Spillover: Animal Infections and the Next Human Pandemic

by David Quammen

virulence: The first rule of a successful parasite is Don’t kill your host. One medical historian has traced this idea back to Louis Pasteur, noting that the most “efficient” parasite, in Pasteur’s view, was one that “lives in harmony with its host,” and therefore latent infections should be considered “the ideal form of parasitism.”

Macfarlane Burnet agreed: In general terms, where two organisms have developed a host-parasite relationship, the survival of the parasite species is best served, not by destruction of the host, but by the development of a balanced condition in which sufficient of the substance of the host is consumed to allow the parasite’s growth and multiplication, but not sufficient to kill the host.

Case in point: HIV-1. What matters more than whether a virus kills its host is when. “A disease organism that kills its host quickly creates a crisis for itself,” wrote the historian William H. McNeill, in his landmark 1976 book Plagues and Peoples, “since a new host must somehow be found often enough, and soon enough, to keep its own chain of generations going.”

One recent dispatch from the northeastern Uganda borderlands told of a rabies-infected camel that ran mad and “started jumping up and down, biting other animals, before it died.” Another, from Sudan, mentioned that rabid camels get excitable, sometimes attacking inanimate objects or biting their own legs—which can’t do the camels much harm, not at that stage, but does reflect the strategy of the virus.

Some of those papers appeared in august journals such as Nature, Science, and Philosophical Transactions of the Royal Society of London. My own favorite saw print in a more specialized organ called Parasitology. This one, titled “Coevolution of Hosts and Parasites,” appeared in 1982. It began by dismissing those “unsupported statements” in medical and ecological textbooks “to the effect that ‘successful’ parasite species evolve to be harmless to their hosts.”

The first rule of a successful parasite is βN/(α + b + v). The other thing that makes Anderson and May’s 1982 paper vivid is its discussion of myxoma in Australian rabbits.

The match showed that their model, though still crude and approximate, might help predict and explain the course of other disease outbreaks. “Our major conclusion,” wrote Anderson and May, “is that a ‘well-balanced’ host-parasite association is not necessarily one in which the parasite does little harm to its host.”

A glance at his virosphere poster, which portrayed the universe of known viruses as a brightly colored pizza, was enough to support that point. It showed RNA viruses accounting for at least half the slices. But they’re not merely common, Eddie said. They’re also highly evolvable. They’re protean. They adapt quickly.

But what is it about bats? I asked. Why do so many of these zoonotic viruses—or what seems like so many—spill over onto humans from the chiropteran order of mammals? Or is that the wrong question? “It is the right question,” he said. “But I don’t think there’s a good answer for it yet.”

Mainly they raised questions. Is it possible that the cold temperatures endured by hibernating bats suppress their immune responses, allowing viruses to persist in bat blood? Is it possible that antibodies, which would neutralize a virus, don’t last as long in bats as in other mammals? What about the ancientness of the bat lineage? Did that lineage diverge from other mammals before the mammalian immune system had been well honed by evolution, reaching the level of effectiveness seen in rodents and primates? Do bats have a different “set point” for their immune responses, allowing a virus to replicate freely so long as it doesn’t do the animal any harm?

Emphasis, sometimes complete emphasis, on nucleotide sequence characterization rather than virus characterization has led us down a primrose path at the expense of having real viruses with which to work.

“In 1985, the highest rates of HIV were reported in the U.S. and Europe,” Essex and Kanki wrote later, “but disturbing reports from central Africa indicated that high rates of HIV infection and of AIDS prevailed there, at least in some urban centers.”

But the monkeys weren’t sick. They didn’t seem to be suffering from immune deficiency. Unlike the Asian macaques, the African green monkeys “must have evolved mechanisms that kept a potentially lethal pathogen from causing disease,” Essex and Kanki wrote. Maybe the virus had changed too.

The resemblance, according to Essex and Kanki, was “not close enough to make it likely that SIV was an immediate precursor of HIV in people.” More likely, those two viruses represented neighboring twigs on a single phylogenetic branch, separated by lots of evolutionary time and probably some extant intermediate forms.

her team found what they had thought they might: a virus intermediate between HIV and SIV. With the code unblinded, Kanki learned that the positive results came from Senegalese prostitutes.

published to accompany the Japanese paper, celebrated this finding beneath a dogmatic headline: HUMAN AIDS VIRUS NOT FROM MONKEYS. But the headline was misleading to the point of falsity.

The “African green monkey” sampled by the Japanese team, because it was “of Kenyan origin,” probably belonged to the species Chlorocebus pygerythrus.

Tests of other sooty mangabeys at Delta revealed that the virus was “endemic” among them. Other investigators soon found it too, not just among captive sooty mangabeys but also in the wild.

Their work, published in 1989 with Vanessa M. Hirsch as first author, revealed that SIVsm is closely related to HIV-2. So is SIVmac. “These results suggest that SIVsm has infected macaques in captivity and humans in West Africa,” the group wrote, placing the onus of origination on sooty mangabeys, “and evolved as SIVmac and HIV-2, respectively.”

So the spillover had occurred by 1908? That’s much earlier than anyone suspected, and therefore the sort of discovery that gets into an august journal such as Nature. Publishing in 2008, a century after the fact, with a list of coauthors that included Jean-Jacques Muyembe, Jean-Marie Kabongo, and Dirk Teuwen, Worobey wrote: Our estimation of divergence times, with an evolutionary timescale spanning several decades, together with the extensive genetic distance between DRC60 and ZR59 indicate that these viruses evolved from a common ancestor circulating in the African population near the beginning of the twentieth century.

Some very interesting papers have come out of Hahn’s laboratory in the past two decades, many of them published with a junior researcher as first author and Hahn in the mentorship position, last. That was the case in 1999, when Feng Gao produced a phylogenetic study of SIVcpz and its relationship to HIV-1. At the time there were only three known strains of SIVcpz, all drawn from captive chimps, with Gao’s paper adding a fourth. The work appeared in Nature, highlighted by a commentary calling it “the most persuasive evidence yet that HIV-1 came to humans from the chimpanzee, Pan troglodytes.”

Gao study effectively identified both the reservoir and also the geographical area from which AIDS must have arisen. It was a huge discovery, as reflected in the headline of Nature’s commentary: FROM PAN TO PANDEMIC. Feng Gao at the time was a postdoc in Hahn’s lab.

“That was a breakthrough,” Hahn told me, during a talk at her lab in Birmingham. “We weren’t sure it would work.” But Santiago took the risk, cooked up the techniques, and it did work. The very first sample of SIV-positive urine from a wild chimpanzee came from the world’s most famous community of chimps: the ones at Gombe National Park, in Tanzania, where Jane Goodall had done her historic field study, beginning back in 1960.

Near the end, though, the authors let supposition fly: We show here that the SIVcpzPtt strain that gave rise to HIV-1 group M belonged to a viral lineage that persists today in P. t. troglodytes apes in southeastern Cameroon.

Hahn herself, along with three coauthors, had addressed that back in 2000, when she first argued the idea that AIDS is a zoonosis: “In humans, direct exposure to animal blood and secretions as a result of hunting, butchering, or other activities (such as consumption of uncooked contaminated meat) provides a plausible explanation for the transmission.”

“The likeliest route of chimpanzee-to-human transmission would have been through exposure to infected blood and body fluids during the butchery of bushmeat.”

By 1914, Brazzaville contained about six thousand people and was “a hard mission field,” according to one Swedish missionary, where “hundreds of women from upper Congo are professional prostitutes.”

Free women had their special friends, their clients, maybe several contemporaneously, but there was no dizzying permutation of multiple sexual contacts, not yet. One expert has called this “a low-risk type of prostitution,” with regard to the prospects of HIV transmission.

The unpublished report added: Until recently, the Bakweles have been using chimps for this ritual. They claim two chimps could be used for circumcision of as many as 36 people. They amputate the arms of the chimps.

There was even a report, based on genetic analysis of captive animals in the Netherlands, suggesting that chimpanzees had “survived their own AIDS-like pandemic” more than 2 million years ago.

The authors suggested, cautiously but firmly, “that SIVcpz has a substantial negative impact on the health, reproduction and lifespan of chimpanzees in the wild.” So it’s not a harmless passenger. It’s a hominoid killer, their problem as well as ours.

But according to one Belgian doctor, writing in 1953: “The Congo contains various health institutions (maternity centres, hospitals, dispensaries, etc.) where every day local nurses give dozens, even hundreds, of injections in conditions such that sterilisation of the needle or the syringe is impossible.”

large number of patients and the small quantity of syringes available to the nursing staff preclude sterilisation by autoclave after each use.

But the bulk of the caseload, according to Pepin, “consisted of thousands of asymptomatic free women who came for screening because they were required to do so by law, in theory every month.” The colonial government accepted prostitution as an ineradicable fact but evidently hoped to keep the trade hygienic—so les femmes libres were obliged to get checked.

That number was startlingly high, for such a newly arrived virus, and caused Pepin to suspect that “there must have been a very effective amplification mechanism” operating in Haiti during the early years—more effective than sex. He found a candidate: the blood plasma trade.

An entomologist named Alan A. Berryman addressed it some years ago in a paper titled “The Theory and Classification of Outbreaks.” He began with basics: “From the ecological point of view an outbreak can be defined as an explosive increase in the abundance of a particular species that occurs over a relatively short period of time.”

That growth curve, on a coordinate graph, looks like the southwest face of El Capitan. Another way to comprehend it is this: From the time of our beginning as a species (about 200,000 years ago) until the year 1804, human population rose to a billion; between 1804 and 1927, it rose by another billion; we reached 3 billion in 1960; and each net addition of a billion people, since then, has taken only about thirteen years. In October 2011, we came to the 7-billion mark and flashed past like it was a “Welcome to Kansas” sign

We’re so big, in fact, that the eminent biologist (and ant expert) Edward O. Wilson felt compelled to do some knowledgeable noodling on the matter. Wilson came up with this: “When Homo sapiens passed the six-billion mark we had already exceeded by perhaps as much as 100 times the biomass of any large animal species that ever existed on the land.”

They’re a proxy measure of our appetites, and we are hungry. We are prodigious, we are unprecedented. We are phenomenal. No other primate has ever weighed upon the planet to anything like this degree. In ecological terms, we are almost paradoxical: large-bodied and long-lived but grotesquely abundant. We are an outbreak.

And here’s the thing about outbreaks: They end. In some cases they end after many years, in other cases they end rather soon. In some cases they end gradually, in other cases they end with a crash. In certain cases, even, they end and recur and end again, as though following a regular schedule.

the cyclical pattern “seems to imply a dominant force that should be easy to identify and quantify.

He said that gypsy moth larvae essentially “melt” when infected by NPV. I wasn’t taking copious notes, but I did write the word “melt” on my yellow pad. I also wrote, quoting him: “Epizootics tend to occur in very dense populations.” After a few other general comments, Greg Dwyer went on to discuss some mathematical models. At the coffee break, I buttonholed him and asked if we could talk sometime about the fate of moths and the prospect of human pandemic disease. He said sure.

The Next Big One could very well be flu. Greg Dwyer knew this, which is why he mentioned it. I’m sure you don’t need reminding that the 1918–1919 flu killed about 50 million people; and there’s still no magical defense, no universal vaccine, no foolproof and widely available treatment, to guarantee that such death and misery don’t occur again.

But they don’t have the time or the interest to consider a lot of scientific detail. I can say from experience that some people, if they hear you’re writing a book about such things—about scary emerging diseases, about killer viruses, about pandemics—want you to cut to the chase. So they ask: “Are we all gonna die?” I have made it my little policy to say yes.

Their answers to the first part have ranged from Maybe to Probably. Their answers to the second have focused on RNA viruses, especially those for which the reservoir host is some kind of primate. None of them has disputed the premise, by the way, that if there is a Next Big One it will be zoonotic.

University of Pittsburgh, gave a lecture (later published) back in 1997 in which he listed the criteria that might implicate certain kinds of viruses as likeliest candidates to cause a new pandemic. “The first criterion is the most obvious: recent pandemics in human history,” Burke told his audience.

The next big one

populations.” As examples he returned to retroviruses, orthomyxoviruses, and coronaviruses. “Some of these viruses,” he warned, citing coronaviruses in particular, “should be considered as serious threats to human health. These are viruses with high evolvability and proven ability to cause epidemics in animal populations.” It’s interesting in retrospect to note that he had augured the SARS epidemic six years before it occurred.

The practical alternative to soothsaying, as Burke put it, is “improving the scientific basis to improve readiness.” By “the scientific basis” he meant the understanding of which virus groups to watch, the field capabilities to detect spillovers in remote places before they become regional outbreaks, the organizational capacities to control outbreaks before they become pandemics, plus the laboratory tools and skills to recognize known viruses speedily, to characterize new viruses almost as fast, and to create vaccines and therapies without much delay. If we can’t predict a forthcoming influenza pandemic or any other newly emergent virus, we can at least be vigilant; we can be well-prepared and quick to respond; we can be ingenious and scientifically sophisticated in the forms of our response.

Global Viral Forecasting Initiative (GVFI), financed in part by Google and created by a bright, enterprising scientist named Nathan Wolfe, one of whose mentors was Don Burke.

Whatever happens after that will depend on science, politics, social mores, public opinion, public will, and other forms of human behavior. It will depend on how we citizens respond.