Mutants

by Armand Marie Leroi

  Boys who are castrated before puberty grow up to be tall, unusually so. It is a fact that is largely lost to us now, but that would have been everyday knowledge in fourth-century Athens, a city pullulating with slaves culled from all corners of the Mediterranean, among them many eunuchs. It would also have been known to any fashionable eighteenth-century Italian. The monarchs of the great opera theatres such as La Scala were not, as now, the tenors, but rather the castrati. Feted for the range, power and unearthly quality of their voices, some castrati became rich, famous and influential. Farinelli sang for Phillip V of Spain and was given the title Caballero; Cafarelli became a duke and built a palazzo in Naples; Domenico Mustapha became a papal knight and Perpetual Director of the Pontifical Choir. Rossini, Monteverdi, Handel, Gluck, Mozart and Meyerbeer all wrote for them. When they sang, audiences cried ‘Eviva il coltello!’ – ‘Long live the knife!’– and swooned in the stalls.

  CASTRATO. SENESINO SINGING HANDEL’S FLAVIO, LONDON C.1723. ATTRIB. WILLIAM HOGARTH.

  The Italian castrati seem never to have been measured, so we do not know exactly how tall they were. But a wealth of anecdotes and images suggests that they were taller than their contemporaries, and somewhat oddly shaped. An engraving attributed to Hogarth shows a castrato performing a piece by Handel. Mouth ajar in soaring bel canto, ungainly limbs akimbo, he towers above his audience. It is a caricature, and a cruel one; all the more so as the castrati suffered from much more than physical inelegance. Beyond the direct consequences of the invariably brutal surgery and the bar to marriage and fatherhood, old age frequently brought severe kyphosis, the broken-back posture that is symptomatic of osteoporosis, otherwise mostly a disease of elderly women. Many castrati also developed large and pendulous breasts. True, they never went bald, and never got prostate cancer, but these were small compensations. In eighteenth-century Italy, some four thousand boys per year lost their testicles for the sake of their golden voices. Few can ever have found the rewards that might have justified the sacrifice.

  Why were the castrati so tall? Italian castrati fell from fashion and were banned by Pope Pius X in 1920; the last Vatican castrato, Alessandro Moreschi, died in 1922. But elsewhere hundreds, if not thousands, of men who had been castrated as boys survived well into the twentieth century. These were the court eunuchs, and there were many of them. At its demise, the Chinese Imperial family, last of the Qings, employed upwards of two thousand eunuchs in the Forbidden City at Peking. The last Chinese court eunuch, Sun Yaoting, was buried only in 1996 – along with his testicles, which had been carefully preserved in a jar. About two hundred eunuchs lived at the Topkapi palace in Istanbul until 1924, when the Sultan whom they had served was sent into exile, and many more must have been scattered about the vast territories once controlled by the Sublime Porte. In the 1920s some of these Istanbul eunuchs were carefully examined by a group of German physicians. What they found was distinctly odd. These elderly men, the last in a chain of eunuchs who had successively served Roman, Byzantine and Ottoman masters, had the bones of adolescents.

  As children approach late adolescence, the growth plates, source of the cells that drive the growth of bones, gradually become sealed over, and it is this that finally causes growth to stop. Radiography can show how far this process has gone, and can even be used to judge the ‘bone age’ of a child. Where an eight-year-old has wide growth plates at each end of his long bones, those of a fourteen-year-old are narrower, while those of an eighteen-year-old are nearly, if not entirely, occluded. A handful of radiographs showed that the Istanbul eunuchs had unsealed growth plates. The inference was clear, if slightly startling: for want of their testicles, they had never stopped growing.

  Testes, then, are not only the source of hormonal signals that regulate gender; they are also the source of at least one hormone that in late adolescence instructs bones to seal their growth plates and so cease growth. The nature of that hormone became apparent in 1994, when a Cincinnati clinician diagnosed a man who showed classical eunuchoid features – those disproportionately long limbs – despite having two perfectly intact and apparently healthy testes. Twenty-eight years old and 204 centimetres (six feet eight inches) in height, he was tall, but not remarkably so. What was peculiar is that, according to his driver’s licence, at the age of sixteen he had been only 178 centimetres (five feet ten inches) tall. Somewhere in the intervening twelve years he had gained nearly ten inches. The molecular fault, when traced, proved to be a surprise: a mutation in the estrogen receptor.

  We think of the estrogens – estradiol and estrone – as being quintessentially female hormones, and so they are. They are the hormones of breasts, periods, pregnancy and menopause. But men produce estrogens as well, and in large quantities; it is the stuff from which testosterone is made. Not all male estrogen is converted, and what remains appears to be critical in stopping the growth of bones. Two other men have been found in recent years – one in Japan, the other in New York – who cannot produce estrogens at all for want of an enzyme. They too were in their twenties and still growing fast. Conversely, children who produce an excess of estrogen tend to go through puberty very early. They grow fast but stop soon and remain short all their lives.

  But there must be more to stopping growth than estrogen. Testicular estrogen may instruct adolescent bones to fuse their growth plates and so cease growing, but men without estrogen or its receptor do not grow at a rate of nearly an inch per year for their entire lives. The eunuchs who guarded Ottoman harems, regulated the affairs of the Celestial Empire and bestrode the stage of La Scala may have been imposing figures, but they were not nine feet tall. This is probably because after adolescence, bloodstream levels of IGF-1 decline, causing a general slowdown in rates of cell division throughout the body. That it does so is probably just as well.

  ON BEING THE RIGHT SIZE

  Growth hormone and IGF are extremely powerful growth-promoting molecules. Vital if a child is to grow to the size that it should, they must also be continually kept in check. If they are not, growth spins out of control, and the result is growth without growth’s checks and balances, or, as it more commonly known, cancer.

  Among the body’s devices that curb IGF-1’s propensity to make cells proliferate is a protein called PTEN. Infants who are born with a single defective copy of the PTEN gene show, initially, little sign that anything is wrong with them; they have, at worst, slightly larger skulls than normal. The problems come later when, as inevitably happens, the second copy of the gene mutates in a few cells of the growing child. In these cells, and their descendants, a want of PTEN protein causes cell division to spin out of control; the result is an exotic array of tumors in the mucosal lining of the mouth, lower colon, breast, ovaries and thyroid and, oddly enough, hair follicles.

  These cancers are often fatal. But inheriting a defective copy of PTEN can have far more devastating consequences than this. Should the second mutation happen to occur in the first cells of the embryo (instead of in late childhood), a large fraction, perhaps even a half, of the infant’s body will be completely devoid of PTEN. The afflicted fraction of the body becomes, in effect, a single, enormous and inexorably spreading tumor.

  The condition is known as Proteus syndrome, named for the most versatile of Greek gods. ‘Some have the gift to change and change again in many forms,/Like Proteus, creature of the encircling sea/Who sometimes seemed a lad, sometimes a lion/Sometimes a snake men feared to touch, sometimes/A charging boar, or else a sharp-horned bull,’ wrote Ovid, who elsewhere calls the sea-god ‘ambiguous’. The syndrome is very rare, known from no more than sixty people worldwide. Children with Proteus syndrome appear normal at birth, but their faces and limbs become increasingly distorted with age as chaotic outgrowths of bone and soft connective tissue expand over their bodies, often just on one side. They have large tracts of creased and crenulated skin, particularly on the soles of their feet, and they usually die before the age of five. In some, the cerebral hemispheres of their brains grow lopsided and t
hey die of neural seizures; others cannot breathe because of overgrown ribs; yet others die when one of the many odd tumors to which they are prone becomes malignant. It is now believed that James Merrick, the so-called ‘Elephant Man’ who died in 1890 at the age of twenty-eight, had Proteus. If he did, then in one sense he was lucky to have lived for as long as he did.

  PROTEUS SYNDROME. JAMES MERRICK (1862–90).

  The intimate relationship between growth and cancer is shown by dogs. A Great Dane puppy has far more IGF circulating in its bloodstream than a Chihuahua puppy does, and grows nearly eight times faster to ten times the size. It pays a cost for doing so. Great Danes, Newfoundlands, St Bernards and many other giant breeds of dogs have a risk factor of osteosarcoma or bone cancer eighty times greater than do smaller breeds. The cancer nearly always begins in one leg, and usually only amputation will prevent its spread.

  Osteosarcoma is also one of the most common cancers in children. As in dogs, it usually begins in the leg bones, and then during the pubertal growth spurt when the cells of the growth plate are dividing most vigorously. In the Hunterian Museum, not too far from Charles Byrne’s skeleton, is a display cabinet containing a desiccated ribcage and larynx taken from a young man who died of advanced osteosarcoma. These macabre specimens have the added horror of being covered in hard, grey nodules resembling lumps of coal. They are secondary tumors, clumps of bone-producing cells that had metastasised from the primary leg tumor – which Hunter had attempted to cure by radical amputation. In children, as in dogs, size is a risk factor for osteosarcoma. More than 50 per cent of cases are found in children who are in the seventy-fifth centile for height at any given age.

  Big dogs and tall children may be more susceptible to cancers simply because they have more cells than smaller dogs and shorter children. More likely, however, it is probably not large size per se that is dangerous, but rather the high levels of growth hormone and IGF that big dogs and children tend to have. Pituitary tumors, of the sort that the giant Charles Byrne must have had as a child, occasionally appear in adults as well. As in Byrne’s case, they produce vast amounts of growth hormone, but this doesn’t cause an increase in height, since the long-bone growth plates have fused. Instead, only the bones of the jaws, hands and feet grow, a condition known as ‘acromegaly’. Often the first sign that an adult has a pituitary tumor is the need for ever-larger shoes. A pituitary tumor is a moderately dangerous and unpleasant thing in itself. But it also has a nasty indirect effect, causing elevated rates of colon, breast and blood cancers (leukaemias). These cancers are not caused by metastasis of the pituitary tumor, which is benign, but rather by something it does: namely, stimulate the entire growth-hormone-IGF system.

  Why this should cause high levels of cancer is not exactly clear, but one idea is that IGF stops sick cells from dying. Cells that are stricken with a potentially carcinogenic mutation often suicide. IGF overrides this altruistic impulse and so acromegalics, big dogs and tall children are relatively prone to cancers. It is as well to be clear about the magnitude of these risks. Of all the spectres that might assail a parent, childhood cancer is the least substantial. Osteosarcoma, though a pernicious and aggressive disease, is very rare: it afflicts only 1 in 300,000 children. The parents of tall teenagers should not worry; the owners of large dogs should.

  The bad news for big dogs does not end there. Many people buy health insurance for their pets so that their faithful companions do not bankrupt them as, in their dotage, the dogs require heart bypass surgery. Insurance companies, seeking as ever to minimise their risk, have collected vast databases on the health and mortality rates of their clients (the dogs, not the premium-paying humans) which show quite clearly that, independent of the risk of osteosarcoma, big dogs age faster than smaller dogs. Great Danes, Newfoundlands, and St Bernards have average lifespans of four to five years; Chihuahuas and toy poodles live about ten years longer. There are about four hundred distinct breeds of dogs: for every kilogram that one of these breeds is heavier than another, it loses eighteen days of life.

  These results seem to tell us that large size is generally unhealthy, but it is just a correlation. Dog breeds differ from each other in so many ways that it is difficult to attribute differences in longevity among them to differences in size alone. Ten thousand years of dog breeding is a magnificent natural experiment, but like all natural experiments, it isn’t really an experiment at all – at least not in the sense of being a controlled manipulation. Fortunately, a real experiment is at hand: dwarf and giant mice. The mutant mice that are so small for want of growth hormone also live up to 40 per cent longer than their normal-sized brothers and sisters. Conversely, mice that are genetically engineered to be giant age fast and die soon. Whatever the causes of the inverse association between body size and ageing, it seems to be found in all mammals.

  I am fascinated by these findings. If dogs and mice, why not people? Could it be that small people are genetically predisposed to live longer than taller people? Some scientists think so. They point to a family with defective pituitaries who live on the Adriatic island of Kruk and who seem to be (despite being both dwarfed and cretinous) rather longer-lived than the average Croatian. Or else to studies that show that the shortest American baseball players outlive taller ones by eight years. Maybe so, but the sample sizes in these studies are small, and large national surveys in Norway, Finland and Great Britain have consistently shown the opposite trend. This is hardly surprising. Socioeconomic factors account for most of a population’s variation in both height and health.

  To be poor is to be both short and at higher risk of nearly any disease you care to name. This effect simply overwhelms any genetic tendency for the opposite trend, if such a tendency indeed exists. Will the poor always be short? Perhaps not. Young Dutchmen are, on average, 184 centimetres (six feet) tall. This makes the Dutch the tallest people in the world, taller even than Dinka goatherds or Masai morani. And they are getting taller: by 2012 their men will be 186 centimetres (nearly six feet one inch) tall, their women 172 centimetres (five feet seven inches). Recently, tall activists have even managed to persuade the Dutch government to raise – by twenty centimetres – the ceiling levels specified in that nation’s building codes.

  This supremacy in centimetres is partly because Holland is a northern country rich in cows. Being northern, it has a population that tends to be genetically rather taller than, say, their southern neighbours the Belgians, who are in turn taller than their southern neighbours, the French. Dutch children also have a high consumption of animal protein – the product of all those placid black-and-white milk cows that give the Dutch landscape its characteristic look, and the Dutch atmosphere its characteristic tang. But Holland’s geographic peculiarities are probably not enough to explain the genial blond giants that can be seen in such numbers on its university campuses; for many years it has had a medical system that is excellent, efficient and egalitarian, if hard on its taxpayers’ wallets, and this must surely also contribute to the general stature of its young citizens. Most remarkably, it is no longer possible to judge the socio-economic background of Dutch children from their height. Decades of social engineering have eliminated the differences that have existed there (and everywhere else) for millennia. Égalité has begun to reach our very bones.

  But not in most countries. Elsewhere, the rich remain tall and the poor short. Young Englishmen are, on average, 176 centimetres tall, a full eight centimetres shorter than young Dutchmen. England is also an exception to the rule that northern peoples are taller than southern ones. The inhabitants of Holland may be taller than the French, and the farmers of Schezwan taller than the Cantonese, but Yorkshire man is shorter than Essex man, and the average Scot is shorter yet. Celtic vs. Saxon genes may make a difference, but most public health experts point to the relative poverty of northern Britain. Notoriously, the inhabitants of some especially forsaken Glasgow council estates can travel for five kilometres in any direction without finding so much as a cabbage for sale.


  The poverty and short stature of the north of England’s people is long-standing. More than 150 years ago, the northern cities of Leeds and Manchester became the site of the first serious investigation into the growth of British children when the social reformer Edwin Chadwick investigated the conditions of children working in the cotton mills. By modern standards, the factory children were remarkably small. Age-for-age, they were shorter than the shortest 3 per cent of modern British children, and the difference persisted, the average eighteen-year-old factory worker being only 160 centimetres (five feet three inches) tall. In 1833, the year that Chadwick published his report, the British Parliament passed a Bill against the employment of children under the age of nine.

  It is precisely the antiquity of the positive association between health and height that probably accounts for the pervasive attractions of height. From George Washington to George Walker Bush there have been forty-three US presidents, and forty of them have been taller than the average American male. James Madison was famously only 164 centimetres (five feet four inches), but then he was also the architect of his nation’s constitution. Presidential candidates are not taller than the people they aspire to govern simply because they are wealthier. Voters actively choose height as well: forty of the forty-three election-winners have been taller than their closest rivals. Women of all cultures seem to prefer men who are on average five centimetres (about two inches) taller than themselves. Professors, who may be expected to value the intellect above all things, behave in the same way. Full professors in American universities are on average three quarters of an inch taller than lowly assistant professors, and department chairmen are taller yet. When asked what height they should like to be, American men of even average height invariably wish themselves taller. And who can blame them?