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In high school biology, we learn that humans are born with either XX or XY chromosomes, and that a person’s internal and external sex organs match those chromosomes. It turns out, however, that sex isn’t that straightforward.

Hosted by: Hank Green

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Image Sources:
https://commons.wikimedia.org/wiki/File:45,X.jpg
https://commons.wikimedia.org/wiki/File:PBB_Protein_SRY_image.jpg
https://commons.wikimedia.org/wiki/File:Pseudoautosomal_region.png
https://commons.wikimedia.org/wiki/File:Androgen_receptor_3-d_model.jpg
https://commons.wikimedia.org/wiki/File:NHGRI_human_male_karyotype.png
[♪ INTRO].

In high school biology, we usually learn that the sexes in humans are fixed and concrete. Whether you’re male or female is black-and-white and rooted in your

DNA: your 23rd pair of chromosomes is either two X chromosomes or an X and a Y. That’s it. End of story. And that’s essentially what scientists thought, too.

But it turns out that sex isn’t that straightforward. In fact, biologists today are saying sex is a spectrum. And the scientific community is still working on understanding and respecting the people who fall in the middle of that spectrum.

To get this out of the way right up front: we’re not talking about gender or sexuality here. Gender refers to social and cultural attributes and understandings of men and women and their roles—though, not every culture has only two categories, and it’s increasingly seen as a spectrum. Plus, the gender you identify as may or may not be the same one as what you express with things like your clothing and behavior, all of which can also be on a spectrum.

Sexuality describes who you are attracted to, and it can be equally complicated and on a spectrum. And where you are on these spectrums isn’t necessarily fixed! But what we are talking about today is your biology, including your chromosomes, your hormones, your gonads, and your genitals.

The catch is that these biological features don’t always agree with each other. And they certainly don’t always conform to those high school health class diagrams that tell us there is a single, universally correct pathway to being male and female. In fact, it’s estimated that nearly 2% of live births are born with congenital conditions of atypical sex development.

That basically means that something in their chromosomes, hormones, gonads, or genitals is different from what many people expect of a “boy” or a “girl.” This used to be known as being intersex, but these days, it’s better described as having differences of sexual development, or DSDs. And while nearly 2% might not sound like a lot, it means there could be 130 million people or more with DSDs. If all those people were in one country, it'd be among the top ten most populous countries in the world!

Plus, DSDs are not always something you can see. People can spend their whole lives thinking they’re one sex based on anatomy only to find at least part of them tells a different story. You see, your sex is the result of both sexual determination and sexual differentiation.

Sexual determination has to do with what chromosomes you get. Those largely determine what happens to your body during sexual differentiation—the process by which you develop the physiological characteristics associated with your sex. And contrary to what you might think, that differentiation doesn’t stop when you’re born—it continues throughout your life.

That means there are a lot of moments where differences between people can happen—so of course there are a ton of different outcomes! We tend to put those outcomes into two boxes based on visible anatomy, or what scientists call phenotypes. Phenotypical males have testicles and a penis, while phenotypical females have ovaries, a uterus, a vagina, and vulva.

But in reality, none of the traits we use to discriminate between the sexes are truly binary. There’s a lot of variation within what we call male or female, and there's a lot of overlap that's normal, too. Anatomically, someone might look phenotypically female on the outside but not have ovaries or a uterus, or have tissue from both ovaries and testes.

And genetics aren’t any clearer, because when it comes to chromosomes, people don’t always get two Xs or an X and a Y. Xs and Ys contain genes that help determine sex, with the Y chromosome conferring the genes that enable you to develop male reproductive parts. But the processes for producing sperm and eggs are really complicated, and they can lead to lots of different results.

In this process, (abbreviated version) specialized cells basically duplicate themselves, then undergo two rounds of division to produce reproductive cells, or gametes, that have half of the parent’s genetic material. So, it makes one set of 23 chromosomes. But sometimes, the chromosomes don’t split into exact sets of 23—and that means there are a whole bunch of possible combinations of Xs and Ys that a person can end up with.

For instance, people can inherit three Xs or an X and two Ys. These folks are normally taller than average. Those with three Xs have slender builds, and sometimes have minor learning disorders.

The people who have an X and two YYs, on the other hand, tend to have more acne because of the extra testosterone in their systems. In both cases, people retain full fertility. Then, there’s Turner syndrome, which happens when you get just one X.

That results in female characteristics, but the people who have it tend to be shorter, don’t really go through puberty, may have mental disabilities, and are sterile. And Klinefelter syndrome, which results from two Xs and a Y, is the most common chromosomal sex anomaly. It happens in one in 600 male births and can cause lower testosterone production and cause incomplete testicular development, though the symptoms can be minor enough that a person isn’t diagnosed until later in life.

Now there’s also the fact that all your cells in your body don’t necessarily have the same chromosomal makeup. Which like, what? Did I learn nothing but lies in high school?

But it’s true—someone with mosaicism can develop from a single fertilized egg, but have a patchwork of genetically different cells. And someone who’s a genetic chimera has different cells because they develop from two different fertilized eggs that merge in the womb. In both cases, it’s possible to end up with a mix of cells with different sex chromosomes.

And depending on the distribution of those cells, mosaicism and chimaerism can result in ambiguous sexual characteristics or both male and female reproductive body parts. It’s even been shown that pregnant people and their fetuses frequently swap stem cells through the placenta in a phenomenon known as microchimerism. That means a chromosomal “female” can be carrying around XY cells, and her son can have XX ones.

In some studies, these cells have been shown to stick around in the mother for several decades. But all that said… there are also plenty of people with double-X or XY chromosomes that also have differences of sexual development. That’s in part because at least 25 genes play a role in sex differentiation.

So both mutations and relocations of these genes can result in a range of differences. Genes necessary for male development can be swapped onto the X chromosome, for example, or someone can end up with multiple or mutated versions of other sex-determining genes. And some of these are on other chromosomes, and are inherited as run-of-the-mill recessive traits.

All of these genes really start to be influential around six weeks of development. You see, at six weeks, the fetus has a pair of bulges called the gonadal ridges next to its kidneys—and they have the potential to develop into ovaries or testes. The fetus at this point also has two sets of ducts.

One set can develop into the uterus and fallopian tubes, while the other set has the potential to become the epididymis, vas deferens, and seminal vesicles. And what happens from there is somewhat of a balancing act of different genes working in concert. Essentially, different networks of genes shout MALE and FEMALE, and when that balance gets knocked slightly askew, it can move a person along the sex spectrum.

Take SRY. Discovered in the 1990s, this is the male programming gene, and it has a big effect on development. If it ends up on the chromosome of someone who is XX, it can cause them to develop testes instead of ovaries.

This can happen because there’s a step in sperm and egg production when chromosomes swap some DNA with their partner chromosomes. And even though the X and Y chromosomes generally don’t join in on this DNA swapping process, they sometimes do. Plus, other mutations that occur during the production of gametes can result in multiple or mutated versions of SRY or other sex-determining genes—because it’s not the only gene that matters.

There are also genes that actively encourage the fetus to develop female characteristics. For instance, the gene WNT4 suppresses testicular development and promotes ovarian development, and multiple copies of it can cause incomplete female gonads to develop in people who are XY. Gonad development also triggers the production of sex-specific hormones, which results in further sex-specific development.

But some people have differences of sex differentiation that limit their ability to respond to those hormones. Complete androgen insensitivity syndrome is one of these. People who have it are unaffected by male sex hormones, because they have some kind of mutation to the protein that these hormones bind to, called the Androgen Receptor.

And that means that while they have testes and a Y chromosome, their exterior genitals appear female or in between. There’s also congenital adrenal hyperplasia, the most common DSD out there. That’s when the adrenal glands underproduce cortisol and overproduce androgens, the male hormone group that includes testosterone.

The underproduction of cortisol can lead to health problems, while the overproduction of androgens can lead to external male genitalia paired with internal female gonads in people with XX chromosomes. Some of these conditions don’t fully present themselves until puberty or later. In fact, some aren’t realized at all until a person seeks some kind of medical care that reveals them.

Like, in 2014, doctors reported one case of a 70-year-old father of 4 whose quote “hernia” turned out to be a uterus with fallopian tubes. But, in many cases, differences in sexual development are notable from birth; for those newborns, it may be possible to assign a gender based on what they are more likely to identify as, as they grow up. The thing is, with all of the things that can happen during sexual development, when a child is born with an obvious difference of sex development, it's not always clear why.

Looking at chromosomes often isn’t enough, and sometimes a hormonal test isn’t either. And even if the child’s doctors have a sense of what’s going on, determining what, if any, treatment is necessary can be challenging. Back in the 1960s, it was thought that growing up without clearly defined sexual organs would cause emotional trauma.

So, there was a push towards performing surgery on infants to clearly assign them a sex. And because of social stigmas surrounding DSDs, parents were often encouraged to keep all this a secret, even from the child. So people grew up without knowing kind of important details about their own bodies.

It’s hard to get numbers on how many of these surgeries were—or even are being—performed. It’s also hard to know exactly how these surgeries affect patients, but as adults, many report pain, scarring, and a loss of sensation. Also, people with DSDs do report high rates of gender dysphoria, where their chosen gender does not align with their assigned sex.

And there is an association between gender dysphoria and mental health issues, like self-harm behaviors, so these surgeries may contribute to mental health problems later in life. Though, it’s important to note that such issues are less likely if people have supportive and affirming parents who accept them as they are. And, sometimes, surgery is medically necessary, like to unblock the urethra.

Also, surgery can help to preserve fertility or, in the case of complete androgen insensitivity syndrome, to reduce the risk of testicular cancer. But from a medical perspective, those surgeries don’t need to be performed on infants. In fact, most of the time, differences in genital anatomy at birth aren’t something that needs to be fixed.

At least, not until the person is old enough to make their own choices about what they want their bodies to look like. So nowadays, healthcare is moving away from a surgical approach. If a DSD is identified at birth, treatment is more likely to include therapy and hormonal replacement than surgery.

Often, a DSD team is involved in care, which can include geneticists, endocrinologists, and psychologists or psychiatrists. They help the family decide if any interventions are immediately and medically necessary, and help provide care and support to the child with DSD and their family throughout childhood. Unfortunately, this kind of care still isn’t available everywhere.

For now, researchers are working to better understand the development of both sex and gender over time, and to gain a clearer sense of when kids begin to understand their own gender identity. The problem, of course, is the fact that from clothes to restrooms to organized sports, they are raised in a society that is set up around a binary that just… isn’t binary. But researchers are thinking about how we can make our overall discussions and understanding of sex even more inclusive—and more accurate.

Because even though biological sex may seem like one of those things that is relatively straightforward in a very, very complicated world… it’s not! And while there’s probably still a long way to go to understand it, we are making progress. Before we go, we’d like to give a special thank you to our patrons on Patreon.

It’s because of their support that we’re able to tackle complex, difficult topics like this one. So thank you, patrons! And if you want to support us, too, you can learn more by joining our patron community at Patreon.com/SciShow [♪ OUTRO].