Mutant (II)

Most bone cells – osteoblasts – are derived from mesoderm, the same embryonic tissue that also gives rise to connective tissue and muscle.

Bone Morphogenetic Protein (BMP): instruct some embryo’s cells to become belly rather than back before the bones are formed, then appear in the condensations of cells that will become future bones.

the gene, which encodes a transcription factor called CBFA1, calculates the fates of osteoblast happens to be the one responsible for ‘Arnold-head’ (heterozygous – missing bones, homozygous – die). In South Africa it is quite opposite, due to excess BMPs, victims usually have recessive extra bones.

Fibrodysplasia ossificans progressiva (FOP): Bruises and sprains, instead of being repaired with the appropriate tissue, are repaired with the appropriate tissue, are repaired with osteoblasts and the new tissue turns to bone.

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 Victor Twitty’s experiment is that it showed that, however important hormones are, they are not responsible for the difference between large and small salamanders.

Auschwitz 1944, Josef Mengele studied and tortured Elizabeth Ovtiz and her siblings.

Pseudoachondroplasia – dwarfism, caused by a dominantly inherited mutation: the mutant protein accumulates in the chondrocytes, poisoning and killing chondrocytes long before their time, 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.

Achodroplasia – dwarfism: a mutation in a receptor for fibroblast growth factors (FGFs act as a brake on the growth of limb).

Myostatin defective – extra muscles at the expense of growth elsewhere such as organs.

Every organ must have devices that tell it to stop growing, and many will be unique to particular organs.

Osteogenesis imperfecta/’glass-bone’: mutations that disable bone collagens; a single mutant gene can wreck any number of triple helices, and so any number of fibrils, and so any number of bones.

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.

Joseph, le Comte de Boruwlaski: the last of the court dawrfs, distinguished age of 98, outlived nearly all his contemporaries; a body the size and proportions of a 4-year-olds, delayed puberty, and a briskly adult inttelect.

At the base of our brains, in a cavity of the skull, lies a gland called pituitary. As big as a pea, it is immensely powerful. The pituitary secretes (mostly growth hormones) six hormones that collectively regulate the development of breasts in pubescent girls and the secretion of milk in mothers; the production of sperm in men and the maturation of ova in women; our allergic responses and the way we cope with stress.

For giant Charles Byrne: pituitary tumor secrete vast amounts of growth hormone, cause the cells in the growth plates of a child’s limbs to divide abnormally fast, which in turns makes for super-charged growth.

The Battle of the Pygmies and the Cranes

Pygmies: most of them from Africa, namely Aka, don’t have a pubertal growth spurt.

The pubertal spurt is driven by a burst of growth hormone; but what Pygmies lack is another growth-promoting molecule called insulin-like growth factor 1, aka IGF-1 (the hormone of sugar metabolism). Growth hormone regulates the IGF gene so that levels of the two hormones in the bloodstream tend to rise and fall in synchrony. But each hormone makes a unique contribution to growth.

Neither the pygmies of the Congo, nor the dwarfs of Ecuador, nor even Joseph Boruwlaski, small as they are, even begin to approach the limits of human smallness.

The enormous differences among people from around the globe show that the size we are is very malleable. We cannot be sure that smallness evolved independently in African pygmies and Asian negritos, but elsewhere in the world, smallness has evolved again and again.

I say evolved, but a note of caution is required. It is even possible that the most recent, and probably the last, pygmy tribe to be discovered will prove not to be pygmies at all, but rather people with a severe and rather specific nutritional deficiency.

Taron (short as pygmies, but rather be called as simply cretins, male average 144 centimeters) themselves claimed that when they had come from China they had been of normal size; only in Burma had they become small. Of the ninety-six living in the two villages, nineteen were mentally defective, several had severe motor-neuron disorders and were unable to walk.

Cretins are people who are afflicted from birth by a mix of neurological and growth disorders. Traditionally, they have been classified into two types: ‘neurological’ cretins who are mentally defective, have severe motor-neuron problems and tend to be deaf-mute; and myxedematous cretins who have severely stunted growth, dry skin, and absence of eyelashes and eyebrows and a delay in sexual maturity.

People and animals alike rely on their food for a ready supply of iodine, but in many parts of the world, especially at high altitude, glaciation and rainfall have leached most of the iodine out of the soil so that the very plants are deprived. Cretinism is caused by a diet that contains too little iodine. Globally, about one billion people are at risk of iodine deficiency; six million are cretins.

Thyroid: a gland that makes and secretes a hormone called thyroxine. The thyroid needs iodine to make this hormone, and should iodine become scarce, the thyroid attempts to restore order by the rather drastic device of growing larger. The result is at first a swollen neck, then a bulging neck, and finally, in elderly people who have lacked iodine all their lives, an enormous bag of tissue that spreads from beneath the chin onto the chest, and that contains vast numbers of thyroid tissue nodules, some of which are multiplying, others of which are dying, yet others of which are altogether spent. In England this is called ‘Derbyshire neck’.

Thyroxine: another hormone promotes cell proliferation in the bones of foetuses and growing children. A foetus gets the thyroxine it needs from its mother; should it not get enough it is born cretinous.

The pituitary monitors the level of thyroid hormone that circulates around the body and, should it perceive a want, begins producing thyrotropin, which then spurs the thyroid to greater efforts – in the extreme, spurs it to make a goitre. Children who have defective pituitaries are dwarfed for want of growth hormone and cretinous for want of thyroxine.

Nearly fifteen hundred years ago, while working on a remote Aegean island, Aristotle made an observation that was at once banal, beautiful and chilling. ‘All animals,’ he wrote, ‘if operated on when they are young, become bigger and better looking than their unmutilated fellows; if they be mutilated when full grown, they do not take on any increase of size… As a general rule, mutilated animals grow to a greater length than the unmutilated.’… Boys who are castrated before puberty grow up to be tall, unusually so.

All the more so as the castrati suffered form much more than physical inelegance… 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.

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 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.

estrogens are quintessentially female hormones, 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…. 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.

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… This is probably because after adolescence, bloodstream levels of IGF-1 decline, causing a general slow-down in rates of cell division throughout the body. That it does so is probably just as well.

PTEN: body devices/ genes that curb IGF-1’s propensity to make cells proliferate.

Proteus syndrome: Inheriting a defective copy of PTEN (should the second mutation happen to occur in the first cells of the embryo), a large fraction of the infant’s body will be completely devoid of PTEN, then afflicted fraction of the body becomes a single enormous and inexorably spreading tumor. James Merrick, the ‘Elephant Man’, died in 1890 at the age of 28, had proteus.

Osteosarcoma: 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. (due to high levels of growth hormone and IGF but fused long-bone growth plates)and lead to pituitary tumor)

Pituitary tumor also has a nasty indirect effect, causing elevated rates of colon, breast and blood cancers. These cancers are rather caused by something it does: namely, stimulate the entire growth-hormone-IGF system.

cells that are stricken with a potentially carcinogenic mutation often suicide, but IGF stops sick cells from dying, overrides this altruistic impulse and so acromegalics, big dogs and tall children are relatively prone to cancers.

The pervasive attractions of height (40 out of 43 US presidents are taller than average) present us with a dilemma. As we learn more about the molecular mechanisms that control height, we will be able to manipulate with ever greater subtlety the size that we, or rather our children, grow to be. But what size should we be? The boundary between normal and pathological height is never distinct: it is a grey zone, dictated by clinical possibility, or even convenience.

Studies of short children have shown what we might have guessed: that of all the things that might affect a child’s chances for happiness and success in life, height is among the least important, far less important than intelligence, health, or the quality of care the child gets from its parents. And as we mark, with pride of anxiety, the progress of our children on doorframes, it is this that we should remember.

April 1838, Abel Barbin(Alexiana, the lesbian?) was lifted to his mother’s breast, it was not a son that she thought she held, but rather an infant girl.

‘A man shall leave his father and his mother and cleave unto his wife and they shall be as one flesh.’ Yes, but only if he is able: the biblical injunction, so blithely given, assumes so much. Not least that we know whether we should be man or wife, but that flesh will permit us to be one with another. But some of us do not know, and for some of us flesh does not permit. When it comes to sex, we are unforgiving of mistakes.

male pseudohermaphrodites: have only testicles; female pseudohermaphrodites: have only ovaries; true pseudohermaphrodites: having both.

His story is more remarkable than any of these. It is about having a body that failed to negotiate either of the two paths to gender in an altogether convincing fashion. It is, fundamentally, a story about genitals.

It was another Paduan anatomist, Renaldus Columbus – the same Columbus who got into trouble over an extra rib – who, in 1559, discovered what Vesalius missed: the clitoris.

but he is also wrong. In 1998, a team of Australian anatomists revealed that the clitoris is not merely the smallish stalk of anatomy textbook and sexological dogma, but a large fork-shaped structure that surrounds the urethra and penetrates the vaginal wall.

vestibular bulbs: two obscure lumps of spongy tissue deeply riven with blood vessels.

The homologies are now clear: penis and clitoris; scrotum and labia major; urethra and labia minora; and a vagina unique to females. (They tell us how Abel nee Alexina Barbin could have both a penis, albeit a small one, and a vagina, albeit a shallow one.) It is as if, as a foetus, he travelled part of the route to maleness, but stopped before completing the journey. Or else that he missed the molecular signposts pointing the way.

In sex determination, as in the tango, the Y commands and the X yields. Y chromosome’s action is dominant over that of the X. That proof came from men who possess a Y but who also, abnormally, possess more than one X (that is, who are XXY, XXXY or even XXXXY). Such people are unambiguously male (and have perfectly normal genitalia), proving that any number of Xs are apparently powerless to curb the action of the male-making Y. True, this power does wane slightly by adolescence, when such males frequently develop breasts and an uncertain sexual orientation. But in the womb it is clear: the presence of a Y chromosome sets a foetus decisively on the route to masculinity.

SRY: sex-determining region on Y.

just as XX males have a working copy of SRY where they should not, it has recently been found that many XY females do not have a working copy of SRY where they should. One gene, SRY, two normal states (present on Y, absent on X), two abnormal states (absent on Y, present on X), and a complete reversal of everything to do with sex. It is as beautiful a demonstration of the workings of a gene as could possibly be desired.

Leydig cells: cells within the gonad that make the hormones that make a mammal male. Without SRY they and the other cells of male gonad would not exist. One of the hormones is testosterone itself, a steroid that Leydig cells manufacture from that much-maligned molecule, cholesterol. The male foetus begins to make testosterone in large quantities at around day 50, peaking at around day 150. Four enzymes are needed to do the job; each of them represents a signpost, which, if awry, can turn an XY foetus back to the freeway of femininity. Mutations have been found in the genes that encode three of them.

the difference between male and female is due to something other than testosterone (though what, exactly, is still a matter for debate).

guevedoche /turnin-man: lack an enzyme called 5-alpha-reductase; 5-alpha-reductase produce DHT (dihydroxytestosterone) to form foetus genitals, but at adolescence it is testosterone itself that does the work.. so they masculinise.

aromatase: enzyme that convert testosterone into estradiol and estrone; aromatase is arguably the single most important regulator of human gender. It sits at the crossroad of testosterone and estrogen production and directs the traffic. Girls who lack aromatase are not only born with masculinised genitalia, but as they grow up tend to be very hairy – sometimes bearded – and have enlarged ovaries. Boys who lack the enzyme, on the other hand, scarcely feel its effects – although, as discussed in the previous chapter, for want of estrogen they keep growing long after they should have stopped.

Such mutations, one would think, are always evolutionary dead-ends. Always? It is difficult to generalise, for so capricious is natural selection, and so readily does it avail itself of whatever genetic variation is to hand, that the most unlikely things can happen in evolution. (spotted hyenas with deficiency of aromatase, so does striped and brown hyenas: female pseudohermaphrodites) albeit ones in which the pathological has become normal.

The cause of our various sexual orientations are so obscure that Aristophanes’ explanation is about as good as many others current today. Perhaps this is why many people resist the search for a biological explanation of sexual orientation. But unless we are Cartesian dualists (and no biologist is), the distinction between body and mind is merely a matter of the degree of our ignorance – bodies being things we understand, minds being all that we do not. And there is no doubt that the complex chain of molecular events that controls the devices of desire, our genitals, also influences its object – whom we choose when we give away our hearts.

social constructivist notions of gender are swiftly losing ground to the molecular genetic study of sexual behaviours.

To become men, Sambian boys must pass through an elaborate and secret set of initiation ceremonies, six in all. As in so many New Guinea cultures, these ceremonies are overtly homoerotic: young initiates must fellate older ones so that they may acquire, as the Sambia believe, a source of future semen.