by Angela Saini
Having just one copy of the genes, only on the X chromosome, can have repercussions for a man’s body. “It’s long been thought, and there is good evidence for this, that having two versions of the gene buffers women against certain diseases or environmental changes,” says Arnold. If a man happens to have a genetic mutation on one of his X chromosomes that causes an illness or disability, he has no way of avoiding it. A woman, on the other hand, will have an extra X chromosome to counteract it, unless she’s unlucky enough to have the same genetic mutation on both X chromosomes, one from each parent. “The simple case would be if one gene works better when it’s cold and another works better when it’s hot. A woman with both of those alleles can be healthy when it’s hot and cold. The male only gets one shot. He only has one copy. So his body either works better when it’s hot or works better when it’s cold, but not both.”
Men are more susceptible to some well-known genetic traits simply because they have one X chromosome. They’re known as “X-linked disorders.” They include red-green color blindness, hemophilia, muscular dystrophy, and IPEX syndrome, which affects immune function. Mental retardation, which affects 2 to 3 percent of people in developed countries and significantly more men than women, also has a strong link to the X chromosome.
This is one reason why, in the effort to understand sex differences in health, Arnold has chosen to zero in on chromosomes. “We went back to the most fundamental biological differences between males and females. From the time of the fertilization of the egg, the only one thing that we know is different between males and females is sex chromosomes. So everything has got to come from that,. . .everything’s downstream of the sex chromosomes.”
“What we know of X-linked diseases is that they’re pretty rare,” says biologist Steven Austad. “But I think there are a lot more X-linked diseases than we think about. . . . This probably underlies a considerable proportion of the sex difference.” One example is respiratory syncytial virus, which infects the lungs and breathing passages and is one of the biggest causes of bronchitis in children under the age of one in Britain and the United States. Researchers have found that the virus tends to hit boys far more than girls, and that something inside one particular gene on the X chromosome might be responsible.
Gender medicine researcher Sabine Oertelt-Prigione agrees that there may be genes linked to resilience, immunity, and disease susceptibility on the human X chromosome that haven’t yet been discovered or understood. “In my school we were taught that the X and Y are basically related to sexual function. That’s it. Nobody was thinking beyond that really at the time, and I’m talking about twenty years ago. Then things slowly started to change,” she explains.
In 1961 English geneticist Mary Frances Lyon found that, even though women have two X chromosomes, one is randomly inactivated in every cell. In other words, only one of them shows up for work. Women are therefore a genetic mosaic in which some cells have genes from one X chromosome, and other cells have genes from the other. Researchers have more recently discovered that some genes on the second X chromosome aren’t actually inactivated at all. Christine Disteche, a professor of pathology at the University of Washington, Seattle, and one of the world’s leading researchers on X inactivation, describes them as “little islands of escape.” In 2009 researchers at Penn State College of Medicine totted up these uninactivated genes to discover that these islands comprise 15 percent of genes on the second X. “We are now looking at huge data sets on gene expression between males and females, in humans and mice, to really try to see what is the extent of these differences,” says Disteche.
“Finding out that one of the two is not completely inactivated, it leads to speculation about lots of interesting aspects of life for women. It may be the reason we live longer,” suggests Oertelt-Prigione.
The problem for all researchers in this area is that it’s not easy to distill the impact of the X chromosome from all the other factors that also cause a person to get sick or die. Most diseases don’t appear to be linked to one or even a few genes in the way that X-linked genetic disorders such as hemophilia and muscular dystrophy are. The things that kill many of us, such as cardiovascular disease, are more complicated than that. Could genes from a second X chromosome have consequences for how the heart works, for instance?
To answer this question, biologist Arnold and his team have used a special laboratory animal, one with absolutely no difference between its males and females except for the number of X chromosomes it has. In nature, these creatures don’t exist. But by using genetic modification, scientists can come close to building them. Since sex hormones before birth have the most obvious impact on male and female bodies (without androgens, a male wouldn’t develop male gonads, for instance), researchers have created laboratory mice for Arnold that don’t produce these hormones. The resulting mice have XY chromosomes, like a male, but also ovaries, like a female. This has allowed Arnold to compare genetically altered XY female mice to normal XX female mice. The only difference between them should be in their chromosomes. If their health differs, it’s purely because of the effects of their genes.
The results have indeed shown a link between the number of X chromosomes a mouse has and its health. Arnold describes “three dramatic cases.” When he and his team looked at body weight, they found that mice get fat if their gonads are removed. But animals with two X chromosomes get a lot fatter than those with just one. It mirrors something we see in human adults—women tend to have a higher percentage of fat mass in their bodies than men. “A second example is that if we give the mouse a heart attack, the animals with two X chromosomes do worse than the animals with one X chromosome,” he adds. “And the third example in the mouse model is with multiple sclerosis, where we induced a multiple sclerosis–like disease in the mouse, and the animals that are XX do worse than the animals that are XY.” Multiple sclerosis in humans, being an autoimmune disease, affects more women than men.
Their take-home message is that many of the sex differences we see in health are rooted deep down in genetics. “The study of mouse models has provided convincing evidence that cells with two X chromosomes are intrinsically different from those with one X chromosome. Sex differences caused by the number of X chromosomes can have a profound effect on disease,” Arnold and his colleagues wrote in their paper about the experiment, published in 2016 in the journal Philosophical Transactions of the Royal Society of London B.
But not everyone is convinced. Some are dubious as to whether rodents can provide quite as much insight as Arnold believes they can. “Personally, I’m not a mouse fan,” says Oertelt-Prigione. “I don’t know how translatable findings in mice are to humans. . . . I think they have given us a lot of information, but I just wonder at this point how far we should pursue that.”
Other criticisms are bigger. In her 2013 book, Sex Itself: The Search for Male and Female in the Human Genome, Harvard University professor of the social sciences Sarah Richardson questions the idea that every cell in the body is intrinsically different depending on someone’s sex, and that this leads to the gaps we see between women and men. “It is a widely shared consensus among social scientists that genomics is transforming social relations,” she writes, adding, “The same may be said of genetic research on sex and gender.” Arnold, for instance, describes the effect of sex-biasing factors in our genes as a “sexome” (like the genome, but for sex difference). “You can think of the cell as this kind of big network,” he tells me. “Males and females are different because they have different levels of sex-biasing factors, and they pull on the network at various points.” This idea is that, even though the sex chromosomes are only one pair in twenty-three of all the pairs of chromosomes we have, their effects stretch much farther.
Richardson warns against this focus on genetics as an umbrella explanation for sex difference because of how it blurs away the effects of society and culture, as well as other biological factors. Age, weight, and race, for example, are known to have a huge impact o
n health. Hormones are important, too. She notes that the body of genetic evidence when it comes to sex differences paints an overwhelming picture of similarity. Indeed, Arnold himself admits to me that his idea of the sexome is “more of an evocative phrase” than a solid theory backed up by research.
The debate about just how deep the dividing line is between women and men continues to rage inside the scientific community. It has been fueled most recently by anger over exactly the opposite problem: the habit of medical researchers to leave women out of tests for new drugs, because their bodies were thought to be so similar to men’s.
“It is much cheaper to study one sex.”
“Let’s face it, everyone in the biomedical community has spent their lives studying one sex or the other. And it’s usually males,” says biologist Steven Austad. When it comes to the basic machinery of our bodies, scientists have often assumed that studying one sex is as good as studying the other.
“I one time looked into the rodent literature on dietary restrictions,” recounts Austad. “There are hundreds and hundreds of studies. And I found that there was only a handful that included both sexes. . . . People seem to be willing to extrapolate from one sex and just assume that everything they find is going to be true in the other sex.”
In 2011 health researcher Annaliese Beery at the University of California, San Francisco, and biologist Irving Zucker at the University of California, Berkeley, published a study looking into sex biases in animal research in one sample year: 2009. Of the ten scientific fields they investigated, eight showed a male bias. In pharmacology, the study of medical drugs, the articles reporting only on males outnumbered those reporting only on females by five to one. In physiology, which explores how our bodies work, it was almost four to one.
It’s an issue that runs through other corners of science, too. In research on the evolution of genitals (parts of the body we know for certain are different between the sexes), scientists have also leaned toward males. In 2014 biologists at Humboldt University in Berlin and Macquarie University in Sydney analyzed more than three hundred papers published between 1989 and 2013 that covered the evolution of genitalia. They found almost half looked only at the males of the species, while just 8 percent looked only at females. One reporter described it as “the case of the missing vaginas.”
When it comes to health research, the issue is more complicated than simple bias. Until around 1990, it was common for medical trials to be carried out almost exclusively on men. And there were some good reasons for this. “You don’t want to give the experimental drug to a pregnant woman, and you don’t want to give the experimental drug to a woman who doesn’t know she’s pregnant but actually is,” explains Arthur Arnold. The terrible legacy of women being given thalidomide for morning sickness in the 1950s proved to scientists how careful they need to be before giving drugs to expectant mothers. Thousands of children were born with disabilities before thalidomide was taken off the market.
“You take women of reproductive age off the table for the experiment, which takes out a huge chunk of them,” continues Arnold. A woman’s fluctuating hormone levels might also affect how she responds to a drug. Men’s hormone levels are more consistent. “It is much cheaper to study one sex. So if you’re going to choose one sex, most people avoid females because they have these messy hormones. . . . So people migrate to the study of males. In some disciplines it really is an embarrassing male bias,” he adds.
This tendency to focus on males, researchers now realize, may have harmed women’s health. “Although there were some reasons to avoid doing experiments on women, it had the unwanted effect of producing much more information about how to treat men than women,” Arnold explains. A 2010 book on the progress in tackling women’s health problems, cowritten by the Committee on Women’s Health Research that advises the National Institutes of Health (NIH), notes that autoimmune diseases—which affect far more women than men—remain less well understood than some other conditions. “Despite their prevalence and morbidity, little progress has been made toward a better understanding of those conditions, identifying risk factors, or developing a cure,” it states.
Another problem is that women may respond differently from men to certain drugs. Medical researchers in the mid-twentieth century often assumed this couldn’t be a problem. “There was a notion that women were more like little men,. . .that if this treatment works in men, it will work on women,” says Janine Clayton, director of the Office of Research on Women’s Health at the NIH in Washington, DC, which funds the vast majority of US health research.
We now know this isn’t necessarily true. In 2001 New Zealand–based dermatologist Marius Rademaker estimated that women are around one-and-a-half times as likely to develop an adverse reaction to a drug as men are. In 2000 the US Government Accountability Office looked at the ten prescription drugs withdrawn from the market since 1997 by the US Food and Drug Administration. Studying reported cases of adverse effects, it found that eight drugs posed greater health risks to women than to men. The withdrawn drugs included two appetite suppressants, two antihistamines, and one for diabetes. Four of these were simply given to many more women than men, but the other four showed these effects even when men took them in more equal numbers.
“You have to be concerned that there were serious-enough side effects, not just a minor side effect but a serious-enough adverse effect that resulted in the drug being withdrawn. I think that tells us that we’re only just seeing the tip of the iceberg of this issue,” Clayton tells me. This has become a huge concern for women’s health activists, particularly in the United States, and has been one mandate of the Office of Research on Women’s Health since 1990.
“As clinicians, we know very well that diseases show up differently in men and women. Every day, men and women present to the emergency room with different symptoms with the same condition,” adds Clayton. “So heart attacks, for example, have different symptoms. Our research has shown that women who are going to have a myocardial infarction [heart attack] are more likely to have symptoms like insomnia, increasing fatigue, pain anywhere in the head all the way down to the chest, the weeks before they have a heart attack. Whereas men are less likely to have those symptoms and are more likely to present with the classic crushing chest pain.” Given differences like these, she believes that excluding women from drug trials for so many years must have affected their health. “It’s certainly a real possibility that the reason there are more adverse events in women than in men is because the whole process of drug discovery is tremendously biased towards the male,” agrees Kathryn Sandberg, who researches sex differences in health, aging, and disease.
Again, though, this line of thinking risks drawing divisions between women and men when the picture of disease is far more complicated. While there’s a clear benefit to better understanding women’s bodies and having drugs that suit both sexes, the emphasis on sex difference starts to make it seem as though women’s bodies are from Venus and men’s bodies are from Mars. “Given the well-documented history of methodological problems with sex difference research, as well as harmful abuses of sex difference claims by those who would limit women’s opportunities, it is remarkable to find women’s health activists promoting, with little qualification, sex-based biology’s expansive picture of sex differences,” writes Harvard social scientist Sarah Richardson in her book Sex Itself.
But does it have to be one or the other? Is the only alternative to women being thought of as “little men” to have them treated as an entirely different kind of patient? As more detailed research is done, it’s becoming clear that seeing some variation between women and men when it comes to health and survival doesn’t mean we should ditch the notion that our bodies are in fact similar in many ways, too.
This is the cautionary tale of two drugs.
The first is digoxin, which has long been used to treat heart failure. In 2002 researchers at Yale University School of Medicine decided to take a look at the data around digoxin,
analyzing its effects by sex. Between 1991 and 1996, researchers had carried out randomized trials on heart patients using digoxin. They found that it didn’t affect how long a patient lived, but it did on average reduce their risk of hospitalization. But the Yale team noted that the drug was tested on roughly four times as many men as women, and they didn’t respond identically. A slightly higher proportion of women taking digoxin died earlier than those taking a placebo. For men, the gaps between those taking the drug and the placebo group were much smaller. The sex difference, they concluded, “would have been subsumed by the effect of digoxin therapy among men.”
But science never stands still. The Yale University result later turned out to be not what it seemed. More recent studies, including one with a much larger sample group published in the British Medical Journal in 2012, have suggested that in fact there isn’t a substantially increased risk of death for women from digoxin use at all.
The second example is the insomnia drug zolpidem, commonly sold in the United States under the brand name Ambien. Sleeplessness is big business for pharmaceutical companies. Around sixty million sleeping pills were prescribed in the United States in 2011, up from forty-seven million just five years earlier, according to data collected by the health-care intelligence company IMS Health. And Ambien is among the most popular. Its side effects, however, include severe allergic reactions, memory loss, and the possibility of it becoming habit forming. The effects of zolpidem can also last longer than one night, leading to drowsiness the following day, which can in some cases make it dangerous to drive. Long after it was approved for market, research emerged that women given the same dose as men were more likely to suffer morning drowsiness. Eight hours after taking zolpidem, 15 percent of women but only 3 percent of men had enough of the drug in their system to raise their risk of a driving accident.