By Dr Michael Simmons | Longevity Medicine GP | My Wellness Doctor
A new way of thinking about chronic fatigue may be taking place. Specifically in our understanding of chronic fatigue syndrome (CFS), also known as myalgic encephalomyelitis (ME/CFS)—a condition characterised by intractable fatigue, biological uncertainty and clinical frustration. A recent discovery from the National Institutes of Health (NIH) offers a new mechanistic theory: a structural protein called WASF3 may be interfering with energy production at the mitochondrial level.
Cancer Survivor to Scientist
Amanda Twinam’s story began with a breast cancer diagnosis at age 28, followed by mastectomy & chemotherapy. However, what remained—beyond her oncological recovery—was severe, unrelenting fatigue. Years later, a genetic testing found she carried Li-Fraumeni syndrome, a rare hereditary mutation predisposing individuals to multiple cancers.
But despite this new knowledge, her fatigue remained unexplained—and deeply disabling.
Chance Encounter Leads to Discovery
In 2016, Twinam came across a paper by NIH researcher Dr Paul Hwang, describing how Li-Fraumeni mutations might impair mitochondrial function. On a hunch, she wrote to him. Hwang responded, inviting her to his lab for further study—a meeting that would lead to a multi-year research project.
What his team found was quite striking: Twinam’s cells overexpressed a protein called WASF3. Under normal conditions, WASF3 is involved in cytoskeletal architecture—regulating cell shape and movement. But in excess, it begins to interfere with mitochondrial bioenergetics.
How WASF3 Disrupts Energy Production
Hwang’s group discovered that high levels of WASF3 disrupt the electron transport chain (ETC)—the final step in oxidative phosphorylation within the mitochondria. By inhibiting efficient electron flow across the inner mitochondrial membrane, WASF3 reduces ATP output. In effect, it slows or blocks the machinery that converts glucose into usable cellular energy.
This dysfunction isn’t just metabolic inefficiency—it’s cellular energy poverty. The fatigue that results isn’t psychological or incidental; it’s rooted in a core failure to meet energy demands at the cellular level.
Is This Relevant Beyond Li-Fraumeni?
Hwang suspected so. Collaborating with Dr Brian Walitt, another NIH researcher studying ME/CFS, they extended their investigation. Skin and muscle samples from ME/CFS patients revealed that 9 of 14 also had elevated WASF3. These findings were published in PNAS in August and are now being explored as a potential biomarker—and therapeutic target—for a subset of ME/CFS.
A Possible Treatment?
If confirmed, targeting WASF3—or the pathways it dysregulates—could offer a novel strategy for ME/CFS treatment. Until now, management has largely focused on symptom pacing and supportive care. This research adds molecular traction to a field long mired in diagnostic ambiguity.
Critically, it supports what many patients have long known: that ME/CFS is not a psychosomatic condition, but a biologically real, metabolically rooted disorder.
Why This Matters
For Twinam, the study brought long-overdue validation. But for the broader ME/CFS community, it offers something even more vital: a starting point for rational therapeutic development.
This is not yet a cure, nor a universal explanation. But it is a welcome departure from decades of hand-waving, and a step closer to restoring the dignity—and cellular energy—of millions living in the shadow of chronic fatigue.
My Wellness Doctor 
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