Washington Post article, 8/17/23 - by Brian Vastig - re NIH breakthrough re WASF3

[Mary]

She wrote to a scientist about her fatigue. It inspired a breakthrough.​

https://www.washingtonpost.com/health/2023/09/17/fatigue-cfs-longcovid-mitochondria/

This article was written by ME/CFS patient Brian Vastig. A woman named Amanda Twinam contacted Dr. Paul Hwang at the National Heart Lung and Blood Institute because of a paper he had written having to do with mitochondria and energy. Amanda had had energy problems (lack thereof) for years. And her correspondence and subsequent trip to the NIH for extensive testing with Dr. Hwang apparently is what led to his breakthrough discovery of the protein WASF3 gumming up energy production in ME/CFS patients.

He found that skin cells taken from Twinam appeared to be churning out an excess of a protein called WASF3. Zooming inside Twinam’s mitochondria, Hwang and colleagues eventually saw something stunning: Like a stick jammed into bicycle spokes, the overabundant protein was literally gumming up the gears of energy production.

A final serendipity broadened Hwang’s research from a single patient to an entire population of sick people: He obtained muscle tissue from Walitt’s ME/CFS patients.

Nine out of 14 had similar overabundance of WASF3 as Twinam, and, on average, the group’s levels of this protein were higher than that of healthy volunteers. Although the sample size is small, the finding suggests that this energy-squashing problem is widespread in ME/CFS.

For Hwang, developing a treatment for the illness is now “what keeps me going.” His small laboratory, just four scientists, is planning a clinical trial with a drug that recently came onto the market for another disease.

I'm just amazed that Dr. Hwang responded, and very quickly, to Amanda. He brought her to Washington DC for extensive testing. It's mind-blowing that he was so responsive, and incredible what this led to.

Here's an ongoing thread on PR about Dr. Hwang's paper re WASF3 and ME/CFS: https://forums.phoenixrising.me/threads/wasf3-disrupts-mitochondrial-respiration-and-may-mediate-exercise-intolerance-in-myalgic-encephalomyelitis-chronic-fatigue-syndrome.90582/

 

[datadragon]

Here is a quick summary that may be easier to understand:

Further laboratory studies led the team to a protein called WASF3. This protein, which was boosted in response to cellular stress, disrupted the cells’ energy production. Blocking WASF3 allowed mitochondria to produce energy at normal levels. The team then showed that extra WASF3 in the cells interfered with formation of the structures that mitochondria use to produce energy.

To better understand the role of WASF3, the team engineered mice to produce excess WASF3. They found that, similar to people with post-exertional malaise, muscles in these mice were slow to recover after exercise. The mice also showed a 50% reduction in their ability to run on a treadmill, even though their muscle strength was comparable to mice without extra WASF3.

To see if WASF3 dysfunction might be involved in ME/CFS, the team compared muscle tissue samples taken from 14 people with ME/CFS to samples from 10 healthy volunteers. They found substantially higher levels of WASF3 in most of the people with ME/CFS.

This dysfunctional increase in WASF3 seemed to be linked to impairment of a cellular signaling pathway called the ER stress pathway. When the team treated human muscle cells with a compound known to increase ER stress, they saw a corresponding harmful increase in WASF3.

The researchers treated cells from the initial study participant with an experimental drug, called salubrinal, known to reduce ER stress. After this treatment, WASF3 levels decreased in the cells, more mitochondrial energy complexes formed, and energy production improved.

https://www.nih.gov/news-events/nih...ein-may-be-linked-exercise-intolerance-me-cfs

 

[Judee]

Wanted to ask if people think this could also lead to some sort of biomarker too and hopefully one that could be easily accessible to patients?

 

[Mary]

Another article about the same thing, this time in the Guardian:

https://www.msn.com/en-us/health/me...1&cvid=9da417c60e044617855b361dae7e31b1&ei=92

What I found most interesting was this:

Dr Hwang is now focused on curing ME/CFS, and says this goal is what keeps him going. [I added the bold] His team of four scientists is planning a clinical trial to determine whether a drug that’s new to the market may help patients with the condition.

Both Dr Hwang and Twinam say they’re grateful for the coincidences that led to Twinam’s diagnosis. “Amazing findings in medicine,” Dr Hwang explained, “are sometimes based on one patient.”

 

[Rufous McKinney]

the article above says her only symptom was the fatigue.

I suspect we have a far more complex situation going on. And as usual, in my view, you would need to look at any. number of other syndromes which also include fatigue; or show higher levels of WASF3.

Meanwhile, what is causing higher levels of WASF3? This could be yet another downstream effect but perhaps someting could correct it and we'd luck out.

 

[Osaca]

the article above says her only symptom was the fatigue.

I suspect we have a far more complex situation going on. And as usual, in my view, you would need to look at any. number of other syndromes which also include fatigue; or show higher levels of WASF3.

Meanwhile, what is causing higher levels of WASF3? This could be yet another downstream effect but perhaps someting could correct it and we'd luck out.

She is indeed an extremely special patient with a rare gene mutation and a history of cancer. What they have found so far has been encouraging, but I'm not putting much hope in it.

What has been very positive is the news coverage about ME/CFS and if the NIH investigates ME/CFS more based on these findings than that is a very positive outcome even if the WASF3 findings don't pan out.

 

[Rufous McKinney]

She is indeed an extremely special patient with a rare gene mutation and a history of cancer.

I"m sorry she suffered so much, and grateful they stumbled upon this.

But: gosh she is very special.

Iv'e been sick my whole life, and it dint make a hill of beans difference to anybody.

 

[BaileyBeached]

I"m sorry she suffered so much, and grateful they stumbled upon this.

But: gosh she is very special.

Iv'e been sick my whole life, and it dint make a hill of beans difference to anybody.

I get what you're saying. But I appreciate the article ends with

“There’s this difference between cancer and chronic fatigue syndrome,” a diagnosis her rheumatologist has finally added to her file, she says. “Everybody believes you when you have cancer. You joke about having a ‘cancer card’ to get off from doing things. No one is handing out CFS cards. I can finally say, ‘It’s not psychological. I’m not a malingerer.’ We now have a scientific explanation.”

Recognizing how often csf patients are neglected.

 

[Rufous McKinney]

Recognizing how often csf patients are neglected.

My sister in law experienced a very challenging cancer diagnosis and treatment. I was working full time, sick with this, and barely able to keep my job going, due to this illness, but I never saw my sister in law during all the intense stuff she went through.

But since she "has cancer" she has this legitimate thing, and I exist in a state of illegitimacy. Its largely projection, but since we can't talk about any of it directly, Project Onward.

My brother was never much for discussing personal things, we could not be more different. But I never see them. And plans fail, because I can't fulfill them on my end.

So it's like I''ll never see them again. And that hurts.

I think perhaps they FINALLY understand how sick I am when my entire family came to visit them but I didn't come along with. Maybe they FINALLY grasped that I can't do these simple things others do every day (go visit their relatives, make a phone call, visit with somebody for an hour) go a store, go for a walk.

So you're missing totally missing from normal things nobody thinks twice about. I guess thats why the logo sort of works...except people were supposed to care that we ARE missing.

 

[Violeta]

To see if WASF3 dysfunction might be involved in ME/CFS, the team compared muscle tissue samples taken from 14 people with ME/CFS to samples from 10 healthy volunteers. They found substantially higher levels of WASF3 in most of the people with ME/CFS.

This dysfunctional increase in WASF3 seemed to be linked to impairment of a cellular signaling pathway called the ER stress pathway. When the team treated human muscle cells with a compound known to increase ER stress, they saw a corresponding harmful increase in WASF3.

The researchers treated cells from the initial study participant with an experimental drug, called salubrinal, known to reduce ER stress. After this treatment, WASF3 levels decreased in the cells, more mitochondrial energy complexes formed, and energy production improved.

I hope they spend some time focusing on the root cause and not just on a drug that reverses the ER stress.

Note to self: Spend some time thinking about the root cause.

 

[Rufous McKinney]

Spend some time thinking about the root cause.

yes: your really smart and brain capable......so let me know when you get that all worked out.

 

[Judee]

the article above says her only symptom was the fatigue.

I suspect we have a far more complex situation going on. And as usual, in my view, you would need to look at any. number of other syndromes which also include fatigue; or show higher levels of WASF3.

I think she does have ME/CFS though because she said, "I knew something was wrong at a young age, after a bout of mono, she told The Washington Post. In college, she never felt that exercise gave her the boost it did for other people. Instead, after working out, she said she “felt like garbage”

That last part sounds how someone might describe PEM if they didn't know what PEM is and she said her doctor originally diagnosed it as autoimmune so he probably didn't recognize what was going on with her either. ???

Also it is complex but Murph was asked in a recent thread if this issue with WASF3 could cause the other symptoms too. He said he thought it could. That kinda makes sense to me that if the mitochondria are not generating energy it's going to affect the function of other things as well. ??

Anyway, I'm hopeful. Though I do agree with you that they will have to look at other syndromes to see if this is happening in those as well. This article on the NIH website ends by saying, "Mitochondrial dysfunction has been found in some people with Long COVID and other conditions that include fatigue. More research is needed to understand whether targeting ER stress may also be a promising approach for these conditions."

 

[hapl808]

The very first thing I noticed after getting sick (other than the acute GI problems around onset), was a total lack of endorphins after exercise and a complete lack of any 'benefit' after exercise. I used to go to the gym 3-4 days a week for 1-2 hours, but after getting sick it went to 45 mins, then 30 mins, then 20 mins, then within months I stopped being able to exercise completely.

For 20 years I would mention the lack of endorphin thing to doctors. The first time I saw it mentioned was an article about how LDN fixed that, but it didn't work for me when I subsequently tried it.

One big tell: In college, after exercising, Twinam would not experience an endorphin rush.

So that does sound like mild ME/CFS to me.

 

[BaileyBeached]

So you're missing totally missing from normal things nobody thinks twice about. I guess thats why the logo sort of works...except people were supposed to care that we ARE missing.

Yeah I get it, I've had those closest to me do and say some, pretty horrible things. I think you have the right attitude though. I've been bedridden for over a decade and I used to be some combination of shocked and angry. I've been doing my best to move toward trying to help them understand, realizing it will take patience and might end up being futile. I will say, I have recently observed changes for the better I never thought I would see,... it took more than a decade, but things have improved in terms of relationships.

 

[Violeta]

Yeah I get it, I've had those closest to me do and say some, pretty horrible things. I think you have the right attitude though. I've been bedridden for over a decade and I used to be some combination of shocked and angry. I've been doing my best to move toward trying to help them understand, realizing it will take patience and might end up being futile. I will say, I have recently observed changes for the better I never thought I would see,... it took more than a decade, but things have improved in terms of relationships.

This brings up a point about ME/CFS that I've been trying to put into words.

PEM? Some people can't even get out of bed much less exercise or exert themselve in any way at all.

Would this WASF3 theory be adaptable to them?

yes: your really smart and brain capable......so let me know when you get that all worked out.

@mariovitali came down with it from a drug, he just stopped taking it, lists his remedies.

For some people it starts with a virus, but not too many people seem to have been able to deal with that cause. Is there a way to fix whatever is causing the ongoing ER stress or mitochondrial issue from a virus?

Just saw a study about hypoxia causing ER stress. I don't know if that pertains to me or not, or how to fix it.

It was brought up in this thread, I think, about zinc deficiency/copper toxicity biounavailability.

Anything else? Can't think too much tonight, too tired.

We can talk about all these and maybe figure a way to remedy them, but if the big guys don't talk about them, most people will never hear about it.

 

[SlamDancin]

@Violeta One thing you might want to look into are Sigma 1 agonists. Sigma 1 agonists are being trialed for Huntington’s as ER stress inhibitors and if I’m not mistaken Fluvoxamine has shown promise for COVID/LC due to its Sigma 1 agonism

 

[Violeta]

@Violeta One thing you might want to look into are Sigma 1 agonists. Sigma 1 agonists are being trialed for Huntington’s as ER stress inhibitors and if I’m not mistaken Fluvoxamine has shown promise for COVID/LC due to its Sigma 1 agonism

Thank you, I'd never heard about Sigma 1, I had to look it up. Very interesting.

I started taking berberine not too long ago. It's on the list of Sigma 1 agonists.

When my daughter had COVID I started to get symptoms of when I had shingles. The berberine reduced my symptoms overnight.

What drugs are sigma 1 agonists?

"Drugs known to be σ-agonists include cocaine, morphine/diacetylmorphine, opipramol, PCP, fluvoxamine, methamphetamine, dextromethorphan, and berberine."

Also berberine is antiviral.

BBR has the ability to inhibit infection of various viruses including influenza virus, HSV, HCMV and CHIKV, and to reduce virus production.

"Therefore, the antiviral agent that blocks the viral lytic cycle, such as resveratrol, triptolide, and berberine, can provide potential treatment or prevention strategies for EBV-associated diseases."
One more thing:

The anti-depressants effects of berberine were accompanied by reduced the neuroinflammatory response via inhibiting the activation of NLRP3 inflammasome and rescued the neuronal deterioration via suppression of impairments in synaptic plasticity and neurogenesis.

 

[SlamDancin]

@Violeta Be careful with Berberine it can cause low Blood sugar and GI side effects. That’s an intimidating list of agonists there jeez, I promise there are sigma 1 agonists that aren’t schedule 1 narcotics lol. Pregnenolone, DHEA, Resveratrol, Bromantane/Memantine, etc.

 

[Violeta]

@Violeta Be careful with Berberine it can cause low Blood sugar and GI side effects. That’s an intimidating list of agonists there jeez, I promise there are sigma 1 agonists that aren’t schedule 1 narcotics lol. Pregnenolone, DHEA, Resveratrol, Bromantane/Memantine, etc.

I took some this morning before breakfast because of a headache, but I am going to try to only take the berberine after meals so it doesn't cause low blood sugar and at the same time guards against high blood sugar.

I know what you mean, and was wondering what it means that narcotics hit up sigma 1.

I have tried pregnenolone, however a long time ago, and it made me feel pretty bad, unfortunately.Weird.

 

[SlamDancin]

@Violeta Hmm, DXM helps me a lot but it’s a dirty drug along with most of those on that list. Heroin, PCP, Meth have other primary mechanisms that make them what they are. Sigma1 agonism is associated with “drug liking” as in even some pure sigma1 agonists can be addictive but there are those that are not, like Memantine, although even that has other mechanisms involved. Even Berberine obviously will have other mechanisms. Pregnenolone inhibits GABA and CB1 receptors so it makes sense that it doesn’t feel good to some people by the way. I think DHEA is the stronger sigma agonist