Jonathan Edwards
Senior Member (Voting Rights)
Hi, Tom. This is a somewhat 'philosophical' post but one that tries to get at how we structure our disease models at a high (overview) level. My background is in rheumatoid arthritis where our identification of switches from negative to positive feedback loops helped me identify the B cell depleting agent rituximab as a useful therapy.
ME/CFS is another acquired disease that seems to switch on and often persist, although, like RA, sometimes it switches off. I think there must be a similar point where a negative feedback loop gets diverted to a positive loop which gets stuck. Robert Phair suggested this might occur at the itaconate level in an 'itaconite trap'. I find that intuitively implausible but I am not exactly sure why.
I think my argument would be that we need a plausible acquired cellular regulatory change that persists. For 'acquired' mitochondrial myopathies I understand that to be cells with abnormal mDNA competing out other cells. For RA the shift seems to be the generation of new recombinations of Ig genes that encode 'subversive' antibodies. For cancer it is a malignant clone. For BSE it is prion polymerisation. For psychosis it may be synaptic rearrangement that leads to cycles of abnormal cognition.
Basically, I see three ways that an acquired cellular change can persist and cause system-wide disease. One is a change in DNA - cancer, and also RA. Another is a change in nerve connections - psychosis maybe. The third is something I think people miss out on and I would call supramolecular pattern propagation. This would include amyloid and BSE. It might be the basis of Alzheimer's. The error is perpetuated by a pattern of repeating molecules that self-propagates, a bit like the 'flyers' in Conway's Life Game. It is conceivable that this can occur in musculoskeletal tissues with things like TGF beta binding - what I call the 'Writing on the Wall' model.
And my problem with an itaconite trap is that I don't see how, in practice, you get propagation of a switch from a negative loop to a positive one within the metabolic machinery of a cell. Where have the railway points been switched over? For sure, if the cell has been infected with a retrovirus the DNA can do the switch, but where would there be switches within the metabolic pathways that could persists and also propagate from cell to cell. So I look for ways signalling between cells could be switched. And I guess that although I understood the interest of thinks like ITIMs and STAT kinases I always focused on the outside signals.
But, as has already come up in the discussion, there is of course powerful information in knowing the intracellular signals both because they might be blocked by drugs and because their time courses and cross-interactions may be crucial to the clinical expression of the story. I like the idea that we might be able to pin down the delay of PEM by working out the time course of mediating steps. PEM may be too variable to make that easy but there is no doubt that we are dealing with a signalling mechanism that can take many hours.
There is also the interesting question, raised by Hutan here, as to whether metabolic shifts cause symptoms such as difficulty using muscles, directly, or through invoking neural or other indirect signals.
What I am increasingly confident of is that somewhere in all this interaction between immune and nerve signals and internal cell metabolic shifts lies the answer to ME/CFS. I personally doubt that anyone 'runs out of ATP'. I think more likely some cells tell other cells to go on strike and refuse to use their ATP. But the evidence remains very hard to interpret. Hopefully we will have some genetic clues soon, so now is the time to really focus in on this problem.
ME/CFS is another acquired disease that seems to switch on and often persist, although, like RA, sometimes it switches off. I think there must be a similar point where a negative feedback loop gets diverted to a positive loop which gets stuck. Robert Phair suggested this might occur at the itaconate level in an 'itaconite trap'. I find that intuitively implausible but I am not exactly sure why.
I think my argument would be that we need a plausible acquired cellular regulatory change that persists. For 'acquired' mitochondrial myopathies I understand that to be cells with abnormal mDNA competing out other cells. For RA the shift seems to be the generation of new recombinations of Ig genes that encode 'subversive' antibodies. For cancer it is a malignant clone. For BSE it is prion polymerisation. For psychosis it may be synaptic rearrangement that leads to cycles of abnormal cognition.
Basically, I see three ways that an acquired cellular change can persist and cause system-wide disease. One is a change in DNA - cancer, and also RA. Another is a change in nerve connections - psychosis maybe. The third is something I think people miss out on and I would call supramolecular pattern propagation. This would include amyloid and BSE. It might be the basis of Alzheimer's. The error is perpetuated by a pattern of repeating molecules that self-propagates, a bit like the 'flyers' in Conway's Life Game. It is conceivable that this can occur in musculoskeletal tissues with things like TGF beta binding - what I call the 'Writing on the Wall' model.
And my problem with an itaconite trap is that I don't see how, in practice, you get propagation of a switch from a negative loop to a positive one within the metabolic machinery of a cell. Where have the railway points been switched over? For sure, if the cell has been infected with a retrovirus the DNA can do the switch, but where would there be switches within the metabolic pathways that could persists and also propagate from cell to cell. So I look for ways signalling between cells could be switched. And I guess that although I understood the interest of thinks like ITIMs and STAT kinases I always focused on the outside signals.
But, as has already come up in the discussion, there is of course powerful information in knowing the intracellular signals both because they might be blocked by drugs and because their time courses and cross-interactions may be crucial to the clinical expression of the story. I like the idea that we might be able to pin down the delay of PEM by working out the time course of mediating steps. PEM may be too variable to make that easy but there is no doubt that we are dealing with a signalling mechanism that can take many hours.
There is also the interesting question, raised by Hutan here, as to whether metabolic shifts cause symptoms such as difficulty using muscles, directly, or through invoking neural or other indirect signals.
What I am increasingly confident of is that somewhere in all this interaction between immune and nerve signals and internal cell metabolic shifts lies the answer to ME/CFS. I personally doubt that anyone 'runs out of ATP'. I think more likely some cells tell other cells to go on strike and refuse to use their ATP. But the evidence remains very hard to interpret. Hopefully we will have some genetic clues soon, so now is the time to really focus in on this problem.
