NIH Intramural study update

RYO

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A newsletter was sent out today to study participants.
I wish there was more data but I clipped study update section.

“The Post-Infectious Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (PI-ME/CFS) study has been active since fall of 2016. Our team has decided to put together this newsletter in order to keep all study participants updated in regards to our research. Thus far, we have had 51 study participants - 27 ME/CFS patients and 24 healthy volunteers.
Of the 27 ME/CFS patients, 19 have been adjudicated in so far for the second phase of the study after review using an expert physician committee and published guidelines. Basic demographic participant data is shown on the following page.
Currently, sixty-two individuals from fourteen different institutes have collaborated in this study, making it truly interdisciplinary. Wide-ranging data analyses are currently underway. They include, but are not limited to:
• RNA sequencing by Michael N. Sack, MD., PhD and lab (NHLBI)
• Microbiome analysis by Giorgio Trinchieri, MD and lab (NCI/CCR)
• Magnetic Resonance Imaging (MRI) and Transcranial Magnetic Stimulation
analysis by Mark Hallett, MD and lab (NINDS)
• Autonomic function analysis by David S. Goldstein, MD., PhD and lab (NINDS)
• Immunologic function analysis by Dr. Avindra Nath, MD., PhD and Dr. Steven
Jacobson, PhD (NINDS)
The end goal of this study is to explore the clinical and biological phenotypes of PI-ME/CFS, which can then help us generate new hypotheses to understand the mechanistic under- -pinnings of this condition.

9612334C-9920-48A2-BC11-1A4DA7951FBF.jpeg

Figure 1. A map of the United States depicting the residencies of our study participants. ME/CFS Patients (light blue), Healthy Volunteers (mid-blue), and both groups (dark blue). Not pictured is the Canadian territory of Ontario.
Figure 2. Table depicting study participants organized by gender and ME/CFS status.
Age Range of Participants
76543210
Figure 3. Graphical depiction of the range, average, maximum, and minimum values of age of study participants during initial, phenotyping visit.
Gender
Male Female
ME/CFS Healthy Volunteers
14 12 13 12
18 to 24 25 to 34 35 to 44 45 to 54 55 to 60 Age Group
ME/CFS Healthy Volunteers
Number of Participants

The Bioenergetics of ME/CFS
with Dr. Rebekah Feng
Extreme fatigue and post-exertional malaise (PEM) are two cardinal characteristics
of ME/CFS. Both are prominent features of the International Consensus Criteria (ICC),
the Fukuda Criteria, and the Canadian Criteria of ME/CFS. One method by which we can explore these complex symptoms is to understand the processes that lead to the production and utilization of energy.
The fundamental energy currency of our body at the molecular level is
adenosine triphosphate (ATP) [figure 4]. It is required for nearly all cellular processes, including the immune response and muscle contraction. The majority of ATP (nearly 90 per- -cent) is produced by the mitochondria, the “powerhouse” of the cell. Dysfunction of the mitochondria leads to inefficiency of energy production, affecting all systems of the body. For example, the symptoms of many mitochondrial myopathies include exercise intolerance, elevated markers of muscle injury, fatigue, and muscle pain.
H2N
High energy bond N
N
OOO N OPOPOPO ON
OOO
Figure 4. Adenosine Triphosphate. The energy from this molecule comes from the phosphate bonds.
OH OH

One way we are measuring mitochondrial function at the NIH is by using the extracellular flux assay. This work is being overseen by Dr. Rebekah Feng and her lab. “This assay,”
Dr. Feng states, “allows us to examine how efficiently our peripheral blood mononuclear cells are producing energy. Specifically, it measures two variables. The first is oxygen con- -sumption and the second is proton concentration.” Oxygen consumption plays a vital role
in aerobic respiration, the efficient process by which mitochondria produce between 30 and 36 ATP molecules. Proton concentration, on the other hand, allows us to measure glycolysis, the inefficient and anaerobic process by which our cells convert glucose into pyruvate, which produces only 2 ATP molecules. Analyzing the relationship and ratio of rates of these two processes can help us better understand mitochondrial efficiency in ME/CFS.
“In regards to the current project, we have had some pretty interesting findings. Even with the current sample size, the data is still statistically significant. We saw changes in mito- chondrial function from before exercise to after exercise in ME/CFS patients, compared to their matched controls. That tells us that there may be something going on at the cellular level.” says Dr. Feng.
As far as future directions, Dr. Feng and her group are looking to explore bioenergetics in muscle tissue extracted via the muscle biopsies that many of you have undergone, in addition to PBMCs.
Dr. Rebekah Feng is a research fellow at the NIH. She received her Ph.D in Neuroscience from Georgetown
University, and since then has published over thirty peer- reviewed articles in esteemed journals such as Science and Oncology. Her current research focuses on mechanisms of fatigue in chronic conditions such as cancer and ME/CFS.”
 

Wishful

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I'm not all that excited. I still believe that any decrease in ATP in muscles is a secondary effect of ME. To me, "the data is still statistically significant" sounds like it's a small difference, much less than would be expected if ATP production was the critical part of ME. A small but statistically significant difference is what I would expect from a secondary effect of ME.

I'm not a trained biologist (or statistician), so I could be wrong, but my feeling is that this isn't going to lead to a breakthrough. :meh:
 

wabi-sabi

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Statistically significant means that the effect is real, and not due to random chance or variation between people. That they see a statistically significant difference with so small a sample size (where you would expect chance variation to be large) means that there is something really going on here. That's exciting to me.

This statistical result cannot tell us whether the mito problems are a cause or an effect, only that they are real. That's important, because it puts what we know in our bodies to be true into language scientists can understand. One more nail in the BPS coffin!

I am somewhat worried that NIH is repeating research that Dr. Hanson has already done. There was a recent presentation by her student Dr. Mandorano. You can find the link on Dr. Hanson's twitter. https://neuroimmune.cornell.edu/news/ I know science works by repetition, but I hope NIH are aware of what they should be building on and whose research they should look at for guidance.
 
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Thanks for the update.

Really hope a sufficient amount of patients will apply to participate.

This seems like one of the most important studies into ME/CFS ever.
@Michiel Tack
Gosh I wish this will prove to be true. One major difficulty in recruiting patients is that you can't have been sick for more than 5 years. Notice that no one from Massachusetts, 400 miles away, is participating. Everyone I know has been sick for longer.
The study of muscle will unlikely help us understand this disease. Mitochrondriopathies look completely different.
I hope the effort will be mostly on in-depth study of various types of immune cells.
 

RYO

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I think there is a potential that a mitochondrial defect/issue can be pivotal for other abnormalities found in ME/CFS. For example Dr. Systrom‘s research using invasive cardio pulmonary testing showed there may be an issue with oxygen utilization at the tissue level. This may be related to mitochondrial dysfunction in ME/CFS patients.

Mitochondrial dysfunction maybe also be serving as the trigger that leads to changes in immune cells / T cells which Dr Unutmaz’s research may delineate. Dr Navdeep S Chandel Ph.D at Northwestern has been shown that dysfunctional mitochondria can lead to T cell dysregulation. (Regulator T cells that are unable to suppress)
 

bread.

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I can not wrap my head around how anyone on this planet does not try to understand me/cfs as a mitochondrial disorder, it is just plain batshit crazy. Especially when it come to cases that fit Ramsay ME criteria. There is a lack of energy no „faulty tiredness“ in this disease!
 

Wishful

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There is a lack of energy no „faulty tiredness“ in this disease!
No, if there's a lack of ATP in my ME, it seems limited to some brain cells if at all. My muscular strength and endurance is unchanged from pre-ME. I can go for a 6-hr bike ride, including very steep hills, just as before, so no lack of energy there.

I don't rule out mitochondria playing a role, perhaps affecting microglial function or some such thing, but it doesn't seem like a general mito dysfunction. Note that it is possible for cerebral mitochondria DNA to differ slightly from that in the rest of the body, so maybe I have a mt-DNA defect only in my brain cells, that allows the ME state in those cells.
 

Wishful

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That they see a statistically significant difference with so small a sample size (where you would expect chance variation to be large) means that there is something really going on here. That's exciting to me.
When the sample size is small, there should be a higher chance that it's just measuring something other than what you were expecting. Maybe the thirteen controls were all above average in physical activity and the patients were below average (prevented by ME), and you'd see the same 'statistically significant' difference in two healthy groups divided by activity level. Maybe the one in one group had some correlation not covered by the questionnaire, such as eating foods with artificial colouring. That is a problem with small sample sizes.

To me, "the data is still statistically significant" still sounds like a phrase implying that it's a very small effect but it's the only thing they can offer to try to get more funding. I think that a research group would use as dramatic a phrase as they could justify. They're essentially advertising for more funding, so they'd use the marketing techniques of trying to make it sound as good as possible. "Statistically significant" might mean "Just barely above the noise, and we had to do some minor data fudging to get even that".
 

JES

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I can not wrap my head around how anyone on this planet does not try to understand me/cfs as a mitochondrial disorder, it is just plain batshit crazy. Especially when it come to cases that fit Ramsay ME criteria. There is a lack of energy no „faulty tiredness“ in this disease!
I reckon I brought this point up sometimes earlier, but Ron Davis' plasma swap experiment has pretty much proven that ME/CFS is not a mitochondrial disease, at least not in the sense that mitochondrial diseases are traditionally understood. In Davis' plasma swap experiment, which you can read more about here, it turns out ME/CFS cells suddenly start behaving almost completely normally in the nanoneedle when subject to plasma from a healthy control. Likewise, plasma from ME/CFS patients will cause cells from healthy controls to behave abnormally, which is even more significant as it demonstrates that plasma alone can transfer the diseased cellular metabolic state from one person to another.
 

bread.

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I can not wrap my head around how anyone on this planet does not try to understand me/cfs as a mitochondrial disorder, it is just plain batshit crazy. Especially when it come to cases that fit Ramsay ME criteria. There is a lack of energy no „faulty tiredness“ in this disease
I reckon I brought this point up sometimes earlier, but Ron Davis' plasma swap experiment has pretty much proven that ME/CFS is not a mitochondrial disease, at least not in the sense that mitochondrial diseases are traditionally understood. In Davis' plasma swap experiment, which you can read more about here, it turns out ME/CFS cells suddenly start behaving almost completely normally in the nanoneedle when subject to plasma from a healthy control. Likewise, plasma from ME/CFS patients will cause cells from healthy controls to behave abnormally, which is even more significant as it demonstrates that plasma alone can transfer the diseased cellular metabolic state from one person to another.

I am sorry, but this is proof of nothing.
 

bread.

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No, if there's a lack of ATP in my ME, it seems limited to some brain cells if at all. My muscular strength and endurance is unchanged from pre-ME. I can go for a 6-hr bike ride, including very steep hills, just as before, so no lack of energy there.

I don't rule out mitochondria playing a role, perhaps affecting microglial function or some such thing, but it doesn't seem like a general mito dysfunction. Note that it is possible for cerebral mitochondria DNA to differ slightly from that in the rest of the body, so maybe I have a mt-DNA defect only in my brain cells, that allows the ME state in those cells.
if you can go for a 6h bike tour, you by definition have no me/cfs (in my limited understanding), definitely no me and 100% no mitochondrial disease?

I am sorry but part of the problem in this disease is that it is so poorly defined. It is no surprise that there are no clear findings in studies when people with your capacities and people like me who are 100% bedridden and have muscle wasting and fatigue are mixed up. In all likelihood we do not have the same disease.
 
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JES

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I am sorry, but this is proof of nothing.
If healthy cells start behaving abnormally once plasma from patient blood is added and vice versa, then I can't see how this doesn't prove that the problem is elsewhere than in the mitochondria. It is IMO the most significant finding that Ron Davis' group has managed to produce so far because it directly points at the problem being in the blood, not in the mitochondria.

This model also aligns with my own experiences with so called temporary remissions. Once I get ill with a cold, all my ME/CFS symptoms resolve temporarily within 24 hours. Same thing with certain medications and supplements, although frustratingly, they always stop working at some point. Anyway, none of this would be possible if mitochondria were faulty. Davis has also observed this phenomenon, where the patient's cells start behaving more normally in the nanoneedle after the patient had been sick.
 
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If healthy cells start behaving abnormally once plasma from patient blood is added and vice versa, then I can't see how this doesnt't prove that the problem is elsewhere than in the mitochondria. It is IMO the most significant finding that Ron Davis' group has managed to produce so far because it directly points at the problem being in the blood, not in the mitochondria.

This model also aligns with my own experiences with so called temporary remissions. Once I get ill with a cold, all my ME/CFS symptoms resolve temporarily within 24 hours. Same thing with certain medications and supplements, although frustratingly, they always stop working at some point. Anyway, none of this would be possible if mitochondria were faulty. Davis has also observed this phenomenon, where the patient's cells start behaving more normally in the nanoneedle after the patient had been sick.
The two theories aren't mutually exclusive - it can be in the blood and be impacting the mitochondria. A real world example is the disease Primary Biliary Cholangitis, which is caused by the M2 anti-mitochondrial antibody. This antibody/immunoglobulin inhibits the PDH complex in the mitochondria, which leads to constant debilitating fatigue + post exertional malaise. The medical community can treat the liver failure caused by PBC, but we still don't have answers for how to fix the fatigue these patients experience due to these antibodies. If finding a single antibody was the answer to ME/CFS, then we wouldn't still be here speculating about these things - but it is possible that a byproduct of a dysfunctional system/process in the body is producing something that is causing major mitochondrial-based metabolic dysregulations.
 

Jessie 107

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if you can go for a 6h bike tour, you by definition have no me/cfs (in my limited understanding), definitely no me and 100% no mitochondrial disease?

I am sorry but part of the problem in this disease is that it is so poorly defined. It is no surprise that there are no clear findings in studies when people with your capacities and people like me who are 100% bedridden and have muscle wasting and fatigue are mixed up. In all likelihood we do not have the same disease.
I agree, how on earth can someone have M. E and be able to bike ride for six hours with no PEM!!!?!? Not possible.
 

JES

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The two theories aren't mutually exclusive - it can be in the blood and be impacting the mitochondria. A real world example is the disease Primary Biliary Cholangitis, which is caused by the M2 anti-mitochondrial antibody. This antibody/immunoglobulin inhibits the PDH complex in the mitochondria, which leads to constant debilitating fatigue + post exertional malaise. The medical community can treat the liver failure caused by PBC, but we still don't have answers for how to fix the fatigue these patients experience due to these antibodies. If finding a single antibody was the answer to ME/CFS, then we wouldn't still be here speculating about these things - but it is possible that a byproduct of a dysfunctional system/process in the body is producing something that is causing major mitochondrial-based metabolic dysregulations.
Yep, no disagreement here. A big part of the issues people experience with ME/CFS might indeed be produced by mitochondrial dysfunction. But if we use the example of a single autoantibody causing mitochondrial dysfunction, then I believe the disease would fall under "autoimmune" since the upstream cause is the autoantibody. Take away the autoantibody, problem solved in this case. As a side note, this kind of filtering of autoantibodies is exactly what Dr. Scheibenbogen is doing in her POTS patient trial.
 

Wishful

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agree, how on earth can someone have M. E and be able to bike ride for six hours with no PEM!!!?!? Not possible.
No, I'm not the only one here with ME and still able to do physical activities. My ME symptoms seem purely neurological: mental lethargy, neuropathic pain, general malaise. The rise in temperature correlating with the other symptoms is physical, but probably due to neurochemicals (picolinic acid would do it). It seems to involve my microglial cells.

Yes, I don't get PEM from a long bike ride or hike. However, I do get physically-induced PEM from a few minutes of physical activity that uses my muscles in unusual ways, such as washing windows overhead or climbing a ladder. My trigger seems to be muscle cell tearing (which activates t-cells), rather than simple exertion. I also get cerebrally-induced PEM from driving or socializing.

In all likelihood we do not have the same disease.
I think it's the same core dysfunction. We just differ in triggers, responses and downstream effects.
 
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If healthy cells start behaving abnormally once plasma from patient blood is added and vice versa, then I can't see how this doesn't prove that the problem is elsewhere than in the mitochondria. It is IMO the most significant finding that Ron Davis' group has managed to produce so far because it directly points at the problem being in the blood, not in the mitochondria.
.
There is another thread titled "New Research Suggests genetic material from Mitochondria can cause an immune response". It seems possible that an issue in the Mitochondria could in turn cause autoimmunity.

Also the thread in other research called "Something in the blood" has found fully functioning mitochondria in Plasma. Up to now that was completely unknown.

Here is a link to an overview of the research https://newatlas.com/biology/unexpected-new-component-discovered-bloodstream/

It could be (total speculation on my part) that the mitochondria are the source of the problem.
 
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No, if there's a lack of ATP in my ME, it seems limited to some brain cells if at all. My muscular strength and endurance is unchanged from pre-ME. I can go for a 6-hr bike ride, including very steep hills, just as before, so no lack of energy there.
I feel that this is definitely the exception rather than the rule in me/cfs. It doesnt mean you don't have it, but it does seem to mean that you might not make the cut for a study like the NIH one or Ron Davis, bc you might dilute the signal or be an outlier.
I reckon I brought this point up sometimes earlier, but Ron Davis' plasma swap experiment has pretty much proven that ME/CFS is not a mitochondrial disease, at least not in the sense that mitochondrial diseases are traditionally understood. In Davis' plasma swap experiment, which you can read more about here, it turns out ME/CFS cells suddenly start behaving almost completely normally in the nanoneedle when subject to plasma from a healthy control. Likewise, plasma from ME/CFS patients will cause cells from healthy controls to behave abnormally, which is even more significant as it demonstrates that plasma alone can transfer the diseased cellular metabolic state from one person to another.
However, I agree with this. There are definitely substantial metabolic problems in me/cfs but it is not a primary mitochondrial disorder

however there are definitely some people that have been diagnosed with me/cfs that end up getting a mitochondrial disease diagnosis. Both in the screening for the NIH study and outside of it