Gene Therapy Induces Sex Changes In Adult Mice

[Zaune]

Discover Magazine

On the surface, it looks as if our identity as male or female is determined in the womb. The decision seems final – a genetic switch flicks towards either setting, and locks into place for the rest of our lives.

This tidy image is wrong. Two recent studies in mice have shown that the switch isn’t locked – it’s held under constant tension by two rival genes – DMRT1 and FOXL2. It’s a tug-of-war fought over sexual fate, which goes on throughout our lives. Take away either contestant, and its adversary pulls the switch to the opposite setting. Ovaries can transform into testes and vice versa, even in adults.

By default, mammal embryos develop as females. A structure called the gonadal ridge eventually gives rise to the ovaries. It’s the presence of a gene called SRY that diverts the embryo down a male route. SRY sits on the Y chromosome and sets of a chain of activated genes that transform the gonadal ridge into testes instead. With SRY, you get a male; without it, a female.

But two years ago, Henriette Uhlenhaut from the European Molecular Biology Laboratory showed that this pivotal moment is not a permanent one. She found that a gene called FOXL2 keeps maleness at bay, long after the gonadal ridge has transformed into ovaries. By deleting it, Uhlenhaut turned the ovaries of female mice into testes. They didn’t produce any sperm, but they cells looked like testicular cells, they had the same portfolio of active genes, and they produced testosterone.

Now, Clinton Matson from the University of Minnesota has found that a gene called DMRT1 acts as FOXL2’s mirror counterpart, suppressing femaleness in male mice.

In fact, DMRT1 and FOXL2 repress each other. Neither can rise to power while the other is strong – this is why sex appears to be so stable. Matson dispelled this illusion by removing DMRT1 in both embryonic and adult mice.

When he bred mice that lacked DMRT1, males would grow up as females. Their gonadal ridges begin to transform into testes, but they are eventually waylaid by the feminising FOXL2. Even when Matson deleted DMRT1 in adult mice, FOXL2 was released and started switching on ovarian genes. Within a month, the testicular cells had been reprogrammed into ovarian ones. These cells produced oestrogen, and flooded the rodents’ bloodstreams with this hormone; meanwhile, their testosterone levels fell.

You can see this clearly in the photo above. The main image is a slice through the organ that would normally be the testes, in a male mouse that lacks DMRT1. The inset is a similar slice through the ovaries of a normal female mouse. Both have two types of cells found in the ovary – granulosa cells (round and magenta) and theca cells (long and magenta, surrounded by green). The magenta colour reveals the presence of FOXL2.

Mathias Treier, who led Uhlenhaut’s FOXL2 study, welcomes the new study. “When we tried to publish our paper that ovaries can be reprogrammed to testis, we were fighting an uphill battle against an old dogma that mammalian sex determination is final,” he says. “It is gratifying for us to see that the reverse is also possible.”

DMRT1 and FOXL2 are not the only genes involved in setting and maintaining our male or female identities. Both of them activate and repress a swarm of other masculinising and feminising genes. But it’s clear from Uhlenhaut and Matson’s experiments that this duo plays a central role in the genetic battle of the sexes.

Of course, these studies were done in mice, but there’s every reason to think that the same antagonism rages on in humans. For a start, both DMRT1 and FOXL2 have very similar counterparts across a wide range of species, and they’re all involved in determining sex. Chickens and medaka fish with silenced versions of DMRT1 will grow up as females even if they are genetically male.

Both genes are also involved in human genetic disorders. People who inherit faulty copies of FOXL2 can develop a rare disease called BPES, which often leads to infertility because the ovaries don’t develop properly. On the flipside, people who are born without any copies of DMRT1 can develop Swyer syndrome. Even if they have a Y chromosome, their testes never develop properly and they are born as normal girls, complete with uterus and vagina. But they don’t have proper ovaries either and as such, they don’t go through puberty – that’s what usually gives away their missing genes.

Understanding how sex is determined could help us better understand these disorders and develop treatments for them. “Both findings will have huge implications for reproductive biology. We may have to look in a new way at reproductive disorders,” says Treier. It might even change how doctors carry out gender reassignment therapies, paving the way for genetic approaches rather than multiple painful surgeries.

Reference: Matson, Murphy, Sarver, Griswold, Bardwell & Zarkower. 2011. DMRT1 prevents female reprogramming in the postnatal mammalian testis. Nature http://dx.doi.org/10.1038/nature10239

Well, if that's not the biggest breakthrough in treating Gender Identity Disorder since it became widely accepted as a medical condition, I have no idea what is.

[His Divine Shadow]

Discover Magazine

On the surface, it looks as if our identity as male or female is determined in the womb. The decision seems final – a genetic switch flicks towards either setting, and locks into place for the rest of our lives.

The sex is already determined by the sperm. The father provides an Y or X chromosone in a sperm, while the mother always provides the X.

[Simon_Jester]

Assume for the sake of argument that we're talking about phenotype sex, not genotype sex.

"Flip the switch" in an adult XY mouse that is biologically male here, and that mouse's testes will start producing estrogen and feminize the mouse.

Keep it up long enough and you will have a mouse that, on physical examination, will appear to be a female mouse (albeit presumably with structurally malformed genitals, since a lot of the physical layout of the genitals occurs in the womb).

The mouse still has XY chromosomes, but... are they 'male?' It depends on whether by 'male' you mean phenotypical or genotypical.
_________________________________

Now, if we're looking at this with an eye toward gender identity issues in humans, some points to make:

1) The last common ancestor of humans and mice was alive when dinosaurs roamed the earth. Literally. So it's not a foregone conclusion that the sex-determination "switch" in humans is as simple, or as adjustable, as it is in mice. We've had a hundred million years of parallel evolution in which to develop a strange or unnecessarily complicated biological mechanism to handle that, and evolution creates unnecessarily complicated mechanisms all the time.

2) Mice whose phenotypical sex is 'flipped' by this sort of gene therapy are, I suspect, sterile. Ova develop very early, so 'flipping' a mouse's testes into estrogen-makers probably won't cause them to start spontaneously producing ova. The equivalent may or may not be true if a mouse's ova are 'flipped' to act as testes.

That's still going to be an issue if the technique does generalize to humans. Then again, it would have been an issue anyway because all the existing methods of sexual reassignment involve bombarding the person's gonads into irrelevance with massive hormone doses, surgically removing them, or both.

3) As noted above, the basic physical layout of a mammal's genitals is determined before birth. Even if you have a gene therapy that causes someone's gonads to "flip," they will still require extensive surgery in order to have genitals that are typical for members of the same sex.

[HMS Sophia]

2) Mice whose phenotypical sex is 'flipped' by this sort of gene therapy are, I suspect, sterile. Ova develop very early, so 'flipping' a mouse's testes into estrogen-makers probably won't cause them to start spontaneously producing ova. The equivalent may or may not be true if a mouse's ova are 'flipped' to act as testes.

That's still going to be an issue if the technique does generalize to humans. Then again, it would have been an issue anyway because all the existing methods of sexual reassignment involve bombarding the person's gonads into irrelevance with massive hormone doses, surgically removing them, or both.

3) As noted above, the basic physical layout of a mammal's genitals is determined before birth. Even if you have a gene therapy that causes someone's gonads to "flip," they will still require extensive surgery in order to have genitals that are typical for members of the same sex.

I am tired, and not willing to get into an argument about phenotypal/genotypal sex/gender right now, but just to come at these points from a trans persons point of view:
The article states that the organs produced by this process are sterile, that is they produce neither ova nor sperm. However, they do produce hormones that would be 'normal' for that organ, so an new ovary will produce oestrogen and a testes will produce testosterone. So yes, while a trans person who undergoes this sort of treatment (assuming it ever becomes available to humans) would still require SRS in order to fully transition if they so desire, they would not have to undergo HRT. Instead, they could replace, say, Oestrogen production centres with Testosterone production centres. Would it be perfect? I doubt it. Would it require monitoring and such? Hell yes. Would it save trans people the 'joys' of HRT? Presumably.
Tl;dr This is a hopefully awesome breakthrough for trans people, and I for one am kinda hopeful we'll see it happen for humans.

[Simon_Jester]

2) Mice whose phenotypical sex is 'flipped' by this sort of gene therapy are, I suspect, sterile. Ova develop very early, so 'flipping' a mouse's testes into estrogen-makers probably won't cause them to start spontaneously producing ova. The equivalent may or may not be true if a mouse's ova are 'flipped' to act as testes.

That's still going to be an issue if the technique does generalize to humans. Then again, it would have been an issue anyway because all the existing methods of sexual reassignment involve bombarding the person's gonads into irrelevance with massive hormone doses, surgically removing them, or both.

3) As noted above, the basic physical layout of a mammal's genitals is determined before birth. Even if you have a gene therapy that causes someone's gonads to "flip," they will still require extensive surgery in order to have genitals that are typical for members of the same sex.

I am tired, and not willing to get into an argument about phenotypal/genotypal sex/gender right now, but just to come at these points from a trans persons point of view:

The article states that the organs produced by this process are sterile, that is they produce neither ova nor sperm. However, they do produce hormones that would be 'normal' for that organ, so an new ovary will produce oestrogen and a testes will produce testosterone. So yes, while a trans person who undergoes this sort of treatment (assuming it ever becomes available to humans) would still require SRS in order to fully transition if they so desire, they would not have to undergo HRT. Instead, they could replace, say, Oestrogen production centres with Testosterone production centres. Would it be perfect? I doubt it. Would it require monitoring and such? Hell yes. Would it save trans people the 'joys' of HRT? Presumably.

Tl;dr This is a hopefully awesome breakthrough for trans people, and I for one am kinda hopeful we'll see it happen for humans.

I agree with literally every word you just said and don't feel even the slightest urge to argue, so your lack of interest in arguing with me is no problem at all.

I guess I was just trying to head off anyone who looks at this and goes "oh, this is a magic button that turns phenotypical men into phenotypical women" or anything like that.

[HMS Sophia]

I agree with literally every word you just said and don't feel even the slightest urge to argue, so your lack of interest in arguing with me is no problem at all.

I guess I was just trying to head off anyone who looks at this and goes "oh, this is a magic button that turns phenotypical men into phenotypical women" or anything like that.

Ah fair enough. Yeah, unfortunately we're unlikely to ever get a culture magic pill that transforms external primary sex characteristics from one formation to another. Even something totally insane like a total conversion of that irritating spare Y chromosome wouldn't do much (I'm talking out of my ass on that, feel free to correct me). But hey, surgery is getting better as time goes on.

[ray245]

The current surgery is still unable to allow people to reproduce though, at the least their genetic descendants.

[Simon_Jester]

Well, again, that's hard to do- the most likely approach to succeed would be creating the relevant parts in a vat from cloned DNA somehow, then surgically implanting them.

And we're probably at least 20-30 years away from it being possible to do that experimentally, and more like 50-100 years from it becoming a routine medical technique.

[HMS Sophia]

The current surgery is still unable to allow people to reproduce though, at the least their genetic descendants.

Trust me, I noticed. There's a reason my partner and I had children quite so young (you know, aside from loving each other and wanting to start a family).

Well, again, that's hard to do- the most likely approach to succeed would be creating the relevant parts in a vat from cloned DNA somehow, then surgically implanting them.

And we're probably at least 20-30 years away from it being possible to do that experimentally, and more like 50-100 years from it becoming a routine medical technique.

There is that suggestion of successful womb transplants, that with a proper allotment of hormone producers might lead to interesting things. But vat grown is likely one of the few ways that it's going to end up being large scale enough and palatable to the... less accepting portions of the population, if you catch my drift?
A century is probably somewhere around accurate, unfortunately. Outside of my timeline.