Jul 30, 2025
Given what we now know about Yamanaka Factors, *** and “Partial epigenetic reprogramming”, from previous blogs, we know that you can rejuvenate brain or nerve tissue with little fear of loss-of-cell-fate. There are various papers that support that idea, and it could be done with the very commonly used construct, using a Doxycycline promoter and some OKS ( Oct4 /Octamer-binding transcription factor 4, Sox2 /SRY-Box Transcription Factor 2, Klf4 /Kruppel-like factor 4, and c-Myc /a proto-oncogene Yamanaka Factor genes downstream. For mitotic cells the risk is apparently mitigated by strobing the factors off and on at intervals, according to experimental results.
An OKS construct with a Doxycycline promotor might look like this:
DOX====>O_K_S or
Doxycycline Promotor=> Octamer-binding transcription factor 4 ___ SRY-Box Transcription Factor 2 ___ Kruppel-like factor 4
The Thought Experiment
You can find this construct on Addgene and other variations, and grow it up, using normal Biotechnology methods. Isolate the DNA, and perhaps use it in this experiment:
1.miniprep to get DNA construct
2.Get stem cells from person A and grow in mammalian cell culture
3.Insert this DNA construct inframe into a “genomic safe harbor” in this dish of cells from person A. Test, expand minimally. ** Test extracellular vesicles for Yamanaka mRNA, with and without DOX.
4.Condition person A, to clear some niches using new “mobilization drugs” that I mentioned in this older blog. And give them these modified stem cells.
5.Test for engraftment. If these were Hematopoietic (HSC) stem cells, this might be by testing blood for Hematopoietic chimerism, the ratio of recipient to donor cells. (Check DNA in blood cells using PCR, for your DOX construct). Or you could give a dose of DOX and check for Yamanaka effects. This will be your baseline. In later days, redo this test, to see if the stem cells engrafted. If not, the effect will fade away. If so, you will get sustained effect.
Anyway, that is the rough idea, and if any of you can see why this would not work, please let me know. Of course, I have done a bit of hand-waving here, and it isn’t as easy as all of that. For example, how would you “Put” the construct into a safe genome harbor? Which of the putative safe harbors would you choose? (AAVS1 locus on chromosome 19 maybe?) How would you calm the immune system to avoid rejection - umbilical Mesenchymal Stem Cells? Corticosteroids (like prednisone)? Rapamycin? Methotrexate? Imuran (azathioprine)? Cyclosporine?
In any case, many of these details could be fleshed out by searching clinicaltrials.gov, or reading lots of papers in scholar.google.com, but the devil is in the details, as they say.
NOTES
** Any expansion puts you out of the “minimal manipulation” guidelines by the FDA, because you risk altered cells taking over the culture. These could be benign and not effective, or non-benign “fitter” cells.
*** Yamanaka Factors used incorrectly can result in a type of tumor called a Teratoma, composed of many different types of cells. They are OKS ( Oct4 /Octamer-binding transcription factor 4, Sox2 /SRY-Box Transcription Factor 2, Klf4 /Kruppel-like factor 4, and c-Myc /a proto-oncogene genes.