Mutants: On Genetic Variety and the Human Body

In the volume of engraved plates that accompanies the report of their dissection, Ritta and Christina Parodi appear as a pair of small, slender, and quite beautiful infant girls. They have dark eyes, and their silky curls are brushed forward over their foreheads in the fashion of the French Empire, in a way that suggests a heroic portrait of Napoleon Bonaparte. Their brows and noses are straight, their mouths sweetly formed, and their arms reach towards each other, as if in embrace, but their expressions are conventionally grave. Distinct from the shoulders up, their torsos melt gradually into each other; below the single navel the join is so complete that they have, between them, one vulva, one rectum, one pelvis, and one pair of legs. It is a paradoxical geometry. For although the girls are, individually, so profoundly deformed, together they are symmetrical and proportionate; their construction seems less an anomaly of nature than its designed result. It may be thought that this beauty is merely a product of the engraver’s art, but a plaster-cast of their body shows the same harmony of form. If the engraver erred it was only in giving them the proportions of children older than they were; they were only eight months old when they died.

THE APOTHEOSIS OF RITTA-CHRISTINA

The Parodis arrived in Paris in the autumn of 1829. Six months previously they had left Sassari, a provincial Sardinian town, in the hope of living by the exhibition of their children. Italy had been receptive; Paris was not. Local magistrates, ruling on the side of public decency, forbade the Parodis to show their children to the multitude and so deprived them of their only income. They moved to a derelict house on the outskirts of the city, where they received some payment from a procession of physicians and philosophers who came to see the children in private.

What they earned wasn’t even enough to heat the house. The savants, puzzling over what they found, were also continually uncovering the children. Was there one heart or two? The stethoscope gave conflicting results. They were fascinated by the differences between the children. Christina was a delight – healthy, vigorous, with a voracious appetite; Ritta, by contrast, was weak, querulous and cyanotic. When one fell asleep the other would usually do so as well, but occasionally one slept soundly while the other demanded food. Continually exposed to chills, Ritta became bronchitic. The physicians noted that sickness, too, demonstrated the dual and yet intertwined nature of the girls, for even as Ritta gasped for air, her sister lay at her side unaffected and content. But three minutes after Ritta died, Christina gave a cry and her hand, which was in her mother’s, went limp. It was 23 November 1829, and the afterlife of ‘Ritta-Christina, the two-headed girl’ had begun.

The men from the Académie Royale de Médecine were on hand within hours. They wanted a cast of the body. Deputations of anatomists followed; they wanted the body itself. How they got it is a murky affair, but within days the dissection of l’enfant bicéphale was announced. In the vast amphitheatre of the Muséum d’Histoire Naturelle at the Jardin des Plantes in Paris, Ritta and Christina were laid out in state on a wooden trestle table. The anatomists jostled for space around them. Baron Georges Cuvier, France’s greatest anatomist – ‘the French Aristotle’ – was there. So was Isidore Geoffroy Saint-Hilaire, connoisseur of abnormality, who in a few years would lay the foundation of teratology. And then there was Étienne Reynaud Augustin Serres, the brilliant young physician from the Hôpital de la Pitié, who would make his reputation by anatomising the girls in a three-hundred-page monograph.

Beyond the walls of the museum, Paris was enthralled. The Courier Français intimated that the medical men had connived at the death of the sisters; they replied that the magistrates who had let the family sink to such miserable depths were to blame. The journalist and critic Jules Janin published a three-thousand-word j’accuse in which he excoriated the anatomists for taking the scalpel to the poetic mystery that was Ritta and Christina: ‘You despoil this beautiful corpse, you bring this monster to the level of ordinary men, and when all is done, you have only the shade of a corpse.’ And then he suggested that the girls would be a fine subject for a novel.

The first cut exposed the ribcage. United by a single sternum, the ribs embraced both sisters, yet were attached to two quite distinct vertebral columns that curved gracefully down to the common pelvis. There were two hearts, but they were contained within a single pericardium, and Ritta’s was profoundly deformed: the intra-auricular valves were perforated and she had two superior vena cavas, one of which opened into the left ventricle, the other into the right – the likely cause of her cyanosis. Had it not been for this imperfection, lamented Serres, and had the children lived under more favourable circumstances, they would surely have survived to adulthood. Two oesophagi led to two stomachs, and two colons, which then joined to a common rectum. Each child had a uterus, ovaries and fallopian tubes, but only one set of reproductive organs was connected to the vagina, the other being small and underdeveloped. Most remarkably of all, where Christina’s heart, stomach and liver were quite normally oriented, Ritta’s were transposed relative to her sister’s, so that the viscera of the two girls formed mirror-images of each other. The anatomists finished their work, and then boiled the skeleton for display.

A PAIR OF LONG-CASE CLOCKS

The oldest known depiction of a pair of conjoined twins is a statue excavated from a Neolithic shrine in Anatolia. Carved from white marble, it depicts a pair of dumpy middle-aged women joined at the hip. Three thousand years after this statue was carved, Australian Aborigines inscribed a memorial to a dicephalus (two heads, one body) conjoined twin on a rock that lies near what are now the outskirts of Sydney. Another two thousand years (we are now at 700 bc), and the conjoined Molionides brothers appear in Greek geometric art. Eurytos and Cteatos by name, one is said to be the son of a god, Poseidon, the other of a mortal, King Actor. Discordant paternity notwithstanding, they have a common trunk and four arms, each of which brandishes a spear. In a Kentish parish, loaves of bread in the shape of two women locked together side by side are distributed to the poor every Easter Monday, a tradition, it is said, that dates from around the time of the Norman conquest and that commemorates a bequest made by a pair of conjoined twins who once lived there.

By the sixteenth century, conjoined twins crop up in the monster-and-marvel anthologies with the monotonous regularity with which they now appear in British tabloids or the New York Post. Ambroise Paré described no fewer than thirteen, among them two girls joined back to back, two sisters joined at the forehead, two boys who shared a head and two infants who shared a heart. In 1560 Pierre Boaistuau gave an illuminated manuscript of his Histoires prodigieuses to Elizabeth I of England. Amid the plates of demonic creatures, wild men and fallen monarchs, is one devoted to two young women standing in a field on a single pair of legs, flaming red hair falling over their shoulders, looking very much like a pair of Botticelli Venuses who have somehow become entangled in each other.

For the allegory-mongers, conjoined twins signified political union. Boaistuau notes that another pair of Italian conjoined twins were born on the very day that the warring city-states of Genoa and Venice had finally declared a truce – no coincidence there. Montaigne, however, will have none of it. In his Essays (c.1580) he describes a pair of conjoined twins that he encountered as they were being carted about the French countryside by their parents. He considers the idea that the children’s joined torsos and multiple limbs might be a comment on the ability of the King to unify the various factions of his realm under the rule of law, but then rejects it. He continues, ‘Those whom we call monsters are not so with God, who in the immensity of his work seeth the infinite forms therein contained.’ Conjoined twins did not reflect God’s opinion about the course of earthly affairs. They were signs of His omnipotence.

By the early eighteenth century, this humanist impulse – the same impulse that caused Sir Thomas Browne to write so tenderly about deformity – had arrived at its logical conclusion. In 1706 Joseph-Guichard Duverney, surgeon and anatomist at the Jardin du Roi in Paris, the very place where Ritta and Christina had been laid open, dissected another pair of twins who were joined at the hips. Impressed by the perfection of the join, Duverney concluded that they were without doubt a testament to the ‘the richness of the Mechanics of the Creator’, who had clearly designed them so. After all, since God was responsible for the form of the embryo, He must also be responsible if it all went wrong. Indeed, deformed infants were not really the result of embryos gone wrong – they were part of His plan. Bodies, said Duverney, were like clocks. To suppose that conjoined twins could fit together so nicely without God’s intervention was as absurd as supposing that you could take two long-case clocks, crash them into each other, and expect their parts to fuse into one harmonious and working whole.

Others thought this was ridiculous. To be sure, they argued, God was ultimately responsible for the order of nature, but the notion that He had deliberately engineered defective eggs or sperm as a sort of creative flourish was absurd. If bodies were clocks, then there seemed to be a lot of clocks around that were hardly to the Clockmaker’s credit. Monsters were not evidence of divine design: they were just accidents.

The conflict between these two radically different postitions, between deformity as divine design and deformity as accident, came to be known as la querelle des monstres – the quarrel of the monsters. It pitted French anatomists against one another for decades, the contenders trading blows in the Mémoires de l’Académie Royale des Sciences. More than theology was at stake. The quarrel was also a contest over two different views of how embryos are formed. Duverney and his followers were preformationists. They held that each egg (or, in some version of the theory, each sperm) contained the entire embryo writ small, complete with limbs, liver and lungs. Stranger yet, this tiny embryo (which some microscopists claimed they could see) also contained eggs or sperm, each of which, in turn contained an embryo… and so on, ad infinitum. Each of Eve’s ovaries, by this reasoning, contained all future humanity.

Preformationism was an ingenious theory and won prominent adherents. Yet many seventeenth- and eighteenth-century philosophers, among them freethinkers such as Buffon and Maupertuis, preferred some version of the older theory of ‘epigenesis’, the notion that embryonic order does not exist in the egg or the sperm per se, but rather emerges spontaneously after fertilisation. At the time of the querelle, many thought that the preformationists had the better side of the argument. Today, however, it is more difficult to judge a victor. Neither the preformationists nor the epigeneticists had a coherent theory of inheritance, so the terms of the debate between them do not correspond in any simple way to a modern understanding of the causes of deformity or development. Preformationism, with its infinite regress of embryos, seems the more outlandish of the two theories, though it captures nicely the notion that development errors are often (though not invariably) due to some mistake intrinsic to the germ cells – the cells that become eggs and sperm – or at least their DNA. But the epigeneticists speak more powerfully to the idea that embryos are engaged in an act of self-creation which can be derailed by external influences, chemicals and the like, or even chance events within their dividing cells.

HOW TO MAKE A CONJOINED TWIN

What makes twins conjoin? Aristotle, characteristically, covered the basic options. In one passage of The generation of animals he argues that conjoined twins come from two embryos that have fused. That, at least, is where he thought conjoined chickens (which have four wings and four legs) come from. But elsewhere he suggests that they come from one embryo that has split into two.

To modern ears his notion of how an embryo might split sounds odd, but it is a sophisticated account, all of a piece with his theory of how embryos develop. Having no microscope, Aristotle knows nothing of the existence of sperm and eggs. Instead he supposes that embryos coagulate out of a mixture of menstrual fluid and semen, the semen causing the menstrual fluid to thicken rather as – to use his homely metaphor – fig juice causes milk to curdle when one makes cheese. This is epigenesis avant la lettre. Indeed, preformationism was very much an attack on the Aristotelian theory of embryogenesis and, by extension, its account of the origins of deformity. Sometimes, says Aristotle, there is simply too much of the pre-embryonic mix. If there is only a little too much, you get infants with extra or unusually large parts, such as six fingers or an overdeveloped leg; more again, and you get conjoined twins; even more mix, separate twins. He uses a beautiful image to describe how the mix separates to make two individuals. They are, he says, the result of a force in the womb like falling water: ‘…as the water in rivers is carried along with a certain motion, if it dash against anything two systems come into being out of one, each retaining the same motion; the same thing happens with the embryo’.

For Aristotle, the two ways of making conjoined twins bear on their individuality. He rules that if conjoined twins have separate hearts, then they are the products of two embryos and are two individuals; if there is only one heart, then they are one. The question of conjoined twin individuality haunts their history. Thomas Aquinas thought that it depended on the number of hearts and heads (thereby ensuring perpetual confusion for priests who wanted to know how many baptisms conjoined infants required). When twins are united by only by a slender cartilaginous band – the case with the original Siamese twins, Eng and Chang (1811–74) – it is easy to grant each his own identity. More intimately joined twins have, however, always caused confusion. In accounts of Ritta and Christina Parodi, the girls often appear as the singular ‘Ritta-Christina’, or even ‘the girl with two heads’, rather than two girls with one body – which is what they were.

Until recently, the origin of conjoined twins has been debated in much the terms that Aristotle used: they are the result either of fusion or fission. Most medical textbooks plump for the latter. Monozygotic (identical) twins, the argument goes, are manifestly the products of one embryo that has accidentally split into two; and if an embryo can split completely, surely it can split partially as well. This argument has the attraction of simplicity. It is also true that conjoined twins are nearly always monozygotic – they originate from a single egg fertilised by a single sperm. Yet there are several hints that monozygotic twins who are born conjoined are the result of quite different events in the first few weeks after conception than are those who are born separate.

One difference between conjoined and separate twins is that conjoined twins share a single placenta and (as they must) a single amniotic sac. Separate twins also share a single placenta, but each usually has an amniotic sac of its own as well. Since the amniotic sac forms after the placenta, this suggests that the split – if split it is – happens later in conjoined twins than in separate twins.

Another suggestive difference comes from the strange statistics of twin gender. Fifty per cent of separate monozygotic twins born are female. This is a little higher than one would expect, since, in most populations at most times, slightly fewer girls than boys are born. But in conjoined twins the skew towards femininity is overwhelming: about 77 per cent are girls. No one knows why this is so, but it neatly explains why depictions of conjoined twins – from Neolithic shrines to the New York Post – are so often female.

Perhaps the best reason for thinking that conjoined twins are not the result of a partially split embryo is the geometry of the twins themselves. Conjoined twins may be joined at their heads, thoraxes, abdomens or hips; they may be oriented belly to belly, side to side, or back to back; and each of these connections may be so weak that they share hardly any organs or so intimate that they share them all. It is hard to see how all this astonishing array of bodily configurations could arise by simply splitting an embryo in two.

But where are the origins of conjoined twins to be found if not in partially split embryos? Sir Thomas Browne called the womb ‘the obscure world’, and so it is – never more so than when we try to explain the creation of conjoined twins. The latest ideas suggest, however, that Aristotle’s dichotomy – fission or fusion – is illusory. The making of conjoined twins is, first, a matter of making two embryos out of one, and then of gluing them together. Moreover, the way in which two embryos are made out of one is nothing so crude as some sort of mechanical splitting of the embryo. It is, instead, something more subtle and interesting. Indeed, although we perceive conjoined twins as the strangest of all forms that the human body can take (as recently as 1996 The Times referred to one pair of twins as ‘metaphysical insults’), they have shown us the devices by which our bodies are given order in the womb.

ORGANISE ME

On the seventh day after conception, a human embryo begins to dig. Though only a hollow ball made up of a hundred or so cells, it is able to embed itself in the uterine linings of its mother’s womb that are softened and swollen by the hormones of the menstrual cycle. Most of the cells in the hollow ball are occupied with the business of burrowing, but some are up to other things. They are beginning to organise themselves into a ball of their own, so that by day 9 the embryo is rather like one of those ingenious Chinese toys composed of carved ivory spheres within spheres within spheres. By day 13 it has disappeared within the uterine lining, and the wound it has caused has usually healed. The embryo is beginning to build itself.

Its first task is to make the raw materials of its organs. We are three-dimensional creatures: bags of skin that surround layers of bone and muscle that, in turn, support a maze of internal plumbing; and each of these layers is constructed from specialised tissues. But the embryo faces a problem. Of the elaborate structure that it has already built, only a minute fraction – a small clump of cells in the innermost sphere – is actually destined to produce the foetus; all the rest will just become its ancillary equipment: placenta, umbilical cord and the like. And to make foetus out of this clump of cells, the embryo has to reorganise itself.

The process by which it does this is called ‘gastrulation’. At about day 13 after conception, the clump of cells has become a disc with a cavity above it (the future amniotic cavity) and a cavity below it (the future yolk sac). Halfway down the length of this disc, a groove appears, the so-called ‘primitive streak’. Cells migrate towards the streak and pour themselves into it. The first cells that go through layer themselves around the yolk cavity. More cells enter the streak and form another layer above the first. The result is an embryo organised into three layers where once there was one: a gastrula.

The three layers of the gastrula anticipate our organs. The top layer is the ectoderm – it will become the outer layers of the skin and most of the nervous system; beneath it is the mesoderm – future muscle and bone; and surrounding the yolk is the endoderm – ultimate source of the gut, pancreas, spleen and liver. (Ecto-, meso- and endo- come from the Greek for outer, middle and inner derm – skin – respectively.)

The division sounds clear-cut, but in fact many parts of our bodies – teeth, breasts, arms, legs, genitalia – are intricate combinations of ectoderm and mesoderm. More important than the material from which it builds its organs, the embryo has also now acquired the geometry that it will have for the rest of its life. Two weeks after egg met sperm, the embryo has a head and a tail, a front and a back, and a left and a right. The question is, how did it get them?

In the spring of 1920, Hilda Pröscholdt arrived in the German university town of Freiburg. She had come to work with Hans Spemann, one of the most important figures in the new, largely German, science of Entwicklungsmechanik, ‘developmental mechanics’. The glassy embryos of sea urchins were being bisected; green-tentacled Hydra lost their heads only to regrow them again; frogs and newts were made to yield up their eggs for intricate transplantation experiments. Spemann was a master of this science, and Pröscholdt was there to do a Ph.D. in his laboratory. At first she floundered; the experiments that Spemann asked her to do seemed technically impossible and, in retrospect, they were. But she was bright, tenacious and competent, and in the spring of 1921 Spemann suggested another line of work. Its results would provide the first glimpse into how the embryo gets its order.

Then as now, the implicit goal of most developmental biologists was to understand how human embryos construct themselves, or failing that, how the embryos of other species of mammal do. But mammal embryos are difficult to work with. They’re hard to find and difficult to keep alive outside the womb. Not so newt embryos. Newts lay an abundance of tiny eggs that can, with practice, be surgically manipulated. It was even possible to transplant pieces of tissue between newt embryos and have them graft and grow.

The experiment which Spemann now suggested to Hilda Pröscholdt entailed excising a piece of tissue from the far edge of one embryo’s blastopore – the newt equivalent of the human primitive streak – and transplanting it onto another embryo. Observing that the embryo’s tissue layers and geometry arose from cells that had passed through the blastopore, Spemann reasoned that the tissues at the blastopore’s lip had some special power to instruct the cells that were travelling past it. If so, then embryos that had extra bits of blastopore lip grafted onto them might have – what? Surplus quantities of mesoderm and endoderm? A fatally scrambled geometry? Completely normal development? Earlier experiments that Spemann himself had carried out had yielded intriguing but ambiguous results. Now Hilda Pröscholdt was going to do the thing properly.

Between 1921 and 1923 she carried out 259 transplantation experiments. Most of her embryos did not survive the surgery. But six embryos that did make it are among the most famous in developmental biology, for each contained the makings of not one newt but two. Each had the beginnings of two heads, two tails, two neural tubes, two sets of muscles, two notochords, and two guts. She had made conjoined-twin newts, oriented belly to belly.

This was remarkable, but the real beauty of the experiment lay in Pröscholdt’s use of two different species of newts as donor and host. The common newt, the donor species, has darkly pigmented cells where the great-crested newt, the host species, does not. The extra organs, it was clear, belonged to the host embryo rather than the donor. This implied that the transplanted piece of blastopore lip had not become an extra newt, but rather had induced one out of undifferentiated host cells. This tiny piece of tissue seemed to have the power to instruct a whole new creature, complete in nearly all its parts. Spemann, with no sense of hyperbole, called the far lip of the newt’s blastopore ‘the organiser’, the name by which it is still known.

For seventy years, developmental biologists searched in vain for the source of the organiser’s power. They knew roughly what they were looking for: a molecule secreted by one cell that would tell another cell what to do, what to become, and where to go.

Very quickly it became apparent that the potency of the organiser lay in a small part of mesoderm just underneath the lip of the blastopore. The idea was simple: the cells that had migrated through the blastopore into the interior of the embryo were naive, uninformed, but their potential was unlimited. Spemann aphorised this idea when he said ‘We are standing and walking with parts of our body that could have been used for thinking had they developed in another part of the embryo.’ The mesodermal cells of the blastopore edge were the source of a signal that filtered into the embryo, or to use the term that was soon invented, a morphogen. This signal was strong near its source but gradually became fainter and fainter as it dissipated away. There was, in short, a three-dimensional gradient in the concentration of morphogen. Cells perceived this gradient and knew accordingly where and what they were. If the signal was strong, then ectodermal cells formed into the spinal cord that runs the length of our back; if it was faint, then they became the skin that covers our body. The same logic applied to the other germ layers. If the organiser signal was strong, mesoderm would become muscle; fainter, kidneys; fainter yet, connective tissue and blood cells. What the organiser did was pattern the cells beneath it.

It would be tedious to recount the many false starts, the years wasted on the search for the organiser morphogen, the hecatombs of frog and newt embryos ground up in the search for the elusive substance, and then, in the 1960s, the growing belief that the problem was intractable and should simply be abandoned. ‘Science,’ Peter Medawar once said, ‘is the Art of the Soluble.’ But the soluble was precisely what the art of the day could not find.

In the early 1990s recombinant DNA technology was applied to the problem. By 1993 a protein was identified that, when injected into the embryos of African clawed toads, gave conjoined-twin tadpoles. At last it was possible to obtain – without crude surgery – the results that Hilda Pröscholdt had found so many years before. The protein was especially good at turning naive ectoderm into spinal cord and brain. With a whimsy that is pervasive in this area of biology, it was named ‘noggin’. By this time techniques had been developed that made it possible to see where in an embryo genes were being switched on and off. The noggin gene was turned on at the far end of the blastopore’s lip, just where the gene encoding an organising morphogen should be.

Noggin is a signalling molecule – that is, a molecule by which one cell communicates with another. Animals have an inordinate number of them. Of the thirty thousand genes in the human genome, at least twelve hundred are thought to encode proteins involved in communication between cells. They come in great families of related molecules: the transforming growth factor-betas (TGF-?), the hedgehogs and the fibroblast growth factors (FGFs) to name but a few, and some families contain more than a dozen members. The way they work varies in detail, but the theme is the same. Secreted by one cell, they attach to receptors on the surfaces of other cells and in doing so begin a sequence of molecular events that reaches into the recipient cell. The chain of information finally reaches the nucleus, where batteries of other genes are either activated or repressed, and the cell adopts a fate, an identity.

When noggin was first discovered, it was supposed that its uncanny powers lay in an ability to define the back of the embryo from the front – more precisely, to instruct naive ectodermal cells to become spinal column rather than skin. This was the simplest interpretation of the data. Noggin, the thinking went, spurred ectodermal cells on to higher things; without it, they would languish as humble skin.

The truth is a bit more subtle. The probability that a cell becomes spinal column rather than skin is not just a function of the quantity of noggin that finds its way to its receptors, but is rather the outcome of molecular conflict over its fate. I said that our genomes encode an inordinate number of signalling molecules. This implies that the cells in our bodies must be continually bathed in many signals emanating from many sources. Some of these signals speak with one voice, but others offer conflicting advice. Noggin from the organiser may urge ectoderm to become neurons, but as it does so, from the opposite side of the embryo another molecule, bone morphogenetic protein 4 (BMP4) instructs those same cells to become skin.

The manner in which the embryo resolves the conflict between these two signals is ingenious. Each signal has its own receptor to which it will attach, but noggin, with cunning versatility, can also attach to free BMP4 molecules as they filter through the intercellular spaces, and disable them. Cells close to the organiser are not only induced to become neurons, but are also inhibited from becoming skin; far from the organiser the opposite obtains. The fate of a given cell depends on the balance of the concentration between the two competing molecules. It is an ingenious device, only one of many like it that work throughout the development of vertebrate bodies, at scales large and small, to a variety of ends; but here the end is a toad or a child that has a front and a back. In a way, the embryo is just a microcosm of the cognitive world that we inhabit, the world of signals that insistently urge us to travel to one destination rather than another, eschew some goals in favour of others, hold some things to be true and others false; in short, that moulds us into what we are.

It is actually quite hard to prove that a gene, or the protein that it encodes, does what one supposes. One way of doing so is to eliminate the gene and watch what happens. This is rather like removing a car part – some inconspicuous screw – in order to see why it’s there. Sometimes only a rear-view mirror falls off, but sometimes the car dies. So it is with mice and genes. If noggin were indeed the long-sought organising molecule, then any mouse with a defective noggin gene should have a deeply disordered geometry. For want of information, the cells in such an embryo would not know where they were or what to do. One might expect a mouse that grew up in the absence of noggin to have no spinal column or brain, but be belly all round; at the very least one would expect it to die long before it was born. Oddly enough, when a noggin-defective mouse was engineered in 1998, it proved to be really quite healthy. True, its spinal cord and some of its muscles were abnormal, but its deformities were trivial compared to what they might have been.

The reason for this is still not completely understood, but it probably lies in the complexity of the organiser. Since the discovery of noggin at least seven different signalling proteins have been found there, among them the ominously named ‘cerberus’ (after the three-headed dog that guards the entrance to Hades), and the blunter but no less evocative ‘dickkopf’ (German for ‘fat-head’). This multiplicity is puzzling. Some of these proteins probably have unique tasks (perhaps giving pattern to the head but not the tail, or else ectoderm but not mesoderm), but it could also be that some can substitute for others. Biologists refer to genes that perform the same task as others as ‘redundant’ in much the same sense that employers do: one can be disposed of without the enterprise suffering ill-effects. At least two of the organiser signals, noggin and another called chordin, appear to be partially redundant. Like noggin, chordin instructs cells to become back rather than front, neurons rather than skin, and does so by inhibiting the BMP4 that filters up from the opposite side of the embryo. And, like noggin-defective mice, mice engineered with a defect in the chordin gene have more or less normal geometry, although they are stillborn. However, doubly-mutant mice, in which both the noggin and chordin genes have been disabled, never see the light of day. The doubly-mutant embryos die long before they are born, their geometries profoundly disordered. They can only be found by dissecting the mother in early pregnancy.

Hilda Pröscholdt’s results were published in 1924, but she did not live to see them in print. Halfway through her doctoral degree she married Otto Mangold, one of her fellow students in Spemann’s laboratory, and it is by his name that she is now known. In December 1923, having been awarded a doctorate, she gave birth to a son, Christian, and left the laboratory. On 4 September 1924, while visiting her Swabian in-laws, she spilt kerosene while refuelling a stove. Her dress caught alight, and she died the following day of her burns. She was only twenty-six, and in all ways a product of the Weimar. As a student, when not dissecting embryos, she had read Rilke and Stefan George, sat in on the philosopher Edmund Husserl’s lectures, decorated her flat with Expressionist prints, and taken long Black Forest walks. She had only really done one good experiment, but it is said by some that had Hilda Pröscholdt lived she would have shared the Nobel Prize that Spemann won in 1935.

E PLURIBUS UNUM?

When Eng and Chang toured the United States they advertised themselves with the slogan, familiar to any citizen of the Republic, e pluribus unum – out of many, one. It seemed apt enough, but it was only half the truth. Conjoined twins are clearly, in the first instance, a case of ex uno plures – out of one, many.

The similarity of human twins to the conjoined-twin newts made by Hilda Pröscholdt suggests one way how this might happen. All that is needed are two organisers on a single embryo instead of the usual one. Although Pröscholdt doubled the organisers on her newts by some deft, if crude, transplantation surgery, there are much more subtle molecular means of bringing about the same end. The genes that encode the signalling proteins of the organiser – noggin, cerberus, dickkopf and so on – are regulated by yet other ‘master control genes’. The making of two embryos out of one may, therefore, be simply a matter of one of these master control genes being turned on in the embryo where it normally is not. Why this should happen is a mystery – human conjoined twins occur so rarely (about 1 in every 100,000 live births) and unpredictably that there is no obvious way to find out. Perhaps they are caused by chemicals in the environment: at least one drug (albeit a rare and potent chemothera-peutic agent) has been shown to cause conjoined twinning in mice. Whatever the ultimate cause of conjoined twins, the ‘two-organiser’ theory, while a neatly plausible account of how to get two embryos out of one, is not in itself a complete explanation for their existence. The theory has nothing to say about their essential feature: the fact that they are glued together.

One man who thought deeply about the conjoinedness of conjoined twins was Étienne Geoffroy Saint-Hilaire. In 1829 Geoffroy was Professor at the Muséum d’Histoire Naturelle, and next to Cuvier (his colleague and bitter rival) the most important anatomist in France. Geoffroy’s disciple Étienne Serres had written the monograph describing Ritta and Christina Parodi’s autopsy; Geoffroy’s son, Isidore, had organised the event. It is upon Isidore that suspicion falls for having bullied the Parodis into surrendering the corpse.

Geoffroy père was one of the most mercurial intellects of his time: almost everything he wrote has a touch of genius and a touch of the absurd. He was one of nature’s romantics: ostensibly a descriptive anatomist, he investigated the devices by which puffer fish inflate themselves, but did not shy away from larger problems, such as the relationships between the ‘imponderable fluids’ of the universe (light, electricity, nervous energy, etc.), his deductive theory of which never saw print. More reasonably, Geoffroy was also keenly interested in deformity. It is in his hands that teratology first really becomes a science.

In 1799 Geoffroy was among the savants that Napoleon Bonaparte brought to Egypt in his futile attempt to block England’s route to the East. Geoffroy spent his Egyptian sojourn (cut short by the arrival of the British) collecting crocodiles, ichneumons and mummified ibises. Egypt also gave him a way of making ‘monsters’ to order. Geoffroy was a staunch epigeneticist. If monsters were caused by accidents in the womb, he reasoned, it should be possible to engineer them. Since time immemorial, the peasants of the Nile valley had incubated chicken eggs in earthenware furnaces fired by burning cow-dung. Inspired by this, Geoffroy established a similar hatchery where he systematically abused developing eggs by shaking them around, perforating them, or covering them in gold foil. The resulting chicks were mostly more dead than deformed, but some had bent digits, odd-looking beaks and skulls, and a few lacked eyes – unspectacular results, but enough to convince Geoffroy that he had definitively slain preformationism.

From monstrous chickens to monstrous humans was an easy leap and, starting in 1822, Geoffroy published a string of papers on deformed infants, which he classified as zoologists classify insects. A child whose head was externally invisible belonged, for example, to the genus Cryptocephalus. He realised that his ‘genera’ were not specific to humans: dogs, cats, perhaps even fish, could be deformed in the same way; his classification transcended the scale of nature. A few years later Isidore elaborated his father’s classification into a system that is still, with some modification, used by teratologists today, one in which Ritta and Christina, and children like them, are known as ‘Xiphopages’ to the French and ‘parapagus dicephalus tetrabrachius’ (side-joined, two-headed four-armed) conjoined twins to everyone else.

Étienne Geoffroy Saint-Hilaire’s greatest contribution to teratology was, however, the realisation that deformity is a natural consequence of the laws that regulate the development of the human body. Moreover, looked at the right way, such deformed infants can reveal those laws. This, of course, is a very Baconian idea – and in one of his more philosophical tracts the anatomist speaks warmly of the genius of James I’s Lord Chancellor.

Nowhere, for Geoffroy, were those laws more clearly revealed than in conjoined twins. Even before seeing Ritta and Christina Parodi in 1829, he had dissected a number of conjoined twins. Conjoinedness, he argued, was simply a reflection of what normally happens in a single embryo. The organs of an embryo develop from disparate parts that are then attracted to each other by a mysterious force rather like gravity. The intimacy of conjoined twins is caused by this same force, but misapplied so that the parts of neighbouring embryos fuse instead to one another.

Geoffroy was deeply enamoured of this deduction and, in the positivist fashion of his day, made a law of it: le loi d’affinité de soi pour soi – the law of affinity of like for like. In the monograph that Étienne Serres wrote on Ritta and Christina’s dissection, fully the first half is devoted to the soi pour soi and a few other laws of Serres’s own devising. Geoffroy regarded the soi pour soi as his greatest discovery, and in later years elevated it into a fundamental law of the universe, not unlike Goethe’s notion of ‘elective affinities’ to which it is related. This hubristic vision has ensured that the soi pour soi is, today, quite forgotten. This is a pity, since although Geoffroy’s law is unsatisfactorily vague, and wrong in detail, it conveys something important about how human embryos are built. It was the first scientific explanation of connectedness.

CONNECTEDNESS

Eighteen days after conception the embryo is just a white, oval disc about a millimetre long. It has no organs, just three tissue layers and a geometry. Even the geometry is largely virtual: a matter of molecules that have been ordered in space and time, but not yet translated into anything that can be seen without the special stains that molecular biologists use. Within the next ten days all this will have changed. The embryo will be recognisably an incipient human – or at least some sort of vertebrate, a dog, a chicken or perhaps a newt. It will have a head, a neck, a spinal column, a gut; it will have a heart.

The first sign of all this future complexity comes on day 19 when a sheet of tissue, somewhat resembling the elongate leaf of a tulip, forms down the middle of the embryo above the primitive streak. The leaf isn’t entirely flat: its edges show a tendency to furl to the middle, so that if you were to make a transverse section through the embryo you would see that it forms a shallow U. By the next day the U has become acute. Two more days and its vertices have met and touched in the middle of the embryo, rather as a moth folds its wings. And then the whole thing zips up, so that by day 23 the embryo has a hollow tube that runs most of its length, the nature of which is now clear: it is the beginnings of the mighty tract of nerves that we know as the spinal column. At one end, you can even see the rudiments of a brain.

Even as the nerve cord is forming, the foundations of other organs are being laid. Small brick-like blocks of tissue appear either side of incipient nerve cord, at first just a few, but then ten, twenty, and finally forty-four. Made of mesoderm, they reach around the neural tube to meet their opposite numbers and encase the neural tube. They will become vertebrae and muscles and the deepest layers of the skin. Underneath the embryo the endoderm, which embraces an enormous, flaccid sac of yolk, retracts up into the embryo to become the gut. As the gut shrinks the two halves of the embryo that it has previously divided are drawn together. Two hitherto inconspicuous tubes, one on either side, then unite to make a single larger tube running the length of the embryo’s future abdomen, an abdominal tube that echoes the neural tube on its back. Within a few days this abdominal tube will begin to twist and then twist again to become a small machine of exquisite design. Though it still looks nothing like what it will become it already shows the qualities that led William Harvey to call it ‘the Foundation of Life, the Prince of All, the Sun of the Microcosm, on which all vegetation doth depend, from whence all Vigor and Strength doth flow’. On day 21 it begins to beat.

The ability of disparate organ primordia to find each other and fuse to form wholes is one of the marvels of embryogenesis. Underlying it are thousands of different molecules that are attached to the surface of cells and are, as it were, signals of their affiliation, that permit other cells to recognise them as being of like kind. These are the cell-adhesion molecules; molecular biologists speak of them as the Velcro of the body: weak individually, but collectively strong. Even so, the fusion of organ primordia is a delicate business. Neural tube fusion is particularly prone to failure. One infant in a thousand born has a neural tube that is at least partly open – a condition called spina bifida. At its most severe the neural tube in the future head fails to close. The exposed neural tissue becomes necrotic and collapses, leaving a child that has the remnant of a brain stem but in which the back of the head has been truncated, as if sliced with a cleaver.

Such anencephalic infants, as they are known, occur in about 1 in 1500 births; they have heavy-lidded eyes that seem to bulge from their heads and their tongues stick out of their mouths. They die within a few days, if not hours, of being born. As the name suggests, spina bifida is often not just a failure of the neural tube to close, but a failure in the closure of the vertebral column so that instead of being sheltered by bone the nerve cord lies exposed. It is not the only organ prone to this sort of defect. Sometimes the primordia of the heart fail to meet; the result is cardiac bifida, two hearts, each only half of what it should be.

The power of cell–cell adhesion to mould the developing body is startling. In his monograph on Ritta and Christina, Serres describes a pair of stillborn boys who are joined at the head. Oriented belly to belly, their faces are deflected ninety degrees relative to their torsos so that they gaze, Janus-like, in opposite directions. What is remarkable about these children is that each apparent face is composed of half of one child’s face fused to the opposite half of his brother’s. The developing noses, lips, jaws and brains of these two children have found each other and fused perfectly – twice.

The diversity of ways in which conjoined twins can be attached to each other seems to depend on the position of the developing embryonic discs relative to each other as they float on their common yolk sac and when they contact. The embryonic discs that gave rise to Ritta and Christina were side by side, and fused some time after closure of the vertebral column but before formation of the lower gut. In the case of the twins with fused faces the embryonic discs were head to head. The most extreme form of conjoined twinning is ‘parapagus diprosopus’, in which the fusion is so intimate that the only external evidence of twinning is a partly duplicated spinal column, an extra nose and, sometimes, a third eye. At this point all debates over individuality become moot.

Conjoined twins grade into parasites, infants that live at the expense of their siblings. The distinction is a matter of asymmetry. When the young Italian Lazarus Colloredo toured Europe in the 1630s he was celebrated for his charm and breeding even as his brother, John Baptista, dangled insensibly from his sternum. In the late 1800s an Indian boy, Laloo, displayed his parasite, a nameless, headless abdomen with arms, legs and genitals, in the United States. In 1982, a thirty-five-year-old Chinese man was reported with a parasitic head embedded in the right side of his own head. The extra head had a small brain, two weak eyes, two eyebrows, a nose, twelve teeth, a tongue and lots of hair. When the main head pursed its lips, stuck out its tongue or blinked its eyelids, so did the parasitic head; when the main head ate, the parasite drooled. Neurosurgeons removed it. Certain parts of the developing body seem especially vulnerable to parasitism, among them the neural tube, sternum and mouth. Some forty cases have been described of children who have dwarfed and deformed parasites growing from their palates. And parasites may themselves be parasitised. In 1860 a child was born in Durango, Mexico, who had a parasite growing from his mouth to which two others were attached.

Teratomas may be an even more intimate form of parasitism. These are disordered lumps of tissue that are usually mistaken initially for benign tumors, but that after surgery turn out to be compacted masses of differentiated tissue, hair, teeth, bone and skin. They have been traditionally blamed on errant germ cells. Unlike most of the body’s cells, germ cells have the potential to become any other cell type, and it is supposed that occasionally a germ cell that has wandered into the abdomen will, perhaps by mutation, start developing spontaneously into a disordered simulacrum of a child. It is now suspected that some teratomas are, in fact, twins that have become fully enclosed within a larger sibling, a condition known trenchantly as ‘foetus in foetu’. A Dutch child born in 1995 had the remains of twenty-one foetuses (as determined by a leg count) embedded in its brain.

LEFT-RIGHT

There is one more thing that Ritta and Christina can tell us, and that is how we come to have a left and a right. We tend to think of ourselves as symmetrical creatures and, viewed externally, so we are. To be sure, our right biceps may be more developed than their cognates on the left (vice versa for the left-handed minority), and none of us has perfectly matched limbs, eyes or ears, but these are small deviations from an essential symmetry. Internally, however, we are no more symmetrical than snails. The pumping ventricles of our hearts protrude to the left sides of our bodies. Also on the left are the arch of the aorta, the thoracic duct, the stomach and the spleen, while the vena cava, gall bladder and most of the liver are on the right. Christina’s viscera were arranged much as they are in any of us (except for her liver, which was fused with Ritta’s). Ritta’s viscera, however, were not. They were the mirror-image of her sister’s.

This condition, known as situs inversus, literally ‘position inverted’, is common in conjoined twins, as it is rare in the rest of us (who are situs solitus). Not all conjoined twins are situs inversus, but only those that are fused side to side (rather than head to head or hip to hip). Even among side-to-side twins situs inversus is only ever found in the right-side twin – ‘right’ referring to the twins themselves not the observer’s view of them – and then only in 50 per cent of them. This last statistic is intriguing, for it implies that the orientation of the viscera is randomised in right-side twins. It is as if nature, when arranging their internal organs, abandons the determinism that rules the rest of us, and instead flips a coin marked ‘left’ or ‘right’.

In recent years, much has been learned about why our internal organs are oriented the way they are. One source of information comes from those rare people – the best estimates put them at a frequency of 1 in 8500 – who, despite being born without a twin, have internal organs arranged the wrong way round. The most famous historical case of singleton situs inversus was an old soldier who died at Les Invalides in 1688. Obscure in life – just one of the thousands who, at the command of Louis XIV, had marched across Flanders, besieged Valenciennes and crossed the Rhine to chasten German princelings – he achieved fame in death when surgeons opened his chest and found his heart on the right. In the 1600s Parisians wrote doggerel about him; in the 1700s he featured in the querelle des monstres debate; in the 1800s he became an example of ‘developmental arrest’, the fashionable theory of the day. Were he to appear on an autopsy slab today, he would hardly be famous, but would simply be diagnosed as having a congenital disorder called ‘Kartagener’s syndrome’.

It is a diagnosis that allows us to reconstruct something of the old soldier’s medical history. Although the immediate cause of his death is not known, it certainly had nothing to do with his inverted viscera. He was, indeed, in all likelihood oblivious to his own internal peculiarities. Although he was quite healthy (dying only at the age of seventy-two), he probably never fathered any children, and his sense of smell was also probably quite poor. We can guess these things because inverted viscera, sterility and a weak sense of smell are all features of men with Kartagener’s.

That the association between these symptoms was ever noticed is surprising, for they seem so disparate, and even after the syndrome was first defined in 1936 the causal link between them remained elusive for years. But in 1976 a Swedish physician named Bjorn Afzelius found that a poor sense of smell and sterility are caused by defective cilia – the minute devices that project from the surfaces of cells and wave about like tiny oars. Cilia clear particles from our bronchial passages, and the tail that drives a spermatozoon to its destination is also just a large sort of cilium. Each cilium is driven by a molecular motor, a motor that in people with Kartagener’s syndrome does not work. As children, for want of beating cilia to clear the passages of their lungs and sinuses they have chronic bronchitis and sinusitis – hence the poor sense of smell. As adults, the men are sterile for want of mobile sperm. At the heart of the ciliary motor lies a large protein complex called dyenin. It is made up of a dozen-odd smaller proteins, each of which is encoded by its own gene. So far Kartagener’s syndrome has been traced to mutations in at least two of these genes, and it is certain that others will be found.

But it is the situs inversus that is so intriguing. Afzelius noted that not all people with Kartagener’s syndrome have inverted viscera: like conjoined twins, only half of them do. He suggested, insightfully, that this implied that cilia were a vital part of the devices that the embryo uses to tell left from right – but what their role was he could not say. Only in the last few years has the final link been made – and even now there is much that is obscure. It all has to do with (and this is no surprise) the organiser.

I said earlier that the organiser is a group of mesodermal cells located at one end of the embryo’s primitive streak. Each of these cells has a single cilium that beats continually from right to left. Collectively they produce a feeble, but apparently all-important, current in the fluid surrounding the embryo, an amniotic Gulf Stream. This directional movement, and the cilia whose ceaseless activity causes it, is the first sign that left and right in the embryo are not the same. The mechanism, which was only discovered in 1998, is wonderfully simple and, as far as is known, is used nowhere else in the building of the embryo. What the cilia actually do is unclear; the best guess is that they concentrate some signalling molecule on the left side of the embryo, rather as foam accumulates in the eddies of a river.

This model (with its Aristotelian overtones) is frankly speculative, but it makes sense in the light of what happens next. Shortly after the organiser forms, genes can be seen switching on and left and right in the cells that surround it. They encode signalling molecules that transmit and amplify the minute asymmetries established by the organiser’s beating cilia to the rest of the embryo. One might call it a relay of signals, but that suggests something too consensual. It is more like a hotly contested election. In democracies left and right battle for the heart of the polis; so it is in embryos as well.

There is a lovely experiment that proves this. If the various signals that appear early in the embryo’s life on either side of the organiser are indeed involved in helping it tell left from right, then it should be possible to confuse the embryo by switching the signals around. As usual, this is a hard trick to do in mammal embryos, but not that difficult in chickens. By gently cutting open a recently-laid egg and so exposing the embryo as it lies on its bed of yolk, it is possible to gently place a silicone bead soaked in ‘left-hand’ signal on its right (or to place a bead soaked in ‘right-hand’ signal on its left). Either way, the asymmetry of the embryo’s signals is destroyed. And so too, it becomes apparent shortly thereafter, is the asymmetry of the chicken’s heart. Where once it always fell to the left, it now has an even probability of falling to either side. The resemblance of this randomisation to that found in people with Kartagener’s syndrome and in conjoined twins is surely no coincidence. Indeed, it is thought that Ritta’s inverted heart was caused by just such a scrambled molecular signal. When the girls were nothing more than primitive streaks lying side by side, each strove to order her own geometry. But in Ritta’s case this effort was confounded by signals that swept over from her left-hand twin. The molecular asymmetries upon which her future geometry depended were abolished, and from that point on the odds were fifty–fifty that her heart would be placed the wrong way round.

In 1974 Clara and Altagracia Rodriguez became the first conjoined twins to undergo successful surgical separation. Since then, the birth of each new pair – Mpho and Mphonyana (b.1988, South Africa), Katie and Eilish (b.1989, Ireland), Angela and Amy (b.1993, USA), Joseph and Luka (b.1997, South Africa), Maria Teresa and Maria de Jésus (b.2002, Guatemala), to name but a few – has been the occasion of a miniature drama in which surgeons, judges and parents have been called upon to play the part of Solomon. Surgical advances nothwithstanding, had Ritta and Christina Parodi been born today they could not have been separated. But they would surely have lived. Somewhere in America, Brittany and Abigail Hensel, twins even more closely conjoined than they, have recently turned twelve.

Jules Janin never wrote his novel of Ritta and Christina Parodi’s unlived lives. But he did leave an outline of what he had in mind. No translation could do justice to the turbulence of his prose, but a paraphrase gives an idea. In Janin’s world, far from being born to poverty (after all, ‘la misère gâte tout ce qu’elle touche’), the two girls are rather well off. They also, inexplicably, have different-coloured hair. Christina, who is blonde, strong and noble, watches tenderly over her weaker, slightly sinister sibling, who is, inevitably, the brunette. All is harmonious, but suddenly seventeen springs have passed and, arrive l’Amour, in the shape of a bashful Werther who loves, and is loved by, only one of them – Christina, of course. Ah, the paradox! Two women, one heart, one lover; it is too tragic for words. Ritta sickens, and a mighty struggle between life and death ensues, as when un guerrier est frappé à mort. The sisters expire and we leave them having, as Janin puts it, ‘arrived at new terrors, unknown emotions’, and a sense of relief that he never wrote the full version.

The reality was, of course, quite different. When Serres had done with Ritta and Christina he not only kept the skeleton but quite a few other body-parts as well. An old catalogue of the Muséum d’Histoire Naturelle lists, in a copperplate hand, separate entries for the infants’ brains (Cat. No. 1303 and 1304), eyes (1306, 1307), tongues (1308, 1309) and various other bits and pieces. Most of these specimens now seem to be lost, though it is possible that they will one day surface from the museum’s underground vaults. Ritta and Christina’s skeleton, however, is still around – as is the painted plaster-cast of their body. Both are on display in the Gallery of Comparative Anatomy, a steel-vaulted structure with an interior like a beaux-arts cathedral that stands only a few hundred metres from the amphitheatre where the sisters were first dissected.

A Gallery of Comparative Anatomy may seem like an odd place to exhibit the remains of two small girls. Nearly all of the hundreds of other skeletons there belong to animals, arranged by order, family, genus and species. Yet, from one point of view, there could hardly be a better place for them. The gallery represents the cumulative effort of France’s greatest naturalists to impose order upon the natural world; to put each species where it should be; to make sense of them. For Étienne Geoffroy Saint-Hilaire the study of congenital deformity was, in the first instance, much in this spirit – a matter of locating conjoined twins in the order of things. In a gesture that Geoffroy would have loved, Ritta and Christina’s remains share an exhibition case with a pair of piglets and pair of chicks that are conjoined much as they were. Such specimens were, to him, pickled proof that deformity is not arbitrary, a caprice of nature, a cosmic joke, but rather the consequence of natural forces that could be understood. ‘There are no monsters,’ he asserted, ‘and nature is one.’ In the way of French aphorisms, this is a little cryptic. But if you stand in front of the display case containing what is left of Ritta and Christina Parodi and look at the pink plaster-cast of the body with its two blonde heads and four blue eyes, it’s easy to see what he meant.