1 W H S Jones, Malaria, a neglected factor in the history of Greece and Rome, Cambridge University Press, 1907, and Malaria and Greek history, Manchester University Press, 1909, pp. 97–102, cf. N Toscanelli, La malaria nell'antichità e la fine degli Etruschi, Milan, Hoepli, 1927; A Celli, The history of malaria in the Roman Campagna from ancient times, London, Bale & Danielsson, 1933.
2 For example, J Ruffié and J-C Sournia, Les épidémies dans l'histoire de l'homme: essai d'anthropologie médicale, Paris, Flammarion, 1984, p. 209.
3 L Bruce-Chwatt and J de Zulueta, The rise and fall of malaria in Europe: a historico-epidemiological study, Oxford University Press, 1980, pp. 18–25.
4 L del Panta, Malaria e regime demografico: la Maremma grossetana nell'ottocento preunitario, Messina, Università degli Studi di Messina, 1989, on Grosseto in central Italy; M Dobson, Contours of death and disease in early modern England, Cambridge University Press, 1997, on the Kent and Essex marsh parishes.
5 R Sallares, Malaria and Rome: a history of malaria in ancient Italy, Oxford University Press, 2002, gives much more bibliography on the questions considered in this paper.
6P. ovale is not considered any further in this paper since it was never common in Mediterranean countries.
7 S M Rich, M C Licht, R R Hudson, and F J Ayala, ‘Malaria's Eve: evidence of a recent population bottleneck throughout the world populations of Plasmodium falciparum’, Proc. Natl. Acad. Sci. USA, 1998, 95: 4425–30; S K Volkman, A E Barry, E J Lyons, K Nielsen, S Thomas, et al. ‘Recent origin of Plasmodium falciparum from a single progenitor’, Science, 2001, 293: 482–4.
8 A Hughes and F Verra, ‘Very large long-term effective population size in the virulent human malaria parasite Plasmodium falciparum’, Proc. R. Soc. Lond., 2001, B268: 1855–60; A Hughes and F Verra, ‘Extensive polymorphism and ancient origin of Plasmodium falciparum’, Trends in Parasitology, 2002, 18: 348–51; J Mu, J Duan, K D Makova, D Joy, C Huynh, et al., ‘Chromosome-wide SNPs reveal an ancient origin for Plasmodium falciparum’, Nature, 2002, 418: 323–6; D Forsdyke, ‘Selective pressures that decrease synonymous mutations in Plasmodium falciparum’, Trends in Parasitology, 2002, 18: 411–17.
9 D A Joy, X Feng, J Mu, T Furuya, K Chotivanich, et al. ‘Early origin and recent expansion of Plasmodium falciparum’, Science, 2003, 300: 318–21.
10 M Coluzzi, A Sabatini, A della Torre, M Di Deco, and V Petrarca, ‘A polytene chromosome analysis of the Anopheles gambiae species complex’, Science, 2002, 298: 1415–18.
11 A survey of recent work in this field is provided by J Mercader (ed.), Under the canopy: the archaeology of tropical rain forests, Piscataway, NJ, Rutgers University Press, 2002.
12 Bruce-Chwatt and de Zulueta, op. cit., note 3 above, pp. 9–11.
13 For example, Hippocrates, Epidemiae, I.6, I.24, III.12, De aere, aquis, et locis, X–XII, Oeuvres complètes d'Hippocrate, ed. E Littré, Paris, J-B Baillière, 1839–61; K Zysk, Religious healing in the Veda: with translations and annotations of medical hymns from the Rigveda and the Atharvaveda and renderings from the corresponding ritual texts, Philadelphia, Transactions of the American Philosophical Society, 1985, vol. 75, pt.7, pp. 34–44; L Dong, M Xi, and F Thann, Les maux épidémiques dans l'empire chinois, Paris, L'Harmattan, 1996, pp. 95–6.
14 D J Conway, C Fanello, J M Lloyd, B Al-Joubori, A Baloch, et al., ‘Origin of Plasmodium falciparum malaria is traced by mitochondrial DNA’, Mol. Biochem. Parasitol., 2000, 111: 163–71.
15 Celsus, De medicina, III.3.2: “tertianarum vero duo genera sunt. Alterum eodem modo, quo quartana, et incipiens et desinens, illo tantum interposito discrimine, quod unum diem praestat integrum, tertio redit. Alterum longe perniciosius, quod tertio quidem die revertitur, ex quadraginta et octo horis fere triginta et sex per accessionem occupat (interdum etiam vel minus vel plus), neque ex toto in remissione desistit, sed tantum levius est. Id genus plerique medici appellant.”
16 E Marchiafava and A Bignami, On summer–autumn malarial fevers, transl. J Thompson, London, New Sydenham Society, 1894, pp. 231–2. Bruce-Chwatt and de Zulueta, op. cit., note 3 above, pp. 19, 89, accepted Celsus' evidence but incorrectly dated it to the second century AD. This is symptomatic of an unwarranted general tendency on the part of these authors to shorten the chronology for the spread of falciparum malaria in antiquity. The identification of semitertian fever in Celsus was also accepted by G Corbellini and L Merzagora, La malaria tra passato e presente: storia e luoghi della malattia in Italia, Rome, Università di Roma “La Sapienza”, 1998, p. 14.
17 Celsus, De medicina, III.3.1.
18 Plutarch, Moralia, VIII.9.731b–734c, and Pliny, Historia naturalis, XXVI.1–9, both discussed leprosy as a new disease in Hellenistic and Roman times.
19 Quintus Serenus, Liber medicinalis, 51.932–4, ed. R Pépin, Paris, Presses Universitaires de France, 1950.
20 Hippocrates Epidemiae, I.2, op. cit., note 13 above, vol. 2, pp. 606–9: . On the question, raised by Bruce-Chwatt and de Zulueta, op. cit., note 3 above, p. 18, of the association in the Hippocratic texts of semitertian fever with consumption (tuberculosis), see Sallares, op. cit., note 5 above, pp. 136–9.
21 Hippocrates, op. cit., note 13 above, pp. 624–5: . Julian de Zulueta's argument (mentioned by Corbellini and Merzagora, op. cit., note 16 above, p. 22), that sufferers from semitertian fever died too slowly for falciparum malaria to have been the cause, does not take into account the likelihood, discussed below in this article, that by the fifth century BC at least some populations in northern Greece already had a high frequency of human genetic mutations conferring some resistance to malaria. M Grmek, Diseases in the ancient Greek world, Baltimore, Johns Hopkins University Press, 1989, p. 281, accepted the identi fication of falciparum malaria in the Hippocratic texts.
22 Aetius of Amida, Libri medicinales, VI.3.
23 For the problem of whether Macedonia was severely affected by malaria during the time of its rise to power under Philip and Alexander the Great in the fourth century BC, see E Borza ‘Some observations on malaria and the ecology of central Macedonia in antiquity’, Am. J. Ancient Hist., 1979, 4: 102–24.
25 This is a better approach to the problem than assuming, as W H S Jones (op. cit., note 1 above, p. 76) did, that the silence of very scarce earlier sources proves that malaria was unknown in Attica until c. 430 BC.
26 M Grmek, ‘Les ruses de guerre biologiques dans l'antiquité’, Revue des Études Grecques, 1979, 92: 141–63, on pp. 150–61.
27 R Mirisola and L Polacco, Contributi alla paleogeografia di Siracusa e del territorio siracusano (VIII–V sec. a.C.), Memorie, Classe di Scienze Morali, Lettere ed Arti, vol. 66, Venice, Istituto Veneto di Scienze, Lettere ed Arti, 1996, pp. 9–34.
28 Strabo, Geographia, V.4.13.251C.
29 Pliny the Younger, Epistolae, V.6.2.
30 G Facchetti, ‘Qualche osservazione sulla lingua minoica’, Kadmos 2001, 40: 1–38, on p. 14.
31 Marcus Porcius Cato, Origines, II.17; photographs of Graviscae in Sallares, op. cit., note 5 above, pp. 194–5.
32 Asclepiades ap. Caelius Aurelianus, De morbis acutis, II.63–4; Galen, VII.435 and XVIIA.121–2, Opera omnia, ed. C Kühn, Leipzig, C Cnobloch, 1821–33.
33 M McCormick, Origins of the European economy: communications and commerce, A. D. 300–900, Cambridge University Press, 2001, pp. 980–1.
34 Vitruvius, De architectura, I.4.11–12; Strabo, Geographia, V.1.7.213C.
35 Sidonius Apollinaris, Epistulae, I.8.2.
36 M Coluzzi, ‘The clay feet of the malaria giant and its African roots: hypotheses and inferences about origin, spread and control of Plasmodium falciparum’, Parassitologia, 1999, 41: 277–83.
37 On the question of the refractoriness of modern tropical strains of P. falciparum to European mosquitoes, see Sallares, op. cit., note 5 above, pp. 33–6. Refractoriness was probably overcome in North Africa and the Near East in prehistory before P. falciparum had even reached southern Europe.
38 R Miller, S Ikram, G J Armelagos, R Walker, W Harer, et al., ‘Diagnosis of Plasmodium falciparum infections in mummies using the rapid manual ParaSight-F test’, Trans. R. Soc. Trop. Med. Hyg., 1994, 88: 31–2; G Taylor, P Rutland, and T Molleson, ‘A sensitive polymerase chain reaction method for the detection of Plasmodium species DNA in ancient human remains’, Ancient Biomolecules, 1997, 1: 193–203; N Cerutti, A Marin, E Massa, and D Savoia, ‘Immunological investigation of malaria and new perspectives in palaeopathological studies’, Bolletino della Società Italiana di Biologia Sperimentale, 1999, 75 (3–4): 17–20.
39 D Soren, T Fenton, and W Birkby, ‘The late Roman infant cemetery near Lugnano in Teverina, Italy: some implications’, J. Paleopathol., 1995, 7: 13–42; D Soren and N Soren (eds), A Roman villa and a late Roman infant cemetery: excavation at Poggio Gramignano, Lugnano in Teverina, Rome, “L'Erma” di Bretschneider, 1999, pp. 461–651.
40 Sallares, op. cit., note 5 above, pp. 61–3, on the seasonality of malaria in Italy.
41 Unfortunately no corresponding adult cemetery has been discovered.
42 C Shulman, T Marshall, E Dorman, J Bumer, F Cutts, et al., ‘Malaria in pregnancy: adverse effects on haemoglobin levels and birthweight in primigravidae and multigravidae’, Trop. Med. Int. Health, 2001, 6: 770–8.
43 A Barbosa and B López Arjona, El paludismo en el primer año de la vida, Madrid, Sáez Hermanos, 1935, pp. 11–18.
44 R Torpin, ‘Malaria complicating pregnancy’, Am. J. Obstet. Gynecol., 1941, 41: 882–5; C A Gill, The genesis of epidemics and the natural history of disease: an introduction to the science of epidemiology based upon the study of epidemics of malaria, influenza, and plague, London, Baillière, Tindall and Cox, 1928, pp. 74–83.
45 C Luxemburger, R McGready, A Kham, L Morison, T Cho, et al. ‘Effects of malaria during pregnancy on infant mortality in an area of low malaria transmission’, Am. J. Epidemiol., 2001, 154: 459–65; M Cot, J Le Hesran, T Staalsoe, N Fievet, L Hviid, and P Deloron, ‘Maternally transmitted antibodies to pregnancy-associated variant antigens on the surface of erythrocytes infected with Plasmodium falciparum: relation to child susceptibility to malaria’, Am. J. Epidemiol., 2003, 157: 203–9.
46 A Sorgoni, ‘Riflessioni sulla maggior forza, con cui si sviluppano le febbri intermittenti ne' marchegiani abitanti nel territorio di Narni a confronto di quella minore forza colla quale si producono negl'indigeni narniesi’, Giornale Arcadico di Scienze, Lettere ed Arti, 1832, 57: 12–21.
47 For general accounts of Umbria in late antiquity, see G Binazzi (ed.), L'Umbria meridionale fra tardo-antico ed altomedioevo, Perugia, Università degli Studi, 1991; S Bocci, L'Umbria nel Bellum Gothicum di Procopio, Studi pubblicati dall'Istituto italiano per la storia antica, vol. 62, Rome, Istituto italiano per la storia antica, 1996.
48 For details of the methods used, see R Sallares and S Gomzi, ‘Biomolecular archaeology of malaria’, Ancient Biomolecules, 2001, 3: 195–213 (with EMBL/Genbank accession nos. AJ426487–8 for the malaria sequences that were obtained).
49 Determination of the sex of a sample of these infants (see also next footnote) indicated that the infant population had a fairly normal sex ratio (five female and four male). Consequently there is no question of selective exposure of female infants in this cemetery.
50 Only nine out of fifteen of the Lugnano infants that were sampled yielded positive results for sex determination by the amelogenin sex determination system—infant bones cannot be sexed by morphological methods (for details of methods see R Sallares, S Gomzi, A Bouwman, C Anderung, and T Brown, ‘Identification of a malaria epidemic in antiquity using ancient DNA’, in K Robson Brown (ed.), Archaeological Sciences 1999. Proceedings of the Archaeological Sciences Conference, University of Bristol, 1999, Oxford, Archaeopress [BAR S1111], 2003, pp. 120–5). This ratio is comparable to results from other ancient Mediterranean archaeological sites, e.g. M P Evison, ‘Ancient DNA in Greece: problems and prospects’, Journal of Radioanalytical and Nuclear Chemistry, 2001, 247: 673–8; C Vernesi, D Caramelli, S Carbonell i Sala, M Ubaldi, F Rollo, and B Chiarelli, ‘Application of DNA sex tests to bone specimens from three Etruscan (VII–III century B.C.) archaeological sites’, Ancient Biomolecules, 1999, 2: 295–305; M Cipollaro, G Di Bernardo, G Galano, U Galderisi, et al., ‘Ancient DNA in human bone remains from Pompeii archaeological site’, Biochemical and Biophysical Research Communications, 1998, 247: 901–4.
51 Sallares, op. cit., note 5 above, pp. 64–8.
52 Quintus Serenus, Liber medicinalis, 51.935–940, op. cit., note 19 above.
53 Literary evidence for the interaction of magic and religion in Umbria at this time has been discussed by G Bartocci, ‘The cultural construction of the Western conception of the realm of the sacred: co-existence, clash and interbreeding of magic and sacred thinking in fifth- and sixth-century Umbria’, Anthropology and Medicine, 2000, 7: 373–88.
54 G O Tadmouri, N Garguier, J Demont, P Perrin, and A N Başak, ‘History and origin of β-thalassaemia in Turkey: sequence haplotype diversity of β-globin genes’, Human Biology, 2001, 73: 661–74; L Zahed, J Demont, R Bouhass, G Trabuchet, C Hänni, et al., ‘Origin and history of the IVS-I-110 and codon-39 β-thalassemia mutations in the Lebanese population’, Human Biology, 2002, 74: 837–47; S A Tishkoff, R Varkonyi, N Cahinhinan, S Abbes, G Argyropoulos, et al. ‘Haplotype diversity and linkage disequilibrium at human G6PD: recent origin of alleles that confer malarial resistance’, Science, 2001, 293: 455–62; L Luzzatto and R Notaro, ‘Malaria: protecting against bad air’, Science, 2001, 293: 442–3; P C Sabeti, D E Reich, J M Higgins, H Levine, D Richter, et al. ‘Detecting recent positive selection in the human genome from haplotype structure’, Nature, 2002, 419: 832–7.
55 I Hershkovitz, B Rothschild, B Latimer, O Dutour, E Léonetti, C Greenwald, et al. ‘Possible congenital haemolytic anemia in prehistoric coastal inhabitants of Israel’, Am. J. Phys. Anthropol., 1991, 85: 7–13, on the skeleton Homo 25.
56 G Baggieri and F Mallegni, ‘Morphopathology of some osseous alterations of thalassic nature’, Paleopathology Newsletter, 2001, 116: 10–16.
57 F Mallegni and G Fornaciari, ‘Le ossa umane’, in A Ricci (ed.), Settefinestre: una villa schiavistica nell'Etruria romana, 3 vols, Modena, Panini, 1985, vol. 2, pp. 275–7, on skeleton no. 26.203.
58 J C Carter, The chora of Metaponto: the necropoleis, 2 vols, Austin, University of Texas Press, 1998, vol. 2, pp. 527–9, 553–6.
59 Grmek, op. cit., note 21 above, p. 275; M Grmek and D Gourevitch, Les maladies dans l'art antique, Paris, Fayard, 1998, pp. 223–5.
60 G Maat and M Baig, ‘Scanning electron microscopy of fossilized sickle-cells’, Int. J. Anthropol., 1990, 5: 271–6; G Maat, ‘Bone preservation, decay and its related conditions in ancient human bones from Kuwait’, Int. J. Osteoarchaeol., 1993, 3: 77–86.
61 P Hortolà, ‘Red blood cell haemotaphonomy of experimental human bloodstains on techno-prehistoric lithic raw materials’, J. Archaeol. Sci., 2002, 29: 733–9.
62 A Ragusa, M Lombardo, G Sortino, T Lombardo, R L Nagel, and D Labie, ‘βS gene in Sicily is in linkage disequilibrium with the Benin haplotype: implications for gene flow’, Am. J. Hematol., 1988, 27: 139–41.
63 A Kulozik, J Wainscoat, G Serjeant, B Kar, B Al-Awamy, et al., ‘Geographical survey of βS-globin gene haplotypes: evidence for an independent Asian origin of the sickle-cell mutation’, Am. J. Hum. Genet., 1986, 39: 239–44
64 A list of G6PD mutations is given by E Beutler and T J Vulliamy, ‘Haematologically important mutations: glucose-6-phosphate dehydrogenase’, Blood Cells, Molecules, and Diseases, 2002, 28: 93–103.
65 M Cappadoro, G Giribaldi, E O'Brien, F Turrini, F Mannu, et al. ‘Early phagocytosis of glucose-6-phosphate dehydrogenase (G6PD)-deficient erythrocytes parasitized by Plasmodium falciparum may explain malaria protection in G6PD deficiency’, Blood, 1998, 92: 2527–34; K Lang, B Roll, S Myssina, M Schittenhelm, H Scheel-Walter, et al., ‘Enhanced erythrocyte apoptosis in sickle cell anaemia, thalassaemia and glucose-6-phosphate dehydrogenase deficiency’, Cellular and Physiological Biochemistry, 2002, 12: 365–72.
66 Y Abdulrazzaq, R Micallef, M Qureshi, A Dawodu, I Ahmed, et al., ‘Diversity in expression of glucose-6-phosphate dehydrogenase deficiency in females’, Clinical Genetics, 1999, 55: 13–19.
67 For details of the methods used, see Sallares, et al., op. cit., note 50 above. See also A Bouwman and T Brown, ‘Comparison between silica-based methods for the extraction of DNA from human bones from 18th to mid-19th century London’, Ancient Biomolecules, 2002, 4: 173–8. For other work on the G6PD gene in degraded materials, see H Liu, X Huang, Y Zhang, H Ye, A Hamidi, et al. ‘Archival fixed histologic and cytologic specimens including stained and unstained materials are amenable to RT-PCR’, Diagn. Mol. Pathol., 2002, 11: 222–7.
68 F Martinez di Montemuros, C Dotti, D Tavazzi, G Fiorelli, and M Cappellini, ‘Molecular heterogeneity of glucose-6-phosphate dehydrogenase (G6PD) variants in Italy’, Haematologica, 1997, 82: 440–6.
69 A Minà La Grua, Memoria sopra l'itterizia e su le malattie ordinarie dei contadini di Castelbuono, Palermo, Vrizi, 1856.
70 Grmek, op. cit., note 21 above, pp. 210–44; E Lieber, ‘The Pythagorean community as a sheltered environment for the handicapped’, in H Karplus (ed.), International symposium on society, medicine and law (Jerusalem March 1972), Amsterdam, Elsevier, 1973, pp. 33–41, on p. 36.
71 G Gaetani and A Ferraris, ‘Biochemistry of G6PD deficiency and molecular genetics of G6PD variants in Italy’, in L S Greene and M E Danubio (eds), Adaptation to malaria: the interaction of biology and culture, Amsterdam, Gordon and Breach, 1997, pp. 9–31, on p. 20. J V Day, Indo-European origins: the anthropological evidence, Washington, DC, Institute for the Study of Man, 2001, pp. 287–9, discusses the hypothesis of Eugene Giles that G6PD deficiency and the taboo on beans arose among the Proto-Indo-Europeans.
72 Tadmouri, et al., op. cit., note 54 above.
73 A Cao, M Gossens, and M Pirastu, ‘β-thalassaemia mutations in Mediterranean populations’, Br. J. Haematology, 1989, 71: 309–12. Earlier discussions by medical historians and palaeopathologists (e.g. Grmek, op. cit., note 21 above, pp. 254–64) did not employ the evidence of DNA sequence data, which was not yet available.
74 Cao, et al., op. cit., note 73 above.
75 P Perrin, R Bouhassa, L Mselli, N Garguier, V Nigon, et al. ‘Diversity of sequence haplotypes associated with β-thalassaemia mutations in Algeria: implications for their origin’, Gene, 1998, 213: 169–77.
76 C Ramsdale and K Snow, ‘Distribution of the genus Anopheles in Europe’, Eur. Mosq. Bull., 2000, 7: 1–26.
77 W Horsfall, Mosquitoes: their bionomics and relation to disease, New York, Ross, 1955, pp. 94, 103, 107.
78 P Sondaar, ‘Palaeolithic Sardinians: palaeontological evidence and methods’, in M Balmuth and R Tykot (eds), Sardinian and Aegean chronology: towards the resolution of relative and absolute dating in the Mediterranean, Oxford, Oxbow, 1998, pp. 45–51.
79 S Moscati, Italia punica, Milan, Bompiani, 1986, pp. 150–2, 181.
80 G Schilirò, E Mirabile, R Testa, G Russo-Mancuso, and S Dibenedetto, ‘Presence of haemoglobinopathies in Sicily: a historic perspective’, Am. J. Med. Genet., 1997, 69: 200–6.
81 This is the explanation of the problem posed by Bruce-Chwatt and de Zulueta, op. cit., note 3 above, p. 15.
82 Sallares, op. cit., note 5 above, pp. 78–85.
83 M McCormick, ‘The imperial edge: Italo-Byzantine identity, movement and integration, AD 650–950’, in H Ahrweiler and A Laiou (eds), Studies on the internal diaspora of the Byzantine Empire, Washington, DC, Dumbarton Oaks, 1998, pp. 17–52, on pp. 25–31.
84 Grmek and Gourevitch, op. cit., note 59 above, pp. 97–9.
85 J L Angel, ‘Porotic hyperostosis or osteoporosis symmetrica’, in D Brothwell and A Sandison (eds), Diseases in antiquity, Springfield, IL, C C Thomas, 1967, pp. 378–89, argued that there was malaria at Lerna in the Middle Bronze Age.
86 J L Angel, ‘Porotic hyperostosis, anemias, malarias, and marshes in the prehistoric eastern Mediterranean’, Science, 1966, 153: 760–3.