Malaria and Rome: A History of Malaria in Ancient Italy (7 page)

P. falciparum
achieves a very high rate of reproduction in a number of ways, for example by having the ability to invade erythrocytes of all ages, whereas
P. vivax
only invades reticulocytes (immature erythrocytes) with the Duffy antigen.
P. falciparum
may infect up to 80% of all erythrocytes, whereas
P. vivax
does not infect more than about 2%, and
P. malariae
more than about 1% of all red blood cells.

In cold environments, on the other hand, where transmission by mosquito is not possible all the year round, the parasite requires the host to survive during the winter in order to have an opportunity for transmission to new hosts the following year. These ecological considerations explain why extreme virulence is adaptive for
P.

falciparum
in its home in tropical Africa, while avirulence is adaptive for
P. vivax
and
P. malariae
in colder environments. Consequently the extreme virulence of
P. falciparum
does not constitute evidence for a recent evolutionary origin.²

The exponential expansion of DNA sequencing in recent years has yielded the important result that the human parasite
P. falciparum
forms a monophyletic clade with
P. reichenowi
, a malaria species which infects chimpanzees in Africa. This clade is not closely related to any of the other three species of human malaria.

Analysis of DNA sequences from ribosomal RNA genes (see Fig. 1) and from the circumsporozoite protein gene suggests that the ²
e.g.
Fiennes (1978: 105–12) regarded
P. falciparum
as a recent pathogen of man because of its virulence, but Garnham (1966: 279) was sceptical of such theories. Ewald (1994: 42–6), Anderson and May (1991: 648–52, cf. 392–419), and Coluzzi (1999) give various views on the significance of its virulence; Mackinnon and Read (1999
a
) and (1999
b
). Marchiafava and Bignami (1894: 103) observed that ‘malignancy coincides
with an exceptionally abundant quantity of parasitic forms
, a quantity much more abundant—where the cases terminate fatally—in the blood of the viscera than in the blood of the finger’.

26

Evolution of malaria

common ancestor of the
P. falciparum/P. reichenowi
clade diverged from the common ancestor of the
P. vivax/P. malariae
clade about 165 million years ago.
Anopheles
mosquitoes, which transmit human malaria, do not appear in the fossil record until the Oligo-cene period (26–38 million years ago), but studies of molecular evolution suggest that the
Anopheles
family is very ancient. The protein and DNA sequences of the 35kb circular DNA molecule and the enolase gene of
P. falciparum
manifest very ancient kinship, or at least very extensive horizontal transfers of DNA, embracing not only organellar but also nuclear DNA, with a plant-related lineage.³ It remains controversial whether the various species of malaria were originally parasites of vertebrates or parasites of mosquitoes. It is possible that they were originally parasites of vertebrates because of the similarity of their developmental cycles to those of coccidian intestinal parasites of the suborder
Eimeriina
.⁴

However, the most interesting result of this research in molecular biology for current purposes is that statistical analysis of the degree of divergence between the DNA sequences of the human parasite
P. falciparum
and the chimpanzee parasite
P. reichenowi
puts their date of divergence in the time range of 5–11 million years ago.

Given the inevitable margin of error in these statistical calculations, this date approximates the date of divergence between humans and chimpanzees given by palaeoanthropologists. Consequently it is likely that
P. falciparum
has been attacking humans and their hominid ancestors since the dawn of human evolution, the split from the chimpanzee lineage.⁵ Similarly recent research suggests ³ Escalante
et al
. (1995) and Qari
et al
. (1996) on the molecular evolution of Plasmodium from rRNA gene sequences, cf. Escalante
et al
. (1998
a
) for data from the
cytochrome b
gene and Rathore
et al
. (2001) for data from plastid sequences; Capasso (1991), Besansky
et al
. (1992), and Coluzzi (1999) on mosquito evolution; Hyde
et al
. (1994), Read
et al
. (1994) (nuclear DNA), and Köhler
et al
. (1997) (plastid DNA) on the links of
P. falciparum
to plant-related lineages; Felger
et al
. (1997) illustrate the sort of genetic variation which is now being discovered.

⁴ Missiroli (1934: 10–11) was one prominent Italian malariologist who advocated the theory of the close evolutionary relationship of malaria parasites to coccidian intestinal parasites. Capasso (1985: 301) supported the alternative theory that malaria parasites were originally parasites of the salivary glands of mosquitoes. This theory leaves unresolved the transmission question, namely how did the parasites get from mosquito to mosquito, since mosquitoes don’t bite each other. Going back even further in time, Halevy (1998) suggested that plasmodial parasites owe their similarities to plant genomes to descent from toxic algae which infected fish.

⁵ Rich
et al
. (1998
a
) and Ayala and Rich (2000) found a very low rate of synonymous sub-stitutions in housekeeping genes of
P. falciparum
. They drew the inference from the apparent lack of genetic variation in housekeeping genes of modern strains that all currently existing P. falciparum
populations are derived from a single ancestor that lived a few thousand years Evolution of malaria

27

that other major parasitic diseases such as visceral leishmaniasis and trypanosomiasis also co-evolved with humans in Africa.
P.

falciparum
is one of mankind’s oldest, deadliest, and most persistent foes. This conclusion has considerable implications for the question of the size of host population required by
P. falciparum
. Evidently it was able to survive for very long periods during which all humans and their hominid ancestors were hunter-gatherers, long before the invention of agriculture, periods when human population sizes were very small. One thinks for example of the figure of 10,000 frequently given by molecular biologists as the effective population size (i.e. the size of the adult breeding population) of the populations (not necessarily the same population) to which belonged ‘mitochondrial Eve’, the last common female ancestor of all currently existing human mitochondrial DNA genotypes (assuming a rarity of recombination), and her male counterpart, the ‘Adam’

currently being revealed by studies of DNA sequences from the Y chromosome.
P. falciparum
is an extremely ancient human pathogen which was able to survive in small human populations in Africa, the cradle of human evolution.

In contrast,
P. vivax
and
P. malariae
are closely related to malaria parasites of monkeys in south-east Asia,outside the cradle of human evolution.⁶
P. vivax
, for example, closely resembles
P. cynomolgi
, a parasite of
Macaca
monkeys in south-east Asia, in respect of both morphology and DNA sequences.
P. vivax
and
P. malariae
were not originally human diseases. They probably first encountered the evolving hominids when
Homo erectus
spread out from Africa across Asia, probably between one and two million years ago. The ago, even though they accept that the divergence between
P. falciparum
and
P. reichenowi occurred several million years ago. Their controversial theory about
P. falciparum
cannot be discussed in detail here, but it is probably incorrect or, at best, an exaggeration (their views on the evolution of
P. vivax
and
P. malariae
are completely untenable). It does appear that different results are obtained from different parts of the genome, a problem frequently observed in research on molecular evolution (Gillespie (1991: 41) ). Other regions of the
P. falciparum genome currently being studied by other scientists are yielding results incompatible with those obtained by Ayala and Rich (e.g. Verra and Hughes (2000) ). I hope that it will be possible within the next few years to obtain direct evidence from ancient DNA permitting an evaluation of the theory of Ayala and Rich concerning a recent cenancestor of
P. falciparum
.

⁶ Of course the distribution both of species of nonhuman malaria and of other primates might have been different in earlier geological epochs. Skinner
et al
. (1995) suggested that periodic episodes of linear enamel hypoplasia in fossil teeth of
Dryopithecus
apes from Can Llobateres in northeastern Spain, dating to the Miocene period about 9.5 million years ago, might have been caused by malaria.

28

Evolution of malaria

question of the origin of
P. vivax
malaria in humans is tied to the question of the
FY*O
allele in the Duffy blood group locus, which prevents
P. vivax
parasites from adhering to and entering erythrocytes in nearly all members of sub-Saharan African populations. It is not known whether this allele spread in response to an existing parasite burden and drove
P. vivax
out of sub-Saharan Africa (its niche being taken by
P. ovale
), or whether an already high prevalence of this allele (perhaps in response to another pathogen) prevented
P. vivax
from ever establishing itself in Africa in the first place. In the last few years the Duffy negative allele has also appeared in Papua New Guinea, where
P. vivax
is endemic. This is an example of evolution in action in human populations today in response to malaria.⁷

Since
P. falciparum
was present in the heartland of human evolution in East Africa, presumably it would have been carried out of Africa by every successive wave of hominids and humans, from Homo erectus
onwards. Whether it would have prospered outside Africa would have depended on the climate and on whether in new environments it encountered species of mosquito able to transmit it. These two factors are the last two pillars of the theory of the late spread of malaria into Mediterranean countries. Zulueta has quite correctly argued that the climate of Ice Age Europe was too cold both for the completion of the developmental cycle of
P. falciparum itself within the mosquito and for the principal mosquito vector species in Italy,
Anopheles labranchiae
and
A. sacharovi
(=
elutus
).

He then reckoned that it would have taken thousands of years for conditions to become favourable enough for
P. falciparum
and its vectors to spread into southern Europe. However, this argument was based on old and out-of-date literature about the Holocene climate. It ignores the mass of evidence which is now available for what climatologists call the mid-Holocene climatic optimum, a period after the end of the last Ice Age and encompassing the Neolithic period until
c
.3000 , when, owing to periodic shifts in the earth’s position relative to the sun, the northern hemisphere received considerably more insolation than it does today. This resulted in the climate of many parts of the northern hemisphere being up to 2°C hotter than in subsequent millennia. Such temperatures are only now being approached again with the recent ⁷ Livingstone (1984); Zimmerman
et al
. (1999); Hamblin and Di Rienzo (2000).

Evolution of malaria

29

trend towards anthropogenic global warming.⁸ The effects of these climate changes in Italy have recently attracted attention because of their relevance to the preservation of the famous ‘Iceman’ discovered in the Alps (as it turned out, just on the Italian side of the border with Austria). Fortunately for modern archaeologists, the Iceman died towards the end of the mid-Holocene climatic optimum, in the late fourth millennium , at a time when neoglacia-tion was commencing (i.e. the Alpine glaciers were starting to advance again as mean annual temperatures dropped). This covered his body with ice, preserving it until anthropogenic global warming in the last few years caused the glacier to begin to retreat again, exposing the frozen corpse.⁹

The development of
P. falciparum
is heavily dependent on the temperature. Since it requires a minimum temperature of about 20°C for the completion of sporogony inside the mosquito, climatic conditions during the Neolithic period were in fact substantially more favourable
for the spread of
P. falciparum
and its vector mosquitoes into southern Europe than they were in the first millennium 

or any other period after the Neolithic. What are now the Saharan and the Arabian deserts also received substantially more rainfall during the mid-Holocene climatic optimum than they do today, creating more breeding sites for mosquitoes.¹⁰ This would have assisted the spread of malaria from tropical Africa towards the southern shores of the Mediterranean. It is even conceivable that the geographic range of members of the
Anopheles gambiae
complex, the most important vector of malaria in tropical Africa today, may have extended further north in Africa than it has done in recent times. Mosquitoes can evolve very rapidly. For example, populations of
Culex pipiens
confined to London Underground tunnels and separated from above-ground populations have evolved new host preferences (mice, rats, and humans instead of birds), reproductive isolation from above-ground populations, new mating patterns (stenogamy instead of eurygamy), loss of winter diapause, and the possibility of oviposition without prior ingestion of a blood meal, all in no more than about one hundred years. Similarly the most ⁸ Zulueta (1973) and (1987); Sallares (1995) on the mid-Holocene optimum in western Eurasia. Recent research in China, reported in
Nature
, 390 (1997: 209), confirms that it was a worldwide phenomenon. It is estimated that the mean annual temperature was 2–4˚C