Whatever has been shut down must be able to be turned back on surely. I know this is the question that everyone is trying to answer but we're getting close and I can't help but think the answer could be right beneath our noses. What is it that Staphypan/Rituximab for example have in common that helped people? I'm not too technical myself but I know there are people on this forum who can help us get closer to the answer.
Having experienced observing my son go through the nightmare of ME/CFS for 5 years, then seeing him make a dramatic improvement over the past 3 years I have some thoughts. Also, being a Physical Therapist for over 30 years I have had the opportunity to work with huge variety of patients and conditions as well be able to learn from the experts in my field. Based on that, I was intrigued by the title of your post and would agree that turning the switch on (or off in my thinking) is key.
Our son was treated with both infusion and oral Antivirals and had a dramatic improvement in the 12 weeks he received that. He was not 100% recovered at the end of treatment (which he feels he is currently), but he was able to start the process of regaining his ability to function and "rehab" himself over the course of the next 2-3 years. Immediately following his treatment I said word for word "something with his treatment flipped a switch". I do not believe it had to be the Antivirals necessarily, but I do believe it was the Antiviral treatment that changed his physiology.
Interestingly enough, all of his struggles occurred at a time when I professionally was gaining a greater interest in Neuroscience and Neurophysiology through the latest research and clinical findings in the areas of Stroke, Concussion, Head Injury, Neuro-inflamatory agents, Neuro-plasticity and Neuro-protective/Neuro-immune responses. I listened to speakers talk about the Penumbra neurophysiological phenomenon associated with Stroke, I heard and read about Post-concussive patients being successfully treated with Amantadine (Antiviral), I read research on Pain and Chronic Pain and the Bio-molecular Physiology of Pain and listened to the experts in the fields on functional Neuroscience discuss threat responses and immune responses associated with Pain, Fibromyalgia, Concussions, Hemiplegic Migraines and more. I also worked in a 25 bed observation unit seeing many patients come in with Pain issues, stroke like symptoms, vertigo, brain fog, unexplained fatigue, unexplained nausea, autonomic responses of undetermined origin and more.
I say all of this, not to "toot my own horn", but just to get an understanding of the background to my thoughts on ME/CFS. First off, I am 100% confident that ME is physiological. I was 100% confident of this prior to any of the recent research proving it so. Secondly, I am very confident that at its root ME is a Neurophysiological phenomenon in which the protective mechanisms of the Nervous system are activated by any of a number of "threats". This include viral, bacterial, fungal or tick-borne infections, Severe Trauma, severe reactions to medications, severe allergic reactions, severe levels of stress or any other significant condition or event. Why some people develop it and others don't, I have no clue but probably some Genetic component as well as some Neurophysiological predisposition.
The problem as I see it, is that this protective response which can be normal (Cell Danger Response for instance) comes on too strong and/or stays on too long. With the resulting slow down of metabolism, increased Neuro-Inflamatory activity, increased sensitivity to other threats and the downward spiral or cascade of physiological events, the result is Severe Fatigue, intolerance to exertion, Brain fog, pain, weakness, changes in biochemistry related to metabolism and Neuro-inflamation, unusual neurological symptoms of all variety and potential intolerance to any stimuli if the disease is severe or chronic enough.
What does it take to turn this off? I believe there has to be enough reserve built or enough relief on the body systems so the protective response is shut off. In the case of my son, the Antivirals allowed for that. Was it because he had an active and chronic viral infection? I could not say. Was it related to the viral like onset? Possibly. Could he have gotten to that point by another route? Quite possibly.
So yes, I do think the mechanism is beneath our noses, but not so easy to see with our standard tools of investigation. The work at Stanford and Norway as well as the clinicians working all over the world supports this approach to it. I have yet to see anything (although I am admittedly biased) on this sight or in the research that contradicts this line of thinking. I actually feel that this line of thinking is more inclusive than other more "Disease" focused approaches. The good news that I am seeing as of late, is that the research being done is getting us closer to finding a clinical solution for this. Ultimately, I believe that will be a systems approach with Interdisciplinary teams providing treatment that is ultimately aimed at shutting this switch off and restoring function.
Thank you for raising the question as you did. It is a very important one indeed.