Mutants

by Armand Marie Leroi

  37 In the spring of 1920. For the Hilda Mangold (nee Pröscholdt) paper see Spemann and Mangold (1924); for a translation and commentary see Willier and Oppenheimer (1964); for her biography see Hamburger (1988) and Fässler and Sander (1996).

  39 For seventy years. For a brief history of the search for the organiser molecules see Gilbert (2002) A selective history of induction. http://zygote.swath-more.edu/. Spemann quoted in Gilbert (2000).

  40 It would be tedious to recount. ‘Noggin’ is slang for ‘head’. For the initial identification of noggin (602991) see Lamb et al. (1993); for contemporary commentary see Baringa (1993); for a textbook survey of the organiser see Gilbert (2000) pp.303–38; and for a recent technical review see Beddington and Robertson (1999). The number of molecules involved in cell–cell communication includes both signalling molecules and their receptors (International Sequencing Consortium 2001). For the antagonism between BMP4 and chordin (603475) and noggin see Zimmerman et al. (1996) and Piccolo et al. (1996). For the noggin-defective mouse see McMahon et al. (1998); for the noggin and chordin double-defective mouse see Bachiller et al. (2000).

  45 When Eng and Chang. The ‘two organiser’ theory is sometimes called the crowding model to distinguish it from the fission and fusion models (J.-F. Oostra, pers. comm.). Most fusion models postulate separate embryonic discs. My model is very similar to that of Hamburger (1947). It also seems similar to that of Spencer (2000 a; b; 2001) though she is ambiguous as to whether conjoined twins arise from one or two embryonic discs. Although, as stated, the vast majority of conjoined twins have a single amnion and placenta, there is apparently evidence that some have two amnions or even – truly strange this – two placentas. The ‘two organiser’ model would not apply to such twins. For chemical induction of conjoined twins (and mono-amnion monzygotic twins) see Kaufman and O’Shea (1978).

  46 One man who thought deeply. For a history of artificial incubation see Needham (1959) pp.22–5 and 203–4. For Geoffroy’s attempts to artificially create monstrous chickens see Geoffroy Saint-Hilaire (1825); Fischer (1972) and Appel (1987) pp.121–9. See also his son’s account of the influence of these experiments (Geoffroy Saint-Hilaire 1847). Étienne’s major teratological work is Geoffroy Saint-Hilaire (1822) Philosophie Anatomique des monstruosités humaines. The classificatory work was carried on by Isidore in Geoffroy Saint-Hilaire (1832–37) Histoire générale et particulière des anomalies de l’organisation chez I’homme et les animaux. See Morin (1996) for a modern evaluation of Geoffroyean teratology. For some of Geoffroy’s intellectual background see Appel (1987) pp.121–9; for a paen by Geoffroy to Bacon see Geoffroy Saint-Hilaire (1825).

  49 Geoffroy was deeply enamoured. Isidore Geoffroy Saint-Hilaire (1847) claimed that his father first conceived of the soi pour soi in 1826, several years before Ritta and Christina appeared. A full, late statement of the law’s implications can be found in É. Geoffroy Saint-Hilaire (1838); see also Appel (1987).

  51 The ability of disparate organ primordia. For a textbook review of cell adhesion molecules see Alberts et al. (1994) pp.950–1006. Spina bifida (182940) and anencephaly (206500) are both neural defects caused by unknown genetic factors and many environmental ones (Corcoran 1998). For bifid heart see Gilbert (2000) p.474.

  52 The power of cell–cell adhesion. Parasitic conjoined twins have an occurrence of one in a million live births. See Serres (1832) for a description of these cephalothoracoileopagus conjoined twins. See Spencer (2000 a; b; 2001) for a review of conjoined twins and parasites. Park and Daston (1981) and Bondeson (2000) pp.vii–xix tell the story of Lazarus Colloredo; see Thompson (1930; 1994) p.93 for Laloo; Ta-Mei et al. (1982) for the Chinese man and Rodriguez (1870) for the multiple parasites. Spencer (2001) persuasively argues the foetus-in-foetu-teratoma theory. Naudin ten Cate (1995) describes the twenty-one-foetus teratoma.

  56 In recent years, much has been learned. The story of the old soldier is told by Geoffroy Saint-Hilaire (1832–37) volume 3 pp. 8–11; Martin (1880) p.147, and Fischer (1991) p-74. Geoffroy and Martin claim that the old soldier was also the inspiration for Molière’s he Médicin malgré lui (Doctor in spite of himself), a comedy which turned on a doctor who diagnosed a patient’s heart as being on the right side of her chest. Appealing though this is, it cannot be true since Molière composed his comedy in 1666–67, Les Invalides was built in 1671, and the old soldier died in 1688 (J.-L. Fischer, pers. comm.).

  56 It is a diagnosis that allows. Kartagener’s syndrome or primary ciliary dyskinesia (244400) is caused by recessive mutations in the DNAI1 (604366) and DNAH5 (603335) genes (Guichard et al. 2001 and Olbrich et al. 2002). See Afzelius (1976) for the causal link to cilia; see Kosaki and Casey (1998), Casey and Hackett (2000) and Brueckner (2001) for recent reviews.

  58 I said earlier that the organiser is. For ciliary flow around the node see Nonaka et al. (1998). Of course, in a sense the discovery of asymmetrical ciliary movement doesn’t absolutely solve the problem of the embryo’s handedness, since it merely raises the question of why cilia should beat from right to left rather than the other way around. There’s no good answer to this question in mammals at least, but it is worth noting that the embryo is a three-dimensional object, and once two axes (head to tail and back to belly) have been established, the last (left to right) obtains automatically. So a cell that wishes to tell left from right merely needs to know which way its cilia protrude with respect to the rest of the embryo’s geometry. For some conceptual models of symmetry-breaking see Lander et al. (1998).

  59 There is a lovely experiment that proves this. The original path-breaking paper defining the signals that determine left–right asymmetry in chicks is Levin et al. (1995). Since then a large literature has accumulated on left–right signalling in all major vertebrate model systems – and it seems clear that although the precise distribution of the various signalling molecules differs between mice and chickens, the general principles are the same (Tsukui et al. 1999; Meyers and Martin 1999; Casey and Hackett 2000). The differences between mice and chickens also affect the interpretation of Levin et al. (1996) who gave the original explanation for situs inversus in conjoined twins. Their explanation, which is surely correct in essence, was based on the earlier chicken data and now cannot be right in detail.

  62 For Étienne Geoffroy Saint-Hilaire. The quote is from his Philosophic anatomique (1822) and runs in full: ‘les Monstres ne sont plus des jeux de la Nature; leur organisation est soumise à la loi commune; les Monstres sont d’autres êtres normaux; ou plutôt il n’y a pas de Monstres et al Nature est une’.

  CHAPTER III: THE LAST JUDGEMENT

  65 In 1890 the citizens of Amsterdam. For a history of teratology in the Netherlands and a re-evaluation of Vrolik’s specimens see the magnificent series of articles by Vrolik’s successors at the University of Amsterdam: Baljet and Oostra (1998) and Oostra et al. (1998a-e). Baljet and Öjesjö (1994) have suggested that Hieronymus Bosch’s demonic creatures were inspired by human malformations. Most scholars point instead to medieval illustrations or else the gargoyles of Sint Jan’s cathedral, s’Hertogenbosch. Although Bosch surely cannot have seen many deformed infants in the flesh, the correspondence between many of his grotesques and known deformities is certainly striking. See also Bos and Baljet (1999).

  67 Of Willem Vrolik’s published writings. Vrolik’s first major work on cyclopia was a long article in Dutch (Vrolik 1834), followed a decade later by his Tabulae (Vrolik 1844–49). See Baljet (1990) and Baljet et al. (1991) for an account of Vrolik’s work on cyclopia and his collections.

  68 Hesiod says that there were three Cyclopes. Homer The Odyssey (trans. E.V. Rieu. 1946. Penguin Books, Harmondsworth, UK); Ovid Metamorphoses (trans. A.D. Melville. 1986. Penguin Books, Harmondsworth, UK). For classical Cyclopean iconography see Touchefeu-Meynier (1992).

  68 Many teratologists have linked the deformity to the myth. Aetiological explanations of myths have the delightful property that they are more or less unfalsifiable, but that hasn’t s
topped many from proposing them. For arguments that the forms of the various monsters of Greek mythology (the Cyclops, the Hydra, Typhon, the Harpies etc.) are derived from foetuses that show various abnormalities see Schatz (1901). For the claim that the Cyclopes were inspired by the Pleistocene remains of dwarf elephant skulls that have been found on Sicily see Mayor (2000). Far more sophisticated discussions of deformity in ancient Greece and Egypt by a classicist can be found in Véronique Dasen’s numerous papers. The relationships and symbolic meanings of the Cyclopes are discussed by the pre-eminent scholar of comparative mythology G.S. Kirk (1974) pp-85, 207.

  69 Homer to Vrolik. Pliny the Elder Natural history: a selection, (trans. J.F. Healy. 1991. Penguin, Harmondsworth, UK). For an early and important outline of the origin of the Plinian races and their fate in medieval literatures see Wittkower (1942). For much further detail see the very readable Friedman (1981) as well as Kappler (1980), Williams (1996) and Daston and Park (1998).

  71 The first illustration of a cyclopic child. Liceti (1634) also identifies an additional two eyes on the back of the Firme child’s head, but these must be fictitious (he never saw the child himself, but worked from a sketch). The original sketch of the Janus-headed twins with cyclopia is now lost. Some, but not all, features of the presentation and subject in Liceti’s engraving are consistent with it having been derived from an original by Leonardo. No other sketches of teratologies by him are known (Martin Kemp, pers. comm.). The report of a Janus-headed twin with cyclopia is given in Abbott and Kaufmann (1916).

  72 Looking at his bottled babies. For a historical account of causal theories of cyclopia in the nineteenth and twentieth centuries see Adelmann (1936). For the modern definition of holoprosencephaly see Cohen (2001); for the incidence of the disorder see Muenke and Beachy, (2000); for a review of the teratology, Cohen and Shiota (2002); and for the role of veratrum in lamb cyclopia, Incardona et al. (1998).

  74 Most cases of cyclopia. Holoprosencephaly (HPE) consists of at least seven distinct inherited syndromes (HPE1 to HPE7). HPE3 (142945) is due to heterozygosity for mutations or deletions in sonic hedgehog (600725) (Roessler et al. 1996). For the spectrum of Shh mutations see Nanni et al. (1999, 2001). For the Shh knockout mouse see Chiang et al. (1996); for a general revew of the other HPE genes see Muenke and Beachy (2000).

  76 An embryo’s face. See Hu and Helms (1999) for an elegant study of the role of Shh in craniofacial formation and Ditto the pig. GH3 (165240) mutations cause Greig’s cephalopolysyndactyly (175700) which is characterised by hypertelorism among other things. Hypertelorism with nasal bifurcations is characteristic of craniofrontonasal syndrome (CFNS) (304110). The causal gene underlying has not yet been identified.

  78 Among the disorders that appear. For a history of sirenomelia and siren-like iconography see Gruber (1955); for a more recent review see Valenzano et al. 1999). For the CYP26A1 (602239) deletion mice see Sakai et al. (2001) and Abu-Abed et al. (2001). For pigs without eyeballs see Hale (1933); for isotretinoin in humans see Lammer et al. (1985); and for a review of retinoic acid function and gradients in the embryo see Maden (1999).

  83 The consequences of cells. The claim that the lumps on the necks of Pans are supernumerary auricles is made by Sutton (1890); Cockayne (1933) discusses goats. See Boardman (1997a) pp.36–7 for the Hellenistic Pans bearing supernumerary auricles. See Boardman (1997a; b) for a technical synopsis of the history of Pan in Greek and Roman art and a charming essay on his iconography by the famous scholar of Greek art. The girl with four auricles is discussed by Birkett (1858); a more general discussion of supernumerary auricles is given by Bateson (1894) pp.177–80 and Cockayne (1933) pp.339–41.

  86 Homeosis was first identified. Bateson’s (1894) purpose was not, as now, to use homeotic variation as a means for studying development. He was instead struggling towards a theory of inheritance; that is, attempting to fill the gap left by Darwin’s account of evolution. He failed, but he was among the first to retrieve Gregor Mendel’s experiments on peas from the fathomless obscurity of the Verhandlungen des naturforschenden Vereines in Brünn. As such, he is recognised today as one of the fathers of modern genetics.

  87 Over the last eighty-odd years. See Lawrence (1992) for an account of the homeotic genes in Drosophila. Strictly speaking these genes specify parasegments, divisions in the embryo that contribute to, but are out of register with, the segments visible in the larva. The seminal paper on the homeotic genes is Lewis (1978). In 1995, Ed Lewis shared the Nobel Prize with two other Drosophilists, Christiane Nüsslein-Volhard and Eric Wieschaus.

  91 Extra ribs have always caused trouble. See Sir Thomas Browne’s Pseudodoxia epidemica, or, enquiries into very many recieved tenents and commonly presumed truths (1646) in Works (1904) volume III chapter II pp.5–8. Estimates on the variation in rib number come from Bornstein and Peterson’s 1966 study of 1239 skeletons. They found that 9 per cent of their skeletons had thirteen pairs of ribs. Of this fraction, just under 1 per cent were due to the seventh cervical vertebra gaining ribs, about 5 per cent were due to the first lumbar vertebra gaining ribs and 3 per cent were due to a simple increase in the total number of vertebrae, that is, were not due to a homeotic transformation of vertebral type. Other studies, reviewed in Galis (1999), put the incidence of seventh cervical vertebrae ribs somewhat lower, at around 0.2 per cent. Cervical ribs can cause ‘thoracic outlet syndrome’, a compression of the nerves and blood vessels of the neck. Galis (1999) also addresses the fascinating question of why all mammals have just seven cervical vertebrae where the numbers of other vertebrae vary greatly among species. She argues that mutations that cause cervical ribs may be far more pathological than is generally appreciated and so under strong stabilising selection.

  92 It is no surprise, then, that the identity of each vertebra. This account of C7 specification is based on the results of deletions for particular Hox genes in mice. It is probably incomplete and some of the AND statements should be OR (since partial transformations are common, suggesting that other Hox genes can compensate) or else couched in more quantitative terms – but it is a reasonable start. Deletions in the following genes cause C7->T1 transformations: Hoxa4 (Horan et al. 1994); Hoxa5 (Jeanotte et al. 1993); H0XD5 (Rancourt et al. 1995); Hoxa6 (Kostic and Capecchi, 1994); Hoxb6 (Rancourt et al. 1995). Other genes, such as HoXC4, may be affect this vertebra as well, but results disagree (Boulet and Capecchi 1996; Saegusa et al. 1996; Horan et al. 1995a; b)

  93 Distinguishing one vertebra from another. These disorders are caused by deletions in the following genes: anteriorised limbs: Hox5b (Rancourt et al. 1995); partly missing hindbrains: Hoxai (Lufkin et al. 1991; Mark et al. 1993; Carpenter et al. 1993); hernias: Hoxd4 (Ramirez-Solis et al. 1993); no thymus: Hoxa3 (Chisaka and Capecchi 1991); unable to walk: Hoxc8 (Le Mouellic et al. 1992).

  94 The Hox gene calculator. For Hox gene expression in human embryos see Vielle-Grosjean et al. (1997). The embryos used in this study were ‘collected with full ethical permission’. For a discussion of what this means and legislation of such studies in various countries see Burn and Strachan (1995).

  95 Writing of the ‘calculator of fate’. For supernumerary eyelashes or distichiasis (126300) see Cockayne (1933) P-330 who notes, incidentally, that hedgehogs normally have two rows of eyelashes. For the seven-hearted chicken see Taussig (1988) following a 1904 report by the pathologist Verocay who happened to be staying at the inn and who managed to secure the viscera, but not the rest of the chicken, for study. Isidore Geoffroy Saint-Hilaire (1832–37) volume 1 pp.723–9 discusses various putative cases of heart duplications in humans but can come up with only one possibly authentic example, an early-eighteenth-century case of a grossly deformed infant. See Lickert et al. (2002) for extra hearts in ?-catenin-conditional null mutant mice.

  96 And then there is Disorganisation. Disorganisation (223200). The Disorganisation mutation was first studied by Hummel (1958, 1959), then by Crosby et al. (1992). The possibility of a human homologue of Disorganisatio
n was mooted by Winter and Donnai (1989) and Donnai and Winter (1989), who proposed its existence to explain children whose malformations had been previously attributed to a miscellany of other cause. Disorganisation is caused by a dominant mutation on mouse chromosome 14.

  97 The power of the homeotic genes. The evolution of snake limblessness is discussed by Cohn and Tickle (1999). This explanation for the loss of fore-limbs in snakes does not account for the loss of the hind-limbs – which is due to a failure of the limb-buds to grow. Many studies have shown comparable changes in Hox gene expression patterns, particularly in arthropods. And some very recent studies have actually demonstrated that mutations in Hox genes are directly responsible for evolutionary changes in morphology (as a change in Hox gene expression, the snake example implies a mutation in some upstream regulatory factor). Mutations in Emx2 (600035), a human homologue of ems, is responsible for schizencephaly (269160). For a discussion of ems and other conserved brain genes see Reichert and Simeone (2001). Mutations in Pax6 (607108), a human homologue of eyeless, mutations cause aniridia (106210) (Ton et al. 1991). For a review of the conservation of eyeless/Pax6 in eye evolution see Gehring and Ikeo (1999).

  99 In the cyclical way of intellectual fashion. Geoffroy’s major ideas on what we now call homology can be found in his Philosophic anatomique. Des organes respiratoires sous de la déermination et de l’dentité de leurs pièces osseuses (1818) and Considerations generates. Sur la vertèbre (1822) which have been collected by Le Guyader (1998) who also discusses the dispute with Cuvier as does Appel (1987). The revival of the dorso-ventral inversion hypothesis is due to, among others, De Robertis and Sasai (1996); for a sceptical update see Gerhart (2000).

  CHAPTER IV: CLEPPIES

  105 For the mark of Cain see Friedman (1981) pp.87–107. The football coach (p. 106) was Glenn Hoddle. He was sacked (The Times, London, 1 February 1999).