Mutants (13 page)

MUTATIS MUTANDIS

The power of the homeotic genes over the number and kinds of body parts has led some scientists to propose that they must be important in evolution; that they have somehow, worms to whales, provided animals with their staggering variety of forms. There may be something to this. People with extra ribs, specifically those who have extra ribs located on what should be their necks, are, for example, a bit like snakes. Snakes don’t have necks at all: they have rib-bearing vertebrae that run all the way
to their heads. This is because the pattern of Hox gene activity in the somites of snake embryos is quite different from that of necked reptiles, birds and mammals – a difference that also explains, incidentally, why snakes don’t have arms. The position of arms, more generally fore-limbs, is dictated by the same Hox gene calculation that decides the allocation of vertebrae between neck and ribcage. No neck, no arms; it is as simple as that.

The beguiling quality of the homeotic genes has, however, less to do with differences among species than with similarities. These genes have a universality that is simply breathtaking. Flies use them to order their segments; we use them to sort out our vertebrae – but in both there is the common theme of ordering parts along the head-to-tail axis of the body. The similarities between the homeotic genes of vertebrates and insects also go far deeper than their general uses: they go right to the genome.

Homeotic genes come as clusters: groups of genes arrayed side by side on a single chromosome. The first few genes in the fly’s homeotic cluster are involved in giving the head segments of the fly their identities; the next few genes along do the same for the thoracic segments; and the last few do the same for the abdominal segments. There is, it seems, a uncanny correspondence between the order of genes on the chromosome and the order of the fly itself. So, too,
mutatis mutandis
, is it for us. We have four clusters of homeotic genes on four chromosomes against the fly’s one, but within each cluster the genes preserve the order along the chromosome that their cognates have in flies. Just as in flies, the first genes of each cluster are needed for our heads, the last for our tails, and the rest for the parts in between.

Why
the homeotic genes should work in this way, and why they should have stayed doing so, is not clear. Nevertheless, they point to a system of building bodies that evolved perhaps as much as a thousand million years ago in some worm-like ancestor and that has been retained ever since. Indeed, the homeotic genes were merely the first indication that many of the molecular devices that make our bodies are ancient. Over the last ten years it has become plain that we are, in many ways, merely worms writ large. A gene called ems is needed to make a fruit fly’s minute brain. So vast is the evolutionary gulf, both in time and complexity, between a fly’s brain and the hundred-thousand-million-neuron edifice perched upon our own shoulders, that one could hardly expect that the same devices are used in both. Yet mutations in a human cognate of ems cause an inherited disorder that results in a brain abnormally riven with fissures (and so mental retardation and motor defects). Another fly gene called eyeless is needed to make a fly’s compound eyes. Flies devoid of eyeless are, well, eyeless. So, in effect, are humans who inherit mutations in the cognate gene. They are born without irises.

In the cyclical way of intellectual fashion, all this has been said before, albeit far more obliquely. More than 150 years ago, that eccentric genius Étienne Geoffroy Saint-Hilaire – Linnaeus of deformity, discoverer of the universal law of mutual attraction – sought to construct a scientific programme, a
philosophic anatomique
, that would demonstrate that the animal world, seemingly so vast and various, was in fact one.

His initial goal was modest enough. Geoffroy attempted to show that structures that appear in mammals were the same, only modified, as those that appeared in other vertebrates, such as fish, reptiles and amphibians. In other words, he attempted to identify what we now call homologues, arguing, for example, that the opercular bones of fish (which cover the gills) were essentially the same as the tiny bones that make up the middle ears of mammals (the malleus, stapes and incus).

But opercular bones were small beer for a truly synthetic thinker: Geoffroy went on to find homologies between the most wonderfully disparate structures in the most wildly different creatures. Confronted with the exoskeleton of an insect and the vertebrae of a fish, he proposed that they were one and the same. To be sure, insects have an exoskeleton (all their guts inside their hard parts) while fish have an endoskeleton (bones surrounded by soft parts), but where other anatomists saw this as ample reason to keep them distinct, Geoffroy explained with the simple confidence of the visionary that ‘every animal lives within or without its vertebral column’. Not content with this, he went on to show how the anatomy of the lobster was really very similar to that of a vertebrate – if only you flipped it on its back. Where lobsters carry their major nerve cord on their ventral sides (bellies) and their major blood vessels on their dorsal sides (backs), the reverse is true for vertebrates. And then there was the curious case of cephalopods: if one took a duck and folded it in half backwards so that its tail touched its head (an exercise performed, I believe, on paper alone), did its anatomy not resemble that of a cuttlefish?

It did not. Geoffroy’s speculations attracted the wrath of Cuvier, his powerful rival at the Museum. The result was a debate in front of the Académie Française in 1829 that Geoffroy lost – a duck doesn’t look like a cuttlefish no matter how you bend it; even homologies between fish opercula and the mammalian middle ear didn’t bear serious scrutiny. Yet if the particular homologies that he proposed sometimes seemed absurd, even in his day, his general method was not. Different organisms
do
have structures that are modified yet somehow similar. Indeed, the idea of homology is so commonplace in biology today (we speak of homology among genes as easily as among fore-limbs) that it is easy to read into Geoffroy’s claims an evolutionary meaning he did not intend. The homologies that he saw, or thought he saw, were, as far as he was concerned, placed there by the Creator. It was the age of what would be called Transcendental Anatomy.

Today it is scarcely possible to study the development of any creature without comparing it to another. This is because animals, no matter how different they look, seem to share a common set of molecular devices that are the legacy of a common evolutionary history, that are used again and again, sometimes to different ends, but which remain recognisably the same wherever one looks. Indeed, the results of the genome sequencing projects suggest as much. Humans may have thirty thousand genes, but flies have thirteen thousand – a difference in number that is far smaller than one would expect given the seemingly enormous difference in size and complexity between the two species. Another creature much loved by developmental biologists, the
nematode worm
Caenorhabditis elegans
, has nineteen thousand genes – even though the adult worms are only 1.2 millimetres long and have bodies composed of only 959 cells.

Some of Geoffroy’s specific ideas are even being revived. One of these is his notion – on the face of it utterly absurd – that a vertebrate on its four feet is really just a lobster on its back. In the previous chapter I spoke of the signalling molecules that oppose each other to form the front and the back of vertebrate embryos. These same molecules – more precisely, their cognates or homologues – also distinguish back from belly in fruit flies; but with a twist. Where in a vertebrate embryo a BMP4 signal instructs cells to form belly, in flies the cognate molecule instructs cells to form back. And where in vertebrate embryos chordin instructs cells to form back, in flies the cognate molecule instructs cells to form belly. Somewhere in the evolutionary gulf that separates flies and mice there has, it seems, been an inversion in the very molecules that form the geometry of embryos, one that looks uncomfortably like the kind of twist that Geoffroy postulated. Absurd? Perhaps not. It is the sort of uncanny correspondence that one comes to expect in an age of Transcendental Genetics.

[O
N ARMS AND LEGS
]

O
F ALL THE DOCTRINES THAT HAVE BEEN OCCASIONED
by human deformity, none is more dismal than the belief that it is due to some moral failing. We can call this idea ‘the fallacy of the mark of Cain’. For killing his brother, so Judeo-Christian tradition has it, God marked Cain and all his descendants. An apocryphal text from Armenia gives Cain a pair of horns; a Middle Irish history gives him lumps on his forehead, cheeks, hands and feet, while the author of
Beowulf
makes him the ancestor of the monstrous Grendel. None of this can actually be found in Genesis, which is, by comparison, a dull read. There Cain’s punishment is exile, the mark is for his own protection, and its nature is left obscure. But then, the link between moral and
physical deformity has never really required biblical authority. It does not even require iniquitous parents. In 1999 the coach of the English national football team opined to an interviewer: ‘You and I have been physically given two hands and two legs and a half-decent brain. Some people have not been born like that for a reason. The karma is working from another life. What you sow, you have to reap.’ He took his cue from a Buddhist faith healer.

P
HOCOMELIA
. S
KELETON OF
M
ARC
C
AZOTTE, A.K.A.
P
EPIN
(1757–1801). F
ROM
W
ILLEM
V
ROLIK
1844–49
T
ABULAE AD ILLUSTRANDAM EMBRYOGENESIN HOMINIS ET MAMMALIUM TAM NATURALEM QUAM ABNORMEM
.

The fallacy of the mark of Cain flourished in Britain – football coaches aside – as recently as the seventeenth century. In 1685, in the remote and bleak Galloway village of Wigtown, two religious dissenters, Margaret McLaughlin and Margaret Wilson, were tried and convicted for crimes against the state. The infamy of their case comes from the cruelty of the method by which they were condemned to die. Both women were tied to stakes in the mouth of the River Bladnoch and left to the rising tide. Various accounts, none immediately contemporary, tell how they died. McLaughlin, an elderly widow, was the first to go; Wilson, who was eighteen years old, survived a little longer. A sheriff’s officer, thinking that the widow’s death-throes might concentrate the younger woman’s mind, urged her to recant: ‘Will you not say: God bless King Charlie and get this rope from off your neck?’

He underestimated the girl. Some accounts give her reply as a long and pious speech; others say she sang the 25th Psalm and recited Chapter 8 of Romans; all agree that her last words were pure defiance: ‘God bless King Charlie, if He will.’ The officer’s response was to give vent to his talent for vernacular wit. ‘Clep down among the partens and be drowned!’ he cried. And
then
he grasped his halberd and drowned her.

The executioner’s words are interesting. In the old Scottish dialect to ‘clep’ is to call; ‘partens’ are crabs. Thus: ‘Call down among the crabs and be drowned.’ In another version of the story, the officer was asked (by someone who had evidently missed the fun) how the women had behaved as the waters rose around them. ‘Oo,’ he replied in high humour, ‘they just clepped roun’ the stobs like partens, and prayed.’ Either way, it is here that the story slides from martyrology into myth. For it seems that shortly after the officer – a man named Bell – had done his cruel work, his wife gave birth to a child who bore the ineradicable mark of its father’s guilt: instead of fingers, its hands bore claws like those of a crab. ‘The bairn is clepped!’ cried the midwife. The mark of Bell’s judicial crime would be visited on his descendants, many of whom would bear the deformity; they would be known as the ‘Cleppie Bells’.

The spot at which the women are supposed to have died was marked by a stone monument in the form of a stake; today it stands in a reed-bed far from the water’s edge, the Bladnoch having shifted course in the intervening three centuries. Another, far more imposing, monument to the martyrs stands on a hill above the town, and their graves, with carefully kept headstones, may be found in the local churchyard. Here, as elsewhere, the Scots nurse the wounds of history with relish.

There are are other modern echoes of the event as well. As recently as 1900, a family bearing the names Bell or Agnew, and possessing hands moulded from birth into a claw-like deformity, lived in the south-east of Scotland and were said to be descendants of the Cleppie Bells. We know nothing more about them;
they may be there yet. We do know that in 1908 a large, unnamed family, living in London but of Scottish descent, were the subject of one of the first genetic studies of a human disorder of bodily form. Their deformity, known at the time as ‘lobster-claw’ syndrome, is certainly the same malformation that the Cleppie Bells had, though these days clinical geneticists eschew talk of ‘lobster claws’ and speak of ‘split-hand-split-foot syndrome’ or ‘ectrodactyly’, a term rendered palatable only by the obscurity of Greek, in which it reads as ‘monstrous fingers’. This second Scots family may have been related to the Cleppie Bells, but it is quite possible that they were not and that the deformity arose independently in the two families. At one end of this story there is the historical trial and death of Margarets Wilson and
McLaughlin, at the other there are the Cleppie Bells and a clinical literature. The mythical element, of course, lies in the causal connection between the two. Nothing that officer Bell ever did could have caused his descendants to be born with only two digits on each hand, widely spaced apart. If the Bells were clepped, it was because some of them carried a dominant mutation that affected the growth of their limb-buds while they were still in the womb: it certainly had nothing to do with the partens.