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Ask the Expert: The ME/CFS Mystery

Dr Paul Hwang explains a little more about his PNAS paper "WASF3 disrupts mitochondrial respiration and may mediate exercise intolerance in myalgic encephalomyelitis/chronic fatigue syndrome"

Recently we highlighted a new study that may answer the question “how come people with ME/CFS have totally normal looking muscle cells suffer from post exertional malaise?”. This was an exciting study that proposed a biological mechanism for the tired and cramping muscles that so drain ME/CFS sufferers.

In short, it seems that some CFS/ME patients might be suffering from cellular stress. The result of the stress is that a protein called WASF3 intereferes with their ability to convert oxygen and glucose into energy. So some people with ME/CFS can’t replenish the energy stores in their muscles as fast as healthy people can.

We were fortunate to be able to put a few quick questions to the scientist who led the study into WASF3, Dr Paul Hwang.Dr Hwang is a principal investigator at the US National of Heart lung and blood Institute. He primarily researches cardiovascular and cancer genetics. He completed an MD/PhD program in 1993 at the prestigious Johns Hopkins Medical School and has devoted the last 30 years to cutting edge research.

Medical News Bulletin: Why ME/CFS? Did you go into the project hypothesising that there could be a link between WASF3 and ME/CFS, or was it a happy accident?

Dr Hwang: It was a prepared accident. We had been studying the regulation of mitochondria by the mutated TP53 gene which causes the early-onset cancer disorder Li-Fraumeni syndrome (LFS). The patient had LFS but also chronic fatigue symptom which was essentially the opposite of what we had previously reported in individuals with LFS. We felt obligated to investigate this discrepancy, whether the fatigue symptoms were indeed related to mutated p53.

MNB: Do you have an ongoing interest in ME/CFS?

Dr Hwang: Yes, having identified WASF3 in the mitochondria, we are now very interested in studying its role in ME/CFS.

MNB: What was the most surprising aspect of the results?

Dr Hwang: How difficult it can be to find potential genes mediating elusive conditions like ME/CFS.  It seems to have required the alignment of multiple elements:  the accumulation of a critical threshold of background information and resources, such as stored patient samples by the NIH ME/CFS investigators Drs. Avindra Nath and Brian Walitt; the right ME/CFS patient who did her homework and had amazing initiative; someone with the appropriate clinical and scientific background to listen to the patient; and the insights and actual work of gifted scientists Drs. Ping-yuan Wang and Jin Ma, to name just a few.

MNB: Some studies are finding a possible link between ER stress, inflammation, and conditions such as rheumatic and cardiovascular disease.  Can you explain what might cause the ER stress?  Is chronic inflammation a suspect?

Dr Hwang: All good questions for which I am sure there are some answers known by experts in the respective fields, but I would just be speculating.  And yes, I believe that there are plenty of evidence linking inflammation or immune mechanisms to ME/CFS.  My simple understanding is that the cells are not happy, such as due to a viral infection, and they mount a stress response, potentially damaging the mitochondria in the process, intentionally or unintentionally.

MNB: How do you hope this study will impact how ME/CFS is diagnosed and treated?  What further research do you think is needed in this area?

Dr Hwang: In terms of WASF3 as a diagnostic marker, I need to clarify the following:

1) We do not believe that WASF3 is the cause of ME/CFS but rather is one of the factors mediating the energy deficiency in muscle.

2) We observed increased levels of WASF3 in a subset of the 14 ME/CFS patients.  Please understand this is a small sample size.  So WASF3 levels in muscle may explain fatigue in only a subset of patients with ME/CFS diagnosis.

3) There are no clinical or blood tests available to check for WASF3 levels.  In our publication, we used skin biopsy cells grown in tissue culture and muscle tissue samples obtained by needle biopsy to measure WASF3 protein levels. These tests cannot be done in the clinics by physicians.  Importantly, even if they could, more studies are needed in order to understand the meaning of these results.

It would be helpful to have other investigators confirm and extend our findings.  Again, we need to test whether it is feasible to target WASF3 in ME/CFS patients and improve their muscle bioenergetic profile.

MNB: Will you be continuing to look into WASF3 and ME/CFS?  Any hints about what’s next?

Dr Hwang: Yes.  It is exploratory but we need to see if we can target WASF3 in ME/CFS patients and fix the bioenergetic defect that we have described.

MNB: Do you have anything you would like to tell our readers or people who are living with ME/CFS?

Dr Hwang: In our lab we are working on our finding the best that we can realizing that treatment is a priority.

If you’d like some help decoding the oringinal research, we’ve got you covered. Join us at MNB:Journal Club for a break down of the evidence.

Our sincere thanks go to the NIH media centre and Dr Hwang for their kindness and generosity with their time.

Joanna Mulvaney PhD
Joanna Mulvaney PhD
Joanna Mulvaney worked as a bench researcher for much of her career before transitioning to science communication. She completed a PhD in developmental biology focusing on cell signaling in cardiogenesis at the University of East Anglia, Norwich, UK, before moving on to study axial skeleton development and skeletal myogenesis at King’s College London and regeneration of auditory cells in the ear at University of California San Diego Medical School, USA and Sunnybrook Research Institute, Toronto, Canada. When it comes to scientific information, her philosophy is: make it simple, make it clear, make it useful.
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