Mutants

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by Armand Marie Leroi


  Interpreting the meaning of mutations requires the adoption of a reverse logic that is, at first, counter-intuitive. If a mutation causes a child to be born with no arms, then, although it is tempting to speak of a gene for ‘armlessness’, such a mutation is really evidence for a gene that helps ensure that most of us do have arms. This is because most mutations destroy meaning. In the idiolect of genetics, they are ‘loss-of-function’ mutations. A minority of mutations add meaning and are called ‘gain-of-function’. When interpreting the meaning of a mutation it is important to know which of these you are dealing with. One way to tell is by seeing how they are inherited. Loss-of-function mutations tend to be recessive: they will only affect a child’s body when it inherits defective copies of the gene from both its parents. Gain-of-function mutations tend to be dominant: a child need have only one copy of the gene in order to see its effects. This is not an invariable distinction (some dominantly inherited mutations are loss-of-function) but it is a good initial guide. Gain or loss, both kinds of mutations reveal something about the function of the genes that they affect, and in doing so, reveal a small part of the genetic grammar. Mutations reverse-engineer the body.

  Who, then, are the mutants? To say that the sequence of a particular gene shows a ‘mutation’, or to call the person who bears such a gene a ‘mutant’, is to make an invidious distinction. It is to imply, at the least, deviation from some ideal of perfection. Yet humans differ from each other in very many ways, and those differences are, at least in part, inherited. Who among us has the genome of genomes, the one by which all other genomes will be judged?

  The short answer is that no one does. Certainly the human genome, the one whose sequence was published in Nature on 15 February 2001, is not a standard; it is merely a composite of the genomes of an unknown number of unknown people. As such, it has no special claim to normality or perfection (nor did the scientists who promoted and executed this great enterprise ever claim as much for it). This arbitrariness does not diminish in the slightest degree the value of this genomic sequence; after all, the genomes of any two people are 99.9 per cent identical, so anyone’s sequence reveals almost everything about everyone’s. On the other hand, a genome nearly three thousand million base-pairs long implies a few million base-pairs that differ between any two people; and it is in those differences that the interest lies.

  If there is no such thing as a perfect or normal genome, can we find these qualities in a given gene? Perhaps. All of our thirty thousand genes show at least some variety. In the most recent generation of the world’s inhabitants, each base-pair in the human genome mutated, on average, 240 times. Not all of these mutations change the meanings of genes or even strike genes at all. Some alter one of the vast tracts of the human genome that seem to be devoid of sense. Containing no genes that contribute to the grammar of the body, these regions are struck by mutation again and again; the scalpel slices but with no consequences to body or mind. Other mutations strike the coding regions of genes but do not materially alter the sequences of the proteins that they encode; these, too, are silent.

  Of the mutations that alter the meaning of genes, a small minority will be beneficial and will become, with time, more common. So common, in fact, that it is hardly fair to refer to them as ‘mutations’, and instead we call them ‘variants’ or, more technically, ‘polymorphisms’. In Africa, the Δ32 polymorphism of the CCR5 gene is currently increasing in frequency because it confers resistance to human immunodeficiency virus and so to AIDS. This is something new, but many polymorphisms are ancient. They are the stuff from which human diversity is made. They give us variety in skin colour, height, weight and facial features, and they surely also give us at least some of our variety in temperament, intelligence, addictive habits. They may cause disease, but mostly the diseases of old age such as senile dementia and heart attacks.

  How common does a mutation have to be before it becomes a polymorphism? The answer is a bit arbitrary, but if a variant sequence has a global frequency of 1 per cent or more it is assumed that it cannot have caused much harm in its history, and may even have conferred some benefit to its carriers. By this criterion, at least one polymorphism has been detected in about 65 per cent of the human genes in which they have been sought, but some genes have dozens. This variety should not overwhelm us. Most human genes have one variant that is far more common than all others, and it is quite sensible to speak of that variant as being normal, albeit only in the statistical sense.

  Perfection is far more problematic. The only reason to say that one genetic variant is ‘better’ than another is if it confers greater reproductive success on those who bear it; that is, if it has a higher Darwinian fitness than other variants. It is likely that the most common variant is the best under most circumstances, but this cannot be proved, for the frequencies of gene variants are shaped by history, and what was best then need not be best either now or in the future. To prefer one polymorphism over another – or rather to prefer the way it surfaces in our looks – is merely to express a taste. By this I mean the sort of claim made by the great French naturalist George Leclerc Buffon when he asserted that, for their fair skin and black eyes, the women of the Caucasus Mountains were lovelier than all others. Or when Karen Blixen eulogised the beauty of the Masai morani. Recognition of, even a delight in, human genetic diversity does not, however, commit us to a thorough-going genetic relativism. Many of the mutations that batter our genomes do us harm by any criterion.

  Each new embryo has about a hundred mutations that its parents did not have. These new mutations are unique to a particular sperm or ovum, were acquired while these cells were in the parental gonads and were not present when the embryo’s parents were themselves embryos. Of these hundred mutations, about four will alter the meaning of genes by changing the amino acid sequences of proteins. And of these four content-altering mutations, about three will be harmful. To be more precise, they will affect the ultimate reproductive success of the embryo, at least enough to ensure that, with time, natural selection will drive them to extinction.

  These are uncertain numbers: the fraction of deleterious mutations can only be estimated by indirect methods. But if they are at all correct, their implications are terrifying. They tell us that our health and happiness are being continually eroded by an unceasing supply of genetic error. But matters are worse than that. Not only are we each burdened with our own unique suite of harmful mutations, we also have to cope with those we inherited from our parents, and they from theirs, and so on. What is the total mutational burden on the average human being? The length of time that a given mutation will be passed down from one generation to the next depends on the severity of its effects. If we suppose that an average mutation has only a mildly deleterious effect upon reproductive success and so persists for a hundred generations, an estimate of three new mutations per generation yields the depressing conclusion that the average newly conceived human bears three hundred mutations that impair its health in some fashion. No one completely escapes this mutational storm. But – and this is necessarily true – we are not all equally subject to its force. Some of us, by chance, are born with an unusually large number of mildly deleterious mutations, while others are born with rather few. And some of us, by chance, are born with just one mutation of devastating effect where most of us are not. Who, then, are the mutants? There can be only one answer, and it is one that is consistent with our everyday experience of the normal and the pathological. We are all mutants. But some of us are more mutant than others.

  II

  A PERFECT JOIN

  [ON THE INVISIBLE GEOMETRY OF EMBRYOS]

  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.

  CONJOINED TWINS: PYGOPAGUS. JUDITH AND HéLèNE (1701–23). FROM GEORGE LECLERC BUFFON 1777 Histoire Naturelle GéNéRale Et ParticulièRe.

  CONJOINED TWINS: PARAPAGUS DICEPHALUS TETRABRACHIUS. RITTA AND CHRISTINA PARODI (1829). FROM ÉTIENNE SERRES 1832 Recherches d’anatomie transcendante et pathologique.

  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.

  CONJOINED TWINS: PARAPAGUS DICEPHALUS DIBRACHIUS. NORMANDY. FROM PIERRE BOAISTUAU 1560 Histoires prodigieuses.

  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.

 

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