work on ME/CFS continued.
Lombardi’s well aware of ME/CFS’s big problem: lots of people desperately need treatments, but because the disease lacks treatment targets – specific biological factors that drugs can be aimed at – doctors are mostly shooting blind. They’re trying to reduce symptoms without knowing how they are produced.
Vincent Lombardi is looking for a target doctors can aim a drug at in ME/CFS.
Vincent Lombardi hopes to change that. In his 2018 Ramsay Award, he’ll be trying to pinpoint a specific treatment target in hopes of finding a drug to stop the inflammation in ME/CFS in its tracks. He’ll be doing this by digging deep into inflammatory cascades to identify the transcription factors that tell our cells to pump out cytokines.
This is a timely award. Finding ways to turn off inflammation early in the process has become a hot area of drug development. Several of these drugs (called “Jak-Stat” inhibitors) have been approved and at least 15 are in clinical trials. If Lombardi can identify specific upregulated transcription factors in people with ME/CFS, he may be able to open the door to treatment opportunities in a booming field of drug development.
A Mast Cell Master Takes on ME/CFS
Mast cells are becoming a big deal in ME/CFS, but grants for mast cell research in this disease have been few and far between. How better to get mast cell research in ME/CFS going than with the “mast cell master” himself – Theoharis Theoharides. Theoharides, a Tufts University professor, recently penned a hypothesis paper proposing that mast cell activation in the hypothalamus is causing ME/CFS.
Could the Brain’s Mast Cells Be Causing Chronic Fatigue Syndrome (ME/CFS)?
Theoharides, who has co-authored hundreds of papers, has long been at the forefront of mast cell research. He was among the first to show that mast cells are prime triggers of the microglia – the immune cells believed to cause neuroinflammation in ME/CFS.
With his 2018 Ramsay Award study, Theoharides is turning to a new area of immune research involving exosomes – small extracellular vesicles emitted by cells which are believed to play important roles in autoimmune diseases and others.
Exosomes, which can carry all kinds of cell-regulating factors, travel through the bloodstream until they come upon a cell which they attach to and disgorge their contents into – causing the cell to act in different ways. They constitute a recently discovered communication network and are the subject of much research, including three ME/CFS studies from Theoharides, Maureen Hanson and the Williams/Ariza group at Ohio State. Theoharides will be examining the contents of the exosomes in ME/CFS to determine how they may be influencing the mast cells and microglia in ME/CFS patients.
Unstable Cellular Energy
Next, the SMCI turned to an area of research they’ve excelled in funding – energy production. SMCI-funded studies have examined the effects pathogens may be having on energy production and the effect energy problems may be having on immune functioning. Now they’re turning to an entirely new area – genomics – to find if complex genetic issues in ME/CFS are harming energy production.
They’re bringing in a researcher new to the ME/CFS field – Liz Worthey, PhD, of the HudsonAlpha Institute for Biotechnology, which specializes in genomic medicine. Worthey, who’s developed new ways of probing the genome, is an interesting blend of geneticist and bioinformatics specialist.
Worthey will use novel analyses to find genes hampering energy production in ME/CFS.
She’ll use algorithms, including one called “custom network analysis” to examine all sorts of genomic abnormalities (single nucleotide substitutions, structural variants, fusion products, expanded tandem repeats, and variants in regulatory regions) that may be whacking away at the metabolic pathways in ME/CFS.
She believes that genetic alterations in ME/CFS may be altering metabolic pathways, leading to an unstable cellular energy state. The type of ME/CFS you have simply depends on which metabolic pathway your genes are interrupting.
She’ll be working with former Ramsay Award winner, Jarred Younger, who recently gave a talk on ME/CFS at HudsonAlpha.
Merging Mitochondrial Dysfunction and Autoimmunity in ME/CFS
“My explanatory model is that you can become immune to your own mitochondria.” Jonas Blomberg
The SMCI may have been saving the best for last. Jonas Blomberg is a member of Ron Davis’s Working Group and has been active in ME/CFS for quite some time. Just a month or so ago, he and his co-award winner, Anders Rosen, published a hypothesis suggesting ME/CFS may begin in the gut – long before the disease actually strikes – and end by slamming patients’ ability to produce energy.
They propose that a leaky gut created a population of auto-reactive B-cells that remained mostly inactive or quiescent (in a state of anergy) – almost like undercover agents infiltrating a city, waiting for the signal to pounce. At some point, a “decisive” immune event flipped them into action, and an autoimmune disease – ME/CFS – was born.
A well-published researcher with a long history of pathogen research, Blomberg, an MD and PhD, hails from Uppsala University in Sweden. He’s been an active player in ME/CFS issues in Sweden and Europe. He’s on the Board of Directors of the Gottfries Clinic – one of the few Swedish clinics which offers adequate care for people with ME/CFS – and is a member of the Biomarkers Working Group of EUROMENE, a European organization fighting for more ME/CFS funding.
Blomberg may be unique in that this is his second Ramsay award. His first, which involved Jonas Bergquist and Carl-Gerhard Gottfries, also focused on autoimmunity and energy production.
I spoke to Blomberg at the Stanford Working Group meeting at the end of September. He said, “So many things indicate that the mitochondria are not faring well in ME/CFS”.
Blomberg will hunt for signs that the immune system is attacking the mitochondria in ME/CFS.
The 2018 award will allow Blomberg and Rosen to further explore their thesis that an autoimmune process is pummeling ME/CFS patients’ mitochondria. If they’re right, ME/CFS wouldn’t be the first disease in which this has happened. In primary biliary cirrhosis (PBC) – a disease they’re using as a model for ME/CFS – autoantibodies attack the very same enzyme – pyruvate dehydrogenase – that so much interest has centered on in ME/CFS. (Ironically, the PBC study showing it was an autoimmune mitochondrial disease was published in the Lancet – the same journal which defies anything other than a biopsychosocial interpretation of ME/CFS.)
Bob Naviaux came to mind when Blomberg compared the mitochondria to an octopus, gathering information from and interacting with so many different components of our immune system. (Blomberg’s partner in the study, another PhD/MD – Dr. Anders Rosen – is an expert in mitochondrial signaling.)
Blomberg and Rosen will be looking for targets on the mitochondria and energy production system – on the pyruvate dehydrogenase enzyme – where the immune system might be pummeling ME/CFS patients’ energy production system.
He has his eye on an overarching model of ME/CFS in which an infection, through a process called molecular mimicry, triggers a kind of metabolic meltdown. What an intriguing idea – an autoimmune-mitochondrial model of ME/CFS. It would explain so much.
Expect a paper on Blomberg’s findings out soon.
The 2018 Ramsays
The 2018 Ramsay Awards feature some ambitious projects. They continue the SMCI’s focus on the energy production problems in ME/CFS and the immune system. Plus, they’re bringing one new researcher (Worthey) into the fold and an established mast cell researcher. Ramsay would undoubtedly be pleased at the focus on the immune system and energy:
- Finding a drug target for ME/CFS
- A genetic link to poor energy production
- Vesicles that trigger microglial and mast cell activation
- Uncovering an autoimmune link to poor energy.
The 2016 Ramsays set a high bar. Time will tell if the 2018’s can match that, but in the meantime, let’s wish them good luck in generating some good pilot data, which they then turn into studies and major grant awards – something this field vitally needs.
Thanks for the good report once more!
Would you happen to know if any of these researchers is investigating/revisiting “dismissed” pathogens?
Upon trying to understand my odd gut issues I came upon the observation that several bacteria don’t show up in blood tests because they combine two properties:
* They are living in near all human bodies, so a test that would highlight their presence would show nothing but false positives. For sure such test would be considered not useful and therefore not be considered a test.
* They provoke a very general/broad immune response so the immune markers are not truly specialized nor specific either. That may well make an activation of the immune system by these bacteria unremarkable even if it was somewhat higher then normal. ME patients are often believed to have a general/broad immune response. In fact a body wide CDR could well be part of such general/broad immune response.
For example Helicobacter Pylori, the bacteria causing stomach ulcers, has long been such inconspicuous bacteria while it is known now to worsen many cases of ME/CFS. Nobody was looking for it as bacteria weren’t supposed to be able to thrive in the stomach. And apparently it didn’t give a clear marker for bacterial infection in blood tests either as it would have alarmed doctors decades earlier.
It’s a very early hypothesis, needs plenty of work and has plenty of chances to fail the test of true improvement. But for my particular case the combination of plenty of food intolerances and Propionibacterium Acnes, a very common bacteria causing acne seem to be able to explain most of my health issues way better than all of the patchwork I found before combined.
On top of that, recent research found it infecting the inner eye, the gastrointestinal tract, hart valves, joints, the prostate, the blather, herniated discs and it’s suspected to be a main source of neuroinflammation in Alzheimer disease.
It’s also a common contaminant in blood and cerebrospinal fluid cultures. But is it called a contaminant because it is is available in the environment and not supposed to be there or can it still be found after taking very strict measures to avoid it?
It’s often introduced on places it’s not supposed to be by surgery, a common ME trigger. It has some more virulent strains. Infected sites are often populated by a large array of other opportunistic pathogens. Above all it has an array of very potent digestive enzymes damaging the tissue it’s located in. Combine all of that in the gut and it’s nothing short from continuing sepsis.
I do know it is a very far stretch, but the things mentioned here only start to enumerate some of the numerous ways this bacteria can contribute to chronic ME-like illness.
One can argue that if one particular bacteria were to cause ME then it would have been found long ago. I would argue that it is not one specific bacteria I suspect. I rather suspect that plenty of causes of ME might be strongly related to an unhappy combination of several factors including a common “house and garden” pathogen that normally is harmless.
In my case that combination may well be Propionibacterium Acnes plus my many food intolerances. A bowel is a thin walled organ made in part of epithelial cells, just like the skin. This bacteria digests cells just underneath the skin and delaminates cell layers. Apply this strategy to the very thing bowel and even a relatively small infection can create havoc. All these bacteria plus the opportunistic bacteria the lesions house have full and superb access to the entire bloodstream. That’s a text book sample for sepsis. On my skin small amounts of mechanical friction or contact with common chemical products worsens my acne. If they infected my bowel and caused it to inflame then the alternating diarrhea and constipation plus the effect of food I am intolerant to making contact with the inflamed bowel would make healing of the situation near impossible.
If this model were remotely true, then why hasn’t it been detected yet? Well, for starters it involves common supposedly harmless pathogens that are not looked after. But sure it must pop up somewhere?
Well, let us assume that there are about 10 such common supposedly harmless pathogens. With that I mean that there are 10 common pathogens that are more harmful to a subgroup of people with a specific genetic weakness towards that pathogen. The Borrelia bacteria for example is still considered fairly harmless by plenty doctors and researchers. Suppose there are another 10 such common triggers/activators like severe food intolerance or
having sleep apnea. That still is a fairly low amount.
Now suppose you need at least one of each category, then there are 10*10=100 combinations that could trigger an “unusual strong pathogenic effect” that is far stronger then what the pathogen by itself can do in a person with normal resistance to that pathogen.
Now, just for sake of fairness suppose only 30 out of these 100 combination would cause ME/CFS. Then we’d end up with 30 subgroups. Unless one subgroup is far more present then any of the other, any research onto the relation between a particular pathogen and ME/CFS will fail to find any statistical relevant relationship pointing at this one particular pathogen causing ME.
As a matter of fact, plenty of previous research has shown that “pathogen X” is responsible for causing ME/CFS just to be refuted later in large scale trials. It’s been sort of a pattern over the last few decades.
That is close to the statistical pattern one would expect to see with this kind of “genetic weakness towards common pathogen + trigger”. A doctor/researcher sees a lot of patients with a certain pathogen coming down with ME. He recognizes the characteristics of it an therefore unconsciously includes them more as typical ME cases. This subgroup ends up being over represented in the small scale trial. Add statistical variation and you have for example a 1 in 5 chance the findings are statistically relevant/convincing. Do the trial over with a large group of patients and a doctor not recognizing the characteristics of the subgroup and the trial is bound to fail.
-> Maybe we do need to revisit both the pathogens that popped out in passed failed research and the harmless ones that are excluded from tests because they are to common?
As always very interesting De Jurgen. It reminds me of Robert Phair’s search for common (not rare) mutations. I have heard that people with ME/CFS have a rather scattershot immune reaction – seemingly pointing everywhere but seemingly hitting nothing.
I think Blomberg would agree with your gut ideas. I’m so intrigued by the findings that sepsis has cardiovascular implications.
We’ll see what Blomberg’s search finds as well as Mark Davis’s T-cell search and in the Bateman Horne’s antibody search as well which appears to be coming up with something – https://batemanhornecenter.org/category/research-news/
I have had such a huge mast cell issues with my cfs – i noticed from day one how ill i always get after I eat – literally feel like Im poisoned and dying .. i am often getting butterfly rashes too and although over time changing diet has helped significantly but i still get days when my body cant take anything whatever i eat
It’s definitely a burgeoning field. I was surprised at how many time mast cells issues were mentioned at the Dysautonomia conference. Health Rising has some mast cell resources here – https://www.healthrising.org/forums/resources/categories/mast-cell-activation-syndrome.196/
If there is an autoimmune link to the plummeted energy production would we be able to repurpose immunosuppressant drugs or need a new drug.. Probably hard to tell right now but hopefully something will be available to bring us out of our houses even for a bit longer!! Also Cort, how long will Lombardi study be? If a drug could be identified it would be miraculous.
That’s exactly what Lombardi wants to do – identify a target in ME/CFS for which a drug is either already available or will become available in the near future. He hopes to able to identify a couple of targets which conform to different subsets.
I think it’s a fascinating idea – I hope it works!
I AM EXPERIENCING ALL OF WHAT YOU’VE SAID!
Merry
Hi, any follow-up on this study?
Maybe the idea of “pre-selecting” ME patients groups holds here as well? Many researchers are first and foremost doctors/professors with a specialization.
I can for example imagine that Fluge and Mella had far more ME patients with cancer in their small scale trials then average, just because it was easy to recruit their own patients and every single one of their own patients came to them for a cancer cure in the first place.
After having two successful small scale tests, the third big scale test failed. Maybe a redo of a big scale test with a large amount of ME patients that have at least a single relative that came down with a type of cancer where rituximab is used for might yield different results? I can imagine the same could hold for other drugs that had two successful small scale trials and failed in a larger trial with a more diverse ME patient mix of more different subgroups.
Maybe some of those drug trials that failed in a late state may reveal both a subgroup and a fairly successful drug for that subgroup.
I completely agree Dejurgen. Maybe Rituximab is still a suitable drug for some patients, notably the Peterson atypical subset.
For reasons I fail to understand, “[m]ast cells have long been regarded as an appendix of the human immune system”. [1] Professor Theoharides’ new project is long overdue and I hope it will prod more researchers into exploring the role of mast cells in ME.
Cort, do you know if this project will involve patients? The Solve write-up doesn’t say. I find travel to be very difficult, but I would seriously consider a trip to Boston in order to participate in this study.
[1] Matsumoto et al; Brain Mast Cells Act as an Immune Gate to the Hypothalamic-Pituitary-Adrenal Axis in Dogs; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2193441/
The study abstract doesn’t say so but I imagine that it will.
https://solvecfs.org/ramsay-2018-meet-professor-theoharis-theoharides-md-phd/
Is it possible to explain what the drugs could do to fix this state -if possible?
And if he has a hypothesis about that an already excisting drug could work, do you have any idea which he has in mind? And last 🙂 My daugther has gradually onset, storting with nausea and IBS. Now she also has lots of burning pain, does nevroinflammation fits this hypothesis? Thank you again Cort for bringing hope, updates and extreemly valuable information ❤
With your daughter: Read ‘Life Changing Foods’ by Anthony William.
It (and his other 3 books) helped me get over my FM pain & vagus nerve issues, and now I am working on the ME/CFS (poor sleep, brain fog, slow exercise recovery). My CFS Energy Index Point Score (0-10) has gone from a 1 to a 3 or 4 in the past 4 years, with occasional setbacks.
Right now, letting ‘Food be thy Medicine’ is the best bet until someone comes up with The Magic Pill (in 20+ years until FDA approved?). I can not wait that long.
Cutting out gluten, soy, GMO corn, and all dairy (=mucus causing and inflammatory foods) and eating more phytonutrient rich organic veggies+greens and anti-oxidant rich fruits& berries noticeably helps.
Found that taking ‘Iodoral’ (12.5mg), 200mcg selenium, and ‘whole food’ Vit C complex helped, due to their anti-viral & anti bacterial properties, and it improved my thyroid function (no more cold hands & feet!). Heart is stronger now, too.
I can ride my bicycle again, but have found my VO2max is still in the toilet from the muscle cells being unable to fully use blood oxygen. My oxygen-starved cells made my EPO & ferritin go high so as to adapt, but it didn’t help.
I am hoping the researchers (above) studying the pyruvate hydrogenase reaction come up with something to work around the underlying virus’s epigenetic alteration to it, since out of all the studies Cort has published as to the cause of the ‘exercise mailase’, that seems to be the closest I saw; Curious to hear others thoughts.
However, it seems the current researchers as a whole do not study what other researchers (worldwide) have already found out, and so many are chasing recently proven dead ends.
One thing that is known is that oxygen is toxic to many virus and bacteria, and it seems to me that the underlying mutated HHV virus strain(s) that are thought to cause ME/CFS are doing some ‘terraforming’ of it’s environment so as to cut down on oxygen.
Whatever is causing the damaging changes is in the serum, not the cell mitochondria (per a study Cort posted) which narrows down things. Epigenetic changes can be reversed, which is the good news.
Is anyone looking at that?
…Given the previous research findings, it seems like the logical next step.
So far I have found that Cordyceps Mushrooms helps with cellular oxygen usuage, both by reading studies and trying it out before bike rides (friends & I), so that is a place to start: See if a Cordyceps derivative affects the enzyme reaction?