Mutants (10 page)

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.

C
YCLOPIA WITH CONJOINED TWINNING
. A
TTRIBUTED TO
L
EONARDO DA
V
INCI
. F
ROM
F
ORTUNIO
L
ICETI
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.

C
YCLOPIA
. S
TILLBORN
CALF
. F
ROM
W
ILLEM
V
ROLIK
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.

C
YCLOPIA
. S
TILLBORN
INFANT
. F
ROM
B.C. H
IRST AND
G.A. P
IERSOL
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.

W
ILD 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’.

D
UPLICATION OF FACE IN A PIG
: ‘D
ITTO
’.

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.