Inferior: How Science Got Women Wrong – and the New Research That’s Rewriting The Story. Angela Saini

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      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.’

      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 of the 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 un-inactivated genes to discover that they comprise 15 per cent of genes on the second X. ‘We are now looking at huge datasets 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 distil the impact of the X chromosome from all the other factors that can 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 haemophilia 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, Arthur Arnold and his team have used a special kind of laboratory animal, one with absolutely no difference between its males and females except for the number of X chromosomes they have. In nature, these creatures don’t exist. But by using genetic modification, scientists can come close to building them. Since sex hormones have the most obvious impact on male and female bodies before birth (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 you remove their gonads. But animals with two X chromosomes get a lot fatter than those with just one. This 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,’ says Arnold. ‘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.

      The take-home message from this research 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 Series 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 Sabine 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 go further. 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. ‘The same may be said of genetic research on sex and gender.’ Arthur 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 suggests that even though the sex chromosomes are only one of the twenty-three pairs of chromosomes we have, their effects are wide-ranging.

      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 on 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 around just how deep the dividing line is between women and men continues to rage inside the scientific community. It has been fuelled most recently by anger over exactly the opposite problem: the habit in medical research of leaving women out of tests for new drugs, because their bodies are thought to be so similar to men’s.

      ‘It’s 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 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. And to me that just typifies the fact that 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 towards males. In 2014 biologists at Humboldt University in Berlin and Macquarie University in Sydney analysed more than three hundred papers published between 1989 and 2013 that covered the evolution of genitalia. They found that almost half looked only СКАЧАТЬ