CYCLOPS WOOING GALATEA. FROM BLAISE DE VIGENèRE 1624
Les images Philostratus.
The first illustration of a cyclopic child, as distinct from a Cyclops, was given by Fortunio Liceti. In the 1634 edition of his De monstrorum he describes an infant girl who was born in Firme, Italy, in 1624 and who, he says, had a well-organised body but a head of horrible aspect. In the middle of her face, in place of a nose, there was a mass of skin that resembled a penis or a pear. Below this was a square-shaped piece of reddish skin on which one could see two very close-set eyes like the eyes of a chicken. Although the child died at birth she is depicted with the proportions of a robust ten-year-old, a legacy of the giants that preceded her.
Liceti describes another case of cyclopia as well, this time in a pair of conjoined twins whose crania are fused so that they face away from each other in true Janus style. Conjoined twinning and cyclopia is an unusual combination of anomalies, and one would be inclined to doubt its authenticity but for a 1916 clinical report of a pair of conjoined twins who showed much the same combination of features. And then there is the unusual provenance of Liceti’s drawing. It is, he says, a copy of one preserved in the collection of His Eminence the Reverend Cardinal Barberini at Rome, and the original, which now seems to be lost, was drawn by Leonardo da Vinci.
CYCLOPIA WITH CONJOINED TWINNING. ATTRIBUTED TO LEONARDO DA VINCI. FROM FORTUNIO LICETI 1634
De monstrorum natura caussis et differentiis.
Looking at his bottled babies, Willem Vrolik recognised that some were more severely afflicted than others. Some had only a single eyeball concealed within the eye-orbit, but in others two eyeballs were visible. Some had a recognisable nose, others had none at all. Modern clinicians recognise cyclopia as one extreme in a spectrum of head defects. At the other extreme are people whose only oddity is a single incisor placed symmetrically in their upper jaw instead of the usual two.
The single eye of a cyclopic child is the external sign of a disorder that reaches deep within its skull. All normal vertebrates have split brains. We, most obviously, have left and right cerebral hemispheres that we invoke when speaking of our left or right ‘brains’. Cyclopic infants do not. Instead of two distinct cerebral hemispheres, two optic lobes and two olofactory lobes, their forebrains are fused into an apparently indivisible whole. Indeed, clinicians call this whole spectrum of birth defects the ‘holoprosencephaly series’, from the Greek: holo – whole, prosencephalon – forebrain. It is, in all its manifestations, the most common brain deformity in humans, afflicting 1 in 16,000 live-born children and 1 in 200 miscarried foetuses.
CYCLOPIA. STILLBORN CALF. FROM WILLEM VROLIK 1844–49
Tabulae ad illustrandam embryogenesin hominis et mammalium tarn naturalem quam abnormem.
The ease with which foetuses become cyclopic is frightening. Fish embryos will become cyclopic if they are heated, cooled, irradiated, deprived of oxygen, or exposed to ether, chloroform, acetone, phenol, butyric acid, lithium chloride, retinoic acid, alcohol or merely table salt. In the 1950s an epidemic of cyclopic lambs in the western United States was caused by pregnant ewes grazing on corn lilies, a plant of the subalpine meadows which has leaves rich in toxic alkaloids. In humans, diabetic mothers have a two-hundred-fold increased risk of giving birth to cyclopic children, as do alcoholic mothers.
Most cases of cyclopia are not, however, caused by anything the mother did (or did not do) during her pregnancy. Mutations in at least four and perhaps as many as twelve human genes also cause some form of holoprosencephaly. One of these genes encodes a signalling protein called sonic hedgehog. This molecule received its name in the early 1980s when a mutant fruit fly was discovered whose maggot progeny had a surplus of bristles covering their tiny bodies. ‘Hedgehog’ was the obvious name for the gene, and when a related gene was discovered in vertebrates, ‘sonic hedgehog’ seemed the natural choice to a postgraduate student who perhaps loved his gaming-console too much. The sonic hedgehog mutations that cause cyclopia in humans are dominant. This implies that anyone who has just a single copy of the defective gene should have cyclopia or at least some kind of holoprosencephaly. But for reasons that are poorly understood, some carriers of mutant genes are hardly affected at all. They live, and pass the defective gene on to their children.
CYCLOPIA. STILLBORN INFANT. FROM B.C. HIRST AND G.A. PIERSOL 1893 Human monstrosities.
The fact that sonic hedgehog-defective infants have a single cerebral hemisphere tells us something important. When the forebrain first forms in the normal embryo it is a unitary thing, a simple bulge at the end of the neural tube – only later does it split into a left and right brain. This split is induced by sonic which, like so many signalling molecules, is a morphogen. During the formation of the neural tube, sonic appears in a small piece of mesoderm directly beneath the developing forebrain. Filtering up from one tissue to the next it cleaves the brain in two. This process is especially obvious in the making of eyes. Long before the embryo has eyes, a region of the forebrain is dedicated to their neural wiring. This region – the optic field – first appears as a single band traversing the embryo forebrain. Sonic moulds the optic field’s topography, reducing it to two smaller fields on either side of the head. Mutations or chemicals that inhibit sonic prevent this – thus the single, monstrous, staring eye of the cyclopic infant.
But sonic does more than give us distinct cerebral hemispheres. Mice in which the sonic hedgehog gene has been completely disabled have malformed hearts, lungs, kidneys and guts. They are always stillborn and have no paws. Their faces are malformed beyond cyclopic, reduced to a strange kind of trunk: they have no eyes, ears or mouths. These malformations suggest that sonic is used throughout the developing embryo, almost anywhere it is growing a part. It even seems to be used repeatedly in the making of our heads.
WILD TYPE MOUSE (LEFT); SONIC HEDGEHOG-DEFECTIVE MOUSE (RIGHT).
An embryo’s face is formed from five lumpy prominences that start out distinct, but later fuse with each other. Two of them become the upper jaw, two become the lower jaw, while one in front makes the nose, philtrum and forehead. These five prominences secrete sonic hedgehog protein. Sonic, in turn, controls their growth, and in doing so the geometry of the face. More exactly, it regulates its width. It sets the spaces between our ears, eyes and even our nostrils. We know this because chicken embryos whose faces are dosed with extra sonic protein develop unusually wide faces. If the dose is increased even further their faces become so wide that they start duplicating structures – and end up with two beaks side by side. Something like this also occurs naturally in humans. Several genetic disorders are marked by extremely wide-set eyes, a trait known as hypertelorism. One of these is caused by mutations in a gene that normally limits sonic’s activity. Patients with another hypertelorism syndrome even resemble the sonic-dosed chickens in having very broad noses, or else noses with two tips, or even two noses.
Disorders of this sort prompt the question of just how wide a face can be. If, as a face becomes wider and wider, parts start duplicating, might one not ultimately end up with a completely duplicated face – and so two individuals? It is not an academic question. One San Francisco-born pig arrived in the world with two snouts, two tongues, two oesophagi and three eyes each with an optic stalk of its own. It may have started out as two twin embryos that later conjoined in extraordinary intimacy. But given that the duplication was confined to the face and forebrain it may also have grown from a single primordial embryo, but one with a very wide head. The pig’s head is preserved in a jar at the University of California San Francisco, a suitable object for philosophical reflection. Was it one pig or two? It’s a question that would have stumped Aquinas himself. Not so the scientists who cared for the beast. They ignored the metaphysics, hedged their bets, and dubbed their friend(s) ‘Ditto’.
DUPLICATION OF FACE IN A PIG: ‘DITTO’.
SIRENS
Among the disorders that appear regularly in the great teratology collections
– the Vrolik devotes a whole cabinet to it – is a syndrome called sirenomelia. The name is taken from siren, the creatures that tempted Ulysses, and melia, for limb, but the English name, ‘mermaid syndrome’, is no less evocative. Instead of two good legs, sirenomelic infants have only one lower appendage – a tapering tube that contains a single femur, tibia and fibula. They resemble nothing so much as the fake mermaids concocted by nineteenth-century Japanese fishermen from the desiccated remains of monkeys and fish. More than Homeric echoes link cyclopia and sirenomelia. Just as cyclopia is a disorder of the midline of the face, a failure of its two sides to be sufficiently far apart, so sirenomelia is a failure in the midline of the lower limbs. A sirenomelic infant has neither a left nor a right leg but rather two legs that are somehow fused together.
SIRENOMELIA OR MERMAID SYNDROME IN A STILLBORN FOETUS. FROM B.C. HIRST AND G.A. PIERSOL 1893
Human monstrosities.
The causes of sirenomelia are still not entirely known. But recently two groups of scientists independently engineered mouse strains that were defective for a particular gene. Unexpectedly, when the mice were born they had no tails and, just as sirenomelic infants do, fused hind limbs. To all appearances they were mermaid mice.
The mermaid mice were made by deleting the CYP26A1 gene. It encodes an enzyme that regulates a substance called retinoic acid. Most of the important molecules that control the construction of the embryo – that are a part of the genetic grammar – are proteins, long chains of amino acids. Retinoic acid, however, is not. Rather it is a much smaller and simpler sort of molecule, just a hydrocarbon ring with a tail. It is also one of the more mysterious of the embryo’s molecules. Because it is not a protein it has been difficult to study. For one thing, it can’t be seen in the embryo. The special stains that can be used to visualise proteins can’t be used for hydrocarbon rings. And then, because it is not a protein there is no ‘retinoic acid gene’ – no single stretch of DNA that directly encodes the information needed to make it. Instead there are just genes which encode enzymes that manufacture retinoic acid or degrade it – a frustratingly indirect relationship between gene and substance.
Even so, there have long been hints that retinoic acid is important. Embryos manufacture their retinoic acid from vitamin A – the need of which has been clear since 1932, when a sow at a Texas agricultural college that had been fed a vitamin A-deficient diet gave birth to eleven piglets all of which lacked eyeballs. Conversely, the consequences of too much retinoic acid became apparent in the 1980s when a related molecule called isotretinoin was extensively prescribed for severe acne. The drug was taken orally, and though its teratogenic effects were by this time well known some women took it while unwittingly pregnant. In one study of thirty-six such pregnancies, twenty-three superficially normal infants were born, eight ended in miscarriages, and five infants were malformed, their defects including cleft palates, heart defects, disordered central nervous systems and missing ears.
Some scientists have tried to repeat this unplanned experiment by bathing animal embryos in retinoic acid and then looking for malformations. Often the outcome is just a miscellany of deformities, rather like those shown by isotretinoin-exposed infants. But sometimes the results can be spectacular. If a tadpole’s tail is amputated, it normally grows another one in short order. But if the tail is amputated and the stump is painted with a solution of retinoic acid, the tadpole grows a bouquet of extra legs. This experiment clearly shows that retinoic acid is powerful stuff. It also suggests that tadpoles may use retinoic acid to regulate their rears. It does not, however, prove it. One could object that retinoic acid is, in effect, an exotic sort of poison, one that interferes in a completely unnatural way with the normal course of the embryo’s progress.
Hence the importance of the mermaid mice. They give, for the first time, some real insight into what embryos use retinoic acid for. It seems it is a morphogen, one of the most important in the embryo. Indeed, one might almost call it an Über-morphogen that acts the length and breadth of the embryo. Being a hydrocarbon ring, however, it works rather differently from most other morphogens. Where protein-signalling molecules are too big to enter cells and so bind to receptors on their surfaces, retinoic acid penetrates the cell membrane and attaches to receptors within the cell that go right to the nucleus where they turn genes on and off.
Where does retinoic acid come from? And what, exactly, does it do? The CYP26A1 gene encodes an enzyme that degrades retinoic acid. Thus CYP26A1-defective mice have too much of it. Their mermaid-like limbs are caused by an anomalous surplus of retinoic acid in the embryo’s rear. The rear of an embryo is not the only place affected by high levels of retinoic acid. Sirenomelic infants and mice also usually have head defects – implying that retinoic acid is normally lacking there too. Indeed, it is currently thought that could the concentration gradient of retinoic acid across an embryo be seen, it would resemble a hill with a peak somewhere near the embryo’s future neck and slopes in all directions: sides, front and back. It would show a carefully constructed topography maintained by a balance of enzymes that make and degrade the morphogen, which in frogs with extra legs, mermaid mice, sirenomelic infants and foetuses exposed to acne-medications has been eroded away leaving only an ill-defined plateau.
THE CALCULATOR OF FATE
The morphogens that traverse the developing embryo – be they protein or hydrocarbon ring – provide cells with a kind of coordinate grid that they use to find out where they are and so what they should do and be. A cell is thus rather like a navigator who, traversing the wastes of the ocean, labours with sextant and chronometer to find his longitude and latitude. But there is one difference between navigator and cell: while the navigator’s referents, the stars and planets, are always where they should be, the cell’s sometimes are not. Sirenomelia and cyclopia are two instances where mutation has warped the universe that cells refer to or even caused its total collapse.
Yet even bearing this difference (inevitable when comparing the clockwork motions of the physical world with the jerry-built devices of biology) in mind, the analogy still has force. For all the constancy of the heavens, navigators have always lost their way – perhaps because the instruments by which they read the heavens become maladjusted. In the same way, the receptors which allow cells to perceive morphogens and measure their concentrations can also go awry – and any number of congenital disorders are caused by mutations that affect them.
But perhaps the deepest level of the analogy comes when we consider the calculations that navigators must make in order to establish where they are. Cells, too, calculate – and they do so with great precision, absorbing information from their environment, adding it up and arriving at a solution. This calculator – one might call it a calculator of fate – is composed of a vast number of proteins that combine their efforts within each cell to arrive at a solution. Of course, the calculator is not infallible: just as navigators occasionally get their sums wrong, so too, occasionally, do cells.
The consequences of cells making mistakes of this sort are beautifully illustrated by one of the more curious pieces of erotica dug from the ruins of Herculaneum. It is a small marble statue – no larger than a shoebox – that depicts Pan the goat-god, whom the Romans knew as Faunus, raping a nanny goat. Masterfully combining the animal and the human in equal parts, the unknown artist has given his Pan shaggy legs, cloven hooves, thick lips, a flattened snout and an expression of concentrated violence. He has also given the god an unusual anatomical feature. Suspended from his neck, just above the clavicles, are two small pendulous lobes that in life would be no more than a few centimetres long.
SUPERNUMERARY NECK AURICLES ON GOAT AND SATYR. PAN RAPING A GOAT. ROMAN COPY OF HELLENISTIC ORIGINAL, SECOND–THIRD CENTURY BC.
These lobes, which are very distinctive, only appear in Pans of the second or third century bc, or, as in this statue (now in the Secret Cabinet of the Naples Archaeological Museum), in later Roman copies of Greek originals. The innumerable go
at-gods who chase across the black- or red-figure vases of the Classical period wooing shepherds or grasping at nymphs do not have them, nor do the allegorical Pans of the Renaissance and Baroque such as those in Sandro Botticelli’s Mars and Venus or Annibale Carracci’s Omnia vincit Amor. Neck lobes would also be quite out of place in the beautiful but vapid Pans of the Pre-Raphaelites.
The origin of the god’s lobes is plain enough: they are echoed by an identical pair of appendages on his victim, the neck lobes frequently found on domesticated goats (German goatherds call them Glocken – bells). The sculptor of the original Pan Raping a Goat was clearly an acute observer of nature, and incorporated the lobes as one more detail to signify the goatishness of the god. Neck lobes, however, occur not only in goats but also, albeit rarely, in humans. In 1858 a British physician by the name of Birkett published a short paper describing a seven-year-old girl who had been brought to him with a pair protruding stiffly from either side of her neck. The girl had had them since birth. Birkett was not sure what they were, but he cut them off anyway and put them under the microscope, where he discovered that they were auricles – an extra pair of external ears.
SUPERNUMERARY AURICLES. EIGHT-YEAR-OLD GIRL, ENGLAND 1858. FROM WILLIAM BATESON 1894 Materials for the study of variation.
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