I can’t remember the exact details, but there is a mechanism that recruits methyltransferases in dividing cells to copy methyl marks on DNA.
i.e.: A copy of the original DNA is replicated in a dividing cell, then epigenetic marks in the original strand are copied to the replicated strand.
Histone marks have been shown to be heritable as well.
I’m listing all the following information that I have on Epigentic therapies that may be used for fellow PFSers in the future. If you’re interested in this field of study research epigenome editing and epigenome technology.
A good overview of epigenetics for a non molecular biologist. Also some info on how some drugs are being used to reverse epigenetics.
In the above article it specifically mentions the drug dectabine to reverse epigenetic changes in cancer cells. It seems that this might work for PFS patients if indeed our condition is caused by epigenetic changes to some of our cells. Has this been discussed before? I wonder how difficult it would be to get this drug to try it. I assume it would be expensive but it seems plausible.
“Further research is needed before the base editor can be used for clinical application,” de Poel said. “However, in part due to this study, the first clinical applications may already happen in the coming five years.”
They have corrected a methylation issue that occurs in the brain.
“We showed that this disorder is reversible at the neuron level,” says Liu. “When we removed methylation of CGG repeats in the neurons derived from fragile X syndrome iPS cells, we achieved full activation of FMR1.”
The CRISPR/Cas-9-based technique may also prove useful for other diseases caused by abnormal methylation including facioscapulohumeral muscular dystrophy and imprinting diseases.
“This work validates the approach of targeting the methylation on genes, and it will be a paradigm for scientists to follow this approach for other diseases,” says Jaenisch.
This is interesting research. Also, this was not done by chumps. Jaenisch is a godfather of epigenetics.
I wish we could get them to test this shit on us. But I guess we would have to prove methylation first
We’d have to figure out what’s been methylated across patients.
It would be easier to start with the key genes and work from there. We don’t need to know and fix every gene at the beginning and no Crispr tech would be able to take on such a challenge. So we start small but relevant.
How many would take a partial recovery now or choose to wait 10 years for something more. Life is happening right now.
Melcangi has the lit the torch, now let’s carry it…
I’m sure tons of us would take a some improvements for now rather than wait until we can fix everything in it’s entirety but we still currently can’t do that with CRISPR because we’re not sure what the root cause of this entire mess is. We know 5AR2 has shown higher levels of methylation in PFS patients, but it is incredibly unlikely that reverting this would provide any symptomatic relief, for the following reasons (from Melcangi’s study):
"In PFS patients, neuroactive steroid CSF levels were
not significantly related to the percentage of SRD5A2 gene
promoter methylation "
So neurosteroid levels had no correlation to 5AR2 methylation status.
"We next evaluated whether the clinical parameters reported earlier (18) were related to the SRD5A2
methylation status. No differences were observed in the degree of erectile dysfunction (P=0.362, Pearson’s chisquare test). Accordingly, the five international indexes of erectile function (IIEF-15) domains, identified as erectile function, orgasm, sexual desire, intercourse satisfaction and overall satisfaction, did not differ between groups (P=0.710, P=0.456, P=0.535, P=0.805 and P=0.620,
respectively). Similarly, the depressive status previously demonstrated in these PFS patients (18) did not change between SRD5A2 methylated and unmethylated subjects, considering K-10 (P=0.890) and BDI and BAI (P=0.475 and P=0.485, respectively). The depression and anxiety degree frequency did not change between two groups ."
5AR2 methylation levels appear to have not dictated symptom severity either.
I think it’s more than likely that it’s simply a downstream effect of this entire mess, or something from before PFS (as Melcangi postulates).
Also regarding no CRISPR variants being able to fix everything, I’m not sure if that’s true. But if it is, then Inshallah/God willing/whatever your believe in, the tech will catch up soon.
I have written about this in great detail elsewhere. I am disappointed to see none of it has made a dent.
I didn’t say anything about 5AR1 or 5AR3. I am aware that 5AR1 is primarily responsible for neurosteroid synthesis, but I assumed you already read Melcangi’s findings.
The SRD5A1 gene promoter was completely unmethylated in all samples analysed, irrespective whether blood- or CSF-derived DNA.
How does that suggest that lack of 5ar2 is not causative for PFS, combined with your subsequent statements which seem to acknowledge that 5ar2 is not primarily responsible for neurosteroids?
Because the subsequent quote states that there was no correlation between methylation status of 5AR and any other symptoms either?
We next evaluated whether the clinical parameters reported earlier (18) were related to the SRD5A2
methylation status. No differences were observed in the degree of erectile dysfunction (P=0.362, Pearson’s chisquare test). Accordingly, the five international indexes of erectile function (IIEF-15) domains, identified as erectile function, orgasm, sexual desire, intercourse satisfaction and overall satisfaction, did not differ between groups
That’s your second, independent reason, I thought. So your first reason, about 5ar2, is not relevant?
As for the second reason, no correlation between methylation status and symptoms - that could easily be explained if the people with unmethylated 5ar2 had symptoms secondary to a different reason. In other words, there may two types of PFS. I believe this conjecture is supported by a lot of other evidence as well.
An alternative explanation is that 5ar2 not in spinal fluid but in other tissues is primarily responsible for sexual dysfunction in PFS. Therefore, 5ar2 in spinal fluid will not be correlated with sexual dysfunction.
With my first point, I was clarifying that 5AR2 being a cause of PFS was unlikely to explain the mental symptoms people were facing (if they are caused by a deficiency in neurosteroids).
As for the second reason, no correlation between methylation status and symptoms - that could easily be explained if the people with unmethylated 5ar2 had symptoms secondary to a different reason. In other words, there may two types of PFS. I believe this conjecture is supported by a lot of other evidence as well.
Except that’s just speculation on your part. None of the research done on PFS patients so far explains that, and if we’re considering anecdotal experiences, neither does the vast majority of patient experiences (not all, but most). It is of the essence that we unite behind a single theory, not just because for research it’s the ideal scenario, but because it is what appears to be the most likely.
There’s an unbiased study that showed AR overexpression in the penile tissue of all the PFS patients it surveyed, and found a correlation between the degree of overexpression and symptom severity, why aren’t you giving that more weight in your thought process?
Many of our symptoms relate to testosterone and dht deficiencies. What if the underlying issue is simply that our bodies couldn’t deal with dht suppression and became sick. No single switch to turn back on. We start by trying to restore correct methylation throughout the body that relates to testosterone and dht. We ensure that the body has correct amounts of testosterone and dht in all relevant tissues. Receptors should be functioning properly by correcting methylation. That’s a big task in itself.
Nobody knew that dht inhibitors could cause so much damage and nobody really knows what will happen if we try to undue the damage one step at a time. Melcangis work does not relate to every area of the body that’s been affected. I don’t believe we need to find the bottom of the rainbow to fix PFS and we won’t really know until we try.