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

Elsewhere, child mortality statistics bear this out. For every thousand live births in sub-Saharan Africa, ninety-eight boys compared with eighty-six girls die by the age of five. Research Lawn and her colleagues published in the journal Pediatric Research in 2013 confirmed that a boy is 14 per cent more likely to be born prematurely than a girl, and is more likely to suffer disabilities ranging from blindness and deafness to cerebral palsy when he’s at the same stage of prematurity as a girl. In the same journal in 2012 a team from King’s College London reported that male babies born very prematurely are more likely to stay longer in hospital, to die, or to suffer brain and breathing problems.

‘I always thought that it was physically mediated, because boys are slightly bigger, but I think it’s also biological susceptibility to injury,’ says Lawn. One explanation for more boys being born preterm is that mothers expecting boys are, for reasons unknown, more likely to have placental problems and high blood pressure. Research published by scientists from the University of Adelaide in the journal Molecular Human Reproduction in 2014 showed that newborn girls may be healthier on average because a mother’s placenta behaves differently depending on the sex of the baby. With female foetuses, the placenta does more to maintain the pregnancy and increase immunity against infections. Why this is, nobody understands. It could be because, before birth, the normal human sex ratio is slightly skewed towards boys. The difference after birth might simply be nature’s way of correcting the balance.

But the reasons could also be more complicated. After all, a baby girl’s natural survival edge stays with her throughout her entire life. Girls aren’t just born survivors, they grow up to be better survivors too.

‘Pretty much at every age, women seem to survive better than men,’ confirms Steven Austad, chair of the biology department at the University of Alabama at Birmingham, who is an international expert on ageing. He describes women as being more ‘robust’. It’s a phenomenon so clear and undeniable that some scientists believe understanding it may hold the key to human longevity.

At the turn of the millennium, Austad began to investigate exactly what it is that helps women outlive men at all stages of life. ‘I wondered if this is a recent phenomenon. Is this something that’s only true in industrialised countries in the twentieth century and twenty-first century?’ Digging through the Human Mortality Database, a collection of longevity records from around the world founded by German and American researchers in 2000, he was surprised to discover that the phenomenon really does transcend time and place.

The database now covers thirty-eight countries and regions. Austad’s favourite example is Sweden, which has kept some of the most thorough and reliable demographic data of any country. In 1800 life expectancy at birth in Sweden stood at thirty-three years for women and thirty-one for men. In 2015 it was around eighty-three for women and around seventy-nine for men. ‘Women are more robust than men. I think there’s little doubt about that,’ Austad says. ‘It was true in the eighteenth century in Sweden, and it’s true in the twenty-first century in Bangladesh, and in Europe, and in the US.’

I ask Austad whether women might be naturally outliving men for social reasons. It’s reasonable to think, for instance, that boys are generally handled more roughly than girls are. Or that more men than women take on risky jobs, such as construction and mining, which also expose them to toxic environments. And we know that in total across the world, far more men than women smoke, which dramatically pushes up mortality rates. But Austad is convinced that the difference is so pronounced, ubiquitous and timeless that it must mean there are features in a woman’s body that underlie the difference. ‘It’s hard for me to imagine that it is environmental, to tell you the truth,’ he says.

The picture of this survival advantage is starkest at the end of life. The Gerontology Research Group in the United States keeps a list online of all the people in the world that it has confirmed are living past the age of 110. I last checked the site in July 2016. Of all these ‘supercentenarians’ in their catalogue, just two were men. Forty-six were women.

Yet we don’t know why.

‘I’m absolutely puzzled by it,’ says Austad. ‘When I first started looking into this, I expected to find a huge literature on it, and I found virtually nothing. There’s a big literature on “Is this a difference between men and women?”, but the underlying biology of the survival difference, there’s very little on that. It’s one of the most robust features of human biology that we know about, and yet it’s had so little investigation.’

For more than a century, scientists have painstakingly studied our anatomy, even collected thousands of litres of horse urine in their attempts to isolate the chemicals that make men more masculine and women more feminine. Their search for sex differences has had no boundaries. But when it comes to why women might be more physically robust than men – why they are better survivors – research has been scarce. Even now, only scraps of work here and there point to answers.

‘It’s a basic fact of biology,’ observes Kathryn Sandberg, director of the Center for the Study of Sex Differences in Health, Aging and Disease at Georgetown University in Washington, DC, who has explored how much of a role disease has to play in why women survive. ‘Women live about five or six years longer than men across almost every society, and that’s been true for centuries. First of all, you have differences in the age of onset of disease. So, for example, cardiovascular disease occurs much earlier in men than women. The age of onset of hypertension, which is high blood pressure, also occurs much earlier in men than women. There’s also a sex difference in the rate of progression of disease. If you take chronic kidney disease, the rate of progression is more rapid in men than in women.’ Even in laboratory studies on animals, including mice and dogs, females have done better than males, she adds.

By picking through the data, researchers like her, Joy Lawn and Steven Austad have come to understand just how widespread these gaps are. ‘I assumed that these sex differences were just a product of modern Westernised society, or largely driven by the differences in cardiovascular diseases,’ says Austad. ‘Once I started investigating, I found that women had resistance to almost all the major causes of death.’ One of his papers shows that in the United States in 2010, women died at lower rates than men from twelve of the fifteen most common causes of death, including cancer and heart disease, when adjusted for age. Of the three exceptions, their likelihood of dying from Parkinson’s or stroke was about the same. And they were more likely than men to die of Alzheimer’s Disease.

When it comes to fighting off infections from viruses and bacteria, women also seem to be tougher. ‘If there’s a really bad infection, they survive better. If it’s about the duration of the infection, women will respond faster, and the infection will be over faster in women than in men,’ says Kathryn Sandberg. ‘If you look across all the different types of infections, women have a more robust immune response.’ It isn’t that women don’t get sick. They do. They just don’t die from these sicknesses as easily or as quickly as men do.

One explanation for this gap is that higher levels of oestrogen and progesterone in women might be protecting them in some way. These hormones don’t just make the immune system stronger, but also more flexible, according to Sabine Oertelt-Prigione, a researcher at the Institute of Gender in Medicine at the Charité University Hospital in Berlin. ‘This is related to the fact that women can bear children,’ she explains. A pregnancy is the same as foreign tissue growing inside a woman’s body that, if her immune system was in the wrong gear, would be rejected. ‘You need an immune system that’s able to switch from pro-inflammatory reactions to anti-inflammatory reactions in order to avoid having an abortion pretty much every time you get pregnant. The immune system needs to have mechanisms that can, on one side, trigger all these cells to come together in one spot and attack whatever agent is making you sick. But then you also need to be able to stop this response when the agent is not there any more, in order to prevent tissues and organs from being harmed.’

The hormonal changes that affect a woman’s immune system during pregnancy also take place on a smaller scale during her menstrual cycle, and for the same reasons. ‘Women have more plastic immune systems. They adapt in different ways,’ says Oertelt-Prigione. Many types of cell in the body are involved in immunity, but the kind that come into closest contact with viruses and bacteria are known as T cells. They inject substances into bacteria to kill them, or secrete other substances that call more cells to action, some of which ‘eat up’ infected cells and bacteria, like Pac-Man in the video game, she explains. Researchers know that a certain type of T cell that’s crucial to managing the body’s response to infections becomes more active in the second half of a woman’s menstrual cycle, when she’s able to get pregnant.

The discovery that sex hormones and immunity might be linked is fairly recent. In men, scientists have explored connections between testosterone and lower immunity, although the evidence is relatively thin. In 2014, for example, Stanford University researchers found that males with the highest levels of testosterone had the lowest antibody response to a flu vaccine, which meant they were the least likely to be protected by the jab. As yet, though, it’s an unsubstantiated link. In women, the connection is far clearer. So much so that patients themselves have noticed these fluctuations. For years, doctors assumed that a woman’s immunity didn’t change during her menstrual cycle. If she did report a difference in pain levels, doctors might dismiss it as premenstrual syndrome, or some vague psychological complaint. It was only when these links were increasingly backed up by hard research that scientific interest was sparked, and more research began to flourish.

This problem runs all the way through research into women’s health. If a phenomenon affects women, and only women, it’s all too often misunderstood. And this is compounded by the fact that even though they’re better at surviving, women aren’t healthier than men. In fact, quite the opposite.

‘If you could add up all the pain in the world, all the physical pain, I suspect that women have way, way more of it. This is one of the penalties of being a better survivor. You survive, but maybe not quite as intact as you were before,’ says Steven Austad. Statistically, this could explain why women seem proportionally sicker than men. ‘Part of the reason that there are more women than men around in ill health is to do with the fact that women have survived events that would kill men, and so the equivalent men are no longer with us.’

Another reason is that women’s immune systems are so powerful that they can sometimes backfire. ‘You start regarding yourself as foreign, and your immune system starts attacking its own cells,’ explains Kathryn Sandberg. Diseases caused in this way are known as autoimmune disorders. The most common include rheumatoid arthritis, lupus and multiple sclerosis. ‘It’s kind of a double-edged sword with the immune system. In some ways it’s better to have a female immune system if you’re fighting off infection of any kind, but on the other hand, we are more susceptible to autoimmune diseases, which are very problematic.’

This isn’t to say that autoimmune disease is always hardest on women. When men get multiple sclerosis, they tend to get it worse. Women also survive with it longer than men do. Even so, of the roughly 8 per cent of Americans who suffer from auto-immune diseases, estimates suggest that at least three-quarters are women.

‘In autoimmune diseases, they almost all tend to get worse right before the menstrual cycle in women who are premenopausal,’ says Sabine Oertelt-Prigione. In the same way that varying hormone levels may boost a woman’s immunity at different times of the month, there are theories that they might also affect her experience of illness. There are reports, for instance, that women with asthma are at highest risk of an attack just before or at the start of their period. As oestrogen and progesterone levels drop in the years following the start of the menopause, a woman’s immunity advantage starts to drop away as well.

When it comes to viral infections, too, a woman’s strong immune response may be a problem as well as a benefit. Research on influenza by Sabra Klein, an immunologist at the Johns Hopkins Bloomberg School of Public Health in Baltimore, has shown that while women are generally hit by fewer viruses during an infection, they tend to suffer more severe flu symptoms than men do. She reasons that this may be because women’s immune systems mount sturdier counter-attacks against viruses, but then suffer when the effects of these counter-attacks impact their own bodies.

Women also tend to get more painful joint and muscle diseases, observes Steven Austad. Part of this is down to autoimmune diseases that affect the joints, such as arthritis. The physical toll of childbearing and the hormonal changes of menopause may also leave women with physical problems and disabilities, especially in later life. Bone density is known to fall short-term after pregnancy, and after the menopause. Weight gain is now also recognised as a symptom of menopause.

But the overall picture of pain and ill-health is complicated. ‘Cross-culturally, women just report more physical limitations and more disabilities. It’s really widespread,’ says Austad. When it comes to biological clues about the underlying reasons for this sex difference in disease or survival, however, he adds, ‘I don’t feel very confident of any explanation.’

It’s difficult to tear apart biology from other effects. Society and the environment can sometimes impact illness more than a person’s underlying biology. ‘Women are less likely to go to the hospital when they’re feeling chest pain than men,’ says Kathryn Sandberg, who has looked at gender differences in heart disease in particular. There are countless other ways in which men’s and women’s health habits differ throughout the world. Sabine Oertelt-Prigione points out that where families eat collectively and food is scarce, women are sometimes the last to eat and are the most likely to go without food, which can raise their risk of malnutrition. This in turn can affect their susceptibility to disease.

Not only a woman’s own behaviour, but that of others around her, can affect her health. From the second a girl is born, she’s placed in a different box from a boy. She may be handled differently, fed differently and treated differently. And this marks the beginning of a lifetime of differences in the way doctors and medical researchers approach her as well. Only very recently, for instance, have doctors begun to acknowledge the severity of some women’s experience of period pain. In 2016, professor of reproductive health at University College London, John Guillebaud, told a reporter that period pain can be ‘almost as bad as having a heart attack’, and admitted that it hasn’t been given the attention it deserves, partly because men don’t suffer from it. In 2015, a team of British researchers studying cancer diagnosis in the UK found that it took longer for women to be diagnosed after going to a doctor in six of the cancers that affect both men and women, including bladder and lung. For gastric cancer, a woman waited on average a full two weeks longer for a diagnosis.

If there are underlying biological sex differences in health, and the differences aren’t largely down to society and culture, then scientists need to go deeper inside the body to find them.

‘Females get sicker but males die quicker,’ says Arthur Arnold, a professor at the University of California, Los Angeles. It’s an old adage, bandied among his undergraduates. It reflects what doctors all over the world have observed, and Arnold is convinced that it reveals the long roots of sex differences in health. He runs a laboratory studying the biological factors that make females different from males, and edits the journal Biology of Sex Differences. His work has taken him beyond looking at organs and sex hormones, and down to the fundamental level of the gene.

The human body is made up of trillions of cells. Every one of them has genetic information stored in packages known as chromosomes, explaining to our bodies how to build themselves up from the subtlest hormones all the way up to skin and bone. We have forty-six chromosomes in total, split into twenty-three pairs, and the roots of the genetic differences between men and women lie in our twenty-third pair, known as the sex chromosomes. In women, they’re called XX, with one X chromosome inherited from each parent. Men’s sex chromosomes are called XY, with the X coming from the mother and the Y from the father. For a long time it was assumed that these sex chromosomes were mainly concerned with reproduction and not much else. Today some scientists, including Arnold, believe that the consequences of this seemingly tiny genetic difference may stretch much further.

Every chromosome in a pair carries the same genes in the same locations, known as alleles. The one for eye colour from a person’s father, for example, will be matched by another one for eye colour in the same place from the mother. That’s true of a female’s two X chromosomes too. For males with XY sex chromosomes, however, a matching allele isn’t always there. X and Y don’t have the same genes in the same locations. In fact, the Y is far smaller than the X.

Having just one copy of the genes 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 of her 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.’

There are some well-known genetic traits to which men are more susceptible than women simply because they have one X chromosome. These X-linked disorders include red-green colour blindness, haemophilia, muscular dystrophy and IPEX syndrome, which affects immune function. Mental retardation, which affects 2 to 3 per cent of people in developed countries, and significantly more men than women, also has a strong link to the X chromosome.

This is a reason why, in the effort to understand sex differences in health, Arthur 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 fertilisation 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 Steven Austad. ‘But I think there are a lot more X-linked diseases than we think about. I think 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.

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.