Mutants (17 page)

A
ROUND
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.

T
HANATOPHORIC DYSPLASIA
. S
TILLBORN INFANT
, A
MSTERDAM
c. 1847. F
ROM
W
ILLEM
V
ROLIK
1844–49
T
ABULAE AD ILLUSTRANDAM EMBRYOGENESIN HOMINIS ET MAMMALIUM TAM NATURALEM QUAM ABNORMEM
.

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.

F
IBRODYSPLASIA OSSIFICANS PROGRESSIVA
. H
ARRY EASTLACK, USA
1953.

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.

F
IBRODYSPLASIA OSSIFICANS PROGRESSIVA
. H
ARRY
E
ASTLACK
(1930–73).

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.