Another form of chimaerism, however, is now known to be widespread. Termed microchimaerism, it happens when stem cells from a fetus cross the placenta into the mother’s body, and vice versa. It was first identified in the early 1970s — but the big surprise came more than two decades later, when researchers discovered how long these crossover cells survive, even though they are foreign tissue that the body should, in theory, reject. A study in 1996 recorded women with fetal cells in their blood as many as 27 years after giving birth13; another found that maternal cells remain in children up to adulthood14. This type of work has further blurred the sex divide, because it means that men often carry cells from their mothers, and women who have been pregnant with a male fetus can carry a smattering of its discarded cells.

Microchimaeric cells have been found in many tissues. In 2012, for example, immunologist Lee Nelson and her team at the University of Washington in Seattle found XY cells in post-mortem samples of women’s brains15. The oldest woman carrying male DNA was 94 years old. Other studies have shown that these immigrant cells are not idle; they integrate into their new environment and acquire specialized functions, including (in mice at least) forming neurons in the brain16. But what is not known is how a peppering of male cells in a female, or vice versa, affects the health or characteristics of a tissue — for example, whether it makes the tissue more susceptible to diseases more common in the opposite sex. “I think that’s a great question,” says Nelson, “and it is essentially entirely unaddressed.” In terms of human behaviour, the consensus is that a few male microchimaeric cells in the brain seem unlikely to have a major effect on a woman.

Scientists are now finding that XX and XY cells behave in different ways, and that this can be independent of the action of sex hormones. “To tell you the truth, it’s actually kind of surprising how big an effect of sex chromosomes we’ve been able to see,” says Arnold. He and his colleagues have shown17 that the dose of X chromosomes in a mouse’s body can affect its metabolism, and studies in a lab dish suggest18 that XX and XY cells behave differently on a molecular level, for example with different metabolic responses to stress. The next challenge, says Arnold, is to uncover the mechanisms. His team is studying the handful of X-chromosome genes now known to be more active in females than in males. “I actually think that there are more sex differences than we know of,” says Arnold.

Beyond the binary

Biologists may have been building a more nuanced view of sex, but society has yet to catch up. True, more than half a century of activism from members of the lesbian, gay, bisexual and transgender community has softened social attitudes to sexual orientation and gender. Many societies are now comfortable with men and women crossing conventional societal boundaries in their choice of appearance, career and sexual partner. But when it comes to sex, there is still intense social pressure to conform to the binary model.

This pressure has meant that people born with clear DSDs often undergo surgery to ‘normalize’ their genitals. Such surgery is controversial because it is usually performed on babies, who are too young to consent, and risks assigning a sex at odds with the child’s ultimate gender identity — their sense of their own gender. Intersex advocacy groups have therefore argued that doctors and parents should at least wait until a child is old enough to communicate their gender identity, which typically manifests around the age of three, or old enough to decide whether they want surgery at all.

This issue was brought into focus by a lawsuit filed in South Carolina in May 2013 by the adoptive parents of a child known as MC, who was born with ovotesticular DSD, a condition that produces ambiguous genitalia and gonads with both ovarian and testicular tissue. When MC was 16 months old, doctors performed surgery to assign the child as female — but MC, who is now eight years old, went on to develop a male gender identity. Because he was in state care at the time of his treatment, the lawsuit alleged not only that the surgery constituted medical malpractice, but also that the state denied him his constitutional right to bodily integrity and his right to reproduce. Last month, a court decision prevented the federal case from going to trial, but a state case is ongoing.

“This is potentially a critically important decision for children born with intersex traits,” says Julie Greenberg, a specialist in legal issues relating to gender and sex at Thomas Jefferson School of Law in San Diego, California. The suit will hopefully encourage doctors in the United States to refrain from performing operations on infants with DSDs when there are questions about their medical necessity, she says. It could raise awareness about “the emotional and physical struggles intersex people are forced to endure because doctors wanted to ‘help’ us fit in,” says Georgiann Davis, a sociologist who studies issues surrounding intersex traits and gender at the University of Nevada, Las Vegas, who was born with CAIS.

Doctors and scientists are sympathetic to these concerns, but the MC case also makes some uneasy — because they know how much is still to be learned about the biology of sex19. They think that changing medical practice by legal ruling is not ideal, and would like to see more data collected on outcomes such as quality of life and sexual function to help decide the best course of action for people with DSDs — something that researchers are starting to do.

Diagnoses of DSDs once relied on hormone tests, anatomical inspections and imaging, followed by painstaking tests of one gene at a time. Now, advances in genetic techniques mean that teams can analyse multiple genes at once, aiming straight for a genetic diagnosis and making the process less stressful for families. Vilain, for example, is using whole-exome sequencing — which sequences the protein-coding regions of a person’s entire genome — on XY people with DSDs. Last year, his team showed20 that exome sequencing could offer a probable diagnosis in 35% of the study participants whose genetic cause had been unknown.

Vilain, Harley and Achermann say that doctors are taking an increasingly circumspect attitude to genital surgery. Children with DSDs are treated by multidisciplinary teams that aim to tailor management and support to each individual and their family, but this usually involves raising a child as male or female even if no surgery is done. Scientists and advocacy groups mostly agree on this, says Vilain: “It might be difficult for children to be raised in a gender that just does not exist out there.” In most countries, it is legally impossible to be anything but male or female.

Yet if biologists continue to show that sex is a spectrum, then society and state will have to grapple with the consequences, and work out where and how to draw the line. Many transgender and intersex activists dream of a world where a person’s sex or gender is irrelevant. Although some governments are moving in this direction, Greenberg is pessimistic about the prospects of realizing this dream — in the United States, at least. “I think to get rid of gender markers altogether or to allow a third, indeterminate marker, is going to be difficult.”

So if the law requires that a person is male or female, should that sex be assigned by anatomy, hormones, cells or chromosomes, and what should be done if they clash? “My feeling is that since there is not one biological parameter that takes over every other parameter, at the end of the day, gender identity seems to be the most reasonable parameter,” says Vilain. In other words, if you want to know whether someone is male or female, it may be best just to ask.