Inferior: How Science Got Women Wrong – and the New Research That’s Rewriting The Story
Год издания: 2018 год
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Females Get Sicker But Males Die Quicker (#u0bc67060-a13d-5f77-853b-86359a55f230)
The evidence is clear: from the constitutional standpoint woman is the stronger sex.
Ashley Montagu, The Natural Superiority of Women (1953)
‘It’s wonderful,’ says Mitu Khurana, a hospital administrator living in New Delhi. ‘When you have your first pregnancy, everyone is very excited. It is a feeling beyond description.’
The time she’s so fondly remembering was a decade ago. She had become pregnant with twins just a few months after getting married, and she assumed that nothing could ruin her happiness. Raised in a family of sisters, Mitu didn’t care whether she was having boys or girls, or one of each. ‘I just wanted the children to be healthy,’ she tells me.
But her husband and his family didn’t feel the same way. They wanted sons.
So begins a common story. It’s one that has been repeated in millions of homes across India, China and other parts of South Asia, where cultures unashamedly prize sons above daughters. They are cultures, as Mitu learned all those years ago, that will sometimes go to terrible lengths to stop a girl from even being born. Some women keep having children until they finally have a boy. Others are pressured to abort female foetuses, even to the point of torture. If they do make it to the day of their birth, many female babies and young girls are routinely treated worse than boys. In the most appalling cases, they are killed. In 2007, police in Orissa in the east of India found skulls and body parts of what they believed to be three dozen female foetuses and infants down a disused well. A news report in 2013 described a baby buried alive in a forest in the central state of Madhya Pradesh. Another in 2014 told of a newborn in Bhopal dumped in a rubbish bin.
That year, a United Nations report described the problem as having reached emergency levels. India’s 2011 census had already revealed that there were more than seven million fewer girls than boys aged six and under. The overall sex ratio was more skewed in favour of boys than it had been a decade ago. Part of the reason was the growing availability of prenatal scans, which for the first time allowed parents to find out the sex of their babies easily, and early enough to have selective abortions.
In 1994 the Indian government outlawed sex selection tests, but unscrupulous independent clinics and doctors still offer them for a fee, in private and under the radar. Mitu never wanted to have one of these prenatal scans, she tells me. But in the end, she wasn’t given the choice. During her pregnancy, she claims she was tricked into eating some cake that contained egg, to which she is allergic. Her husband, a doctor, then took her to a hospital, where a gynaecologist advised her to have a kidney scan under sedation. It was then, she believes, that her husband found out the sex of her unborn babies without her consent or knowledge.
‘I knew it from his behaviour that I’m getting daughters,’ she explains. He and his family immediately began pressing her to have an abortion. ‘There was a lot of pressure.’ She says she was denied food and water, and was once pushed down the stairs. Desperate and frightened, Mitu went to stay with her parents, and eventually gave birth to her daughters there.
She managed to save her girls. But things didn’t change. ‘They were not at all warm,’ she recalls of her husband and his family’s attitude towards her daughters. A few years later she stumbled on an old hospital report revealing the sex of her foetuses. She read it as proof that her husband had indeed carried out an ultrasound scan on her while she was pregnant, without her consent. As a result of that discovery she launched a legal case against both him and the hospital, which is still making its way through the notoriously slow Indian courts at the time I interview her, ten years after the birth of her daughters. Her husband and the hospital have both strongly denied her allegations.
Now long-separated from her husband and awaiting a divorce, Mitu has become famous in India for being among the first women to take this kind of legal action. Taking her campaign across the country has confirmed to her just how widespread a problem this is, blind to class or religion. ‘I’m fighting because I don’t want my daughters to go through this. Women are wanted as wives and girlfriends, but not as daughters,’ she says. ‘Society has to change.’
However well-hidden the selective abortions, murders and abuse of mothers and their daughters, the countrywide statistics don’t lie. Reality is laid bare in the grotesquely uneven sex ratios. The 2015 United Nations report The World’s Women says, ‘For those countries in which the sex ratio falls close to or below the parity line, it can be assumed that discrimination against girls exists.’
It is a situation familiar to Joy Lawn, director of the Centre for Maternal, Adolescent, Reproductive and Child Health at the London School of Hygiene and Tropical Medicine. ‘You go to hospitals in South Asia and there can be whole wards of kids with illnesses, and you will find 80 per cent of them are boys, because the girls aren’t being brought to the hospital,’ she tells me. A similar gender imbalance was uncovered in a 2002 study in Nepal by public health researchers Miki Yamanaka and Ann Ashworth, also from the London School of Hygiene and Tropical Medicine. They looked at how much work children are expected to do to support their families, and found that girls worked twice as long as boys, and that their work was also heavier.
The effects that society can have on gender differences are profound, and include the taking of life itself. What makes the mortality figures even more shocking is that, contrary to assumptions about women being the weaker sex, a baby girl is statistically more robust than a baby boy. She’s naturally better built to live. As scientists explore the female body in fuller detail, they are learning just how powerful a girl’s survival edge is – even in a world that doesn’t always want her.
‘Pretty much at every age, women seem to survive better than men.’
We often think of males as being the tougher and more powerful sex. It’s true that men are on average six inches taller and have around double the upper-body strength of women. But then, strength can be defined in different ways. When it comes to the most basic instinct of all – survival – women’s bodies tend to be better equipped than men’s.
The difference is there from the very moment a child is born.
‘When we were there on the neonatal unit and a boy came out, you were taught that, statistically, the boy is more likely to die,’ explains Joy Lawn. Besides her academic research into child health, she has worked in neonatal medicine in the United Kingdom and as a paediatrician in Ghana. The first month following birth is the time at which humans are at their greatest risk of death. Worldwide, a million babies die on the day of their birth every year. But if they receive exactly the same level of care, females are statistically less likely to die than males. Lawn’s research encompasses data from across the globe, giving the broadest picture possible of infant mortality. And having researched the issue in such depth, she concludes that boys are at around a 10 per cent greater risk than girls in that first month – and this is at least partly, if not wholly, for biological reasons.
Thus, in South Asia, as elsewhere in the world, the mortality figures should be in favour of girls. The fact that they’re not even equal, but are skewed in favour of boys, means that girls’ natural power to survive is being forcibly degraded by the societies they are born into. ‘If you have parity in your survival rates, it means you aren’t looking after girls,’ says Lawn. ‘The biological risk is against the boy, but the social risk is against the girl.’
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.
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