What if We Didn't Need HRT Anymore?

DMRT-1 and what medical transition might look like in the future

Foreword: this article discusses reproductive anatomy in a purely scientific context. Reader discretion, as appropriate, is recommended.

One of the most important parts of good science is forming a hypothesis—asking, in other words, what might be. Taking what we know now, in other words, and looking to the future. You ask an investigative question, bring out the data we have available to us, and judge the most likely outcome.

So, let’s build a hypothesis. I’ll even make it provocative.

In 20 or 30 years, medical transition will require two injections over the course of a lifetime.

Intrigued? What if I told you that we’ve got good science available to us today that not only tells us it’s possible, but exactly how to do it?

And that the only reasons we can’t do it today is because our tools are too clumsy and the money to do the research isn’t there.

Let me introduce you to DMRT-1, a strange piece of our genetic code that is, at once, absolutely essential to sexual differentiation and something you’ve probably never heard of before, even in advanced biology coursework.

SRY, the sex gene you’ve probably heard about

If you’re trans and you’ve looked into the genetic underpinnings of sex and gender, you’ve definitely heard of the SRY gene. SRY is a gene that typically (but not always!) appears on the Y chromosome of pair 23. When activated during gestation, it triggers a huge cascade of changes in a fetus, transforming that fetus into a male.

Wait a tick, you say? What do you mean, it transforms the fetus into a male?!

Well, when you were first formed as a fetus, you began to develop, just like you learned about in biology class. And you’ve probably heard lots and lots about babies that were identified as female using an ultrasound, but then popped out of mama and turned out to be male, right? That happens because all fetuses begin development with a vulva. Everyone.

Now, it’s not accurate to say everyone starts off as a female, as has historically been claimed. It’s better to say that everyone starts off with all of the ancestral structures you need to develop into any given sex, depending on instructions the fetus receives as it develops, and looking like a female. This is, for instance, why males have nipples, and why intersex people are so common. This is also why sex, as a category, is so fuzzy—and why it is not commonly used as a precise scientific term in genetics anymore.

Sexual differentiation—when a fetus becomes male, female, or intersex—is an active progress, no matter what sex a fetus turns out to be. That said, the fetal change to become a male is probably the more dramatic change, as the clitoris fuses with the urethra and grows massively, the gonads differentiate into testes, and the vulva literally turns itself inside out to form the scrotum. (A bit of trivia: if you have a scrotum, you can examine it and there’ll be a line right down the middle. That’s where the deepest point of what was once your vulva was.) All of these changes and many more are triggered by the SRY gene. Now, the genetic triggers of female differentiation are a little more subtle, and don’t have a single genetic trigger, like male differentiation does, so I’m going to gloss over that part a little bit here, in the interest of space and for one more reason you’ll see in the next section. The same basic process happens, and in the same way, but it takes a bunch more details and asterisks to explain because there are more moving parts. A uterus is a tricky thing to build.

So, when transfeminine people in particular focus on how and why they came out of the womb phenotypically male, SRY tends to get a lot of hate—and that hate isn’t really warranted, because SRY is actually only active for a very short period of time. We’re talking days, at most, in an entire lifespan.

To make an analogy, if we imagine the process of transforming a fetus into a male was like launching a rocket, SRY is just the button that starts the main engines. By itself, it doesn’t do anything. It’s the engines, the fuel tanks, the navigation systems that do the actual work of launching the rocket. The button just says when it’s okay for them to go.

DMRT-1 is the fuel system. It tells our bodies what fuel our rockets are going to need, and how to build factories to produce it. If it’s off, your gonads will produce estrogen. If it’s on, testosterone. Those engines, that navigation system—they’re designed to work on either fuel, and are quite happy to use whatever comes down the pipeline.

Unlike SRY, though, DMRT-1 is active for your whole entire life, once activated.

One of the most important sex genes you’ve never heard of

Okay, so what does DMRT-1 really do?

Let’s start with the acronym: DMRT-1 is short for Doublesex and Mab-3 Related Transcription factor 1, which is really complicated genetics English that’s super duper coded, so that geneticists can talk about specific genes that appear in multiple species. We could break down what each of those initialisms mean, but it’s a little easier to look at the effects of this gene instead.

DMRT-1 is the gene that determines whether your gonads turn into testicles or ovaries, and that’s the only thing it seems to do. It’s a toggle-switch gene, that’s either on or off, and it runs for your whole life. If it’s off, you have ovaries. If it’s on, you have testicles. The only part of the human body it seems to have any effect on whatsoever is your gonads, and it is an ooooooold part of our genome. How old?

Well, you’ve seen Finding Nemo, right? Remember Marlin, Nemo’s dad? Clownfish, like wrasses and a whole bunch of other fish are what’re called sequential hermaphrodites. While sequential hermaphroditism works a little differently in each species, in clownfish like Marlin, every young clownfish begins life as a male. They swim around, eat, reproduce, all that jazz. But when there’s no dominant female in the area, the largest local male transforms into a female. She becomes bigger, her testes become ovaries, and she develops eggs. That, in turn, means that Marlin must be female during the main events of the movie—since there are no other clownfish nearby, he would’ve become a female pretty much as soon as Coral, his mate, died. Disney probably didn’t intend to write him as their first trans character, but he is, no matter how you slice it; either he’s a woman, in which case he’s transitioned, or he’s a man, in which case he’s a trans man.

Why am I talking about Marlin and Finding Nemo? Because DMRT-1 is the gene that turns an adult male clownfish’s testicles into ovaries.

Yes, the same DMRT-1 gene that we have.

It’s a conserved gene from our deep, deep evolutionary ancestors who were fish, and it’s still doing its job! If it’s toggled on, it keeps testicles testicles. Turn it off…?

Well, if you turn DMRT-1 off in an adult male—and we’ve done this in mice, to which humans are 97.5% genetically identical—his testicles will undergo an incredible transformation. The cells will change shape, come to resemble ovary cells, and they’ll start secreting estrogen instead of testosterone. And if you do the opposite in an adult female mouse? Her ovaries will transform into pseudo-testicles and begin secreting testosterone instead of estrogen.

In adults. Not children. Not fetuses.

Adults.

There are limitations, for sure! If you change your testes into pseudo-ovaries, for instance, you won’t get any eggs, so you’d never be able to provide an egg for reproduction. And, if you do the inverse, it looks like your existing eggs will all be destroyed in the metamorphosis. The human body is incredibly plastic, but there are limitations, and we’re very different, physiologically, from our fishy ancestors. We’ve lost other genes that might’ve allowed for those other changes.

But remember, the D in DMRT-1 means Doublesex. This capability is deep in our genetic code.

You mean we can just… change our gonads? Like, today?

Kind of.

You could, theoretically, go into an office somewhere, get the shots to deliver the CRISPR gene editing—which is how we do this work right now—and have your gonads transform. And then, if things progressed like they do in the mouse studies, you’d die a little while after.

CRISPR… has problems. Big problems.

If we want to make an analogy again, using CRISPR is like pulling out a big ol’ pair of kitchen shears, or even hedge clippers. It’s an incredibly powerful tool for gene editing. But precise? CRISPR doesn’t really do precise. And the more specific you need to be in your genetic targeting, the worse CRISPR is. DMRT-1, unfortunately, is a highly specific and fairly small chunk of genetic code. CRISPR just can’t toggle it without wreaking havoc to a whole bunch of nearby genes, and that pretty much always leads to life-ending complications of one form or another. We need a scalpel to do this sort of work, not kitchen shears.

So yeah, don’t do this. Not today. Just because you can, doesn’t mean you should.

What we need, first and foremost, is a much more precise and safe alternative to the CRISPR gene editing tool as a whole. The good news is that research on those exact kinds of tools is advancing quickly because gene editing technology, if we can make it safe, is very likely where a true cure for cancer is going to come from, if we ever find one.

For instance, Prime Editing—and yes, as much as it pains me to say so, as an Amazon technology, the name does come from where you think it does—is dramatically more accurate than CRISPR, and is a real candidate for the sorts of gene editing we’d need to toggle DMRT-1. And Prime Editing isn’t the only advanced candidate technology out there, either! There are over a dozen tools that look incredibly promising right now, both emerging ones and even a couple of older ones, like TALEN, that’ve had new life breathed into them after the discoveries made with CRISPR. Right now, today, there are hundreds of active trials using various gene editing technologies, any one of which stand, potentially, to transform the field.

It’s incredibly cool stuff.

Why 20-30 years before this can happen, then?

Well, in a nutshell, time, money, and focus.

There’s absolutely gobs of money being poured into gene editing research right now because it’s such an incredibly promising treatment for cancer, MS, and a huge number of other deadly diseases. But imagine that we develop a gene editing technology that’s an effective treatment for cancer quickly—say in the next 5 years, which would be incredibly fast. This sort of treatment wouldn’t be a one-size-fits-all approach, because there are over 200 different subtypes of cancer (depending how finely you need to split hairs, and in this case you need to split them very finely indeed). For each subtype of cancer, you need to test, get regulatory approval, and then deploy your gene editing treatment, and that takes time, money, and work from top genetic researchers, who only have so many work hours in a day, week, or year. These things take time, and they should take time. Fast medicine is almost always bad medicine.

And when you get right down to it, the basic rules of ethical medicine say that we should treat the people in greatest need first. Trans people have pretty decent HRT right now. Not amazing, but solid. I honestly think it’s best to get better treatment to the people who need it most—and, as someone who lost her father to pancreatic cancer, let me tell you that there are a lot of cancers where current treatments are pretty terrible. And… trans folks get cancer too. We’d benefit from these new cancer treatments too.

Ultimately, trans people are going to have to wait until the most direly urgent medical research—the immediately lifesaving stuff—is done and proven before the researchers, the smart people who develop these technologies, will turn to DMRT-1. Right now, the money is in cancer research, which means that that’s where the best minds and their research labs are working.

And yeah, that sucks, but it won’t always be that way.

For our children, and their children

These technologies won’t be for us. I need to be clear: I don’t think that anybody reading this article today will benefit from these technological innovations.

But our children will. And their children will.

In many ways, that’s the burden and the joy of our generation of trans people, and not just in terms of this specific technology. We will build a world, medically, socially, politically, and educationally, which will allow our trans descendants to live lives of simple ease and joy, even if it’s a life we will never get to lead ourselves.

But, then again, the generation that came before us built a world where we could be out and proud, if we choose to be.

And the generation before them built a world where they could be demedicalized.

And the generation before them built a world where they could be recognized.

And the generation before them built a world where they could medically transition at all.

We stand on the shoulders of giants, and I, for one, would be proud to leave something to our children which is indisputably, measurably better than it is right now.