Dihydrofolate reductase

With tacrolimus, this requires FKBP12, the protein, or at the gene level, FKBP1A, and simply deletion of that gene is sufficient to confer resistance to tacrolimus, and that doesn't appear to have any deleterious effects on the T cell.

It seems like the only biological purpose for FKBP1A is really to serve as a drug-binding ligand, whereas DHFR or IMDPH2 These are genes that have important biological roles.

If you just deleted them, they would actually be more mimicking the action of the drug than conferring resistance.

So you need something that's more precise, that can confer drug-binding interfering mutations that don't interfere with the function of the gene.

But even after that stringent selection, we never really saw the percentage editing efficiency of resistant cells increase above 55 to 60%, which to us is really consistent with the idea that these cells need a certain gene dosage in order for tacrolimus to exert its effect.

And many of these cells would have been biallelically edited, but a proportion would alleles remain in the wild type setting, it's probably the case that those cells are heterozygous and the loss of one copy of FKBP1A is sufficient to confer resistance.

For DHFR and INPDH2, it more makes sense that autosomal dominant effects would confer resistance because the substrate discrimination problem is revealed if there's just one copy of edited protein.

Is there anything else that you'd like to share with our listeners today regarding your recent work?

And FOLR1 is the doorway that gets the folate into your brain.

And then there's a gene called the DHFR, And I want you to remember this one because it's at the heart of why I don't really like folic acid, which is the synthetic substance.

form that has been man-made, and I'll come back to it in a little while.

Now here's the part almost nobody talks about.

Well, if you're eating a lot of those, you're getting a lot of folic acid.

Now, the problem is your body has to convert folic acid before it can use it.

And the first step relies on that gene I told you to remember before, which was the DHFR gene.

Now, in humans, that enzyme is incredibly slow compared with animals.

There were two things actually stuck out.

Not only the video you've done on Marmite, but you talk about DHFR.

Yes.

Dihydrofolate.

But actually, it turns out all rodents have an amazing enzyme compared with us.

So our enzymes are 56 times slower than rats.

And folic acid is processed 1,300 times slower than a natural folate through our DHFR.

So you get this massive problem with a backlog that isn't forever.