Mutants: On Genetic Variety and the Human Body

AROUND 1896, a Chinese sailor named Arnold arrived at the Cape of Good Hope. We do not know much about him, nor are there any extant portraits. We can, however, suppose that he was rather short and that he had a bulging forehead. He was probably soft-headed – not a reflection on his intelligence, but rather on the fact that he was missing the top of his skull. He probably did not have clavicles, or if he did, they may not have made contact with his shoulderblades. Had someone stood behind him and pushed, Arnold’s shoulders could have been induced to meet over his chest. He may have had supernumerary teeth or he may have had no teeth at all.

We can guess all this because Arnold was exceptionally philoprogenitive, and many of his numerous descendants carry these traits. Arriving in Cape Town, he converted to Islam, took seven wives, and submerged himself in Cape Malay society. The Cape Malays are a community of broadly Javanese descent, but one that has absorbed contributions from San, Xhoi-Xhois, West Africans and Malagasys within its genetic mix. Traditionally artisans and fishermen, the Cape Malays made the elegant gables of the Cape Dutch manors found on South Africa’s winegrowing estates, gave the nation’s cuisine its Oriental tang, and the Afrikaans language a smattering of Malay words such as piesang. A 1953 survey revealed Arnold’s missing-bone mutation in 253 of his descendants. By 1996, the mutation had been transmitted to about a thousand people. Fortunately, a lack of clavicles and the occasional soft skull are not very disabling. Arnold’s clan are, indeed, quite proud of their ancestor and his mutation.

MAKING BONE

Perhaps because they are the last of our remains to dissipate to dust, we think of bones as inanimate things. But they are not. Like hearts and livers, bones are continually built up and broken down in a cycle of construction and destruction. And though they seem so separate from the rest of our bodies, they originate from the same embryonic tissues that make the flesh that covers them. In a very real sense, bone is flesh transformed.

The intimate relationship between bones and flesh can be seen in the origin of the cells that make them. Most bone cells – osteoblasts – are derived from mesoderm, the same embryonic tissue that also gives rise to connective tissue and muscle. The relationship can also be seen in the way that bones form. Buried within each bone are the remains of the cells that made it.

Our various bones are made in two quite different ways. Flat bones, such as those of the cranium, start out in the embryo as a layer of osteoblasts that secrete a protein matrix. Calcium phosphate spicules form upon this matrix and encase the cells. As the bone grows, layers of osteoblasts are added and each is, in turn, entombed by its own secretions. Long bones, such as femurs, do things a bit differently. They start out as the condensations of cells that are visible in an embryo’s developing limbs. These cells, which are also derived from mesoderm, are called chondrocytes and they produce cartilage. The cartilage is a template for the future bone, one that only later becomes invaded by osteoblasts. When the template first appears, it is bone in form but not in substance.

One of the molecules that controls these condensations is bone morphogenetic protein (BMP). It is convenient to speak of it as one molecule, but it is really a family of them. Like so many families of signalling molecules, the BMPs crop up in the most unexpected places in the embryo. It is a BMP that, long before the bones are formed, instructs some the embryo’s cells to become belly rather than back. In older embryos, however, BMPs appear in the condensations of cells that will become future bones. In children and adults, they appear around fractured bones. The remarkable thing about BMPs is their ability to induce bone almost anywhere. If one injects BMPs underneath the skin of a rat, nodules of bone will form that are quite detached from the skeleton, but that look very much like normal bone, even to the extent of having marrow.

To make bone it is not enough that undifferentiated cells condense in the right places and quantities. The cells have to be turned into osteoblasts and chondrocytes. To return to a metaphor that I used earlier, they have to calculate their fates. The gene that calculates the fates of osteoblast happens to be the one responsible for ‘Arnold-head’. This gene encodes a transcription factor called CBFA1. It may be thought that CBFA1 is not very important, since mutations in it result only in a few missing bones. However, Arnold’s descendants are heterozygous for the mutation: only one of their two CBFA1 genes carries the mutant copy. Mice heterozygous for a mutation in the same gene also have soft heads and lack clavicles. But mice that are homozygous for the mutation are literally boneless. Instead of skeletons they have only bands of cartilage threading through their bodies, and their brains are protected by little more than skin. They are completely flexible and they are also dead. Boneless mice die within minutes of being born, asphyxiated for want of a ribcage to support their lungs.

By one of those quirks of genetic history, South Africa is also home to a mutation that has the opposite effect of Arnold’s: one that causes not a deficiency of bone, but rather an excess. Far from having holes in their skulls, the victims of this second mutation have crania that are unusually massive. The mutation’s effects are not obvious at birth. The thick skulls and coarse features that characterise this syndrome only come with age. Unlike the boneless mutation, the extra-bone mutation is often lethal. Its victims usually die in middle age from seizures as the excess bone crushes some vital nerve. Again, unlike the boneless mutation, the thick-skull mutation is recessive and so is expressed in only a handful of people – inbred villagers descended from the original Dutchmen who founded the Cape Colony in the seventeenth century.

The mutation that causes this disorder disables a quite different sort of gene from CBFA1. The protein itself is called sclerostin, after the syndrome sclerosteosis. It is thought to be an inhibitor of BMPs – perhaps it binds to them and so disables them. This is how many BMP inhibitors work. In the early embryo, organiser molecules such as noggin restrict the action of BMP in just this way. Indeed, noggin mutations are responsible for yet another bone-overgrowth syndrome that affects only finger-bones and causes them to fuse together with age, rendering them immobile.

Surplus-bone disorders illustrate the need that our bodies have to keep BMPs under control. Yet fused fingers and even thick skulls are relatively mild manifestations of the ability of BMPs to produce bone in inconvenient places. Another disease shows the extent of what can go wrong when osteoblasts proliferate throughout the body and make bone wherever they please. The disorder is known as fibrodysplasia ossificans progressiva or FOP. It is rare: estimates put the number of people afflicted with it worldwide at about 2500, but only a few hundred are actually known to specialists in the disease. Its most famous victim was an American man by the name of Harry Raymond Eastlack. In 1935, Harry, then a five-year-old, broke his leg while playing with his sister. The fracture set badly and left him with a bowed left femur. Shortly afterwards, he also developed a stiff hip and knee. The stiffness was not, however, caused by the original break, but rather by bony deposits that had grown on his adductor and quadriceps muscles.

As Harry grew older, the bony deposits spread throughout his body. They appeared in his buttocks, chest and neck and also his back. By 1946 his left leg and hip had completely seized up; his torso had become permanently bent at a thirty-degree angle; bony bridges had formed between his vertebrae, and the muscles of his back had turned to sheets of bone. Attempts were made to surgically excise the bone, but it grew back – harder and more pervasive than before. At the age of twenty-three, he was placed in an institution for the chronically disabled. By the time of his death in 1973, his jaws had seized up and he could no longer speak.

Harry Eastlack requested that his skeleton be kept for scientific study, and today it stands in Philadelphia’s Mutter Museum. Bound in extra sheets, struts and pinnacles of bone that ramify across the limbs and ribcage, the skeleton is, in effect, that of a forty-year-old man encased in another skeleton, but one that is inchoate and out of control. The cause of the disease is understood in general terms. The bodies of FOP patients do not respond to tissue trauma in the normal way. Bruises and sprains, instead of being repaired with the appropriate tissue, are repaired with osteoblasts and the new tissue turns to bone. This has all the hallmarks of an error in BMP production or control, but the mutation itself has not yet been identified. The search may well be a long one. FOP patients rarely have children, so the causal gene cannot be mapped by searching through long pedigrees of afflicted families.

GROWING BONES

A newly born infant has a skeleton of filigree fineness and intricacy, a skull as soft as a sheet of cardboard but scarcely as thick, and femurs as thin as pencils. By the time the child is an adult all this will have changed. The femur will have the diameter of a hockey stick, and will be able to resist the impact of one as well, at least most of the time. The skull will be as thick as a soup plate and capable of protecting the brain even when its owner is engaged in a game of rugby or the scarcely less curious customs of the Australian Aborigines who ritually beat each other’s skulls with thick branches.

What makes bones grow to the size that they do? In 1930 a young American scientist, Victor Chandler Twitty, tackled this question in a very direct way. Taking a cue from the German Entwicklungsmechanik, Twitty chose to study two species of salamanders: tiger salamanders and spotted salamanders. Closely related, they differ in one notable respect: tiger salamanders are about twice as big as spotteds. The experiment he carried out on them was of such elegance, simplicity and daring that seventy years later it can still be found in textbooks.

Twitty began by cutting the legs off his salamanders. The Italian scientist Lazzaro Spallanzani of Scandiano had discovered in 1768 that salamanders can regrow, should they need to, their legs and tails. Since then, thousands of the creatures have lost their legs to science. One luckless animal had a leg amputated twenty times – and grew it back each time. It is sometimes facetiously remarked among scientists that happiness is finding an experiment that works and doing it over and over again. Twitty, however, was more ingenious. As the stumps of his salamanders healed, and as their tissues reorganised into limb-buds, he once again put them to the knife. He then took the severed limb-buds of each species and grafted them onto the stumps of the other.

The question was, how big would the foreign limbs grow? There were, Twitty reasoned, two possibilities. As the grafted buds grew into legs, they might take on the properties of their host, or they might retain their own. If the first, then a spotted salamander limb-bud grafted onto a tiger salamander should grow into a hefty, tiger salamander-sized leg. Alternatively, the spotted salamander limb-bud might simply grow into the small leg that it usually does. The result would be tiger salamanders with three large legs and one tiny grafted one, and spotted salamanders with three tiny legs and one large grafted one – in short, lopsided salamanders.

Twitty expected that the foreign legs would grow as large as the host salamanders’ normal legs. By the 1930s it was known that hormones have an immense influence over human growth. One, produced by the pituitary gland, had even been dubbed ‘growth hormone’, and clinicians spoke of people with an excess or deficiency of this hormone as ‘pituitary’ giants and dwarfs. If tiger salamanders were larger than spotted salamanders, it was surely because they had more growth hormone (or something like it) than their smaller relatives. Foreign limbs should respond to the hormone levels of their hosts no less than ordinary limbs and should become accordingly large or small. The control of growth would be, in a sense, global – a matter of tissues being dictated to by a single set of instructions that circulate throughout the whole body.

There is no doubt that hormones do play a role – a vital role – in how large salamanders, people, and probably all animals become. But the beauty of Twitty’s experiment is that it showed that, however important hormones are, they are not responsible for the difference between large and small salamanders. Against expectation, his salamanders proved lopsided. It seemed as if the grafted limbs, in some ineffably mysterious way, simply knew what size they should be regardless of what they were attached to. It was an experiment that showed the primacy of the local over the global, and that each salamander leg contains within itself the makings of its own fate.

The reward of these experiments was, for Twitty, enduring fame of a modest sort. More immediately, in 1931 he got to go to Berlin. He went to work at the laboratory of Otto Mangold, husband of Hilda Pröscholdt of organiser fame, at the Kaiser Wilhelm Institute. There he met some of the great biologists of the day: Hans Spemann, Richard Goldschmidt and Viktor Hamburger, who together had made Germany pre-eminent in developmental biology. Neither Twitty’s research at the Kaiser Wilhelm, nor his later career as a much-loved Stanford professor, are of particular interest to us, but the time and the country are. Four hundred kilometres to the south, in Munich, another young scientist with similar research interests, but of a rather different stamp, had just started medical school. This was Josef Mengele.

AUSCHWITZ, 1944

The man whose name forever casts a shadow over the study of human genetics came from a well-to-do family of Bavarian industrialists. Handsome, smooth and intelligent, he refused to join the family firm and instead studied medicine and philosophy at Munich University. He was ambitious, and desired ardently to make a name for himself as a scientist, the first of his family. By the mid-1930s he had moved to Frankfurt where he became the protégé of Otamar Freiherr von Verschuer, head of another Kaiser Wilhelm Institute, but one devoted to anthropology. The dissertation that Mengele wrote there in 1935 reflects the prevailing obsession of German anthropology with racial classification and involved the measurement of hundreds of jawbones in a search for racial differences. Two later papers are about the inheritance of certain disorders such as cleft palate. All these works are dry, factual, and rather dull. They contain no hint of the young scientist’s future career.

Mengele arrived at Auschwitz on 30 May 1943. He had been urged to go there by his mentor, von Verschuer, and it was von Verschuer too who had urged Mengele to take advantage of the, as it was put to him, ‘extraordinary research opportunities’ he would find there. By the time he arrived at the concentration camp, it contained just over a hundred thousand prisoners and the killing-machine was fully engaged.

Mengele was only one of many medical staff at Auschwitz-Birkenau, and he was not particularly senior. But after the war, it would be Mengele whom the survivors would remember. They would remember him for his physical beauty, the exquisiteness of his uniform, his charm, and his smile. They would remember him for the unfathomable quality of his personality: he was a man who could speak kindly to a child and then send it to a gas chamber. They would remember him because he was ubiquitous, and also because he was often the first German officer they saw. As the prisoners stepped from the cattle-cars onto the platform at Birkenau, they would hear him shout ‘Links‘ or ‘Rechts‘. ‘Left’ and they would die immediately, ‘Right’ and they were spared, at least for a time.

Among those spared was a thirty-year-old Jewish woman named Elizabeth Ovitz. She and her siblings arrived at Auschwitz-Birkenau on the night of 18 May 1944. They were brought there in a cattle-car containing eighty-four other people. Weak and disoriented from the journey, the Ovitzes stood on the Birkenau railway platform under the glare of arc lights. Elizabeth asked a prisoner, a Jewish engineer from Vienna, where they were. He replied, ‘This is the grave of Israel,’ and pointed to the smokestacks that towered over the camp. Forty-three years later she would write: ‘Now we realised everything that we knew before, and had tried to erase from our consciousness, would actually come about.’ Elizabeth and her siblings, twelve in all, were herded to one side. It was then that they met Mengele. Surveying them with fascination he declared: ‘Now I will have work for the next twenty years; now science will have an interesting subject to consider.’

The Ovitzes were Transylvanian Jews. Their father, Shimshon Isaac Ovitz, had been a scholar and Wonder-rabbi. He had a form of dwarfism called pseudoachondroplasia that leaves much of the body unaffected but causes the limbs to grow short and bowed. Rabbi Ovitz was renowned for his wisdom and compassion. Many Romanian Jews believed that, having been denied normal height by God, he was instead endowed with extraordinary and rare virtues. Amulets containing bits of parchment decorated in his finely curling Rashi script were said to have healing powers. Rabbi Ovitz had nine children of whom seven, including Elizabeth, were dwarfed. This is consistent with a diagnosis of pseudoachondroplasia, which is caused by a dominantly inherited mutation.

When Elizabeth was nine years old, her father died suddenly. His young widow, a resourceful woman, reasoned that the short stature of her children could be used to their advantage and gave them a musical education so that they could eventually form a troupe. Even as Romania and Hungary were drawn within the orbit of Nazi Germany, the Ovitz family took their ‘Jazz Band of Lilliput’ through the provincial towns of the fragmented and unstable states of Central Europe. In May 1942 Elizabeth Ovitz, now twenty-eight, met a young theatre manager named Yoshko Moskovitz. He was tall and handsome and besotted with her. He wrote to his sister that he had met a woman, small in size, but well endowed with talent, wisdom and industriousness. They married in November of the same year, but only ten days after the wedding Yoshko, a yellow Star of David on his coat sleeve, was drafted into a labour battalion. The couple would not see each other again until after the war. Concealing their Jewish identities, the Ovitzes continued to tour for another two years, but in March 1944 German troops occupied Hungary and, as the last and greatest of all pogroms rolled across the country, they were caught.

At Auschwitz, Elizabeth and her siblings were kept in a separate room so that they would not be crushed by the other five hundred inmates of the block; they were also allowed their own clothes and enough food to live on. For a while they were able to stay together as a family, and managed to persuade Mengele that they were related to another family from their village. They paid for survival by being given starring roles in Mengele’s bizarre and frenetic programme of experimental research.

As Elizabeth Ovitz would write: ‘the most frightful experiments of all [were] the gynaecological experiments. Only the married ones among us had to endure that. They tied us to the table and the systematic torture began. They injected things into our uterus, extracted blood, dug into us, pierced us and removed samples. The pain was unbearable. The doctor conducting the experiments took pity on us and asked his superiors to stop them, otherwise our lives would be in jeopardy. It is impossible to put into words the intolerable pain that we suffered, which continued for many days after the experiments had ceased.

‘I don’t know if our physical condition influenced Mengele or if the gynaecological experiments had simply been completed. In any event, the sadistic experiments were halted, and others begun. They extracted fluid from our spinal chord and rinsed out our ears with extremely hot or cold water which made us vomit. Subsequently the hair extraction began again and when we were ready to collapse, they began painful tests on the brain, nose, mouth and hand regions. All stages of the tests were fully documented with illustrations. It may be noted, ironically, that we were among the only ones in the world whose, torture was premeditated and “scientifically” documented for the sake of future generations…’

In this, however, Elizabeth was wrong. Mengele tortured many other people as well, including a large number of twins whom he ultimately killed and dissected for the sole purpose of documenting the similarity of their internal organs. The Ovitz family walked the tightrope of Mengele’s obsessions for seven months. Once, when Mengele unexpectedly entered the compound, the youngest of the family, Shimshon, who was only eighteen months old, toddled towards him. Mengele lifted the child into his arms and softly enquired why the child had approached him. ‘He thinks you are his father.’ ‘I am not his father,’ said Mengele, ‘only his uncle.’ Yet the child was emaciated from the poor food and the incessant blood sampling.

Mengele displayed the Ovitzes to senior Nazis. He lectured on the phenomenon of dwarfism and illustrated it with the family, who stood naked and shivering on the stage. The experiments continued until October 1944. Even as the Third Reich entered its death-throes, Mengele still brimmed with maniacal purpose, producing a collection of glass eyes from which he sought a match to Elizabeth’s brown ones. As with all he did, his reason for doing so remains unfathomable.

Auschwitz was liberated on 27 January 1945. For Elizabeth and her family the arrival of Soviet troops lifted a sentence of certain death. Nearly all of Mengele’s experimental subjects were killed once he had done with them. During the following four years the family would shuttle about the wreckage of Eastern and Central Europe. Reforming their troupe, they choreographed a grim tango that they called their Totentanz. Each night Elizabeth, partnered by one of her brothers, would dance the part of Life to his Death. In 1949 the family emigrated to Israel. Elizabeth Ovitz died in Haifa in 1992. Josef Mengele was never tried for his crimes, but died on a Brazilian beach in 1979.

THE BRAKE

Of the many grim ironies that the history of the Ovitz family presents us with, perhaps the greatest is that when Josef Mengele perceived that they were remarkable, he was right. People with disorders such as pseudoachondroplasia do tell us something important about how bones grow to the lengths that they do, and how tall we become. Mengele did not discover what this is, nor could his pointless experiments ever have told him. But half a century later it is clear that the stubby, bent and warped limbs that are the consequence of so many bone disorders speak of the phenomenon that Victor Twitty discovered: the local control of growth.

Nowhere is the dynamic nature of bone more apparent than at the ends of an infant’s long bones. Each end has a region, the growth plate, from which the bone grows. Unlike the rest of the bone, which is encased in calcium phosphate, the growth plates are soft and uncalcified. On a radiogram they appear as transverse shadows that bisect the white tips of each bone. They can be seen throughout childhood and adolescence, ever decreasing in size, until by age eighteen or so they become sealed over and linear growth stops.

Each growth plate contains hundreds of columns of chondrocytes dividing and differentiating in lock step. Born at the end of the growth plate furthest away from the bone-shaft, they then swell with proteins from which they spin a cartilaginous matrix around themselves and then die. Osteoblasts march over the graves of chondrocytes, deposit calcium phosphate and yet more matrix, and at both ends the bone pushes ever further out into space.

Pseudoachondroplasia – the disorder that afflicted the Ovitzes – throws this sequence of events into disarray. The mutation occurs in a gene that encodes one of the proteins that goes into the cartilaginous matrix that chondrocytes make. Instead of being secreted, hoewever, the mutant protein accumulates in the chondrocytes, poisoning and killing them long before their time. Not all of the chondrocytes die, but the toll is enough to drastically slow growth. The result is short, bent limbs, but a torso and face that are hardly affected at all.

Pseudoachondroplasia is only one of several disorders that cause very short limbs. Another is the disorder with which it was long confused – achondroplasia itself. From Ptah-Pataikoi, dwarf deity of youth, creation and regeneration in Egypt’s New Kingdom (1539–750 BC) to television advertisements for carbonated soft-drinks, there is no more common disorder in the iconography of smallness. Like its namesake, achondroplasia is caused by a shortage of chondrocytes travelling up the growth plate – but a shortage that has a very different origin.

Achondroplasia is caused by a mutation in a receptor for fibroblast growth factors. FGFs are the signalling molecules involved in the molecular clock regulating the near to the far axis of the foetal limb. After birth, however, FGFs, far from promoting the outgrowth of the limb, inhibit it.

We know this because 99 per cent of all cases of achondroplasia are caused by a mutation in which an amino acid (a glycine) at a particular location in the FGFR3 protein sequence (position 380) is replaced by another (an arginine). This mutation has the peculiar property of causing the FGFR3 molecule to become hyperactive. Nearly all of the mutations discussed in this book cause a deficiency in the quantity or efficacy of some protein, often by causing it to be completely absent. If the protein is a signalling molecule like FGF, the disorder that we see is due to an absence of some critical piece of information that the cells require. The achondroplasia mutation is, however, different in that it occasionally causes the receptor to transmit a signal into the interior of the cell even if no FGF is bound to it. The effect is like a switch that spontaneously flips on when it should be off, and that transmits a blast of unwanted information to the cells of the growing limb.

If an excess of FGF signalling causes limbs to be unusually short, then the usual role of FGFs must be to act as a brake on the growth of the infant limb. They do this by limiting the rate at which the cells of the growth plate divide. The bones of achondroplastic children have growth plates that are only a fraction of the size they should be. They contain far fewer dividing chondrocytes than those of normal children, and fewer yet that swell and form cartilage.

Achondroplasia is a relatively mild disorder. However, a surplus of FGF signalling can, in the extreme, have terrible consequences. Among the many skeletons in Amsterdam’s Museum Vrolik is one that belonged to a male infant stillborn sometime in the early 1800s. When you look at the skeleton, now labelled M715, you can see quite clearly that there is something the matter with it. The child’s vertebrae, ribs and pelvis are all truncated, bowed or flattened, and the skull is enormously enlarged. In his great 1849 teratological treatise, Willem Vrolik depicts the child’s forehead as a large tuberose object. The stunted limbs and the large head are both characteristic of ‘thanatophoric dysplasia’ – death-bringing dysplasia. As the name suggests, it is fatal at birth.

Thanatophoric dysplasia is also caused by activating mutations in the FGFR3 gene, but of a far more destructive variety than those responsible for achondroplasia. The havoc they wreak shows that FGFs control the growth not only of the limbs, but of some other parts of the skeleton as well, such as the skull. The mildly domed foreheads of many achondroplastic dwarfs remind us that their disorder is a weaker version of a lethal one. Should a foetus inherit two copies of the achondroplasia mutation (by virtue of having two achondroplastic parents), it too will die shortly after birth with all the symptoms of thanatophoric dysplasia.

FGF must be only one molecule among many that limit the growth of this or that part of the body. Every organ must have devices that tell it to stop growing, and many will be unique to particular organs. There is hardly a part of the body that is not stunted or overgrown in some genetic disorder or other. Some mutations cause children to be born with tongues that are too large for their mouths; others result in intestines that do not fit inside abdominal cavities. Even muscles have their own devices for regulating growth. Belgian blues, a breed of beef cattle, are remarkable for having about a third more muscle than normal cows; their flanks resemble the thighs of Olympic weightlifters. They lack a protein called myostatin (related, as it happens, to BMPs) that instructs muscles to stop their growth. Myostatin-defective mice have about two or three times the normal muscle mass, but this gain seems to be bought at the expense of growth elsewhere, since they also have smaller than normal internal organs. Myostatin-defective people surely also exist, but there seems to be no record of them. Perhaps extra muscles are not noticed or, if noticed, are not something worth worrying about.

RENEWAL

The pseudoachondroplasia gene encodes one part of the matrix that chondrocytes spin about themselves. But it is only a minor one. Indeed, mice in which the protein has been engineered out altogether seem to suffer no ill-effects at all. One has to wonder just what it’s doing there in the first place. Not so for the rest of the matrix. Most of the cartilage is made of collagen. Humans have about fifteen different types of collagens that make up about a quarter of the total protein in our bodies. Collagens are found in our connective tissue and skin. They are the stuff that holds our cells together. And they give bone much of its flexibility and strength.

Mutations that disable bone collagens cause a disorder called osteogenesis imperfecta. There are at least four forms of the disease, some of which are lethal in infancy. The most characteristic symptom of the disorder is the extreme fragility of its victim’s bones. For this reason it is often known as ‘glass bone disease’. The mutations have their devastating effects because of the hierarchical nature in which collagens are organised. Any given collagen protein is made up of three peptides – strings of amino acids – wrapped together in a triple helix. The triple helices are in turn grouped together in enormous fibrils that, woven together, make up the structure of connective tissue and cartilage. Each peptide is encoded by a different gene, but a single mutant gene can wreck any number of triple helices, and so any number of fibrils, and so any number of bones.

Osteogenesis imperfecta is the disorder that afflicted the French painter Achille Empéraire (1829–98), who was himself painted by Cezanne, and the French jazz pianist Michel Petrucciani (1962–99). These artistic associations have lent the disorder, at least in France, a spurious romance (the ‘glass-bone man’ in Jean-Pierre Feunet’s film Le fabuleux destin d’Amélie Poulain springs to mind). The reality is more mundane. Children with osteogenesis imperfecta often suffer minor bone fractures of which their parents are quite unaware. When, after a more severe fracture, the children finally wind up in hospital, radiographs reveal a long history of broken and healed bones. Suspicions of child abuse often follow. In the United States, afflicted children have been taken into care by over-zealous social workers; some parents have even been jailed.

Even once our growth plates are sealed and growth has stopped, there is no rest for the skeleton. The interiors of most adult bones are fully replaced every three or four years, while their outer peripheries, being harder, turn over about once every decade. This cycle of destruction and renewal is the product of an engagement between osteoblasts and other cells that continually wear the skeleton away, taking minute bites from its fabric and reducing it to its constituent parts, rather in the manner of so many chisels. These are the osteoclasts: giant cells that attach to fragments of bone and dissolve them using protein-chewing enzymes and hydrochloric acid. Bones may be built by osteoblasts, but they are carved by osteoclasts, for it is these cells that hew the ducts, channels and cavities through which nerves and blood vessels thread, and bone marrow percolates.

There are many ways to upset the balance between growth and destruction that is found in every bone. An excess of bone may be due to an excess of osteoblasts, but it can also be caused by a want of osteoclasts. Osteopetrosis, literally bones-like-rock, is an osteoclast disorder, the opposite of the far more familiar osteoporosis that is the bane of post-menopausal women. Having bones-like-rock can be lethal. There is a particularly harsh variety of the disorder that affects children and usually kills them before they turn twenty. Often they die of infections because bone accretes in the cavities where marrow is manufactured, marrow being one of the main sources of immune-system cells. Somewhat paradoxically, the bones of people with osteopetrosis also tend to fracture rather easily, the probable consequence of an architecture that has gone awry. And when fractures do occur they are not easily repaired, for among the things that osteoclasts do is to smooth away the jagged edges of our bones should we break them.

Osteopetrosis, albeit of a fairly mild variety, is thought by some to be responsible for the shortness of Henri de Toulouse-Lautrec. This is just one of several retrospective diagnoses – achondroplasia and osteogenesis imperfecta among them – that have been attempted of the French painter. None is particularly convincing, but then bone disorders are so many, and their symptoms so various and subtle, that they are easily mistaken for one another, particularly when all we know of the patient comes from biography, a handful of photographs, and a selection of self-portraits, mostly caricatures. Yet the search for ‘Lautrec’s disease’ goes on. Part of his fascination, particularly for French physicians, comes from the fact that he was a scion of one of France’s most noble houses, the Comtes de Toulouse-Lautrec, a dynasty of rambunctious southern noblemen who had, at one time or another, ruled much of Rouergue, Provence and the Languedoc, sacked Jerusalem, dabbled in heresy, been excommunicated by the Pope (on ten separate occasions) and, in the thirteenth century, felt the military wrath of the French Crown. But more than this, the impulse to diagnose Henri Toulouse-Lautrec comes from the belief that this gifted painter made his deformity part of his art.

There may be something to this. As one walks through the Musée d’Orsay in Paris or else the museum at Albi, not too far from Toulouse itself, which is dedicated to his work, what strikes you are the nostrils. In painting after painting – of the dancer La Goulue, the actress Yvette Guilbert, the socialite May Milton, or the many other anonymous Parisian demi-mondaines who inhabit Lautrec’s art – what we see are nostrils, gaping, dark and cavernous. It is hardly a flattering view, but perhaps it is one that would have come quite naturally to the artist, for he was rather short. By the time he was full grown, Lautrec was only 150 centimetres (four feet eleven inches) tall. Critics have also argued that Lautrec’s disorder had a more subtle effect on his art: a tendency after 1893 to truncate the limbs of his models so that only the heads and torsos remain in the frame, a device for excluding that part of his own anatomy that he would much rather forget: his legs.

Lautrec’s legs caused him much grief. He seems to have had a fairly healthy childhood, but by the time he was seven his mother had taken him to Lourdes, where she hoped to find a cure for some vaguely described limb problem. He was stiff and clumsy and prone to falls, and only went to school for one year, leaving when he proved too delicate for schoolyard roughhousing. By the age of ten he was complaining of constant severe pains in his legs and thighs, and at thirteen minor falls caused fractures in both femurs which, to judge from the length of time during which he supported himself with canes, took about six months to heal. He would use a cane nearly all his adult life; indeed, friends believed that he walked any distance only with reluctance and difficulty.

As he grew, Lautrec also underwent some unusual facial changes. A pretty infant, and a handsome boy, he later developed a pendulous lower lip, a tendency to drool, and a speech impediment rather like a growling lisp, and his teeth rotted while he was still in his teens – traits which his parents, who were notably good-looking, did not share. He was self-conscious about his looks, wore a beard all his adult life, and never smiled for a camera. Many critics have argued that it was a sort of physical self-loathing that caused him to seek and portray all that was most vicious and harsh in his milieu. But then, fin-de-siècle Paris could be a vicious and harsh place. One night at Maxim’s, when Lautrec had sketched some lightning caricatures of his neighbours, one of them called to him as he hobbled away. ‘Monsieur,’ he said, gesturing to a pencil stub left on the table, ‘you have forgotten your cane.’ On another occasion, looking at one of the many portraits he had done of her, Yvette Guilbert remarked, ‘Really, Lautrec, you are a genius at deformity.’ He replied, ‘Why, of course I am.’

Lautrec is thought to have been afflicted by a variety of osteopetrosis called pycnodysostosis. It is caused by a deficiency in the enzyme that osteoclasts use to dissolve the protein matrix of bones. During adulthood the activity of this enzyme is partially repressed by hormones, and it is the declining levels of estrogen in post-menopausal women – and hence the unwarranted activity of the enzyme – that causes osteoporosis. Lautrec was diagnosed with pycnodysostosis in 1962 by two French physicians, Pierre Maroteaux and Maurice Lamy, but their claim has not gone unchallenged. Lautrec’s most recent biographer, Julia Frey, concedes that at least some of his symptoms are consistent with the disorder, but points out that others are not. Where pycnodysostosis patients typically have soft heads – rather in the manner of the boneless Cape Malays – there does not seem to be any evidence that Lautrec’s head was anything but solid.

Whatever his disorder, it seems that he shared it with several other members of his family. By the time Henri Marie Raymond, Comte de Toulouse-Lautrec-Montfa, was born in 1864 his family, though still rich, was quite inbred. The Napoleonic abolition of primogeniture had prompted an already much-reduced French nobility to keep what wealth remained in their families by the simple expedient of not marrying out of them. Henri’s parents were first cousins, as were his aunt and uncle: between them they produced sixteen children, of whom four including Henri were dwarfed, the other three far more severely than he. Indeed, it is likely that at least some surviving members of that noble house still carry the mutation, though it is not likely to be expressed if they have discontinued their consanguineous habits.

Lautrec himself had no doubts about the ultimate cause of his malady. One night, in one of his favourite haunts, Montmartre’s Irish and American Bar, two women were arguing about a pitiful dog whose legs shook from hip dysplasia. The dog’s owner conceded that the animal wasn’t handsome, but insisted nevertheless that it was pure-bred. ‘Are you kidding, that dog has a pedigree? Have you taken a look at his ugly fur and his twisted feet?’ laughed her friend. ‘He makes you feel sorry for him.’ ‘You obviously don’t know anything about it,’ said the dog’s owner, and turned to Henri who was sitting next to her. ‘Tell her, Monsieur, that my dog can perfectly well be ugly and still be pedigreed.’ Henri, getting down from his high barstool and standing up to his full four feet eleven inches, saluted her with a charcoal-stained hand and murmured, ‘You’re telling me.’