Spillover: Animal Infections and the Next Human Pandemic (17 page)

He began the 1916 paper by professing surprise that “
so little mathematical work should have been done
on the subject of epidemics,” and noted without false modesty (or any other kind) that he himself had been the first person to apply a priori
mathematical thinking (that is, starting with invented equations, not real-world statistics) to epidemiology. He nodded politely to John Brownlee’s “excellent” work and then proceeded to dismiss it, rejecting Brownlee’s idea about loss of infectivity and offering instead his own theory, supported by his own mathematical analysis. Ross’s theory was that epidemics decline when, and because, the density of susceptible individuals in the population has fallen below a certain threshold. Look and see, he said, how nicely my differential equations fit the same sets of epidemic data that Dr. Brownlee adduced. Brownlee’s hypothetical “loss of infectivity” was unnecessary for explaining the precipitous decline of an epidemic, whether the disease was cholera or plague or influenza or something else. All that was necessary was the depletion of susceptibles to a critical point—and then,
shazam
, the case rate fell drastically and the worst was over.

Ross’s a priori
approach may have been perilous, at such an early stage of malaria studies, and his attitude a little arrogant, but he produced useful results. His insight about susceptibles has met the test of time, coming down through the decades of theoretical work on infectious diseases to inform modern mathematical modeling. He was right about something else, too: the difficulty of extirpating malaria “once and forever.” Although the control measures he advocated were effective toward reducing malaria in certain locales (Panama, Mauritius), in other places they failed to do much good (Sierra Leone, India) or the results were transitory. For all his honors, for all his mathematical skills, for all his combative ambition and obsessive hard work, Ronald Ross couldn’t conquer malaria, nor even provide a strategy by which such an absolute victory would eventually be won. He may have understood why: because it’s such an intricate disease, deeply entangled with human social and economic considerations as well as ecological ones, and therefore a problem more complicated than even differential calculus can express.

25

W
hen I first wrote about zoonotic diseases, for
National Geographic
in 2007, I was given to understand that malaria was not one. No, I was told, you’ll want to leave it off your list. Malaria is a
vector
-
borne
disease, yes, in that insects carry it from one host to another. But vectors are not hosts; they belong to a different ecological category from, say, reservoirs; and they experience the presence of the pathogen in a different way. Transmission of malarial parasites from a mosquito to a human is not spillover. It’s something far more purposive and routine. Vectors seek hosts, because they need their resources (meaning, in most cases, their blood). Reservoirs do not seek spillover; it happens accidentally and it gains them nothing. Therefore malaria is not zoonotic, because the four kinds of malarial parasite that infect humans infect
only
humans. Monkeys have their own various kinds of malaria. Birds have their own. Human malaria is exclusively human. So I was told, and it seemed to be true at the time.

The four kinds of malaria to which these statements applied are caused by protists of the species
Plasmodium vivax, Plasmodium falciparum, Plasmodium ovale,
and
Plasmodium malariae
, all of them belonging to the same diverse genus,
Plasmodium
, which encompasses about two hundred species. Most of the others infect birds, reptiles, or nonhuman mammals. The four known for targeting humans are transmitted from person to person by
Anopheles
mosquitoes. These four parasites possess wondrously complicated life histories, encompassing multiple metamorphoses and different forms in series: an asexual stage known as the
sporozoite
, which enters the human skin during a mosquito bite and migrates to the human liver; another asexual stage known as the
merozoite
, which emerges from the liver and reproduces in red blood cells; a stage known as the
trophozoite
, feeding and growing inside the blood cells, each of which fattens as a
schizont
and then bursts, releasing more merozoites to further multiply in the blood, and causing a spike of fever; a sexual stage known as the
gametocyte
, differentiated into male and female versions, which emerge from a later round of infected red blood cells, enter the bloodstream en masse, and are taken up within a blood meal by the next mosquito; a fertilized sexual stage known as the
ookinete
, which lodges in the gut lining of the mosquito, each ookinete ripening into a sort of egg sac filled with sporozoites; and then come the sporozoites again, bursting out of the egg sac and migrating to the mosquito’s salivary glands, where they lurk, ready to surge down the mosquito’s proboscis into another host. If you’ve followed all that, at a quick reading, you have a future in biology.

This elaborate concatenation of life-forms and sequential strategies is highly adaptive and, so far as mosquitoes and hosts are concerned, difficult to resist. It shows evolution’s power, over great lengths of time, to produce structures, tactics, and transformations of majestic intricacy. Alternatively, anyone who favors Intelligent Design in lieu of evolution might pause to wonder why God devoted so much of His intelligence to designing malarial parasites.

Plasmodium falciparum
is the worst of the four in terms of its impact on human health, accounting for roughly 85 percent of reported malaria cases around the world—and for an even larger proportion of the fatalities. This form of the disease, known as falciparum malaria or malignant malaria, kills more than a half million people annually, most of them children in sub-Saharan Africa. Some scientists have suggested that the high virulence of
P. falciparum
reflects the fact that it’s relatively new to humans, having shifted to us within the recent past from another animal host. That suggestion has led researchers to investigate its ancestral history.

Of course, everything comes from somewhere, and because we humans ourselves are a relatively new primate, it was always logical to assume that our oldest infectious diseases had come to us—transmogrified at least slightly by evolution—from other animal hosts. It was always sensible to recognize that the distinction between zoonotic diseases and nonzoonotic diseases is slightly artificial, involving a dimension of time. By a strict definition, zoonotic pathogens (accounting for about 60 percent of our infectious diseases, as I’ve mentioned) are those that
presently and repeatedly
pass between humans and other animals, whereas the other group of infections (40 percent, including smallpox, cholera, measles, and polio) are caused by pathogens descended from forms that must have made the leap to human ancestors sometime in the past. It might be going too far to say that
all
our diseases are ultimately zoonotic, but zoonoses do stand as evidence of the infernal, aboriginal connectedness between us and other kinds of host.

Malaria exemplifies this. Within the
Plasmodium
family tree, as revealed by molecular phylogenetics over the last two decades, the four human-afflicting kinds don’t cluster on a single branch. They are each more closely related to other kinds of
Plasmodium
, infecting nonhuman hosts, than to one another. In the lingo of taxonomists, they are
polyphyletic
. What that suggests, besides the diversity of their genus, is that each of them must have made the leap to humans independently. Among the questions that continue to occupy malaria researchers are: Which other animals did they leap from, and when?

Falciparum malaria, because its global impact in death and misery is so high, has received particular attention. Early molecular research suggested that
P. falciparum
shares a close common ancestor with two different kinds of avian plasmodia, and that the parasite must therefore have crossed into humans from birds. A corollary to that idea, based on sensible deduction but not much evidence, is that the transfer probably happened just five or six thousand years ago, coincident with the invention of agriculture, which allowed for sedentary settlement—crop fields and villages—constituting the first sizable and dense aggregations of humans. Such gatherings of people would have been necessary to sustain the new infection, because malaria (like measles, but for different reasons) has a critical community size and tends to die out locally if the hosts are too few. Simple irrigation works, such as ditches and impoundments, may have increased the likelihood of transfer by offering good breeding habitat for
Anopheles
mosquitoes. Domestication of the chicken, about eight thousand years ago in Southeast Asia, may have been another contributing factor, since one of the two forms of bird plasmodia in question is
Plasmodium gallinaceum
, known for infecting poultry.

That view of falciparum malaria’s avian origins was propounded in 1991, a relatively long time ago in this field, and lately it doesn’t look so persuasive. A more recent study suggested that the closest known relative of
P. falciparum
is
P. reichenowi
, a malarial parasite that infects chimpanzees.

Plasmodium reichenowi
has been found in wild and (wild-born) captive chimps in both Cameroon and Côte d’Ivoire, suggesting that it’s widespread across chimpanzee habitat in Central and West Africa. It contains a fair degree of genetic variation—more than
P. falciparum
worldwide—suggesting that it may be an old organism, or anyway older than
P. falciparum
. Furthermore, all known variants of
P. falciparum
seem to be twigs within the
P. reichenowi
branch of the
Plasmodium
family tree. These insights emerge from data gathered by a team of researchers led by Stephen M. Rich, of the University of Massachusetts, who proposed that
P. falciparum
has
descended from
P. reichenowi
after spilling over from chimps into humans. According to Rich and his group, the spillover probably occurred just once, as early as 3 million years ago or as recently as ten thousand years ago. Some mosquito bit a chimpanzee (the insect becoming thereby infected with
P. reichenowi
gametocytes) and then also bit a human (delivering sporozoites). The transplanted strain of
P. reichenowi,
despite finding itself in an unfamiliar sort of host, managed to survive and proliferate. It passed from sporozoites into merozoites into gametocytes again, filled the bloodstream of that first human victim, and then caught itself another mosquito ride. From that insect it traveled onward, further vector-borne, to other humans as they foraged in the forest. Along the way it was changed by mutation and adaptation:
P.
 
reichenowi
became
P. falciparum.

This scenario implies that largish agricultural settlements
weren’t
necessary for the disease to take hold among humans, since no such settlements existed in those areas of Africa ten thousand (let alone 3 million) years ago. Rich’s group evidently considered the agricultural factor unnecessary. The genetic evidence they offered was compelling. Among Rich’s coauthors were a handful of luminaries in the fields of anthropology, evolution, and disease. Their paper appeared in 2009. But it wasn’t the last word.

Another group, led by a French anthropologist named Sabrina Krief and the malaria geneticist Ananias A. Escalante, published an alternative view in 2010. Yes, they agreed,
P. falciparum
may be more closely related to
P. reichenowi
than to any other known plasmodium. And yes, it seems to have spilled into humans within the relatively recent past. But look here, they said, we’ve located another host of
P. falciparum
itself—a host in which that parasite seems to have evolved
before
spilling into humans: the bonobo.

The bonobo (
Pan paniscus
) is sometimes known as the pygmy chimpanzee. It’s an elusive beast, limited in numbers and distribution, not often displayed in Western zoos, and (though much prized, alas, as an item of cuisine by the Mongo people of the southern Congo basin) very closely related to humans. Its native range is along the left bank of the Congo River, in the forests of the Democratic Republic of the Congo, whereas the common chimpanzee (
Pan troglodytes
), more burly and familiar, lives only on the right bank of the big river. Screening blood samples from forty-two bonobos resident at a sanctuary on the outskirts of Kinshasa, the Krief group found four animals carrying parasites genetically indistinguishable from
P. falciparum
. The most plausible explanation, Krief’s group wrote, is that falciparum malaria spilled over originally from bonobos into people, probably sometime within the last 1.3 million years. (An alternative explanation, offered by other researchers in a critical comment on the Krief paper, is that the bonobos in their small sanctuary, so near Kinshasa, had been infected by mosquitoes carrying
P. falciparum
from humans—sometime within recent years or decades.) The bonobos testing positive for
P. falciparum
had shown no overt signs of illness and low levels of parasites in their blood, which seemed consistent with an ancient association. To these descriptive and data-based results, Krief’s team added a hypothesis and a caveat.

Their hypothesis: If bonobos carry a form of
P. falciparum
that is so similar to what humans carry, those parasites may still be passing back and forth between bonobos and us. In other words, falciparum malaria may be zoonotic—in the strict sense of the word, not just the loose sense. Humans in the forests of DRC might be infected on a regular basis with
P. falciparum
from the blood of bonobos, and vice versa.