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Excitingly trans-genic mice
July 24, 2011 11:47 PM   Subscribe

"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."
posted by Blasdelb (54 comments total) 28 users marked this as a favorite

 
So it's a crap-shoot then.
posted by bwg at 11:57 PM on July 24, 2011


So it's a crap-shoot then.

Been shootin' craps and gamblin'
Mama and I done got broke
posted by flapjax at midnite at 12:02 AM on July 25, 2011 [1 favorite]


Umm, transexuals? Switch didn't seem to get flipped there.
posted by Gilbert at 12:12 AM on July 25, 2011


So if I feel like being a woman on the weekend so I can get like all the easy sex I want down at the bar, but during the work week, if I want that extra 10 to 15% salary that men get, I flip to male, then this is my ticket, yeah?
posted by spicynuts at 12:18 AM on July 25, 2011 [9 favorites]


f I want that extra 10 to 15% salary salary that men get

I think the difference is close to twice that amount.
posted by Poet_Lariat at 12:21 AM on July 25, 2011


Poet_Lariat: Did you read the link you posted? [The figure of 77%] doesn't account for individual differences between workers. Once you control for factors like education and experience, notes Francine Blau — who, along with fellow Cornell economist Lawrence Kahn, published a study on the 1998 wage gap — women's earnings rise to 81% of men's. Factor in occupation, industry and whether they belong to a union, and they jump to 91%.

Presumably, of spicynuts is flipping the switch, spicynuts is also controlling for those factors, since they remain the same before and after the flip switch...

/derail

Cool FPP, by the way.
posted by Philosopher Dirtbike at 12:37 AM on July 25, 2011


Mostly I just want to be able to walk down to a bar, flash my bits, and be having sex within minutes.
posted by spicynuts at 12:43 AM on July 25, 2011 [1 favorite]


Yeah
As a shorty playing in the front yard of the crib
Fell down, and I bumped my head
Somebody helped me up and asked me if I bumped my head
I said "Yeah"
So then they said "Oh so that mean we gon, you gon switch it on 'em?"
I said "Yeah, Flipmode, Flipmode is the greatest"
posted by bwg at 12:47 AM on July 25, 2011 [11 favorites]


Kidding aside, I suspect that when the US wakes up, there will be a nice little rage on about the use of the word 'identity' in this article. A sentence like this "Ovaries can transform into testes and vice versa, even in adults" says nothing about gender identity and speaks only of biology. Not the same thing.
posted by spicynuts at 12:49 AM on July 25, 2011 [1 favorite]


I was just reading that Neil Gaiman story...
posted by Scattercat at 2:26 AM on July 25, 2011 [2 favorites]


Blasdelb: Erm, I don't think that your third link ("studies") is pointing to the right place. It's an awesome picture, but unlikely to change anyone's sex outside of a particularly nightmarish horror movie.

It's a fascinating set of results, though. From reading the Nature paper, they turned the genes off using a cre-recombinase system.* I assume that this was systemic, as they don't seem to say otherwise? Because if you could do it by knocking out the gene in a specific tissue, that's something that could be very achievable using gene therapy. An adeno-associated virus vector can be used to target gonads pretty efficiently, for example, and deliver DNA encoding an shRNA to knock out the sex gene of choice. There'd be plenty of potential problems -- not least concerns about introducing mutations into gametes, which is an instant refusal for licensing gene therapy trials -- but if these could be smoothed out this could be a very powerful tool for sex change interventions.

Also, it's another trick in the arsenal of "practical jokes for biologists". It's already pretty simple to make guys lactate or influence someone's skin colour (assuming you have access to a biochemist's lab and no morals); changing someone's sex with a single injection is just another escalation in the evil genius' prank war ;).

spiceynuts - I suspect that when the US wakes up, there will be a nice little rage on about the use of the word 'identity'
Eh, words mean different things in different contexts. Scientists do tend to have very mechanistic views of the world, doing the work and letting others project politics onto it as they see fit. They're just using "identity" with a different meaning than more humanities-oriented people are used to. Not necessarily wrong, just different.

*For the uninitiated, the cre system is a very powerful research tool, but useless therapeutically. Basically, using some DNA wizardry you breed an animal that has a short snippet of bacterial DNA (called "loxP") each side of the gene that you want to be able to turn off. You also insert a viral gene called cre. cre is expressed -- i.e. used as a template to make a functional protein -- constantly, but we've modified it to make the protein produced inactive. So the cells are expressing the targeted gene (in this case, the sex gene) as normal, and are expressing cre but it isn't doing anything. When your animal has reached the age or developmental stage you're interested in, you treat it with a drug called tamoxifen. Tamoxifen gets into virtually all the cells in the body, sticks to the cre molecules and activates them. Activated cre then starts recognising the LoxP sites each side of your target gene, makes a cut at those sites then re-links the DNA, neatly snipping your targeted gene out of the genome. After that, the targeted gene can't be expressed any more, and you see what happens to your animal.

It's a powerful tool which, with some tweaks, can be used to switch genes on instead and/or only operate in specific tissues and cell types. But not useful in therapy, because the starting point is an organism that has been specially bred to have the LoxP sites in the correct positions.

Modifying gene expression in an alread-living animal is just about possible, but tricky. The most popular approach is to take a virus (vastly smaller than a cell) and modify it so that, when it invades a cell, it expresses your therapeutic gene instead of its normal viral genes. You can also use a technique called RNAi (of which shRNA is a variant) to provoke what's effectively an intra-cellular immune system into switching any given gene off. However, using a virus means that the patient's own immune system will be fighting hard against the therapy, so you get problems with efficiency of delivery and longevity of the gene expression or knockdown. Once these problems are overcome -- for which there are some very promising avenues being explored -- we'll have a huge amount of fun replacing missing or faulty genes (e.g. Haemophilia, for which at least one clinical trial is ongoing and showing excellent early results) or knocking out harmful gene variants (e.g. huntingtin for Huntington's Chorea). Mind you, cynics say that it's a bit like fusion: gene therapy is just 10 years away and always will be...

posted by metaBugs at 2:52 AM on July 25, 2011 [27 favorites]


"On the surface, it looks as if our identity as male or female is sexual organs are 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 can be screwed with by scientists in mice. 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 natural state of tension maintained 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 mice."


There, I've fixed that for you.
posted by londonmark at 2:55 AM on July 25, 2011 [11 favorites]


Umm, transexuals? Switch didn't seem to get flipped there.

Can't speak to that, but one prominent blogger found her sex switched by itself in middle age (not going to link for obvious reasons). No idea if it's related to this, though.
posted by ArmyOfKittens at 3:09 AM on July 25, 2011


They're just using "identity" with a different meaning than more humanities-oriented people are used to. Not necessarily wrong, just different.

The header is from Discover magazine, which is not a science journal but a general distribution magazine for light science. Editor should know better.
posted by spicynuts at 3:09 AM on July 25, 2011 [2 favorites]


It’s a tug-of-war fought over sexual fate, which goes on throughout our lives.

It's really true. I knew a guy who had this problem. She kept changing genders throughout his life. This guy, who for privacy I will will call "Miss H", changed genders so often she bought condoms and tampons for his typical night out, never sure which way the night would lead. He was brilliant though, and I miss her.
posted by twoleftfeet at 3:33 AM on July 25, 2011 [6 favorites]


This is interesting.
posted by pracowity at 3:36 AM on July 25, 2011


spicynuts - The header is from Discover magazine, which is not a science journal but a general distribution magazine for light science. Editor should know better.

Ah, I missed that. For some reason (most likely idiocy) I thought it was a quote from one of the researchers. Yes, someone writing for a popular audience should pay attention to these things, although I'd be willing to bet that only a small proportion of the target audience will notice or understand the distinction.

Of course, my boss consistently says "gender" when talking about animals' biological sex so I'm coming from a slightly warped perspective of how these words are used.
posted by metaBugs at 4:00 AM on July 25, 2011


Of course, my boss consistently says "gender" when talking about animals' biological sex so I'm coming from a slightly warped perspective of how these words are used.

That annoys me so much. I think it comes solely from uncomfortableness with the word "sex".
posted by Philosopher Dirtbike at 4:26 AM on July 25, 2011 [1 favorite]


I read this and said "what"?? Adults had their ovaries turn to testes? How inconvenient for pants shopping. Then I got to "in mice". Nevermind.....
posted by mermayd at 4:47 AM on July 25, 2011


Poet_Lariat: I think the difference is close to twice that amount.

This statistic gets trotted out a lot to show sexism, and it's incredibly misleading.

The methodology of the study basically works like this:

1. Add up the money made by all women in the country.
2. Add up the money made by all men in the country.
3. Find that women only made, in total, x% of what men made.

From the second paragraph of your linked article:

The answer depends on whom you ask — and so does the size of the gap. Some say 77% is overly grim. One reason: it doesn't account for individual differences between workers. Once you control for factors like education and experience . . . women's earnings rise to 81% of men's. Factor in occupation, industry and whether they belong to a union, and they jump to 91%. That's partly because women tend to cluster in lower-paying fields. The most-educated swath of women, for example, gravitates toward the teaching and nursing fields. Men with comparable education become business executives, scientists, doctors and lawyers — jobs that pay significantly more.

Consider, also, that women are more likely to leave work to stay home with children. And with the grossly disproportionate control of wealth in the United States . . . well, how many Bill Gates and Koch Brothers and Warren Buffets does it take to really skew those numbers?

I'm not arguing that there aren't issues with gender roles and sexism. But that statistic is so misleading; it has a lot of people believing that given a man and a woman with the same education and experience, doing the same job, the woman only gets paid $0.77 to the man's $1.00, and that isn't the case at all.
posted by Vox Nihili at 4:50 AM on July 25, 2011 [4 favorites]


Ok this thread is about magic tricks with gonads, not about gender based earnings gaps. I'm sorry my little joke is causing derail but let's focus.
posted by spicynuts at 4:53 AM on July 25, 2011 [1 favorite]


Ok this thread is about magic tricks with gonads,

Add in a few more tircks, and you've got a Cosmo article.
posted by Bulgaroktonos at 4:56 AM on July 25, 2011 [6 favorites]


Over the past decades I've become accustomed to certain proclivities and tastes, so you can stick your DMRT1 and FOXL2 wherever it feels good, mm'kay?
posted by Brandon Blatcher at 5:03 AM on July 25, 2011 [1 favorite]


This miniscule percentage of the population and its peculiar preoccupation somehow wields extraordinary influence over the cultural discussion (especially in academia). They have what appears to be a non-specific grievance agenda that they inflict upon homosexual and heterosexual discourse alike.

They pounce on small pieces of news like this mouse study, and offer them up as if they were extraordinarily proofs that we've all been breathlessly awaiting -- the final evidence that will convince mainstream society that the man-women dichotomy is an illusion and usher in the golden age of unisexuality.


I'm sure no one ever said anything like this about homosexuals back in the day
posted by showbiz_liz at 5:09 AM on July 25, 2011


BY THE WAY, as a straight heterosexual, I too am fascinated by gender and where it ends, where it begins, where it blends, and where it grows in on itself. This is because I think the vagaries of human experience enrich our understanding of humanity as a whole, and am not a narrow-minded reactionary.
posted by showbiz_liz at 5:15 AM on July 25, 2011 [4 favorites]


They pounce on small pieces of news like this mouse study, and offer them up as if they were extraordinarily proofs that we've all been breathlessly awaiting -- the final evidence that will convince mainstream society that the man-women dichotomy is an illusion and usher in the golden age of unisexuality.

Your extraordinarily hyperbolic assessment makes me think you have an axe to grind. Surely I'm wrong. In case I am wrong and you really don't understand why people think this is important, let me explain.

Traditionally in our culture, male and female have been considered fixed categories, made by God and enforced by his will. These categories also mapped onto who one was supposed to be attracted to and have intercourse with, as well as the role one played in society. Evidence of deviation from this was seen as a purposeful deviation from God's will and plan. This is still believed by a large segment of society.

The apparently fixed and binary nature of the underlying biology has been used as evidence that the strong dichotomy in sex, gender, and social role is "natural", and hence "good", even by those who don't believe that God put the dichotomy in place. This has led to the harassment and killing of those who didn't fit the perceived dichotomy.

Research showing the flexibility of sex in mammals calls into question the foundations of the logic of the "created" or "natural" categories. Nobody (well, almost nobody) wants everyone to be "unisexual". But they do want people who don't fit the mould that the majority enforces to be able to live in peace, as that are.
posted by Philosopher Dirtbike at 5:22 AM on July 25, 2011 [9 favorites]


"as that are"->"as they are", ugh.
posted by Philosopher Dirtbike at 5:23 AM on July 25, 2011


Mostly I just want to be able to walk down to a bar, flash my bits, and be having sex within minutes.

Yeah, hey, welcome to the world of female orgasms, which are a little bit more complicated to achieve than just sticking something in there. But to compensate, you do get more than one, provided the other person knows what they're doing.

Probably better practise with your Hitachi Magic Wand first.
posted by emjaybee at 5:29 AM on July 25, 2011 [4 favorites]


So it's a crap-shoot then.

Darn right it's a crap-shoot. Beside the genes in the article, there is this syndrome, resulting in a normal female phenotype, sometimes only discovered when the patient comes in for testing as a teenage because she is not menstruating.

Then there is this case. My lab received the blood of a ten year old boy as part of a family genetic testing. We did the karyotype and the result 45,X which indicates a Turner syndrome female. Naturally there was a lot of yelling about lab error, lab error. It wasn't the lab switching specimen, it was a tinsy, tiny translocation, only discovered by high resolution banding. The part of the Y chromosome that matters for maleness was translocated to another chromosome, and the rest of the Y, which is mostly non-coding (I said mostly), lost.

Then there is uniparental disomy, which is due to gene methilation at the right time, and again you are screwed.

Anytime a creationist mentions the perfect design of humanity I laugh.
posted by francesca too at 5:53 AM on July 25, 2011 [4 favorites]


That annoys me so much. I think it comes solely from uncomfortableness with the word "sex".

Gender is for nouns and prudes.
posted by atrazine at 6:00 AM on July 25, 2011 [1 favorite]


I think the majority of people who use the word 'gender' just don't understand the difference, right?
posted by TheRedArmy at 6:04 AM on July 25, 2011


Yeah, hey, welcome to the world of female orgasms, which are a little bit more complicated to achieve than just sticking something in there.

Note my objection to the use of the word 'identity' in the article. I'm assuming I'd still be mentally a dude. So...sticking somethin in there might just be enough.
posted by spicynuts at 6:08 AM on July 25, 2011 [1 favorite]


Ovaries can transform into testes and vice versa, even in adults.

Nooooooooooooooooo my balls
posted by nathancaswell at 6:09 AM on July 25, 2011


Gender is for nouns and prudes.

Well, once you get past the idea that it's some sort of simple binary, divinely-appointed, and obvious situation, having different words for the physical, mental, and social constructs revolving around the significant variation within each category (and the categories' effects on each other) is pretty useful. Of course, once you have words, people will misuse them, but, hey....
posted by GenjiandProust at 6:11 AM on July 25, 2011 [1 favorite]


one prominent blogger found her sex switched by itself in middle age (not going to link for obvious reasons).

Why not? Is the blog not about the fact that her gender switched by itself? Cause I'd read that blog.
posted by nathancaswell at 6:17 AM on July 25, 2011 [1 favorite]


Of course, my boss consistently says "gender" when talking about animals' biological sex .....

That annoys me so much. I think it comes solely from uncomfortableness with the word "sex".


I've used 'gender' when the correct term is 'sex' to prevent a room full of 19-year-olds from giggling uncomfortably when they should be thinking about statistics. Mind you, I also refer to 'a single dice' a opposed to the correct 'a die' so that the non-native-English speakers don't get confused either.
posted by benito.strauss at 6:26 AM on July 25, 2011 [1 favorite]


I've used 'gender' when the correct term is 'sex' to prevent a room full of 19-year-olds from giggling uncomfortably when they should be thinking about statistics. Mind you, I also refer to 'a single dice' a opposed to the correct 'a die' so that the non-native-English speakers don't get confused either.

I also teach statistics to 19 year olds, and I do exactly the opposite in both cases. Are you...me posting from the negaverse? Or maybe I'm you posting from the negaverse!

I find that my abbreviation for "the standard error of x-bar", SE(X) (where X has a bar over it) gets giggles, but having noticed it, I refuse to change it out of principle.
posted by Philosopher Dirtbike at 6:34 AM on July 25, 2011 [1 favorite]


Cause I'd read that blog.

Mefimail me if you're still interested and I'll throw you the link later/tomorrow.
posted by ArmyOfKittens at 7:25 AM on July 25, 2011


This statistic gets trotted out a lot to show sexism, and it's incredibly misleading...how many Bill Gates and Koch Brothers and Warren Buffets does it take to really skew those numbers?

I agree with your broader point about that statistic being misleading, however, I would like to point out that it's based on median income, not mean income, so extreme outliers will have basically no effect on that figure. (source)
posted by jcreigh at 8:15 AM on July 25, 2011 [1 favorite]


Bill Gates and Koch Brothers and Warren Buffets (skewing those numbers)

If we were talking about female vs male earning, I would imagine that the lack of preposterously wealthy women would be the sort of thing you'd want to look into.
posted by Phalene at 9:22 AM on July 25, 2011


[fixed the link per OP request, carry on]
posted by jessamyn at 9:25 AM on July 25, 2011


@flapjax, ftfy:

>Been shootin' craps and gamblin'
>Mama and I done got broke

--Blind Willie McTell
posted by inkisbetter at 10:17 AM on July 25, 2011


I also teach statistics to 19 year olds, and I do exactly the opposite in both cases. ... I refuse to change it out of principle.

You probably have tenure. I'm a Visiting Lecturer.
posted by benito.strauss at 11:00 AM on July 25, 2011


These scientists need to grow some balls.
posted by Kabanos at 11:13 AM on July 25, 2011


Would a site called DMRT1 Ate My Balls be too dated at this point?
posted by newmoistness at 11:29 AM on July 25, 2011


I became a man the first time I tasted single malt scotch. That was about three years ago.
posted by Decani at 12:42 PM on July 25, 2011 [1 favorite]


Ok this thread is about magic tricks with gonads

Illusions with gonads! "Tricks" are something whores do for money. Or candy.
posted by rusty at 1:01 PM on July 25, 2011 [1 favorite]


Hens, traditional ones anyway, go off-lay and off-female by extension, over winter, re-feminising, to lay eggs again, each spring: except, some years, some of them stay 'male' and act it.
posted by maiamaia at 2:24 PM on July 25, 2011


metaBugs, a few questions:

What's the point of cre? If the loxP is already marking the spot, why can't you just inject an already-functional protein (some tamoxifen-cre complex) which cuts the target gene? Secondly, even if cre *is*necessary, why can't you just toss the cre genes into the genome the way you tossed loxP genes in; why complicate the process by requiring a virus in every subject?

That was one of the most fascinating things I've read in some time, thanks. I dragged my girlfriend out of her book so I could clumsily explain it.
posted by Buckt at 5:26 PM on July 25, 2011


Buckt,

For the cre system to work you do need to toss it into the genome with the loxP snippets in the right spots. The whole point of the cre system is that it destroys a gene, thus also the protein it produces, but it doesn't serve an active function in the organism. Putting cre, active or otherwise into the mouse on its own would be pointless, really there are much easier ways to delete a gene. What makes the cre system so cool is that you can delete anything any time, even essential genes. Injecting functional proteins into healthy in situ adult cells is not really practical, cells across every domain of life need serious protection against foreign proteins. What the cre system does to get around this is exactly what metaBugs explained, cre is constitutively expressed but inactive until tamoxifen, a hormone that can make its way into cells, activates it.

This way you can make a critter with an active and functional gene, then make the gene go poof.
posted by Blasdelb at 9:33 PM on July 25, 2011


This is the original paper demonstrating the concept. It like most of the tools in molecular biology comes from a phage.
posted by Blasdelb at 9:46 PM on July 25, 2011


@flapjax, ftfy:

The ftfy is, presumably, for the attribution? Since there was no author credit after the quote? Well, dunno if that constitutes fixing, exactly, but anyway, yeah, thanks for the attribution, for those out there who didn't know the author. Some might have only heard the more recent Bob Dylan cover. As for me, yeah, I'd heard both.
posted by flapjax at midnite at 11:18 PM on July 25, 2011


Ah, my explanation wasn't very clear. Thanks for cleaning it up, Blasdelb.

For the sake of redundancy and practicing my communication skills:

What's the point of cre? If the loxP is already marking the spot, why can't you just inject an already-functional protein (some tamoxifen-cre complex) which cuts the target gene?

Yes, LoxP is a signal that says "cut here", while cre is what does the cutting (properly, cre is the gene and Cre is the protein product of that gene). In principle, you could just inject already-active Cre as a drug, to get into cells and find the LoxP sites. In its natural state it's already active; the version that's actually used was deliberately modified to require tamoxifen. However, delivering proteins as a drug is hard: firstly the immune system does its best to mop them up before they get anywhere, secondly cells tightly control which large molecules get in and out, so you'd need some way of persuading the target cells to import the Cre protein. This is not impossible (there are various "import me!" signals that we can spoof), but it's hard to do with any decent efficiency.

In contrast, tamoxifen is a modified hormone: a small (and non-protein) molecule with a structure perfectly suited to be ignored by the immune system and to make its way into cells without assistance.* So getting the cells to manufacture defective Cre internally and then administering tamoxifen to switch it on is much easier to do.

Secondly, even if cre *is*necessary, why can't you just toss the cre genes into the genome the way you tossed loxP genes in; why complicate the process by requiring a virus in every subject?

My explanation wasn't very good here, sorry. Yes, if you're already mucking about with the genome to put LoxP sites in, chucking the cre gene in at the same time is pretty easy, and that's what is typically done.

The DNA sequences for LoxP and cre are originally from a virus but that virus isn't actually used at any point, just these snippets of DNA based on it. Virtually all of the tools we have for cutting, copying and stitching together DNA are proteins that have been directly copied from various bacteria and viruses, tweaked here and there to better suit our purposes.

My next paragraph about inserting new genes into cells (gene therapy) using viruses was just me scurrying away on a tangent, with little relevence to the knock-out system.

*I'm a martyr to this sort of tangent. Very briefly, the outer membrane of a cell is a "lipid bilayer", basically a thin film of fat. Water and most stuff that's dissolved in water can't get through this "hydrophobic" layer, especially if they're something large-ish like a decently sized protein. There are exceptions to that, but it's a good rule of thumb... basically, anything charged and big-ish will be stopped.

So to get water, salts, nutrients, etc. in and out, the membrane is studded with big protein structures that make channels through the cell membrane. Most of these channels are specific and gated, so they'll only open to allow certain things through and only in response to what's going on elsewhere in the cell. Many are powered, spending energy to actively pump their target in or out of the cell, across the membrane. A cell can also import stuff by extending the membrane to envelop something on the outside then, when it's surrounded, sealing off the top of the invagination. Now the imported object is inside the cell, surrounded by its own membrane bubble.

Anyway, tamoxifen has the advantage of being very small and, for the most part, being very weakly charged. Being small, weakly charged and similar to stuff already in the body means that the immune system will pretty much ignore it. These factors also make it able to just drift through the plasma membrane into the cell, pretty much unimpeded. Lots of hormones are similarly tiny and based on the same "steroid ring" structure, for the same reasons.

posted by metaBugs at 4:57 AM on July 26, 2011 [1 favorite]


Old post, but many thanks Blastdelb and metaBugs. I understand the point of having a lipid activate the protein; very cool. Many thanks for the detailed responses.
posted by Buckt at 7:51 AM on July 31, 2011 [1 favorite]


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