Our cells carry their own sexual identity. That's science, not ideology

On Jan. 13, in response to President Trump's order for federal agencies to dismantle webpages that included "gender ideology extremism," the National Institutes of Health removed or made unavailable all pages that mention sex as a biological variable. Agencies have discouraged researchers from using certain words considered "woke" by the Trump administration, and they have flagged funding proposals for review based on whether the proposals include any of the words on a long list, The New York Times reported. As a result, opponents of sex and gender studies in science may think they've successfully done away with "gender ideology."

But they've done a lot more than that. The impact of sex as a biological variable is far more subtle and pervasive than it may seem. In fact, sex-based differences with implications for our health exist even at the very "sciencey"-seeming level of cell and molecular biology. By censoring or defunding work that mentions sex as a biological variable, research on pretty much all cell biology relevant to human health is now at risk. That's because sex — and gender roles, too —permeates all the way down to the most unreproductive of cell types. If you want to do science about animals including humans, sex as a biological variable is a factor you simply cannot ignore. Studies of cancer treatments, for example, or Alzheimer's disease or drug safety or heart attack risk are all topics at risk in the current war on sex differences research.

Developmental biology researcher Bruno Hudry, a scientist at the Institut de Biologie Valrose in Nice, France, told Salon it is accurate to say that cells — not just the cells of the ovaries or testes — have a sexual identity. "In many animals, the development of male or female sex organs is guided by specific genetic elements known as sex chromosomes. These chromosomes are present in every cell of the body — not just in the reproductive organs. As a result, every cell carries an intrinsic sexual identity, a concept I refer to as cellular sex," he said.

The XX chromosome that in reproductive tissues results in production of eggs, and the XY chromosome that results in sperm production, are also present in all body cells. This means that "each cell has the potential to use sex chromosome genes to create sex-specific differences. In many cases, this potential remains unexploited, and the presence of sex chromosomes doesn’t result in obvious physiological changes. This is why studying cellular sex is important: to uncover when and where it plays a role, and to understand how it influences organ development, function or disease in specific biological contexts," Hudry said.

There are believed to be two ways in which sex chromosomes can cause sex-specific differences, also called sexual dimorphism, in cells. One relates to the presence or absence of the Y chromosome. Genes found on the Y chromosome are only active in cells that have the XY chromosome. Researchers have found that these so-called Y-linked genes can be active ("expressed") in many tissues beyond reproductive tissues. That means it's entirely possible to have sex chromosomes to drive what Hudry calls functional differences in the brain, the liver or the immune system. Secondly, people (or animals) that have XX cells instead get two copies of the X chromosome, which means that genes on that chromosome can be expressed at higher levels in those cells, while XY cells only get one copy of those genes.

Hudry, working with fruit flies (which are functionally surprisingly similar to humans), showed that intestinal stem cells have an intrinsic sexual identity that results from the expression, or activation, of a gene that's active only in flies that have two X chromosomes. That gene makes the gut of the female about 20% bigger than the gut in male fruit flies, and makes the female more prone to tumors by activating proteins that cause cell division. Researchers can create genetically-modified female flies that don't activate that particular gene in their intestine cells, or they can create various combinations of mice with XX and XY sex chromosomes paired with either ovaries or testes to separate the action of sex hormones from the action of sex chromosomes. This painstaking research ultimately clarifies what is going on.

How might sex chromosomes might affect a particular organ in humans? Let's take the example of cells from a single tissue type: the kidneys. Whether we're assigned male or female at birth, we all have kidney cells, and if all goes well we each have two kidneys. There are all sorts of differences between male and female kidneys, from the impact of testosterone to the biological effects of behavioral differences resulting from gender roles. Most of these differences might affect cells, but they aren't the result of differences in kidney cells depending on the type of sex chromosomes those cells have. Some of them are: Nephrologist Sofia Ahmed, a teacher at the University of Alberta in Canada, noted that male kidneys are larger and weigh more than female kidneys. While humans are often said to have about a million nephrons (the functional units of the kidney) per organ, and though the number actually varies widely among individuals, male kidneys actually have more nephrons than female kidneys, even in female children versus male children. And there are other differences, such as in how male and female kidneys process salt. "At the cellular level, there is differential expression of these transporters of salt and other electrolytes in female kidneys versus male kidneys," Ahmed told Salon. That difference at the cellular level is important, because women tend to have more salt-sensitive hypertension, a risk factor for cardiovascular disease, than men, especially in the menopausal phase.

"There are differences between female and male kidneys that are further exacerbated by the presence or absence of sex hormones like estrogen... so if we just did studies on only one sex, and we didn't do them across different hormonal exposures — and we haven't even talked about how age can independently further exacerbate changes — then this is not how we optimize health for everyone, right?" Ahmed said.

Brain cells and heart tissue cells likewise offer good examples of cell-level differences in addition to other levels at which sexual dimorphism makes male and female brains and hearts different, Ahmed noted.

Sex differences play out in brain cells, too.

"Neuroscientists will do the same genetic manipulation [on male and female mice, and] the female will have a phenotype that is depressed, but the male won't. And then similarly, there are other genetic manipulations where the male mouse will appear depressed, but the female mouse won't. And so this suggests that there are different pathways that we should be looking at... I'm not even speaking about gender-based and societal or environmental-based factors that clearly influence the prevalence of depression. But this is strictly from the purely cellular level. There are differences by sex," Ahmed explained. And while historically it has been women who have been neglected in medical research, resulting in treatments and understanding about the body that are based on studies in men, all sexes are at risk if this research becomes difficult or impossible to do.

"While it's a lot more rare in men to get breast cancer, as we know, the mortality rate is much higher in men, and that probably reflects the fact that the treatments for breast cancer from the cellular level all the way to clinical trials have primarily or solely included women," said Ahmed. Another example might be myocarditis, an important cause of sudden cardiac death that is more common in men than women, at least until the age of 50 or menopause. The biomarkers, immune response and biochemical pathways involved in inflammation that occur in myocarditis differ between men and women (or between people with XX chromosomes and XY chromosomes in their heart tissue). But research on exactly how these differences play out are still in the early stages.

This leaves scientists with the choice of leaving their profession or switching their focus, said Ahmed, who serves as president of the Organization for the Study of Sex Differences, an international organization headquartered in Texas.

"Researchers need funding in order to do their work, and so if they can't use certain words to do that work, they can't get funding to do that work," said Ahmed. "But it's not a question of someone's dilettante interest. This is actually really important to advancing people's health. And so there's a lot of .. moral distress if you can't do sex differences research," Ahmed said.

Hudry, in France, said his research "relies heavily — on a daily basis — on access to databases and stock centers for model organisms, most of which are based in the U.S. and funded by the NIH. Any restriction to these essential resources — whether due to the research topic or the geographic origin of the research team—would be highly detrimental to our work." So far, he says, this has not been an issue.

"Our team has developed new model organisms and made them openly available to the scientific community, enabling researchers to explore the impact of cellular sex on virtually any biological process. We ourselves do not have expertise in many fields — such as immunology — so it’s critical that these tools reach other researchers who do, and who can apply them to diverse questions. If access to these resources were to be blocked simply because the research focuses on sex differences, it would not only hinder scientific progress — it would be a real loss for the broader research community," Hudry said.

Then there's epigenetics, which is the way in which your environment or behavior can change the way your body reads your DNA, turning gene activity on or off as a result of your experiences or things you do. It's the link between nature and nurture, and you could say it almost if not quite justifies the idea that cells are gendered, not just differentiated on the basis of biological sex — for example, epigenetic factors can alter brain cells, including sex-linked aspects of them. In the brain, sexual differentiation starts before birth and results from a combination of sex chromosomes in brain tissue, sex hormones produced by the testes or ovaries and the environment. The second X chromosome in XX individuals can mean a double-dose of some genes, while it also repress certain genetic factors affecting the cell, while the Y chromosome means that XY individuals have some genes that XXers don't get at all. Stress, medications or drugs, and diet can all affect brain cells, sometimes reducing existing chromosomal sex differences. For example, studies in mice show that stress from early-life separation from their mothers, social isolation in adolescence and cocaine exposure in late adolescence can all decrease sex differences in the expression of genes in a part of the brain associated with addiction.

"If we go back to the biological definition of sex as anisogamy — the production of different gametes — there’s a great deal of plasticity in how sexual phenotypes are expressed across the animal kingdom. Some organisms are hermaphroditic, producing both male and female gametes. Others can change sex over time or in response to environmental cues. In these cases, individuals can be male, female, both, or neither, depending on their developmental stage or context. So, while we lack direct evidence, it’s possible in principle that gender roles could also impact the expression or function of cellular sex," Hudry said.

What we know right now is that if you were to ban every bit of research on the social determinants of health, on the different experiences people have depending on their gender roles or even on the effects of hormones on your body, you'd still be left with very critical differences between people born with one X and one Y chromosome (male), people born with two X chromosomes (female) and people born with another combination of sex chromosomes (such as XXY, XYY, XXX, or XO). These include differences that have nothing to do with sex or reproduction, and that don't take place in our reproductive cells but in the various other cells that make up our body tissues. But they are vitally important differences, determining what medicines we need and what diseases we're susceptible to, among other things.

"If we have created an environment where it's not possible to study sex differences or hormonal exposures then we are literally erasing an aspect of science, which is going to have negative downstream effects on everyone's health," Ahmed said.