WASF3 disrupts mitochondrial respiration and may mediate exercise intolerance in myalgic encephalomyelitis/chronic fatigue syndrome, 2023 Hwang et al

[SNT Gatchaman]

Thread on Hacker News.

From a quick scan there seems to be little to no discussion of the study itself.

Yes, that's absolutely true. The link under discussion (or not!) was to the Science article, rather than to the paper itself.

and all of the usual misinformed easy opinions about ME and FND

Also true, but there are some personal lived experience comments and some good pushback comments which I hope were noted.

Spoiler: Eg 1

Doctors literally say "you're making it up." In those exact words. There is no misunderstanding.

My wife had an emergency department refuse to treat her because they disagreed with an unrelated diagnosis that was in her medical record. Until she admitted that she was "making it up" and didn't have it, so they could "correct" the record, they would not treat her. She ended up having to leave and go to another hospital.

Spoiler: Eg 2

I am not buying that psychiatry actually helped. With this type of condition, some people get better over time. So those people would have gotten better anyway without the psychiatry. I also think the medical community should also rethink the notion some symptoms are psychosomatic. Why is that true? Because doctors can't spot the cause, so it must be psychosomatic? Maybe the cause is there but undetectable or not understood yet.

I think it's worth noting that it got some attention there. That site has a minimalist text style, but does have significant mind share, said to be about 3M views per day, so to have ME/CFS on the front page is probably a good thing in terms of awareness. It is also frequented by venture capitalists, some of whom operate in the bio portion of the tech sphere and are on the lookout for unicorn ROIs.

 

[Jaybee00]

Just curious -- when you say you don't see much in the pipeline for this, do you mean in terms of potential treatments? (Just wanting to better understand

In terms of compounds to address this pathway there isn’t much besides salubrinal—seems like pharma isn’t interested. By constrast the IDO pathway, where pharma is interested because of cancer, there are a bunch of compounds in development— Phase 1 and preclinical
https://www.s4me.info/threads/prolo...2-infection-2023-guo-et-al.34402/#post-489210

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8221258/

 

[Jaybee00]

TUDCA is licensed in Italy as Tudcabil for the treatment of bile production disorders. 20 250mg tablets cost about €11.

An affordable self-administered drug like this for ME/CFS would be amazing.

Combine TUDCA with sodium phenylbutyrate which you can get for about $1000/kg and you have a drug that costs $160,000 per year—amazing how that works.

 

[Dakota15]

From Dr. Whittmore at NINDS:

"The recent publication from Dr. Hwang’s group at NIH is a collaboration with NINDS and Dr. Nath as part of the NIH Intramural research on ME/CFS. I think the results are very interesting and potentially very important, but need to be replicated by another group and in a larger number of individuals with ME/CFS. I don’t have an update on the publication (ME/CFS Intramural Study). Last I heard it was still under review at the journal."

[We’re at month 4 of review for whichever journal this went to for publication (as it was submitted in late April). *Hopefully* it won’t be too much longer..?]

From Dr. Koroshetz at NINDS:

"Yes, this is interesting. It actually is the result of a collaboration between Dr. Avi Nath the NINDS investigator on the NINDS ME/CFS protocol and Dr. Hwang in NHLBI who analyzed the muscle biopsies from the ME/CFS protocol patients. Dr. Nath emailed me today saying they are continuing to collaborate.

There are two other papers that came out about findings studying Long Covid that might be relevant to ME/CFS more broadly. (attached)"

https://www.science.org/doi/10.1126/scitranslmed.abq1533#:~:text=Overall, autopsy heart tissue from,and lymph node autopsy samples

https://www.biorxiv.org/content/10.1101/2023.02.09.527892v2

 

[Ben H]

Fascinating stuff. I hope the concerns that @DMissa has noted can be answered, that would be really helpful.

It feels very on-form that the tenacity of a single patient is a large reason this study progressed/exists, by the sounds of it (maybe I’m misreading that). Look forward to reading the story behind it, @B_V .

Tentatively hopeful.

 

[DMissa]

Okay, I have answers! Yay.

1) Aspects of fibroblast cell culture that I raised appear to be handled sensibly, carefully, thoroughly and attentively. I am pleased with the information provided by email. Amazing.
2) Protein assay involved lysis (from email) which negates potential small concerns of cell monolayer disarrangement (my thoughts). Whether or not a protein assay is appropriate for the application can be left to your interpretation based on available evidence (my thoughts, not from email). No need to force my opinion again, it is not an objective flaw, just a preference of my own.
3) Cohort information: Average age believed to be similar, females believed to be present in higher proportion. No specifics, but it was acknowledged that it should have been in the paper.
4) Activity information was not known due to samples being anonymised.

So basically the remaining question marks are:

-detailed specifics of the cohorts, but given the acknowledgement by Paul Hwang I assume they will include them in future papers.
-unknown activity levels for the muscle samples.

Cheers folks.

 

[SNT Gatchaman]

I don't know if techniques can translate between cell types, but if the same thing can be shown in endothelial cells to explain orthostatic intolerance and in PBMCs as a proper mechanistic biomarker in liquid biopsy, that would be ... quite helpful.

 

[DMissa]

I don't know if techniques can translate between cell types, but if the same thing can be shown in endothelial cells to explain orthostatic intolerance and in PBMCs as a proper mechanistic biomarker in liquid biopsy, that would be ... quite helpful.

Generally speaking yes but depends on specifics of:

1) is the signal being measured detectable in the other particular cell type. Eg: mito function troublesome to measure in quiescent cells

2) utility of doing it depends on whether the pathology is tissue- or cell type-specific (don't know this yet, so comparisons are valuable and worth attempting)

 

[Midnattsol]

Forskning.no wrote about the study today, and I am always so happy when there is an article about ME without any reference to the "two sides" etc.

 

[wastwater]

https://en.m.wikipedia.org/wiki/WASF3
Wiskott-Aldrich syndrome protein family member 3 is a protein that in humans is encoded by the WASF3 Gene

Wiskott-Aldrich syndrome is the rare genetic disease that WASF3 is associated with

https://www.msdmanuals.com/en-gb/ho...deficiency-disorders/wiskott-aldrich-syndrome
Wiskott-Aldrich syndrome is a hereditary immunodeficiency disorder characterized by abnormal antibody (immunoglobulin) production, T-cell (lymphocyte) malfunction, a low platelet count, and eczema.

 

[SNT Gatchaman]

I don't understand this comment @wastwater.

 

[Trish]

Maybe the NIH National Library of Medicine information is more reliable that the Wikipedia one:
WASF3 WASP family member 3 [ Homo sapiens (human) ]
Gene ID: 10810, updated on 21-Jun-2023

Summary
This gene encodes a member of the Wiskott-Aldrich syndrome protein family. The gene product is a protein that forms a multiprotein complex that links receptor kinases and actin. Binding to actin occurs through a C-terminal verprolin homology domain in all family members. The multiprotein complex serves to tranduce signals that involve changes in cell shape, motility or function. A pseudogene of this gene have been defined on chromosome 6. Alternative splicing results in multiple transcript variants [provided by RefSeq, May 2014]
Expression
Broad expression in brain (RPKM 34.0), fat (RPKM 12.7) and 15 other tissues

 

[Marky]

@Jonathan Edwards Do you have any thoughts about this research?

 

[Jonathan Edwards]

@Jonathan Edwards Do you have any thoughts about this research?

I am a bit cautious. As someone said we really need to see scatter plot data to get a feel for the consistency of the difference between ME and control. The story does not seem thong together that well in that other approaches have not clearly shown a mitochondrial respiratory defect either in terms of chemistry or function on a bike.

It sounds like a potentially interesting molecule involved in signalling, including tissue response to endotoxin - which is the original cause of 'malaise'.

Muscle biopsy is a very difficult thing to work with quantitatively because there are lots of reasons for systematic bias between populations in terms of sampling, fibre type etc..

 

[B_V]

https://en.m.wikipedia.org/wiki/WASF3
Wiskott-Aldrich syndrome protein family member 3 is a protein that in humans is encoded by the WASF3 Gene

rare

Genes are often named for the first thing they're associated with. In this case, the gene was first identified in this syndrome so it's stuck with that name forever, but now our understanding of it is deeper.

 

[mariovitali]

Snapshot from a document I circulated to ME/CFS researchers in October 2017. We see the output from an algorithm called XGBoost identifying medical concepts and compounds relevant to symptoms of ME/CFS :

P53 (TP53), ER (Endoplasmic Reticulum) among the top rated medical concepts which are also relevant to this study . I believe autophagy could also be something of interest to Dr Hwang.

 

[Sly Saint]

***"Science Magazine
A new study offers clues as to how exhaustion could arise in people with myalgic encephalomyelitis/chronic fatigue syndrome (#ME/CFS) - and potentially related conditions such as #LongCovid."
Links to article shared upthread at science.org

 

[Robert 1973]

It sounds like a potentially interesting molecule involved in signalling, including tissue response to endotoxin - which is the original cause of 'malaise'.

Apologies if I’m being dim but I don’t understand what you mean by the original cause of malaise. Can you explain?

 

[Hoopoe]

Endotoxin causes malaise.

 

[Jonathan Edwards]

Apologies if I’m being dim but I don’t understand what you mean by the original cause of malaise. Can you explain?

Malaise in medical jargon refers to the general bad feeling that in the past was largely associated with infection. Some of that was viral but historically much of it was bacterial - tuberculosis, renal sepsis, streptococcal infection, staph carbuncles. Bacteria generate malaise through endotoxin - a mix of lipopolysaccharides and other things that stimulate production of IL-1, TNF and IL-6 through a group of receptors in eluding CD14. Gamma interferon is probably more important for viral malaise.