Some mammals, specifically marsupials such as the kangaroo and koala, have only a pseudo-placenta, which means that they must give birth at a very early stage of gestation. After that point, the embryo – looking something like squirming larva – crawls from the womb and finds its way to the pouch covering the mother’s nipples, where it can suckle milk. The joey continues to develop there, technically outside of the mother’s body, for many months. The pseudo-placenta in marsupials does not last long, nor is it very sophisticated.
The strange and complex approach to making babies in marsupial mammals reflects the strange and complex evolutionary history of the organ. In fact, the placenta has actually been ‘invented’ many times, in different families of animals. Fish have a version, in varying forms, and some sharks have a very advanced placenta, but no species have placentas quite like those found among mammals. Mammalian placentas are extremely complex and structurally diverse, with up to six layers that connect the mother with the developing embryo. Genes have arisen to adapt the mammalian placenta to a range of reproductive environments, to cater for situations as diverse as the twelve offspring expected after a mouse’s twenty-day gestation, to the lone calf that results from an elephant’s two-year pregnancy. How the placenta evolved to meet these needs, and everything in between, remains a mystery.
The last common ancestor of mammals, birds, and reptiles is likely to have had only the chorion, the outermost of a true placenta’s four layers, and a very basic one at that. Today, you can see a chorion when you peel a hard-boiled egg; it is the delicate layer that you find sticking to the shell, just inside. In modern birds and most reptiles, this thin, translucent membrane allows gases to be exchanged between the egg and the outside air. Our last common ancestor would also have had a yolk sac, which in modern birds, reptiles, marsupials, and some fish circulates nutrients to the developing embryo; it would also have had a primitive allantois, another sac-like tissue that gives rise to the blood vessels of the mammalian placenta as well as the umbilical cord. In chickens, the chorion and part of the allantois fuse together, forming a layer thick with blood vessels that pulls calcium from the eggshell to help nourish the embryo. In most marsupials, the allantois develops no blood vessels, since the embryo remains in the pseudo-placenta for only four or five weeks; instead it serves to store waste from the foetus’s kidneys, a critical job ensuring that the embryo doesn’t abort from toxicity. In other mammals, though, the allantois serves this purpose but is wound up in the wiring of the umbilical cord. Somehow it is these basic layers, the chorion and the allantois, that in mammals became the complex placenta.
Early in human development, after sperm meets egg and the DNA from father and mother have fused, the fertilized egg divides into two cells, as we saw in the last chapter. But the story is not as simple as that: the two cells are not equal. One of the cells is larger, and will continually and rapidly outgrow the other, as it divides over and over again. As the larger cell masses into a solid ball, it is surrounded by a flattened ring of tissue, constructed through the labour of the smaller, more slowly dividing cell. In nine months, it is the solid ball of cells that will be pulled screaming from the womb as a newborn child. The outer ring, called the trophoblast, will never become a part of the baby. It is the precursor of the placenta.
As the trophoblast grows into the life-support system for the embryo, in humans it will twice invade and destroy the lining of the mother’s womb. The first time happens within a week of conception. Fifteen weeks after conception, the second incursion occurs. This time the cells penetrate far deeper into the uterus, boring one-third of the way into the womb’s walls and entwining itself there in a structure that resembles a labyrinth, ensuring that nutrients can be leached from the mother in order to feed the foetus. A cycle of creation and destruction appears even here.
In primates, including humans, biologists believe that, over evolutionary time, the trophoblast gradually infiltrated the mother’s womb more and more deeply as the size of the foetal brain grows larger and larger. The brain, for instance, needs about sixty percent of the total nutrition supplied to a human foetus, compared with about twenty percent in non-primate mammal embryos. This may be why the human trophoblast invades the womb twice – something not seen in any other mammal.
The human placenta’s progressive and deep invasion into the womb poses a considerable challenge to the mother’s body. The mother’s immune system should protect her from infections and other foreign threats. But when she is pregnant, her immune system is forced to tolerate certain foreign material – the embryo and the placenta, both of which grow from that first cell that is half derived from the father’s DNA. From the body’s point of view, these growths are parasites, sucking life from the mother’s body for their own existence. Detection by the immune system of such foreign tissue would usually lead to organ rejection, and preventing rejection is a necessity when it comes to making babies.
To ensure their survival, the embryo and the placenta cannot simply suppress the mother’s immune system, as this would expose her (and her developing foetus) to the risk of infection – even possibly death. Instead, the trophoblast produces a special subset of MHC class I molecules that protect the foetus from natural killer cells in the mother’s womb. These particular molecules work only in the vicinity of the placenta – a neat biological trick. Still, these molecules are not all-important. If you were to destroy them, a mother would not immediately reject her foetus or its placenta. How could that be?
There must be at least one other strategy that prevents full-blown immunological warfare between mother and child. As it happens, the genetic compromise does not seem to have been developed specifically to adapt to life with a placenta. Instead, it depends on the fact that there is another, completely different source of DNA in the body. The cells that give rise to the placenta, and which protect the inner layer of cells destined to become the baby from attack by the mother’s immune system, are unique: not only do they exclusively come from the father, some of those genes are not even human. They are the DNA of ancient viruses.
Among egg-laying animals, which do not have placentas, contact between mother and foetus is very limited, of course. It is the shell that shields the embryo from the mother, and the mother from the embryo, and the shell is created entirely by contributions from the mother. The egg also does not stay inside the mother’s body for very long after it is fertilized. Incubating a fertilized egg inside the mother’s body required an ingenious ploy. In 1997, Luis Villarreal, a molecular biologist at the University of California, Irvine, wrote an article entitled ‘On Viruses, Sex, and Motherhood’ in which he recounted his theory of a very clever leap in evolution. In this article, published in the Journal of Virology, he proposed that viral DNA played an essential role in the evolution of mammalian pregnancy.
Viruses are among the oldest and most successful life forms on the planet, and Villarreal and others believe that the virus in question would have infected a distant ancestor in our primate lineage as far back as twenty-five million to forty million years ago. When you look at the genome of vertebrates, you find thousands of foreign elements that look a lot like the genetic information harboured in retroviruses, a form of virus that creates DNA out of RNA (opposite to most viruses, which make RNA out of DNA) and integrates this new DNA into its host. Indeed, nearly ten percent of human DNA today appears to be made up of old retroviruses. The most well-known retrovirus is HIV, the cause of AIDS, which shuts down the immune system, but other retroviruses have been linked to tumour cell growth.
Deploying some of the same tactics that viruses use to evade our immune system, the viral DNA in mammals allowed another invader into the body: the foetus. These genes, known as syncytin genes, allow the body to protect, nourish, and incubate the foetus, giving it time to mature without the threat of rejection by the ‘host’ immune system. Without viral DNA, humans and many other mammals might still be laying eggs. And syncytin genes are targeted on making the placenta, specif
ically at the level of the trophoblast ring of cells – exactly where exchanges between the foetus and the mother take place. Importantly, syncytin genes instruct cells to fuse with each other. That is, they are able to force cells from the lining of the mother’s womb, comprised solely of the mother’s DNA, to fuse with cells from the trophoblast, which is designed by DNA from the father alone.
It is important to note that syncytin genes work as diplomats rather than combatants in the war between different DNA: they do not affect the embryo’s development or the actions of the immune cells; instead, they temporarily cloak the embryo, keeping it from being recognized and destroyed by the mother’s immune system. When a particular syncytin gene, syncytin-A, is disabled in mice, the entire architecture of the trophoblast changes dramatically. Embryos begin to grow, but at a slow rate, and fewer blood vessels form to feed them. The pregnancies invariably end in miscarriage. A faulty placenta does not make for a healthy pregnancy, and this is exactly what the scientists attempting to create fatherless mice were fighting. Their early experiments kept showing that when they tried to produce offspring with DNA originating only from sperm, the embryo struggled to develop; when they did the same with DNA only from eggs, the embryos developed normally but the placenta and other supporting tissues failed to thrive.
But this raises a more perplexing question. Why would a father’s genetic contribution be necessary in making a placenta, when viral DNA appears in the genome of both sexes? Why didn’t evolution give females the capacity to make a placenta all on their own?
The evolution of the placenta must have been something of a double-edged sword for our ancestors. While being able to gestate inside an adult afforded unprecedented protection for vulnerable young, mammalian embryos functioned like a parasite on the mother. Apart from the challenges to the mother’s immune system, the embryo drained nutrients via the newly designed placenta. This nutrient flow has to be regulated by the body, so that neither mother nor embryo is starved. Ancient viral DNA cannot handle this; new genes with new instructions had to tackle the task.
Not all genes in our cells work all of the time or in all parts of our bodies. Some, for instance, only work in the limbs when a foetus is developing in the womb; some only in the brain of an adult. As this indicates, genes have to be turned ‘on’ to have an effect, a phenomenon known as gene expression. Gene expression can be understood as the process by which the letters of the DNA code are ‘read’ and start the production of certain proteins, which tell cells (and thus everything in the organism) what to do and when to do it. For some parts of the genome in animals, the expression of a particular gene is determined by whether it was inherited from the mother or the father.
As the placenta gradually evolved in mammals, evolution had to find a way to tell the viral genes and the newer genes when to start working and when to stop. Sometime around a hundred and forty-eight million years ago, certain genes vital for the healthy development of the placenta started to become locked and unusable – coded so that they could never be read, or expressed, since they sometimes mucked up the works. So even though the mother’s genome still contains all the genes it takes to grow a complete baby from one of her eggs, only some of them are allowed to function. The same is true for some of the father’s genes. This sexual selection in whether a certain gene can be expressed is called genomic imprinting.
There is nothing inherently ‘wrong’ in the coding of these genes that don’t work. Imprinting doesn’t involve a mutation or a mistake that stops the gene from working – think of it as a padlock that means the gene’s DNA cannot be accessed. But just as a door can be opened if you find the right key, imprinted genes can be unlocked, even erased, by different conditions. The process is by no means static. And of the twenty-three thousand human genes that can be expressed by making proteins, only about eighty are ever silenced by imprinting. What is interesting is that many of these genes that are imprinted dictate not what we will look like, but are able to manipulate the growth and nutrition of the foetus in the womb. It seems that when evolution invented sex, it used imprinting as a way of ensuring that the female needed the male to reproduce. The health and survival of any offspring depends heavily on the father’s genes for making the placenta, since the mother’s genes have been locked. It seems that sperm do more than just deliver packets of DNA into eggs – they regulate pregnancy itself.
Imprinted genes, like viral DNA, are a frontline in a battle: two beings fighting over scarce resources, with some genes trying to ensure the best result for the child at the expense of the mother, and others, for the mother at the expense of the child. The majority of genes that are locked in the mother’s DNA but not in the father’s directly influence how many nutrients a foetus is able to extract from the mother’s body. A father’s genes benefit if his offspring are larger and stronger when they are born, because that gives them a better chance of surviving to adulthood and the father’s genes being passed on further – for the father, there’s no personal risk involved. In contrast, many of the mother’s genes that do work at this stage are trying to curb the foetus’s growth – to keep those nutrients for the mother. Consider, too, that if every time she became pregnant, the mother could restrict foetal growth, she would secure a better chance of producing more children from limited resources, and she would be less likely to die from complications of childbirth. Evolutionarily speaking, this is to the advantage of her genes, which would have more opportunities to be passed on to a future generation.
This strategy is custom-made for polygamous reproduction. When each female regularly bears offspring of several different males, the mother has an equal genetic stake in each embryo and will achieve the best outcome for her genes if resources are allocated equally to each one; the father is better served, however, if his particular embryos grow faster and extract a greater share of resources from the mother than do the siblings in which he has no genetic stake. So silencing certain genes in the placenta ensures that every foetus has an equal chance of survival. The ability of a father’s genes to influence how an embryo acquires resources from its mother is rare, but it does also appear in some plants. In these plants, including maize (Zea mays, or corn), the mother nourishes the growing embryo for an extensive period after fertilization, whereas the father experiences negligible costs – just its seed.
In theory, imprinting does not make sense for a monogamous species. A father who intends to have multiple children with just one female partner should co-operate with her for resources rather than try to extract everything he can for the benefit of his genes. Take, for example, what happens when a strait-laced oldfield mouse (Peromyscus polionotus) is crossed with its promiscuous relative, the deer mouse (Peromyscus maniculatus). To be precise, the oldfield mouse is not strictly monogamous in the wild; it’s just that the females don’t change partners nearly as often as their polygamous relatives. So when biologists decided to poke into the question of whether any monogamous animals have imprinted genes, the short answer was that they did, in part because they are somewhat promiscuous and had fully polygamous ancestors. Nevertheless, the experiments still yielded some extremely interesting results.
In oldfield mice, the male and the female are about the same size, which is generally the case with monogamous species, and even though polygamous animals usually exhibit a substantial difference in size and appearance between the sexes, deer mice are roughly the same size as oldfield mice. The animals seemed well suited to be mates. Despite this, when a female deer mouse was crossed with a male oldfield mouse, their offspring grew up to be forty percent smaller than either parent. And when a male deer mouse was crossed with a female oldfield mouse, the babies were oversized, bearing enlarged tongues that made it difficult for them to eat and swallow; for the most part, they did not survive. And it was not just that the embryos were overgrown – the placentas that nurtured them were overgrown, too – around six times bigger than in a pregnancy involving two monogamous or two polygamous mice. As a consequence, oldf
ield mice mothers often died in labour, while trying to push the babies out through the birth canal.
Though both mouse species had imprinted genes, the polygamous females were better equipped to do battle against the monogamous males’ genes. The embryos were restricted in taking resources from the mother’s body. Similarly, the polygamous males were better able to extract nutrients from the mother for the offspring, building a supersized placenta to increase the foetuses’ (and the genes’) access to the resources. If there is a mismatch in the genes that are silenced between the mother and the father, however, fatal mistakes can result.
A pregnant woman’s body is constantly negotiating with the foetus over the share of nutrients each one gets. Among the body’s main energy-supplying fuels is the sugar glucose. To control glucose, you need to control the hormone essential in the body’s proper use of sugar: insulin. And when the body is not producing enough insulin, or becomes resistant to its effects, you suffer from diabetes. Up to fourteen percent of women suffer with diabetes during pregnancy, and although the condition usually disappears after the baby is born, nearly one in five of these women go on to develop Type 2 diabetes within nine years; they may also be at greater risk of developing heart disease. The reason for this lies with imprinted genes.
During pregnancy, the placenta pumps out various hormones that block the usual action of insulin so that the foetus will gain greater access to the glucose circulating in the mother’s blood. Effectively, the mother is left unable to control or use her own glucose, making her insulin-resistant, and glucose does not enter her own cells as it should. Glucose levels rise in her bloodstream, and, in something of a vicious cycle, her body needs to produce more insulin to overcome this spike. If it does not, she develops diabetes for the duration of the pregnancy. In adults, both the mother’s and the father’s copies of the human insulin gene, known as INS, work just as well as each other. In the embryo, however, INS is one of the small number of genes that are imprinted, so that only the father’s copy of the gene functions. The same story plays out for a related gene called IGF2, which makes insulin-like growth factor-2. The gene plays a vital role in the growth of the foetus and the placenta: too much insulin-like growth factor-2 makes huge placentas and severely oversized babies – rather like what happens in the pairing of the monogamous oldfield mouse female with a polygamous deer mouse male.
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