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[ljimbo423]

Though I find it hard to see how the forces of evolution would create a human body so shoddy that it falls into these self-sustaining metabolic traps. Our genetic makeup has evolved over billions of years, and Prof Paul Ewald argues that any gene which gives rise to disease would have been eliminated by now (with certain exceptions). So from this Ewald perspective, it's hard to explain how a self-sustaining metabolic trap would arise genetically. This is why Ewald argues that diseases are most likely caused by exogenous agents in the form of pathogens.

I agree completely. It doesn't make sense to me that the CDR would somehow become locked or stuck. I think he's got this wrong and there has to be something keeping the CDR in place.

I also think that a pathogenic cause will be found. It just seems to fit to me.

 

[ljimbo423]

I wonder if the cell danger response could occur primarily in brain cells. It does seem possible. The CDR theory does seem to fit how I think ME works.

I don't know if the CDR happens in the brain like it does in the body. Makes sense that it would in the immune cells like microglia, etc. Like I said in my last post though, it just don't make sense to me that it could get stuck, without a consistant trigger of some kind.

 

[Wishful]

Though I find it hard to see how the forces of evolution would create a human body so shoddy that it falls into these self-sustaining metabolic traps.

I find it easy to see. Evolution doesn't work towards a perfect goal; it makes tiny incremental changes in what's already there. It's like choosing a path that looks easy, and then finding out it leads to an obstacle. Example: the laryngeal nerve which detours around a major blood vessel. Terrible design, but sensible in terms of tiny evolutionary changes. To me it seems quite reasonable for some cellular function to evolve towards improvement in some way, and end up causing trouble another way. We're not at the end of evolution; we're still evolving.

 

[Hip]

Evolution doesn't work towards a perfect goal; it makes tiny incremental changes in what's already there.

Yes, that's true. But nevertheless, any bad disease-causing gene which tends lead to non-survival or non-reproduction will slowly be eliminated, just by the fact that people who have it will tend not to survive and reproduce, so the gene is not passed on to future generations.

On this basis, Paul Ewald argues that something like schizophrenia cannot be substantially genetic in etiology, because those with schizophrenia rarely reproduce (have children). Thus if schizophrenia were genetic, that bad gene would soon eliminate itself from the human genetic pool.

Ewald says that the only time evolution selects for bad disease-causing genes is when the gene provides some compensating benefit. An example he gives are the genes behind sickle-cell disease: although those genes cause a disease, they also happen to protect against the malaria parasite, and in Africa were malaria is rife, that more than compensates for the disease it may cause.

 

[Wishful]

But nevertheless, any bad disease-causing gene which tends lead to non-survival or non-reproduction will slowly be eliminated, just by the fact that people who have it will tend not to survive and reproduce, so the gene is not passed on to future generations.

Yes, but if ME is a genetic metabolic trap, when did the mutation occur? If it's recent, and linked to a new environmental hazard, it wouldn't have had time to be lost. Furthermore, it may not be harmful enough to reduce the rate of reproduction (doesn't kill outright, often happens past initial childbearing age, etc). I think there are plenty of hereditary genetic diseases that have been around a very long time and not been eliminated.

 

[lukesirde]

Vaccines . . .
For me, it's one of the only things that fits the picture (and even the timeframe).
AISA syndrome has already been talked about in this article back in 2011.
https://www.ncbi.nlm.nih.gov/m/pubmed/22054760/

 

[Hip]

if ME is a genetic metabolic trap, when did the mutation occur? If it's recent, and linked to a new environmental hazard, it wouldn't have had time to be lost.

I think if chronic diseases in general were due to metabolic traps, then we would notice a different behavior when it comes to chronic disease progression. If the metabolic trap was a common cause of diseases, you might expect that serious diseases would frequently just spontaneously disappear, as an event happens which knocks the body out of its metabolic trap. After all, if something can nudge your body into a metabolic trap, then something else may nudge it back out.

But in reality, we rarely see any spontaneous full remissions in most diseases. If you have Parkinson's, Alzheimer's, ALS, diabetes, etc, these are permanent conditions, which you get no spontaneous remissions from.

Multiple sclerosis though sometimes involves temporary remissions; I am not sure if those remissions ever become permanent in some cases (ie, the disease disappears forever in that person).

 

[Wishful]

If the metabolic trap was a common cause of diseases, you might expect that serious diseases would frequently just spontaneously disappear, as an event happens which knocks the body out of its metabolic trap.

In the early days of my ME, I had several stemporary full remissions. The frequency of these gradually decreased. It did feel like I was balanced near a cusp, and factors could push me out of the ME state, but other factors pushed me back in. As time progressed, I moved further down from the cusp, making it harder to push into the non-ME state.

I'm not claiming that the metabolic trap is a common cause of chronic diseases. I think there's some sort of positive feedback loop (not necessarily metabolic) involved in ME.

Back to the 'bad genes go away' theory: is our defective vitamin C producing gene beneficial in some way? I suppose it must be, for it to take over and the functional gene faded away.

 

[Hip]

Back to the 'bad genes go away' theory: is our defective vitamin C producing gene beneficial in some way? I suppose it must be, for it to take over and the functional gene faded away.

That's an interesting question, and is something I've thought about previously. Why did humans lose a gene necessary to synthesize their own vitamin C? I understand that vitamin C synthesis is a 3-step metabolic pathway, and humans still retain functioning genes for 2 of those steps, but the gene for the third step acquired a mutation which rendered it dysfunctional.

My guess is that this mutation may have accidentally occurred at a time when our species was surrounded by lots of vitamin C-containing foods (fruits and vegetables), so the mutation actually brought no disadvantage, and went "unnoticed", so to speak.

Still, it would be nice to have that gene returned to full functioning, and I would expect that in hundreds of years time, when we start cleaning up the human genome, removing the bad mutations and deleting the endogenous retrovirus genes, we might also fix our vitamin C genes.

 

[Wishful]

Yes, we survived with the defective gene because of our diets then and there, but I haven't come across an explanation for why it dominated. Maybe producing VitC consumed a more limiting resource that we didn't get from our diets. Maybe the dysfunctional gene just copies better. It is an interesting question.

 

[Hip]

I haven't come across an explanation for why it dominated.

Just found some hypotheses about the benefits of losing our ability to make vit C in this paper:

• The ‘ascorbate-rich diet hypothesis’: This hypothesis tries to explain the inactivation of L-gulono-lactone through the presence of adequate vitamin C within the diet. In the habitat of our ancestors, abundant fruits containing ascorbate were available [4, 5]. Therefore, the GLO lacking species were adequately supplied with this micronutrient and antioxidant and did not need an endogenous synthesis.

• The ‘ascorbate and fertility hypothesis’: This hypothesis proposes that older individuals required more vitamin C than younger individuals did. It is argued that when this essential substance became rare, older and less reproductive, individuals died and the younger and fitter ones survived and reproduced more successfully [6].

• The ‘better electron ratio hypothesis’: During ascorbate biosynthesis, one ascorbate molecule is produced by consumption of glutathione (GSH) and by generation of one hydrogen peroxide molecule [7]. The net redox potential of this synthesis is electron neutral. Therefore, it was beneficial to pick up the required ascorbate by diet, which leads to an increase in the antioxidative capacity.

• The ‘free radical’ hypothesis was postulated by Challem and Taylor in 1998 [8] They hypothesized that not a mutation but a retrovirus inactivated the GLO. The decreased ascorbate concentrations led to generation and accumulation of more radical substances attacking the DNA. This should led to a higher rate of molecular evolution due to DNA oxidation, and consequently enabling faster adaptation to environmental changes.

 

[Wishful]

You say 'hypotheses', I say 'wild guesses'. I do kind of like the last one: that we became civilized tool users because of that defective gene. I'll wait for evidence.