Dear Alex,
Certainly we should do the science - and that is happening. But you do need to know where to start looking! So hypothetical speculation isn't trivial. In my career it was 90% of the battle in getting a treatment tried and proved. Similarly, Fluge and Mella tried rituximab in ME because of a hypothetical speculation. The sort of dialogue we are having on this thread to me is remarkably reminiscent of the lab meetings we used to have at UC on a Friday afternoon with a couple of bottles of wine - which is where the whole rituximab idea for autoimmunity began. The evidence we needed was already there or easy to find, we just needed to argue through how to make sense of it. And we went through the same sorts of argument about how it could be like this - no it couldn't - yes it could - how come - maybe like this - OK maybe it could - but would n't that mean that we'd find this... and so on. In the end it was like we had done the whole jigsaw but somebody had not noticed we had it the wrong way up for the edge bits.
I agree about the three systems all working together - particularly that hormones sort of cut across the other two with molecules that do things in both.
We tend to see more discussion of endocrine hormones, nervous systems, vasculature and immunity interacting. While the intra-cellular is seen as 'separate'. It's important to remember that what happens in cells causes what happens outside them. Equally external stimuli affect cells. E.g. thyroid follicular cells require iodine & selenium (& more) to produce T3 & T4. T3 via nuclear receptors stimulates ATP production. T4 stimulates a variety of enzymes. There are many circular relationships between the cellular and the 'hormonal'.
Your first point about ME vs Chronic Fatigue Syndrome vs Chronic Fatigue. Each includes the next as symptom but they are very far from synonymous. ME gives us a much clearer target (PEM) for testing the rationality of hypotheses than does Chronic Fatigue Syndrome. ME has a unique symptom , CFS does not.
As for the subtypes: my suspicion (or crackpot theory) is that no person with ME has a single huge dysfunction but at least two smaller ones thus producing a compound effect. This would explain why it's been so hard to pin down, why no treatment is universal, and symptoms vary. My guess despite that is that we will still end up with some common subtypes as per diabetes & thyroid disease.
One obvious challenge here: if there is an inherent mitochondrial problem each cell (and organ by extension) will stress in proportion to its distinct load, the load will then 'ripple out' through the biochemistry. This could make it difficult to separate trigger based phenotypes from those based on inherent physiological weaknesses.
An examples: sublinical cystinosis risks depletion of ATP + Glutathione, sub-optimal mito function lowers supply of ATP, poor T4 to T3 conversion lowers stimulus of ATP production.
That is one physical phenotype with three methods of reducing ATP.
Drinking too much red wine would concentrate free radicals and affect cystine.
Too much sport would stress ATP synthase.
etc etc
So we have two very complex dimensions
#1 mix of minor deficits
#2 mix of behaviours & triggers
