anciendaze
Senior Member
- Messages
- 1,841
The discussion of mitochondrial heteroplasmy in the linked article looks like it was tacked on as an afterthought, and not deemed very important.
Let me explain some of the heuristic reasoning I'm using. First, I've assumed competent researchers would have found more about causes by now, if these followed the pattern common in progressive diseases. Since this is clearly a chronic disease, I'm looking for cycles of cause and effect, not simply linear chains. (In fact I suspect we are dealing with interlocking cycles of causation, so that breaking a single cycle is not enough to effect a cure. The unbroken cycle will reintroduce the problem.)
Second, I'm assuming some important characteristic is either tiny or episodic, so that it is easy to miss because it is below your threshold of detection, or simply not present under the conditions in which you normally run tests. Both assumptions lead to the idea that we are experiencing some kind of amplification of small or rare causes into much more powerful and persistent effects.
In biology the standard method of amplification is clonal expansion. We normally associate the term with production of immune cells, but it could equally apply to bacterial pathogens in infectious disease. Immune systems regularly run a kind of race with pathogens, and winning is an existential concern.
Viral infections also involve a kind of clonal expansion, and DNA viruses insert plasmids into nuclei outside of chromosomes, where they are called episomes. Retroviruses go further, inserting DNA sequences transcribed from viral RNA into chromosomes, where this is called provirus. Increasing viral load in a cell means larger numbers of copies. Increasing viral load in an individual means larger numbers of infected cells and/or more copies of viral genomes in infected cells.
Discovering that mitochondria have multiple inherited genomes outside the nucleus implies that they too can experience clonal expansion which will result in apparent changes in cell phenotype without the need to postulate any new mutations. Because mitochondria outnumber cell nuclei by a factor of thousands this tiny loophole can have substantial effects.
Mitochondria can also become targets for intracellular responses that may or may not be called immune. Natural immune behavior is another way to turn a tiny defect we have been missing into a substantial outcome.
We now know that a few patients respond substantially to depletion of CD20+ B-cells. Other evidence says that reducing viral load may cause significant improvements, over a period of months. We still don't know why these interventions sometimes work, but generally do not.
A few patients have had virtually full remissions following stem-cell treatments, though the details have not been published. Generally, these remissions have not lasted, which means the considerable expense would not be justified, even if this applied to all patients. Similar treatments have had promising results in MS patients, though with considerable cost and risk.
From a therapeutic standpoint this is highly unsatisfactory, but from a research standpoint it offers the possibility of comparing those who respond to those who do not to find out what is changing. With tools now available, this presents an excellent prospect for new discoveries, and I have constantly been saying that what we learn from this disease will be important in other medical problems, even if I can't yet say which. There are similarities with a lot of really mysterious medical problems, some rare, some common in old age.
Let me explain some of the heuristic reasoning I'm using. First, I've assumed competent researchers would have found more about causes by now, if these followed the pattern common in progressive diseases. Since this is clearly a chronic disease, I'm looking for cycles of cause and effect, not simply linear chains. (In fact I suspect we are dealing with interlocking cycles of causation, so that breaking a single cycle is not enough to effect a cure. The unbroken cycle will reintroduce the problem.)
Second, I'm assuming some important characteristic is either tiny or episodic, so that it is easy to miss because it is below your threshold of detection, or simply not present under the conditions in which you normally run tests. Both assumptions lead to the idea that we are experiencing some kind of amplification of small or rare causes into much more powerful and persistent effects.
In biology the standard method of amplification is clonal expansion. We normally associate the term with production of immune cells, but it could equally apply to bacterial pathogens in infectious disease. Immune systems regularly run a kind of race with pathogens, and winning is an existential concern.
Viral infections also involve a kind of clonal expansion, and DNA viruses insert plasmids into nuclei outside of chromosomes, where they are called episomes. Retroviruses go further, inserting DNA sequences transcribed from viral RNA into chromosomes, where this is called provirus. Increasing viral load in a cell means larger numbers of copies. Increasing viral load in an individual means larger numbers of infected cells and/or more copies of viral genomes in infected cells.
Discovering that mitochondria have multiple inherited genomes outside the nucleus implies that they too can experience clonal expansion which will result in apparent changes in cell phenotype without the need to postulate any new mutations. Because mitochondria outnumber cell nuclei by a factor of thousands this tiny loophole can have substantial effects.
Mitochondria can also become targets for intracellular responses that may or may not be called immune. Natural immune behavior is another way to turn a tiny defect we have been missing into a substantial outcome.
We now know that a few patients respond substantially to depletion of CD20+ B-cells. Other evidence says that reducing viral load may cause significant improvements, over a period of months. We still don't know why these interventions sometimes work, but generally do not.
A few patients have had virtually full remissions following stem-cell treatments, though the details have not been published. Generally, these remissions have not lasted, which means the considerable expense would not be justified, even if this applied to all patients. Similar treatments have had promising results in MS patients, though with considerable cost and risk.
From a therapeutic standpoint this is highly unsatisfactory, but from a research standpoint it offers the possibility of comparing those who respond to those who do not to find out what is changing. With tools now available, this presents an excellent prospect for new discoveries, and I have constantly been saying that what we learn from this disease will be important in other medical problems, even if I can't yet say which. There are similarities with a lot of really mysterious medical problems, some rare, some common in old age.