War in the Womb by Suzanne SadedinA ferocious biological struggle between mother and baby belies any sentimental ideas we might have about pregnancy
What sight could be more moving than a mother nursing her baby? What better icon could one find for love, intimacy and boundless giving? There’s a reason why the Madonna and Child became one of the world’s great religious symbols.
To see this spirit of maternal generosity carried to its logical extreme, consider Diaea ergandros, a species of Australian spider. All summer long, the mother fattens herself on insects so that when winter comes her little ones may suckle the blood from her leg joints. As they drink, she weakens, until the babies swarm over her, inject her with venom and devour her like any other prey.
You might suppose such ruthlessness to be unheard-of among mammalian children. You would be wrong. It isn’t that our babies are less ruthless than Diaea ergandros, but that our mothers are less generous. The mammal mother works hard to stop her children from taking more than she is willing to give. The children fight back with manipulation, blackmail and violence. Their ferocity is nowhere more evident than in the womb.
This fact sits uncomfortably with some enduring cultural ideas about motherhood. Even today, it is common to hear doctors talking about the uterine lining as the ‘optimal environment’ for nurturing the embryo. But physiology has long cast doubt on this romantic view.
The cells of the human endometrium are tightly aligned, creating a fortress-like wall around the inside of the uterus. That barrier is packed with lethal immune cells. As far back as 1903, researchers observed embryos ‘invading’ and ‘digesting’ their way into the uterine lining. In 1914, R W Johnstone described the implantation zone as ‘the ﬁghting line where the conﬂict between the maternal cells and the invading trophoderm takes place’. It was a battlefield ‘strewn with... the dead on both sides’.
When scientists tried to gestate mice outside the womb, they expected the embryos to wither, deprived of the surface that had evolved to nurture them. To their shock they found instead that – implanted in the brain, testis or eye of a mouse – the embryo went wild. Placental cells rampaged through surrounding tissues, slaughtering everything in their path as they hunted for arteries to sate their thirst for nutrients. It's no accident that many of the same genes active in embryonic development have been implicated in cancer. Pregnancy is a lot more like war than we might care to admit.
So if it’s a fight, what started it? The original bone of contention is this: you and your nearest relatives are not genetically identical. In the nature of things, this means that you are in competition. And because you live in the same environment, your closest relations are actually your most immediate rivals.
It was Robert Trivers, in the 1970s, who first dared to explore the sinister implications of this reality in a series of influential papers. The following decade, a part-time graduate student named David Haig was musing over Trivers’s ideas when he realised that the nurturing behaviour of mammal mothers creates a particularly excellent opportunity for exploitation.
It is in your mother’s genetic interests, Haig understood, to provide equally for all her children. But your father might never have another child with her. This makes her other children your direct competitors, and also gives your father’s genes a reason to game the system. His genome would evolve to manipulate your mother into providing more resources for you. In turn, her genes would manoeuvre to provide you with fewer resources. The situation becomes a tug-of-war. Some genes fall silent, while others become more active, counterbalancing them.
Even with the help of modern medicine, pregnancy still kills about 800 women every day worldwide
That insight led Haig to found the theory of genomic imprinting, which explains how certain genes are expressed differently depending on whether they come from your father or your mother. Armed with this theory, we can see how conflicts of genetic interest between parents play out within the genomes of their offspring.
Because both parental genomes drive each other to keep ramping up their production of powerful hormones, should one gene fail, the result can be disastrous for both mother and infant. Normal development can proceed only as long as both parental genotypes are correctly balanced against one another. Just as in a tug-of-war, if one party drops its end, both fall over. This is one reason why mammals cannot reproduce asexually, and why cloning them is so difficult: mammalian development requires the intricate co-ordination of paternal and maternal genomes. A single misstep can ruin everything.
Diaea ergandros, the ultimate mother, doesn’t have to worry about this, of course. She will never have more than one brood, so there is no need for her to restrain her offspring. But most mammal mothers breed more than once, and often with different males. This fact alone ensures that the paternal and maternal genomes work against one another. You can see the tragic consequences of this hidden war throughout the class Mammalia. Yet there is one species where it ascends to really mind-boggling heights of bloodiness.
For most mammals, despite the underlying conflict, life goes on almost as normal during pregnancy. They flee from predators, capture prey, build homes and defend territories – all while gestating. Even birth is pretty safe: they might grimace or sweat a bit during labour, but that’s usually the worst of it. There are exceptions. Hyena mothers, for example, give birth through an impractical penis-like structure, and about 18 per cent of them die during their first delivery. But even for them, pregnancy itself is rarely perilous.
If we look at primates, however, it’s a different story. Primate embryos can sometimes implant in the Fallopian tube instead of the womb. When that happens, they tunnel ferociously towards the richest nutrient source they can find; the result is often a bloodbath. And among the great apes, things look even dicier. Here we start to see perhaps the most sinister complication of pregnancy: preeclampsia, a mysterious condition characterised by high blood pressure and protein discharge in the urine. Preeclampsia is responsible for around 12 per cent of human maternal deaths worldwide. But it’s very much just the start of our problems.
The mother is a despot: she provides only what she chooses
A list of the reproductive ills that afflict our species might start with placental abruption, hyperemesis gravidarum, gestational diabetes, cholestasis and miscarriage, and carry on from there. In all, about 15 per cent of women suffer life-threatening complications during each pregnancy. Without medical assistance, more than 40 per cent of hunter-gatherer women never reach menopause. Even with the help of modern medicine, pregnancy still kills about 800 women every day worldwide.
So, we have a bit of a mystery here. The basic genetic conflict that makes the womb such a battle zone crops up across innumerable species: all it takes for war to break out is for mothers to have multiple offspring by different fathers. But this is quite a common reproductive arrangement in nature, and as we saw, it doesn’t cause other mammals so many problems. How did we humans get so unlucky? And does it have anything to do with our other extraordinary feature – our unparalleled brain development?
In most mammals, the mother’s blood supply remains safely isolated from the foetus. It passes its nutrients to the foetus through a filter, which the mother controls. The mother is a despot: she provides only what she chooses, which makes her largely invulnerable to paternal manipulation during pregnancy.
In primates and mice, it’s a different story. Cells from the invading placenta digest their way through the endometrial surface, puncturing the mother’s arteries, swarming inside and remodelling them to suit the foetus. Outside of pregnancy, these arteries are tiny, twisty things spiralling through depths of the uterine wall. The invading placental cells paralyse the vessels so they cannot contract, then pump them full of growth hormones, widening them tenfold to capture more maternal blood. These foetal cells are so invasive that colonies of them often persist in the mother for the rest of her life, having migrated to her liver, brain and other organs. There’s something they rarely tell you about motherhood: it turns women into genetic chimeras.
Perhaps this enormous blood supply explains why primates have brains five to ten times larger than the average mammal. Metabolically speaking, brains are extremely expensive organs, and most of their growth occurs before birth. How else is the fetus to fund such extravagance?
Is this unfettered access to maternal blood the key to the extraordinary brain development we see in young primates?
Given the invasive nature of pregnancy, it’s perhaps not surprising that the primate womb has evolved to be wary of committing to it. Mammals whose placentae don’t breach the walls of the womb can simply abort or reabsorb unwanted foetuses at any stage of pregnancy. For primates, any such manoeuvre runs the risk of haemorrhage, as the placenta rips away from the mother’s enlarged and paralysed arterial system. And that, in a sentence, is why miscarriages are so dangerous.
It’s also why primates make every effort to test their embryos before they allow them to implant. The embryo is walled out by the tight-packed cells of the endometrium, while an intimate hormonal dialogue takes place. This conversation is, in Haig’s words, a ‘job interview’. Should the embryo fail to convince its mother that it is a perfectly normal, healthy individual, it will be summarily expelled.
How does an embryo convince its mother that it is healthy? By honestly displaying its vigour and lust for life, which is to say, by striving with all its strength to implant. And how does the mother test the embryo? By making the embryo’s task incredibly difficult. Just as the placenta has evolved to be aggressive and invasive, the endometrium has evolved to be tough and hostile. For humans, the result is that half of all human pregnancies fail, most at the implantation stage, so early that the mother may not even realise she was pregnant.
Embryonic development becomes a trial of strength. And this leads to another peculiarity of the primate reproductive system – menstruation. We have it for the simple reason that it’s not such an easy matter to dispose of an embryo that is battling to survive. The tissues of the endometrium are partially insulated from the mother's bloodstream, protecting her circulatory system from invasion by a placenta she has not yet decided to accept. But that means her own hormonal signals can struggle to be heard inside the womb. So, rather than risk corruption of the endometrial tissue and ongoing conflict with an embryo, what does the mother do? She just sloughs off the whole endometrium after each ovulation. This way, even the most aggressive embryo has to have her agreement before it can get comfortable. In the absence of continual, active hormonal signalling from a healthy embryo, the entire system auto-destructs. Around 30 per cent of pregnancies end this way.
I said that the mother struggles to pass hormonal signals into the womb. The thing is, once the embryo implants, it gets full access to her tissues. This asymmetry means two things. Firstly, the mother can no longer control the nutrient supply she offers the foetus – not without reducing the nutrient supply to her own tissues. Is this unfettered access to maternal blood the key to the extraordinary brain development we see in young primates? Fascinatingly, the intensity of the invasion does seem to correlate with brain development. Great apes, the largest-brained primates, seem to experience deeper and more extensive invasion of the maternal arteries than other primates. In humans – the largest-brained ape of all – placental cells invade the maternal bloodstream earlier even than in other great apes, allowing the foetus unprecedented access to oxygen and nutrients during early development. This would be one of evolution’s little ironies: after all, if it wasn't for the cognitive and social capacities granted by our big brains, many more of us would die from the rigours of our brutal reproductive cycle. One can imagine how the two traits might have arisen in tandem. But the connection remains speculative. Uteri rarely fossilise, so the details of placental evolution are lost to us.
The second major consequence of the foetus’s direct access to maternal nutrients is that the foetus can also release its own hormones into the mother’s bloodstream, and thus manipulate her. And so it does. The mother counters with manipulations of her own, of course. But there is a strong imbalance: while the foetus freely injects its products into the mother’s blood, the mother is granted no such access to foetal circulation. She is walled out by placental membranes, and so her responses are limited to defensively regulating hormones within her own body.
As the pregnancy continues, the foetus escalates its hormone production, sending signals designed to increase the mother’s blood sugar and blood pressure and thus its own resource supply. In particular, the foetus increases its production of a hormone that prompts the mother’s brain to release cortisol, the primary stress hormone. Cortisol suppresses her immune system, stopping it from attacking the foetus. More importantly, it increases her blood pressure, so that more blood pumps past the placenta and consequently more nutrients are available to the foetus.
The mother doesn’t take this foetal manipulation lying down. In fact, she pre-emptively reduces her blood sugar levels. She also releases a protein that binds to the foetal hormone, rendering it ineffective. So then the foetus further increases its production. By eight months, the foetus spends an estimated 25 per cent of its daily protein intake on manufacturing these hormonal messages to its mother. And how does the mother reply? She increases her own hormonal production, countering the embryo’s hormones with her own that decrease her blood pressure and sugar. Through all this manipulation and mutual reprisal, most of the time the foetus ultimately gets about the right amount of blood, and about the right amount of sugar, allowing it to grow fat and healthy in time for birth. This is the living instantiation of Haig’s tug-of-war between maternal and paternal genomes. As long as each side holds its end up, nobody gets hurt.
But what happens when things go wrong? Since the turn of the millennium, the Human Genome Project has provided a wealth of data, most of which remains incomprehensible to us. Yet by looking for signs of genomic imprinting – that is, genes that are expressed differently depending on whether they are inherited from the father or the mother – researchers have been able to pin down the genetic causes of numerous diseases of pregnancy and childhoods. Genomic imprinting, and the maternal-fetal battle behind it, have been shown to account for gestational diabetes, Prader-Willi Syndrome, Angelman Syndrome, childhood obesity and several cancers. Researchers suspect that it may also underlie devastating psychiatric conditions such as schizophrenia, bipolar disorder and autism. In 2000, Ian Morison and colleagues compiled a database of more than 40 imprinted genes. That number had doubled by 2005; by 2010, it had nearly doubled again. Identifying genetic mechanisms does not in itself provide a cure for these complex diseases, but it is a vital step towards one.
Preeclampsia, perhaps the most mysterious disease of pregnancy, turns out to be a particularly good example of the way in which the evolutionary, genetic and medical pictures are all lining up. More than two decades ago, Haig suggested that it resulted from a breakdown in communication between mother and foetus. In 1998, Jenny Graves expanded on this idea, suggesting that it could be explained by failure of imprinting on a maternally inherited gene. It’s only in the past few years, however, that we’ve pieced together how this process occurs.
This story shows how, with the help of evolutionary theory, we are at last starting to make sense of the grim, tangled mess that is human development
So, picture the foetus tunnelling towards the mother’s bloodstream. All else being equal, the arterial expansion of early pregnancy would cause the mother’s blood pressure to drop. Foetal hormones counter this effect by raising her blood pressure.
Several hormones are involved when the maternal arteries expand during early pregnancy. If these chemicals get out of balance, those arteries can fail to expand, starving the foetus of oxygen. If that happens, the foetus sometimes resorts to more extreme measures. It releases toxins that damage and constrict the mother’s blood vessels, driving up blood pressure. This risks kidney and liver damage, if not stroke: the symptoms of preeclampsia.
In 2009, researchers showed that the maternally inherited gene H19 is strongly associated with the disease. This was just as Jenny Graves predicted. H19 is known to be crucial to early growth of the placenta. Changes in several other maternally inherited genes, and some paternally inherited ones, are also suspected of being involved. There’s a lot that has yet to be discovered, but this story shows how, with the help of evolutionary theory, we are at last starting to make sense of the grim, tangled mess that is human development.
Our huge brains and our traumatic gestation seem intimately connected; at the very least, they are both extraordinary features of humanity. Did the ancients guess this connection when they crafted their mythologies? Perhaps the story of Eve, cursed with the sorrows of pregnancy when she ‘ate the fruit of the tree of knowledge’, was once just an intuitive explanation for the cruelty that nature saw fit to visit on our species. Be that as it may, if we want to reduce the danger and suffering of pregnancy, the only way out is through. We need more knowledge – lots of it.
4 August 2014