Spillover

by David Quammen

  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.

  Their caveat: If that’s so, the great dream of malaria eradication becomes even less attainable. Krief and company didn’t press the point but you might read that to mean: We can’t hope to kill off the last parasite until we kill off (or cure) the last bonobo.

  But wait! Still another study of P. falciparum origins, published in late 2010, pointed to still another candidate as its prehuman host: the western gorilla. This work appeared as a cover story in Nature, with Weimin Liu as first author and major contributions from the laboratory of Beatrice H. Hahn, then at the University of Alabama at Birmingham. Hahn is well known in AIDS-research circles for her role in tracing the origins of HIV-1 among chimpanzees, and for developing “noninvasive” techniques of sampling for virus in primates without having to capture the animals. Simply put: You don’t need a syringe full of blood if a little poo will do. Fecal samples can sometimes yield the necessary genetic evidence, not just for a virus but also for a protist. Applying those techniques to the search for plasmodium DNA, Liu, Hahn and their colleagues were able to gather far more data than were previous researchers. Whereas the Krief group had looked at blood samples from forty-nine chimpanzees and forty-two bonobos, most of which were captive or confined within a sanctuary, Liu’s group examined fecal samples from almost three thousand wild apes, including gorillas, bonobos, and chimps.

  They found that western gorillas carry a high prevalence of plasmodium (about 37 percent of the population is infected) and that some of those gorilla parasites are nearly identical to P. falciparum. “This indicates,” they wrote confidently, “that human P. falciparum is of gorilla origin, and not of chimpanzee, bonobo or ancient human origin.”

  Furthermore, they added, the entire genetic range of P. falciparum in humans forms “a monophyletic lineage within the gorilla P. falciparum radiation.” In plain talk: The human version is one twig within a gorilla branch, suggesting that it came from a single spillover. That’s one mosquito biting one infected gorilla, becoming a carrier, and then biting one human. By delivering the parasite into a new host, that second bite was enough to account for a zoonosis that still kills more than a half million people each year.

  26

  Mathematics to me is like a language I don’t speak though I admire its literature in translation. It’s Dostoyevsky’s Russian, or the German of Kafka, Musil, and Mann. Having studied calculus hard in school, as I did Latin, I found that the deep knack wasn’t in me, and the secret music of differential equations fell wasted on my deaf ears, just like the secret music of The Aeneid. So I’m an ignoramus, an outsider. That’s why you should trust me when I say that two other bits of mathematical disease theory, derived from early twentieth century concerns over epidemic malaria and other outbreaks, are not only important but intriguing, their essence quite capable of comprehension by the likes of you and me. One came out of Edinburgh. The other had its roots in Ceylon.

  The first bit was embedded in a 1927 paper titled “A Contribution to the Mathematical Theory of Epidemics,” by W. O. Kermack and A. G. McKendrick. Of these two partners, William Ogilvy Kermack has the more memorable story. He was a Scotsman, like Ross and Brownlee, educated in mathematics and chemistry before he began his career doing statistical analyses of milk yields from dairy cows. Every poet hears his first nightingale somewhere. Kermack went from milk yields into the Royal Air Force, emerged after brief service to do industrial chemistry as a civilian, and then around 1921 joined the Royal College of Physicians Laboratory in Edinburgh, where he worked on chemical projects until a lab experiment blew up in his face. I mean that literally. He was blinded by caustic alkali. Twenty-six years old. But instead of becoming an invalid and a mope, he became a theoretician. Gathering back resolve, he continued his scientific work with the help of students who read aloud to him and colleagues who complemented his extraordinary capacity for doing math in his head. Chemistry led Kermack into the search for new antimalarial drugs. Mathematics engaged him on the subject of epidemics.

  In the meantime Anderson G. McKendrick, a medical doctor who had served in the Indian Medical Service (again like Ross), became superintendent of the Laboratory of the Royal College of Physicians and therefore in some sense Kermack’s boss. On a level transcending hierarchy, they meshed. Sightless yet unquenchably curious, Kermack later worked on various subjects, such as comparative death rates in rural and urban Britain, and fertility rates among Scottish women, but the 1927 paper with McKendrick was his most influential contribution to science.

  It contributed two things. First, Kermack and McKendrick described the interplay among three factors during an archetypal epidemic: the rate of infection, the rate of recovery, and the rate of death. They assumed that recovery from an attack conferred lifelong immunity (as it does, say, with measles) and outlined the dynamics in efficient English prose:

  One (or more) infected person is introduced into a community of individuals, more or less susceptible to the disease in question. The disease spreads from the affected to the unaffected by contact infection. Each infected person runs through the course of his sickness, and finally is removed from the number of those who are sick, by recovery or by death. The chances of recovery or death vary from day to day during the course of his illness. The chances that the affected may convey infection to the unaffected are likewise dependent upon the stage of the sickness. As the epidemic spreads, the number of unaffected members of the community becomes reduced.

  This sounds like calculus cloaked in words; and it is. Amid a dense flurry of mathematical manipulations, they derived a set of three differential equations describing the three classes of living individuals: the susceptible, the infected, and the recovered. During an epidemic, one class flows into another in a simple schema, S → I → R, with mortalities falling out of the picture because they no longer belong to the population dynamic. As susceptible individuals become exposed to the disease and infected, as infected individuals either recover (now with immunity) or disappear, the numerical size of each class changes at each moment in time. That’s why Kermack and McKendrick used differential calculus. Although I should have paid better attention to the stuff in high school, even I can understand (and so can you) that dR/dt = γI merely means that the number of recovered individuals in the population, at a given moment, reflects the number of infected individuals times the average recovery rate. So much for R, the “recovered” class. The equations for S (“susceptibles”) and I
(“infected”) are likewise opaque but sensible. All this became known as an SIR model. It was a handy tool for thinking about infectious outbreaks, still widely used by disease theorists.

  Eventually the epidemic ends. Why does it end? asked Kermack and McKendrick.

  One of the most important problems in epidemiology is to ascertain whether this termination occurs only when no susceptible individuals are left, or whether the interplay of the various factors of infectivity, recovery and mortality, may result in termination, whilst many susceptible individuals are still present in the unaffected population.

  They were leading their readers toward the second of those two possibilities: that an epidemic might cease because some subtle interplay among infectivity, mortality, and recovery (with immunity) has stifled it.

  Their other major contribution was recognizing the existence of a fourth factor, a “threshold density” of the population of susceptible individuals. This threshold is the number of concentrated individuals such that, given certain rates of infectivity, recovery, and death, an epidemic can happen. So you have density, infectivity, mortality, and recovery—four factors interrelated as fundamentally as heat, tinder, spark, and fuel. Brought together in the critical measure of each, the critical balance, they produce fire: epidemic. Kermack and McKendrick’s equations calibrated the circumstances in which such a fire would ignite, would continue to burn, and would eventually smolder out.