Obliterating the androgen machinery
PLEASE DON'T TRY THIS AT HOME! This is highly experimental and incredibly dangerous stuff.
- 1 Let me tell you a story
- 2 But... I want to flip it to zero!
- 3 Hit me up if you wanna work on this!!
Let me tell you a story
Ever wonder why you still have dark body hair, after being on estrogen for two years? Maybe some patches of hair, perhaps on your arms, have lightened up, and you still have brown chest hairs? Why do you have to get laser or electrolysis in the first place?
Life of an Androgen Receptor
Why's masculine body hair dark?
Androgen receptors (ARs) chill in the cytosol, outside the nucleus of a cell, feeling single and lonely. Testosterone swims by outside, doing laps until a hexagonal gate in the cell membrane opens, pulling it in down a slippery slide of electromagnetic charge. The testosterone swims in the cytosol for a while, until it activates an AR. Once testosterone, like a key, fits inside the AR's lock, the ARs twist open to expose a foot. Next, a rowboat comes up, grabs ahold of the two ARs' feet and paddles down to the nucleus, where it's shuttled inside. That's where all the cool DNA hangs out. It's in the VIP room, baby!
Next to the genes for facial and male-pattern body hair (HHA6 and HHA7, I think, too lazy to look it up), there's a little palindrome of DNA (AGAACA, upside-down and reversed on the other strand spells the same) called an Androgen Response Element! (ARE.) Each AR has a single arm on it, which latches onto only that palindrome. Behold! With both their arms, they clamp down on the ARE and snap tight. The AR's other head is a handle for RNA polymerase, which kicks off making the gene south of the ARE into a protein. The AR flips a switch, the HHA6 and HHA7 keratin is made, and your hair is black.
(Btw, if you don't have dark body hair, it's because you have different keratins in your DNA. Each hair is a braid of different keratins.))
Okay, so that stops when I go on blockers, right?
Nope! That AR is good and stuck on there. Your blockers just prevent more T from being produced. But those ARs in the nucleus? That machinery already has its T. And it has staying power! Proteins outside the nucleus get scavenged all the time -- busy like outdoor downtown New York, with street sweepers and trash collectors. But inside? You're in the VIP room! They don't come in there! They need a badge, and the ones they let in are selective.
Okay, but surely there's someone to take the trash out inside the nucleus, right?
Well, kinda. Think of the AR machinery as a button that got pressed. Normally, when you press a button inside the nucleus, you want it to stay pressed. Unless you decide to un-press it, because of the little molecular program you got going on there. Think of DNA binding proteins as 1s in the memory bank of the cell. The absence of a protein is a zero. Testosterone just flips the 0 to a 1, and suddenly the cell's function changes! Fucking magic!
But... I want to flip it to zero!
Okay, story time's over now. Down to business. When someone wants to take a hit out on a 1, they need a... professional. Too chicken, I guess, to do it themself? E3 ubiquitin ligase is the best in the business.... discreet, clean and efficient. But it won't work for free... it needs... you know, payment for services rendered.
We gotta pay for our hit on the androgen receptor.
I'm in. Let's do this.
Okay, so here's the plan: we wanna send in a Proteolysis-targeting chimera. Here's how you build it:
Our in is dioxin. Dioxin's the poison they used on Victor Yushchenko. It works by paying off our professional, E3UL, to remove all the nuclear receptors, indiscriminately. As Paracelsus said, every medicine is at some dose a poison. Every poison at a smaller dose is a medicine! No, really! You're skeptical, but hear me out. We tie dioxin to testosterone, linking it together.
E3UL does good work, as long as he has a contract. We have to tie the money to a particular hit, not just "kill some random guy."
We'll kill all the ARs by making a contract with E3UL, paying it to kill only ARs.
Let's take dioxin and testosterone, and weld them together! Dioxin activates the Dioxin receptor, which is a brand of E3UL. Testosterone loves cozying up to androgen receptors. That'll let us shoot the AR in the head. If we want to shoot AR in the stomach, we can stick something that looks like an AGAACA on it. We can't use straight AGAACA though, because the DNA cops outside the nucleus rip all the DNA they see to shreds. Fucking DNA cops, man. ADNACAB!!! Let's assume we're going with the head-shot for now.
So, we get someone to synthesize our welded T-dioxin kill contract together. It's easy to stick things onto T, so it shouldn't cost much, and you can get batches of this stuff from labs around the world, shipped to your house's door. We don't need much... nowhere near enough to be dangerous like dioxin is. Near-homeopathic amounts of the stuff.
Then all you have to do is inject it, just like you'd do a shot of estrogen! With more careful measuring and your finger on the dial to 911, of course.
...Maybe I should volunteer myself, since I have good health insurance? :)
Hit me up if you wanna work on this!!
For real. I think this would be a real neat thing!!