The conflict between these two radically different positions, between deformity as divine design and deformity as accident, came to be known as la querelle des monstres.
Until recently, the origin of conjoined twins has been debated in much the terms that Aristotle used: they are the result either of fusion or fission.
- Thomas Browne: the making of conjoined twins is, first, a matter of making two embryos out of one, and then of gluing them together….it is, instead, something more subtle and interesting.
- Hilda Proscholdt: had made conjoined-twin newts, oriented belly to belly -> the transplanted piece of blastopore lip had not become an extra newt, but rather had induced one out of undifferentiated host cells.
- If the organiser(morphogen) signal was strong, mesoderm would become muscle; fainter, kidneys; fainter yet, connective tissue and blood cells. What the organiser did was pattern the cells beneath it. (false)
- ‘Science,’ Peter Medawar once said, ‘is the Art of the Soluble.’ But the soluble was precisely what the art of the day could not find.
- Noggin is a signalling molecule – that is, a molecule by which one cell communicates with another.
- In a way, the embryo is just a microcosm of the cognitive world that we inhabit, the world of signals that insistently urge us to travel to one destination rather than another, eschew some goals in fabour of others, hold some things to be true and others false; in short, that moulds us into what we are.
- This multiplicity is puzzling. Some of these proteins probably have unique tasks, but it could also be that some can substitute for others
- eg. chordin and noggin. (However, doubly-mutant mice, in which both the noggin and chordin genes have been disabled, never see the light of day. The doubly-mutant embryos die long before they are born, their geometries profoundly disordered. They can only be found by dissecting the mother in early pregnancy.)
- e pluribus unum – out of many, one.
- ex uno plures- out of one, many.
- The ability of disparate organ primordia to find each other and fuse to form wholes is one of the marvels of embryogenesis.
- The sonic hedgehog mutations that cause cyclopia in humans are dominant. This implies that anyone who has just a single copy of the defective gene should have cyclopia or at least some kind of holoprosencephaly. But for reasons that are poorly understood, some carriers of mutant genes are hardly affected at all. They live, and pass the defective gene on to their children.
- cyclopia(a disorder of the midline of the face, a failure of its two sides to be sufficiently far apart): happened if hedgehog-defective; extremely wide face: happened when too much hedgehog proteins being produced.
- sirenomelic (aka ‘mermaid syndrome’): a failure in the midline of the lower limbs, by deleting the CYP26Ai gene, which regulates a substance called retinoic acid.
- where protein-signalling molecules are too big to enter cells and so bind to receptors on their surfaces, retinoic acid penetrates the cell membrane and attaches to receptors within the cell that go right to the nucleus where they turn genes on and off.
- Extra aurical (ear): an instance of a phenomenon called homeosis in which one part of a developing embryo becomes anomalously transformed into another. (first identified as a distinct phenomenon by the British biologist William Bateson in 1894).
- Homeotic genes: there are eight of them, and they have names like Ultrabithorax, Antennapedia or, less euphemistically, ‘deformed’.
- The segmental calculator is a thing of beauty. It has the economical boolean logic of a computer programme. Each of the proteins encoded by the homeotic genes is present in certain segments..(eg. head, thorax, abdomen), the identity of a segment – the appendages it grows – depends on the precise combination of homeotic proteins present in its cells; they also encode molecular switches: proteins that turn genes on and off.
- most excitingly, if homeobox genes formed the circuits of the fly’s calculator of parts, might they not do so for all creatures, even for humans? Molecular biologists are not a breed much given to hyperbole, but when they found the homeobox, they spoke of Holy Grails and of Rosetta Stones.
- Mammals have thirty-nine homeotic genes, named as : Hoxa3, Hoaxdi3, etc.. The vertebral calculator is not very economical.
- homeotic genes point to a system of building bodies that evolved perhaps as much as a thousand million years ago in some worm-like ancestor and that has been retained ever since. Indeed, the homeotic genes were merely the first indication that many of the molecular devices that make our bodies are ancient. Over the last ten years it has become plain that we are, in many ways, merely worms writ large. A gene called ems is needed to make a fruit fly’s minute brain. So vast is the evolutionary gulf, both in time and complexity, between a fly’s brain and the hundred-thousand-million-neuron edifice perched upon our own shoulders, that one could hardly expect that the same devices are used in both.
- ‘Lobster-claw syndrome’/’ectrodactyly’/Cleppie Bells: two digits on each hand, widely spaced apart.
- The fragments of myth, folklore and tradition that remain to us from a pre-scientific age are like the marks left in sand by retreating waves: void of power and meaning, yet still possessed of some order. Muddied by time and confused causality, they still bear the imprint of the regularities of the natural world.
- acheiropody – from the Greek: absence of hand and foot, the victims of this disorder have limbs that terminate in a tapered stump. The mutation is recessive, only foetuses who have two copies of the mutant gene fail to develop hands and feet.
- The apical ectodermal ridge is the sculptor of the limb. They are rich in signalling molecules, especially fibroblast growth factors (FGFs). Ridge FGFs not only keep mesodermal cells proliferating, they also keep them alive. Yet while mass cell suicide is clearly a bad thing, at least some cell death is needed to form our fingers and toes, for if the ridge is the sculptor of the limb, cell death is the chisel.
- As the limb-bud grows, each of these populations of cells proliferates and expands in turn. When a young limb-bud is deprived of FGFs, all of these variously fated cell populations suffer; when an older limb-bud is deprived only those closest to the tip do, and with them future hands and feet, toes and fingers.
- Phocomelic infants (thalidomide infants/seal-limb). Willem Vrolik gave a portrait of a phocomelic, a famous eighteen-th century Parisian juggler, Marc Cazotte, also known as Le Petit Pepin.
- Polydactyly: extra digits, usually genetic, frequently dominant.
- Sonic hedgehog does not just determine how many fingers and toes we have. It also divides our brains, decides how widely spaced our eyes will be, and regulates much else besides. It is an incorrigibly promiscuous molecules. Could we see the pattern of the sonic hedgehog gene’s activity over time, as in time-lapse photography, we would see it flashing on and off throughout the developing embryo and foetus, now in this incipient organ, now in that one.
- I argued that the acheiropody mutation causes a failure of sonic to appear in the limb. And yet I began this chapter by arguing that infants with amputations in the womb, of whatever severity, were due to failures of the apical ectodermal ridge and the fibroblast growth factors they produce. This may seem like a contradiction, but it is only one if we think of the various limbs’ signals as being independent of each other, when in fact they are not. For one of the most vital roles of sonic hedgehog is to maintain and shape the apical ectodermal ridge and its fibroblast growth factors; and one of the most vital roles of the apical ectodermal ridge is to maintain and shape the production of sonic hedgehog in the zone of polarising activity. There is a reciprocal flow of information as precarious as the flow of batons between two jugglers standing at opposite ends of a stage. Reciprocity of this sort is ubiquitous in the embryo and it alters the way we think about its growth and development. We begin with notions of linear pathways of command and control and simple geometries – and then watch as they unravel. For when, as in the limb, we actually begin to see the outlines of the embryo’s programme, it invariably turns out to resemble a tangle of circuits that loop vertiginously across time and space. Circuits which, in this case, ensure that when we count our fingers and toes we usually come up with twenty.
- Hox mutations affect both limbs and genitals. Many of the molecules that make limbs also make genitals, and it should be no surprise that some mutations afflict both… the positive correlation between foot and penis size also, surprisingly, turns out to be at least partly true (though weak), and then such data as there are concern ‘stretched’ rather than erect penis length, surely the variable of interest.
- Mice that are mutant for Hoxd13 may be polydactylous, but mice that are mutant for Hoxd13 as well as other Hox genes – that is, are doubly or even trebly mutant – have no digits at all… developmental geneticists strip successive Hox genes from the genomes of their mice, they are reversing history in the laboratory; they are plumbing a five-hundred-million-year odyssey that reaches from fish with no fingers to Devonian amphibians with a surplus of them, and that ends, finally, with our familiar five.
- We are a polychrome species. Yet the palette of human colour has only two pigments on it. One, eumelanin, is responsible for the darker shades in our skin, hair and eyes, the browns and the blacks; the other, phaeomelanin, for the fairer shades, the blonds and reds.
- The most common cause of albinism in Africa is homozygosity for a 2.7 kilobase-pair deletion in the P gene. The same mutation is found in the Caribbean and among blacks in the United States as well, carried there by the slave trade.
- Piebalding has nothing to do with albinism but is instead caused by dominant mutations in an altogether different set of genes, and that these mutations can occur in people of any color.
- Melanocytes spend their lives in the skin, but unlike most of the skin which is ectoderm, melanocytes are the products of a tissue called the neural crest. At about day 28 after conception, neural crest cells flow out of the newly formed dorsal nerve cord and pour themselves around the foetal head to make the face. But some neural crest cells travel much further than this. As a river fans out over its delta, streams of neural crest cells course down from the escarpment of the dorsal nerve cord and penetrate to the embryo’s farthest reaches. In one part of the body they form nerves, in another muscles, yet elsewhere they invade developing glands. And some become melanocytes which, early in foetal life, invade the lower layers of the skin where they settle down to produce pigments. Neural crest cells make our faces, and they also lend them color.
- Molecular devices are required to make a naïve neural crest cell form a melanocyte rather than some other kind of cell, and also to guide the melanocytes to their final destinations. Mutations in at least five distinct genes cause piebaldism, and each of them disables one or more of these devices, so causing patches of skin that are devoid of melanocytes and therefore perfectly white.
- Nelson’s syndrome: white skin->black skin-> white skin; occurs in about a third of patients who have adrenodectomies.
- One of the critical tasks that the adrenal gland does (rather like the thyroid) is keep the pituitary gland in check (surplus of pituitary hormone can cause skin to darken).
- Tumors that start in different pituitary cell types can have very different consequences.
- melanotropins circulate throughout the body, and tend to be more discriminating, they affect most spectacularly melanocytes (an excess of melanotropin causes our skin to bronze; children who have no melanotropins are not blonds, but redheads, and they are fat due to lack of binding between alpha-MSH and MC4R that stop them from eating).
- Whether a given genetic sequence is a mutation rather than a polymorphism hinges on two issue: its global frequency and its usefulness – mutations being rare and harmful, polymorphisms being generally neither.
- But the evidence tends to suggest that, delightful though it may be to look at, red hair is not good for anything at all. MC1R in northern Europeans may simply be a gene that is decaying because it is no longer needed, rather as eyes decay in blind cave-fish.
