Mutants (40 page)

What makes physical beauty so wonderful? What enables it to take us by surprise, to prevent us from treating it with indifference no matter how saturated we are by the worlds of advertising and celebrity that have appropriated it, indeed made us suspicious of its power? If the answer that I have sketched contains any truth, then each image of a beautiful face or perfectly turned limb is not really about the subject that it appears to be, but rather what it is not. It is about the imperfections that are absent: the machine errors that arise from the vicissitudes of the womb, childhood, maturity and old age, that are written all over our bodies and that are so ubiquitous that when we see someone who appears to have evaded them, however fleetingly, we pause to look with amazed delight. Beauty, Stendhal says, is only the promise of happiness. Perhaps. But it is equally the recollection of sorrow.

I have accumulated many debts while writing this book. My agent, Katinka Matson at Brockman Inc., first saw what
Mutants
might become. I thank her as well as Karen Murphy at Viking Penguin USA, Maarten Carbo at Contact, Netherlands and, most of all, Michael Fishwick at HarperCollins UK, whose faith in the book’s ultimate existence was tested but never faltered. Robert Lacey, also at HarperCollins, was a wonderful editor. My Dutch translator, Robert Vernooy, was an acute critic. Several friends and colleagues commented on part of the manuscript, among them: Austin Burt, Arnold Heumakers, Barbara van Ijzeren, Marie-France Leroi, Jan-Roelof Oostra, Corinne Pernet and Jonathan Swire. Olivia Judson, Clare Isacke, Jennifer Rohn and Alberto Saez read and commented upon it all; I do not know how to repay them.

Many friends and colleagues answered specific queries, among them: Elizabeth Allen, Alan Ashworth, Peter Beighton, Chin Chiang, François Delange, Frank Dikötter, Saul Dubow, Ademar Freire-Macias, Frietson Galis, Jill Helms, Christiane
Hertel, Annemarie Heumakers, Michael Hochberg, Beatrice Howard, Grace Ioannidou, Martin Kemp, Hannelore Kischkewitz, Deborah Posel, Liesbet Rausing, Raymund Roos and John Wilmoth. Jan-Roelof Oostra in Amsterdam and Cédric Cremiere and Jean-Louis Fischer in Paris were especially generous with their expertise in teratology and its history. Véronique Dasen in Fribourg told me about the teratology of the ancient world; Marta Lahr and Robert Foley at Cambridge showed me their wonderful collection of skulls; Yehuda Koren and Eliat Negev in Jerusalem told me about the Ovitz family in the Third Reich. I have not been able to do their scholarship justice. My pupils Anne Rigby and Sarah Ahmad told me of things that just had to go into the book; Carolyn Richardson and Irin Maier researched and translated texts. I could not have illustrated the book without the help of Miriam Guttierez-Perez at the Wellcome Library for the History of Medicine, London, and Laura Lindgren and Gretchen Worden at the Mütter Museum, Philadelphia.

My greatest debts, however, are to those around me: my colleagues at Imperial and the – sadly neglected – people in my lab; my friends – Austin Burt, Jim Isacke, Olivia Judson, Giorgos Kokkoris, Vasso Koufopanou, Michaelis and Katerina Koutroumanidis, Alexandra Meliadou, Jenny Rohn, Jonathan Swire, Liesbeth Verreijdt; and my family – Marie-France, Harry, Iracema, Joseph, most especially my parents, Antoine and Johanna. But above all it was Clare Isacke who sustained me while writing this book. It is dedicated to her with love.

The clinical and developmental genetic literature is both vast and growing. However, I have attempted to give a guide to where the major results can be found and, occasionally, further details on particular topics. Beyond these notes, the most important source for those seeking further information about particular genetic disorders is Mendelian Inheritance in Man, an on-line database authored and edited by Victor A. McKusick and his colleagues at Johns Hopkins University, Baltimore, and supported by the National Center for Biotechnology Information, USA. It contains continually updated descriptions of each disorder, the mutations that cause them, and the clinical genetic literature. MIM can be found at
http://www3.ncbi.nlm.nih.gov/Omim/
. To assist those who wish to penetrate this difficult literature I give, for each syndrome and gene, the MIM numbers in bold so: achondroplasia (
100800
) is caused by mutations in FGFR3 (
134934
). Neither MIM nor this book should be used for self-diagnosis.

PROLOGUE

xiii
Genetics, to quote one popular writer.
Steve Jones, whose book
The language of the genes
(1993), HarperCollins, London, remains the best popular account of human population genetics.

xiv
On 15 February 2001.
The sequence of the human genome (International Sequencing Consortium 2001).

xv
To learn from animals.
See Gilbert (2000) p.361 for Leonardo’s cow placenta and Needham (1959) p.65 for Cleopatra’s alleged studies of human development.

CHAPTER I: MUTANTS

3
We had heard that a monster had been born at Ravenna.
The monster of Ravenna has been much discussed. See Landucci (1542; 1927) pp.249–50 for a contemporary account of the monster. Jean Céard dicusses its evolution in his edition of Pare’s
Des monstres
(1573; 1971) PP.153–5; Niccoli (1990) pp.35–51 its political meaning; see also Fischer (1991) pp.54–6 and Daston and Park (1998) pp. 177–82. I suggest that the monster’s disorder is Roberts’s syndrome (
268300
), but others (Walton et al. 1993; Martinez-Frias 1993) have suggested cyclopia, sirenomelia or else hydrocephalus. All these diagnoses are guesses – which one you favour is a matter of which depiction of the monster you use, and which of its many odd features you believe are real.

6
In the sixteenth and seventeenth centuries.
My description of Renaissance teratology is indebted to Park and Daston (1981) and Daston and Park (1998), though it has perhaps a more Whiggish flavour than theirs. See Boaistuau (1560, 2000) for a reproduction of an unusually beautiful teratological manuscript of the time, Melancthon and Luther (1523; 1?23) for the Monk-calf, and Paré (1573; 19?2) pp.3–4 for his list of the causes of deformity. For nineteenth-century views on maternal impressions see Gould and Pyle (1?97) and Bondeson (1997) pp.144–69. For the seventeenth-century teratologists see Aldrovandi (1642); the first edition of Liceti’s
De monstrorum
was published in 1616, but I have worked from the second (1634) edition, a synopsis and French translation of which is given by Houssay (1937). A brief account of Liceti’s life and work is given by Bates (2001).

8
There is a moment in time.
For Sir Thomas Browne’s views on deformity in
Religio medici
(1654) see his
Works
(1904) volume 1, pp.26–7. For the shift in opinion of monsters from wrath to wonders of God see Park and Daston (19?1). For William Harvey’s writings on generation
see Anatomical Exercises on the generation of animals; to which are added, essays on parturition; on the membranes, and fluids of the uterus; and on conception
(1650) in his
Works
(1965). The quote, however, is from the 1653 translation by Martin Llewellyn as given by Needham (1959) p.134.

10
It was, however, a contemporary of Harvey’s.
For Bacon’s division of science see Bacon (1620, 2000) pp.14?–9 and 223–4. For an account of
Renaissance collections of marvels see Daston and Park (199?) pp.255–301. Harvey, John Aubrey tells us, thought little of Bacon as either a philosopher or a writer, but Harvey espoused very Baconian sentiments when he wrote: ‘Nature is nowhere accustomed more openly to display her secret mysteries than in cases where she shows tracings of her workings apart from the beaten path.’

13
Most of these people have mutations.
On-line Mendelian Inheritance in Man lists about a thousand genes that cause phenotypic variation, be it pathological or not (e.g. brown eyes).

16
If there is no such thing as a perfect or normal genome.
The estimate of how many times each of the genome’s base-pairs have mutated in the last generation alone is given by Kruglyak and Nickerson (2001). The estimate of 65 per cent of genes as having polymorphisms applies to alleles defined by non-synonymous polymorphisms only. Conversely, my claim that most genes have an overwhelmingly common variant comes from the observation that 35 per cent of genes are monomorphic, and that in the known polymorphic ones, the minor alleles usually have a frequency below 5 per cent. Again, this applies to non-synonymous polymorphisms only (Cargill et al. 1999; Stephens et al. 2001).

18
Each embryo has about a hundred mutations.
Eyre-Walker and Keightley (1999) estimate the rate of production of deleterious mutations in humans. Their estimates are consistent with those from Cargill et al. (1999) and Stephens et al. (2001) obtained by other means. Crow (2000) reviews the fitness effect of novel mutations.

CHAPTER II: A PERFECT JOIN

25
The Parodis arrived in Paris.
Contemporary accounts of Ritta and Christina Parodi are given by Anon (1829 a; b; c); Saint-Ange (1830); Janin (1829) and Danerow (1830). Later accounts by Thompson (1930; 1996) p.84 and Bondeson (2000) pp.168–73.

26
The first cut exposed the ribcage.
The major anatomical monograph on Ritta and Christina is Serres (1832). É. Geoffroy Saint-Hilaire (1829) considers the girls in a small paper and I. Geoffroy Saint-Hilaire (1832–37) in volume 3 pp. 161–74 of his synoptic teratology.

27
The oldest known depiction.
The Anatolian statue, from the Catal Hüyük site, dates from around 6500 BC; the Australian rock carving from 3–4000 BC. For the Molionides brothers, and a more general discussion on con joined twins in ancient Greek art, science and myth, see Dasen (1997; 2002). For Renaissance teratologies see Paré (1573; 1982) and Boaistuau (1560; 2000) pp.134–7. For the Montaigne quote see Montaigne (1603; 1998), and for their intellectual context Daston and Park (1998) pp.205–7. The conflict between Duverney and his rivals is discussed by Fischer (1991) pp.71–4 and Wilson (1993) pp.150–9. For the intellectual context of preformationism and epigenesis see Needham (1959) chapters 3 and 4, and Pinto-Correia (1997).

32
What makes twins conjoin?
Conjoined twins occur at a frequency of 1 in 100,000 live births; monozygotic separate twins occur at a frequency of 1 in 300 live births. For Aristotle on conjoined twins see
The generation of animals
in his
Complete works
volume 1 pp.1192–1996. See Friedman (1981) pp.180–1 on baptising conjoined twins.

33
Until recently, the origin of conjoined twins.
For a typical medical embryology textbook account of conjoined twinning see Sadler (2000) p. 155. Although most conjoined twins seem to be monozygotic (they are nearly always of the same sex) there is at least one case that has been shown, by genetic tests, to be the result of a fusion between dizygotic embryos (Logroño et al. 1997). For the sex ratios of conjoined twins see Steinman (2001 a; b). Spencer (2000 a; b; 2001) gives a detailed critique of the fission model of conjoined twinning based on the geometry of the joins. See Martin (1880) pp. 153–69 for the evolution of theories of the causes of conjoined twins.

35
On the seventh day.
For a description of early human embryogenesis see Beddington and Robertson (1999) and Sadler (2000).

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).