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WOMEN generally outlive men and are less susceptible to certain illnesses 鈥� including covid-19, it now appears. Why health outcomes are so is unclear. But Sharon Moalem, a doctor and genetic researcher based in New York, thinks he has the answer. It isn鈥檛 because women tend to go to the doctor more or have healthier habits, he says. Instead, it鈥檚 because they are typically better equipped, genetically speaking.

In humans, sex is largely determined by chromosomes, the bundles of tightly coiled DNA that carry our genes. The cells of most women possess two X chromosomes while most men have one X and one Y. So that women鈥檚 cells don鈥檛 have to carry two versions of each gene on the X chromosome, one from each X, one of the Xs is mainly switched off. It appears that which one stays active in which cells is chosen seemingly at random some time during the first few weeks of pregnancy. The result is that half a women鈥檚 cells generally use the X chromosome she inherited from her mother, while the other half use the one from her father.

It has long been known that if one X has a harmful mutation, cells that use the other X can compensate. That鈥檚 why, for instance, women are less likely to be colour-blind; a gene important for eye function resides on the X chromosome. Yet Moalem argues that the benefits are far more significant than this alone. He makes the case that even if there is no obviously harmful mutation, women tend to be at an advantage by having bodies made up of two populations of genetically different cells, and that this begins even before birth. He believes this is the reason why women are less vulnerable to certain congenital disorders and better at fighting off infections 鈥� including the coronavirus. As he sees it, women are simply genetically superior. Having two copies of an X chromosome has far more benefits than we realised, and serious implications for medicine.

Clare Wilson: How can women be the stronger sex, when we are generally smaller and physically weaker?

Sharon Moalem: All those things are true 鈥� on average, males have more muscle mass. But I am talking about genetic superiority, and the parameter is survival. We see the consequences in many areas of medicine. When you look at supercentenarians, those over the age of 110, they are 95 per cent female.

But it isn鈥檛 just making it to old age 鈥� females have a survival advantage over the life course. When I was a physician at a neonatal intensive care unit, I saw that more girls make it to their first birthday than boys. And I was seeing lower rates of congenital malformations like tongue-tie and clubfoot. Anything that鈥檚 biologically difficult to form, females do better.

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How is this connected to the X chromosome?

Because there are about a thousand genes on the X. Mammalian females have two populations of cells that are active within them; they are really mosaics in this way. Males have just one copy of the X so they aren鈥檛 mosaics. In females, those two populations build their bodies during fetal life. They cooperate and share not just genetic materials with one another, but proteins and enzymes, which give extra ability to handle disease. While the embryo is developing, you have an immense amount of cell multiplication where cells grow and divide into two, so the cells that have a growth advantage will be the ones that dominate in that tissue. Even in tissues that are initially divided 50:50 between two Xs, that seems to change over the life course; they can skew. If there鈥檚 injury in the skin, for example, and the skin is healing, you can have one population of healing cells taking over. It seems that when their function within the healing is complete, it eventually goes back down to 50:50. Men just have to cope with the genes on their one X.

How might this process affect other parts of the body?

Everywhere we have looked in the body, there can be skewing. In a woman鈥檚 body, if the cells in the heart that carry her father鈥檚 X can survive lack of oxygen during a heart attack, it will be that population that survives. We see that benefit in many parts of the body, including the liver and the kidneys. The toxic compounds that we can鈥檛 withstand or get rid of will kill our cells. The cells with the X genes that can better withstand those toxins outcompete the others.

How does it affect resistance to infections?

Our first understanding of this was with the immune system because it鈥檚 easy to tap 鈥� you just take out some blood. The X is rich in immune-related genes. If a population of a certain kind of immune cell does a better job using genes from the X from the father, that cell population will shift, so you might have 80 or 90 per cent of those cells using the X from the father.

And you believe that鈥檚 why women tend to cope better with the coronavirus?

Yes. There鈥檚 an important group of genes on the X that encode a receptor called toll-like receptor 7 (TLR7), which helps cells recognise single-stranded RNA viruses, such as the coronavirus. Women have two populations of immune cells, each one using a different version of TLR7 to recognise coronavirus. Another interesting layer is that the coronavirus uses a protein on our cells called ACE2 to enter our cells. The gene for ACE2 just happens to be on the X chromosome. Right from the get-go, females have an advantage.

What about behavioural reasons proposed for the female survival advantage in covid-19?

The first explanation I heard from some of my colleagues was that males don鈥檛 wash their hands 鈥� which is nonsense when you see data that says more women are infected than men, and yet more men die. The other thing was that everyone rushed to say it鈥檚 smoking. About 50 per cent of males in China smoke, and about 3 per cent of females smoke. But when you start looking at other countries 鈥� in the US, for example, the rate for male smoking is about 15 per cent, for females 13 per cent 鈥� you still see the same pattern of higher male deaths.

We rush to use behaviour as an explanation because we are told that the biggest differences between the sexes is behaviour. When I started my career, I was told that the reason we see so many more females at the end of life is because more men smoke and drink, and they take risks. All those things may be true, but it鈥檚 ignoring the fact that more girls make it to their first birthday. Girls who have asphyxia at birth do better cognitively as well. It鈥檚 hard to argue that the sexes鈥� behaviours are different in the incubator.

But two X chromosomes don鈥檛 always confer an advantage. Don鈥檛 women have higher rates of autoimmune conditions, where the immune system mistakenly attacks healthy cells?

Yes, the female immune system is more aggressive than the male immune system. Part of that鈥檚 because female hormones called oestrogens stimulate the immune system, while in males, testosterone inhibits it. But what鈥檚 interesting is that even before puberty, autoimmunity is still higher in females. The explanation could be the X chromosome.

In both sexes, in the fetus, thyroid gland immune cells usually go through an 鈥渆ducational process鈥�, where if immune cells recognise other cells from the person鈥檚 own body, the immune cells self-destruct. That鈥檚 to make sure that once the baby is born, autoimmunity doesn鈥檛 happen. The process works relatively well in males. But females, who have two genetically different cell populations, are more likely to fail at destroying all the self-recognising cells. Coming out of the thymus, female immune cells are more likely to recognise their own cells as 鈥渇oreign鈥�. That sets up the perfect storm for autoimmunity.

That鈥檚 a down side of having two X chromosomes?

Yes, but there鈥檚 also an advantage of having a somewhat autoreactive immune system. Many microbes invade and escape detection in the body because they resemble human cells. Females have a better ability to be able to discern this kind of wolf in sheep鈥檚 clothing because they keep cells that are more likely to attack things that resemble themselves. So women have higher rates of autoimmune diseases, like rheumatoid arthritis, lupus, multiple sclerosis. But if it helps you survive covid-19, that鈥檚 the benefit.

Are there any other benefits to a stronger immune system?

More work is needed on this, but perhaps the propensity to autoimmunity is one of the explanations for females having a lower chance of certain cancers. Malignancies begin with our own healthy cells. The possible benefit of having an immune system that鈥檚 more geared to attack your own cells is that you are clearing pre-malignant cells before they are detectable medically.

Couldn鈥檛 that difference also be due to behavioural reasons, like men smoking and drinking more?

Yes, but I believe that that pattern holds true for certain cancers that start before puberty. The major differences in behaviour begin after puberty. But, there鈥檚 no way to know for sure.

If these differences between the sexes are so widespread, why haven鈥檛 we heard of them before?

When you see a six-foot-four man who is an Olympic weight-lifter and you try to say that they don鈥檛 have a survival advantage over a five-foot-three woman, it鈥檚 difficult to understand the difference between biological strength and physical strength. Plus, there鈥檚 resistance to any new paradigm. The current paradigm is that most of the health differences that we are seeing between men and women are behavioural; it鈥檚 very hard for people to let go of behaviour.

My lightbulb moment was in a neonatal intensive care unit. Although I was taught that the difference between the sexes was behaviourally based, I was seeing that it seemed to be driven by biology.

鈥淚t鈥檚 hard to argue that the sexes鈥� behaviour is different in the incubator鈥�

Why does it matter?

Because we need to understand the basis for the biological differences between men and women, in terms of disease susceptibility and sensitivity to medications. In general, drugs are metabolised slower in women, and their gut transit time is slower so women have to wait longer after eating to have an empty stomach. But if people go to their physicians, sex is never considered as a dosing variable and there is no requirement for drug approvals to recognise sex-based differences.

Melanoma kills twice as many young men as women. It鈥檚 a classic example of where we blame men for behaviour: using less sun screen, not going to their doctor. Yet the differences in melanoma risk are actually biological. Women are more protected thanks to stronger immune response and We should be investing in screening for men at a much earlier age. We need to stop treating men and women as if they are biologically the same.