Malaria and Rome: A History of Malaria in Ancient Italy (9 page)

(1997); Zheng
et al
. (1997); Billker
et al
. (1998); Feldman
et al
. (1998); Paskewitz and Gorman (1999); Barillas-Mury
et al
. (2000); Oduol
et al
. (2000).

Evolution of malaria

35

many Old World human populations suggests that they have only recently been exposed to it.²⁶ Grmek rightly observed that the different responses of European mosquitoes to strains of parasite from different geographical areas in fact suggest a long period of separation between the tropical and the subtropical/temperate strains of P. falciparum.²⁷ The experiments at Horton Hospital in England suggested that Italian strains of
P. falciparum
from Sardinia and Salerno were more severe and more virulent and exhibited a faster growth rate than strains originating in tropical countries (with the proviso that the sample sizes in these experiments were small).²⁸

A faster progression of the infection on the part of European strains of
P. falciparum
might well have been an evolutionary adaptation to the shortness of the season each year that was suitable for its reproduction because of the climatic constraints in Europe.

Another crucial argument is that since the western Mediterranean mosquito vector-species
A. labranchiae
is common in North Africa, which in fact is its main area of distribution, as well as in Italy, while
A. sacharovi
, the second major Mediterranean vector with a more easterly distribution, also occurs in the Near East as well as in Greece,
P. falciparum
had every opportunity to evolve adaptation to its European vectors in Africa and in the Near East before even arriving in Europe. The nature of
P. falciparum
malaria in North Africa in the past is an important unresolved question.

The French colonists in North Africa in the nineteenth century had severe problems with malaria. Of course it was in North Africa that Alphonse Laveran discovered malarial parasites, at the hospital in Constantine in 1880. In 1832–3 two earlier French army doctors, Antonini and Maillot, working at the hospital of Bône in Algeria, found that giving high doses of quinine and a generous diet and ending the practice of bleeding reduced malaria mortality rates from 30% to 5%.²⁹ However, it is not clear whether the French colonists encountered the ‘European’ strains of
P. falciparum
, or the tropical strains, or both. Nevertheless, since
A. labranchiae
is abundant in North Africa as well as in Italy, and since the tropical strains ²⁶ Effertz (1909), Dunn (1965), and Cook ((1998: 48–9), wrongly identifying
P. vivax
with quartan fever) on the Americas. Li
et al
. (2001) published molecular evidence for two separate introductions of
P. vivax
to the western hemisphere, possibly both since Columbus.

²⁷ Grmek (1983: 402).

²⁸ Covel and Nicol (1951), reviewed more recently by Gravenor
et al
. (1995). Andrew Read pointed out the last reference to the author.

²⁹ Cohen (1983: 28), citing other literature.

36

Evolution of malaria

spreading with humans across the savannah grasslands in what is now the Sahara during the mid-Holocene climatic optimum would first have encountered
A. labranchiae
in North Africa rather than Italy, the balance of probability is that North Africa is where the ‘European’ strains of
P. falciparum
malaria evolved. Malaria evolution in North Africa would not have been subject to the constraints of the European climate during the glacial periods. Consequently the argument from mosquito refractoriness is as unconvincing as the other arguments used to support late-introduction theories.

Moreover when the mid-Holocene climatic optimum ended,

populations of
P. falciparum
in North Africa would have become isolated from the populations in central Africa. The occurrence of evolution in isolated populations is a standard scenario frequently invoked in theories of evolutionary biology. Today the leading edge of the evolution of drug resistance by malaria is in south-east Asia, a geographical area very far removed from the heartland of P. falciparum in tropical Africa.

Grmek identified the disease which afflicted the Athenians camped outside Syracuse in Sicily in 413 , described by Thucydides, as most probably
P. falciparum
malaria.³⁰ He gave a cogent explanation of the role of malaria in the Syracusan military strategy against the Athenian forces. Unfortunately it is generally ignored by mainstream ancient historians. Grmek argued that the Syracusan generals deliberately confined the Athenian forces to an area which they knew was unhealthy and then waited to let malaria do their work for them. He also discussed the possibility that
P. falciparum
malaria was a new disease then because it took an epidemic form, attacking large numbers of adults (the Athenian soldiers and their allies), who evidently did not have acquired immunity to it and so presumably had not previously experienced it in childhood. This idea may seem plausible, but yet again the most recent scientific research casts doubt on it, even though it is true that in areas where malaria is hyperendemic, as it certainly has been in many places in Tuscany and Latium in recent times, virtually everyone is infected in early childhood. With constant reinfections in childhood acquired immunity develops, with the result that adults seldom have acute attacks of fever and may not appear to have any parasites in their blood upon microscopic examination. There is still ³⁰ Grmek (1979: 150–61), cf. the non-committal opinion of Villard (1994).

Evolution of malaria

37

some experimental support for the older view that acquired immunity to malaria is short-lived and requires constant reinfection under holoendemic conditions to maintain it. However, the new techniques introduced into molecular biology in the last few years (the polymerase chain reaction (PCR); analysis of microsatellites; analysis of restriction fragment length polymorphisms (RFLP) of DNA) have produced new evidence which sheds further light on the situation.

P. falciparum
displays a great deal of genetic variation. All the various stages of development in humans are haploid clones, but in the gut of mosquitoes diploid zygotes are formed, as mixtures of different clones of parasites mate. Recombination of genetic material during meiosis in heterozygotes then yields new genotypes of parasite. Experiments have shown that the extent of recombination in genes coding for cell-surface proteins exported by parasites to the surface of erythrocytes is very considerable. Moreover the genetic diversity generated in this way may date back millions of years, at least partially antedating the split between
P. falciparum and the chimpanzee malaria parasite
P. reichenowi
.³¹ With the mosquito as a secondary host, malaria parasites have access to the evolutionary benefits of sexual reproduction (i.e. the capacity to generate genetic variation to give them the ability to meet new challenges in their environment,
e.g.
variations in their host’s immune response, new drugs used by modern doctors, etc.). PCR

amplification of VNTR (variable number tandem repeat)

sequences of DNA has shown that most individual cases of malaria in tropical countries today are infected with between two and six different haploid clones at the same time. The larger the number of haploid clones in a mosquito’s blood meal, the greater the degree of recombination that is likely to occur. Much earlier, Marchiafava had already reached the conclusion, from examination of parasites visible under the microscope in blood smears, that it was usual for patients in Rome to be infected with at least two different generations of parasites simultaneously. This explains why quotidian fevers, not tertian fevers, were the norm in cases of
P. falciparum ³¹ Conway
et al
. (1999) found evidence for a high recombination rate in the merozoite surface protein 3 gene coding for a cell-surface protein involved in immunological interactions; Hughes (1993), Taylor
et al
. (2000), Ayala and Rich (2000), and Okenu
et al
. (2000) on the antiquity of such polymorphisms; it is the subject of current controversy. Some scientists maintain that genetic polymorphism in
P. falciparum
is primarily generated by mitotic recombination rather than meiotic recombination.

38

Evolution of malaria

malaria in Rome both in the nineteenth century and in antiquity.

There is now some evidence that acquired immunity to
P. falciparum
is clone-specific. Differential expression of surface antigens in erythrocytes is controlled by the recently discovered family of var
genes. Successful reinfection only occurs when a new genotype is encountered. Consequently an individual who has acquired immunity to all the genotypes prevalent in the region of domicile is still vulnerable to different genotypes existing in other areas. The experiments at Horton Hospital in England showed that artificial infection with a strain of
P. falciparum
from India, for example, gave no protection at all against subsequent infection with a strain of P. falciparum
from Sardinia.³²

The relevance of all this to the plight of the Athenians outside Syracuse is that the fact that
P. falciparum
attacked many adults does not prove that it was a new disease then, either in Sicily or in Greece. It may simply have been the case instead that the Athenians and their allies encountered in Sicily a new strain of
P. falciparum which was different from the strains to which they were accustomed in Greece. Nevertheless, Grmek’s identification of
P. falciparum
malaria in the marshes outside Syracuse in 413  should be retained. There is also evidence for malaria in Sicily in the fifth century  at Selinus, Camarina, and Akragas. Consequently it appears that malaria was widespread and severe in Sicily from at least the fifth century  onwards.³³ Later on Sicily became an important source of grain for the city of Rome. Undoubtedly it also supplied malaria to that city. The inevitable result of prolonged ³² Babiker and Walliker (1997); Gupta
et al
. (1994); Kemp
et al
. (1990); Walliker
et al
. (1987); Paul and Day (1998); Marchiafava and Bignami (1894: 93); Smith
et al
. (1995); Su
et al
. (1995); Covel and Nicol (1951); Freitas-Junior
et al
. (2000) explained the very high frequency of recombination in the
var
gene sequences of
P. falciparum
in terms of gene conversion between aligned
var
genes in the adjacent telomeric regions of heterologous chromosomes.

³³ Empedocles diverted two rivers to try to eliminate malaria from the vicinity of Selinus, according to Diodorus of Ephesus: to∏ß Selinount≤oiß ƒmpesÎntoß loimoı di¤ t¤ß åpÏ toı parakeimvnou potamoı duswd≤aß, ¿ste ka≥ aÛtoŸß fqe≤resqai ka≥ t¤ß guna∏kaß dustoke∏n, ƒpino[sai tÏn ∞Empedoklva ka≥ d»o tin¤ß potamoŸß t0n s»negguß ƒpagage∏n jd≤aiß dap¤naiß: ka≥ katam≤xanta gluk[nai t¤ Âe»mata (Since a plague afflicted the people of Selinus because of the evil smell of the adjacent river, causing death and making pregnant women miscarry, Empedocles had the idea of bringing two rivers there at his own expense. By mixing the waters he sweetened them.) (Diogenes Laertius 8.70). The reality of the drainage works is shown by fifth-century coins from Selinus (Pauly-Wissowa,
RE
II A.2, (1923), col. 1281). P. F.

Russell (1955: pl. facing p. 161) illustrates one of these coins. Servius’ commentary on Virgil, Aeneid
3.701,
Greek Anthology
, 9.685, and Suda s.v. m¶ k≤nei Kam3rinan (don’t move Camarina) mention malarial swamps at Camarina in Sicily. For Akragas see Ch. 4. 2 below.

Evolution of malaria

39

exposure to intense endemic malaria in Sicily was the evolution of high frequencies of human genetic mutations giving some resistance to malaria. Besides b-thalassaemia and glucose-6-phosphate dehydrogenase (G6PD) deficiency, which are common in Sicily as in other Mediterranean populations with experience of endemic malaria (see Ch. 5. 3 below), the modern population of Sicily also exhibits a certain frequency (about 2%) of the sickle-cell trait (bS).

Haplotype analysis indicates that the sickle-cell trait reached Sicily from western central Africa. However, it is unclear whether this had already happened in antiquity, perhaps during the period of Carthaginian activity in Sicily, or during the time of the Roman Empire, as a result of the slave trade, or whether it happened later, as a result of the Arab conquests in the early medieval period.³⁴

Besides the G6PD mutations which are characteristic of Mediterranean populations, the principal African variant of G6PD

deficiency (A) also occurs in Sicily. This is further evidence supporting the hypothesis of gene flow from central Africa to Sicily.

The tenor of the discussion so far has been to suggest that none of the arguments that have been proposed in favour of a very late introduction of
P. falciparum
to southern Europe is convincing. On the contrary, the trend of the most recent scientific research is to suggest that
P. falciparum
is an extremely ancient pathogen which has been pursuing humans and their hominid ancestors for as long as they have been present on earth. The conclusions reached here so far are compatible with the opinion of Brunt, who did not find anything in ancient literary sources to suggest that malaria was ever regarded as a new disease in the classical period. The possibility of the emergence of new diseases was certainly explicitly considered in classical antiquity, particularly in relation to leprosy, as is demonstrated by lengthy discussions in Pliny and Plutarch.³⁵ However, no ancient Greek or Latin author ever suggested that the intermittent fevers now called malaria were a new disease. Nevertheless Brunt’s view yields a paradox that requires detailed investigation now. The paradox arises from the fact that the Etruscan cities in the Maremma and southern Etruria and numerous Greek colonies in the coastal regions of southern Italy were situated in locations so heavily infested with malaria in later times as to make it difficult to imagine how they could ever have prospered at all, ³⁴ Ragusa
et al
. (1988); Schilirò
et al
. (1990); Adekile (1992).