Scientists reject a binary view of human sex at NIH symposium

This July, the National Human Genome Research Institute, an institute of the US National Institutes of Health, co-organized a 2-day virtual symposium titled Exploring the Many Dimensions of Sex and Gender in the Genomics Era. Scientists, clinicians, and other experts who work at the intersection of sex and biology were invited to present their knowledge of this topic over Zoom to the public.

The symposium aimed to give participants a comprehensive overview of the biological complexities underlying human sex. During the two days the experts discussed what has been long understood, that human sex isn’t strictly binary, and that sex and gender influence every aspect of human research and clinical care.

A collection of complex traits

The symposium began with several presentations outlining what sex is and what it encompasses.

Julia Serano, a biochemist, transgender activist, and independent scholar, described sex as a collection of traits that includes one’s chromosomes, reproductive organs, hormone ratios, response to those hormones, and secondary sex characteristics such as facial hair and breast development. Some of those traits are outwardly apparent, while others are not, but most are what biologists call complex traits, meaning they are influenced by multiple genes, the environment, and the passage of time.

“Almost all human traits are complex traits,” Serano said. “Complex traits do not act like on or off light switches. They tend to give rise to bell curve–shaped spectrums. Most people are clustered around some kind of average outcome, but there are always going to be outliers from the norm.” For example, some people have no facial hair; others have big, bushy beards; and the rest fall somewhere in the middle. That variation is readily apparent.

More hidden is how hormone ratios can vary. The biochemical pathway that produces testosterone also produces estradiol, a form of estrogen. The estrogen synthetase enzyme converts testosterone to estradiol by removing a methyl group from testosterone and converting one of its rings into an aromatic group. Small changes to the precursor or successor genes and enzymes in that pathway can lead to hormone ratio shifts, and those shifts can then lead to variation in secondary sex characteristics, or even more drastic physiological changes.

Yet in the US and many other countries, the legal definition of sex is based on a visual inspection of a newborn’s genitalia and not a comprehensive analysis of the multiple traits that make up sex. Given the level of variation in sexual characteristics, speakers argue that this practice is flawed.

Not just chromosomes

Throughout the symposium, many speakers argued that any attempt to categorize sex runs into the same issue—human variation always provides an exception to the rule. For example, an introductory biology class might explain that humans have 23 pairs of chromosomes and that 1 of those pairs is defined as sex chromosomes. Generally, students learn, females have 2 X chromosomes and males have 1 X and 1 Y chromosome, and a person’s own set of chromosomes is called their karyotype.

That all sounds relatively simple, but according to Melissa Wilson, an evolutionary biologist studying the evolution of sex at Arizona State University, that explanation is an oversimplification. For one, sex chromosomes have evolved dramatically over time. The versions of X and Y chromosomes in our ancestors didn’t look like they do now. “One hundred fifty million years ago, they were indistinguishable from each other. They were just like every other chromosome pair in our genome,” Wilson said.

Over those many years of evolution, the Y chromosome shrank to contain between 70 and 200 genes, compared with several hundred or thousands of genes found on other chromosomes. One of those Y chromosome genes is SRY, which stimulates the development of reproductive organs that produce sperm. And the gene, to use Serano’s phrase, isn’t like an on-off light switch. SRY influences the expression of several transcription factors and genes along a biological pathway heavily involved in sexual development.

Variations can happen at each step in the pathway, creating opportunities for sex traits to develop in an unanticipated way. For example, somebody born with a defective copy of the gene SRY on their Y chromosome might not develop a penis and testes as expected. This chromosomal variation is called Swyer syndrome, and it’s just one of several sex chromosome karyotypes found in humans. It’s also an example of being intersex, defined as when someone is born with characteristics that don’t fit a binary notion of male or female.

Sex chromosomes also control more than just sex—30% of human tumor suppression genes are on the X chromosome, for example—and sex-influencing genes are also on the other 22 pairs of chromosomes.

Congenital adrenal hyperplasia, which is one of the most common types of intersex variations and can lead to genitals that don’t resemble a typical penis or vulva, is caused by a mutation of the 21-hydroxylase gene on chromosome 6. It can also lead to abnormal development of other organs and biological processes. In some populations, the mutation can be present in 10–15% of individuals (Genet. Med. 2017, DOI: 10.1038/gim.2017.46).

Furthermore, not everyone is born with just two sex chromosomes. Humans have many more sex chromosome karyotypes, all of which influence the expression of sex differently. Those differences are thanks to a process called X inactivation, whereby one X chromosome is fully expressed and any additional X chromosomes get silenced. “It allows us to have this tremendous variation in sex chromosomes,” Wilson said.

Cancers and some other medical conditions can also change a person’s karyotype over time. “Even if you got tested and knew what your sex chromosome complement was at one point in life, it may be different at a later point in life,” Wilson said. But most people never have their chromosomes tested.

One size does not fit all

Some people who advance a binary view of sex have embraced a concept called anisogamy, which defines sex according to gametes—reproductive cells such as sperm and eggs. Anisogamy says that an organism is male if it produces small, mobile gametes and female if it has large, immobile gametes.

This definition supposedly allows for the kind of variation that one sees in nature beyond humans. But like the other definitions of sex, anisogamy doesn’t cover all life. There are several examples of nonhuman species in which the size or mobility of gametes does not vary between sexes (Biol. J. Linn. Soc. 2017, DOI: 10.1111/bij.12874).

And Sam Sharpe, a biologist at Kansas State University and an intersex and transgender peer support advocate, said that humans demonstrate plenty of additional complexity that also makes anisogamy an unfit concept for defining sex. “As soon as we leave the hypothetical and start talking about real individuals, we run into additional complexities,” they said. “Humans are not reproductive at every stage of our lifespan. Until an individual goes through puberty, their ability to [reproduce] is largely hypothetical.” Beyond that, Sharpe explained, some people are born with ovotestes and produce both sperm and eggs.

Speakers cited several examples of recent legislation in the US that seeks to use anisogamy as a means of narrowly defining sex and gender. They say the purpose of this legislation is to restrict gender-affirming care, marriage licenses, bathroom usage, among other reasons. But these definitions often include qualifying language to account for exceptions to the rule—for example, the state of Montana defines female as someone who produces eggs or an “individual who would otherwise fall within this definition, but for a biological or genetic condition,” even though it’s impossible to predict what someone would be if not for that condition.

Sharpe believes that’s a flawed way of looking at things. “A definition of sex that begins and ends with anisogamy is going to be simply not very useful because it will exclude people who need to be included,” they said. Such definitions simultaneously acknowledge the diversity and complexity of human sex while trying to constrain it into a binary.

Shay-Akil McLean, an evolutionary biologist, sociologist, and independent scholar, was one of several at the symposium to argue that those who have changed their understanding of sex to be based on genitalia, then chromosomes, and then gametes are shifting the goalposts and not honestly attempting to recognize the totality of human sex. “Sex is a determination made through the application of socially agreed upon biological criteria,” he said, “not an inherent trait that organisms possess.”

Distinct yet related

Gender and sex are closely related yet distinct concepts—sex is considered a collection of biological characteristics, and gender is considered a collection of socially constructed roles, behaviors, expressions, and identities. Some of those who argue in favor of a restrictive definition of sex occasionally admit that people can reshape their gender expression, but maintain that sex is an immutable part of biology. The researchers presenting at the symposium disagreed.

Anne Fausto-Sterling, a biologist and professor emerita at Brown University, uses the term gender/sex because gender and sex are “constantly reshaping one another,” she said. By that, Fausto-Sterling meant that the biological components that make up sex influence one’s gender roles and how society perceives them, while one’s gender roles also influence those underlying biological characteristics.

For example, at the event, Fausto-Sterling cited a paper from 2011 investigating the relationship between childcare and the drop in testosterone levels that accompanies new fatherhood. New fathers who engaged in 3 or more hours of active childcare per day had a greater reduction in testosterone levels than new fathers who engaged in fewer hours of active childcare (Proc. Natl. Acad. Sci. U.S.A., DOI: 10.1073/pnas.1105403108). That’s just one of several studies she mentioned detailing how social conditions can influence one’s sexual characteristics.

Speakers also shared examples of how gender identity can persist as a variable separate from sex characteristics. Physician Tucker Pyle, from Children’s National Hospital in Washington, DC, shared a case study of a person who was born in the 1980s and raised as a girl but felt like a boy throughout life. As a teenager, he was prescribed feminizing hormones in an effort to help him look and feel more like a woman, but he still experienced dysphoria. It was only years later that he learned that doctors performed surgery on him as a baby to make his genitalia, which weren’t clearly a penis or a vulva, look like a vulva. But he ultimately identified as male and socially and hormonally transitioned.

Pyle said that surgery used to be the norm when babies were born with genitalia outside the expected variation. Increasingly, thanks to decades of efforts by intersex advocates, many physicians strive to only engage in medically necessary intervention. Later in life when people choose to undergo intersex screening, Pyle said, half the time, clinical genetic testing doesn’t reveal a specific condition.

Data should reflect reality

While much of the knowledge shared at the symposium isn’t new, most biomedical researchers haven’t yet incorporated this knowledge into their data collection practices. This is an “ethical, political, and epistemological problem,” said Catherine Clune-Taylor, a professor at Princeton University who studies how sex relates to medical ethics.

Clune-Taylor explained that biomedical researchers often exclude intersex individuals from research populations. Furthermore, those researchers rarely define what sex is with respect to their study population. “We know that it’s important to have subjects in clinical research that are representative of the population. Otherwise, we have limited research,” Clune-Taylor said.

For researchers to be more inclusive, they must collect and validate data related to the multiple components of sex. That could include checking chromosomes and hormone levels and performing organ inventories, according to Clune-Taylor.

Perhaps the reason researchers don’t collect comprehensive data on sex is because it’s challenging. It’s not easy to take what has historically been coded in biomedical research as a single, binary variable and break it down into its underlying components. But challenge alone isn’t a reason to omit relevant information regarding sex and gender when the details can significantly affect health outcomes, Clune-Taylor argued. It is “an issue of justice,” she said.