Spillover: Animal Infections and the Next Human Pandemic

by David Quammen

Habitat alteration was an ancient tradition in Australia, in the form of burning by Aboriginal people, but in recent decades land clearance has become a more drastic and mechanized trend, with less-reversible results, especially in Queensland. Vast areas of old forest have been cut, or chained down with bulldozers, to make way for cattle ranching and urban sprawl. People have planted orchards, established urban parks, landscaped their yards with blossoming trees, and created other unintended enticements amid the cities and suburbs. “So bats have decided that, as their native habitat is disappearing, as climate is becoming more variable, and their food source is becoming less diverse, it’s easier to live in an urban area.” They gather now in larger aggregations, traveling shorter distances to feed, living at closer proximity to humans (and to the horses that humans keep).

They didn’t touch the dead body of their daughter and granddaughter. But patient A did, performing faithfully the service of a close family friend, after which she went back to her life—what was left of it. She resumed her social interactions, and 183 other people caught Ebola and died.

The investigators took swabs from the wall of a hospital room in which one of the patients had been treated, five weeks earlier, and from the soiled frame of a bed in which that patient had lain. None of those surfaces had been cleaned in the meantime; bleach and labor were in short supply. Some swabs, both from the wall and the bed frame, tested positive for Nipah RNA. I’ll repeat that: Fragments (at least) of Nipah virus, left from what the patient had spewed out, were still present after five weeks, invisibly decorating the room. To the sanitarian, such spewing represents contamination. To the virus: opportunity.

Although Gottlieb noted some other symptoms, those three stood out: Pneumocystis pneumonia, oral candidiasis, dearth of T cells.

According to Randy Shilts, author of And the Band Played On (which includes much heroic research and a fair bit of presumptuous reimagining), Dugas himself reckoned that in the decade since becoming actively gay he had had at least twenty-five hundred sexual partners. Dugas paid a price for his appetite and his daring. He developed Kaposi’s sarcoma, underwent chemotherapy for that, suffered from Pneumocystis pneumonia and other AIDS-related infections, and died of kidney failure at age thirty-one.

Retroviruses are fiendish beasts, even more devious and persistent than the average virus. They take their name from the capacity to move backward (retro) against the usual expectations of how a creature translates its genes into working proteins. Instead of using RNA as a template for translating DNA into proteins, the retrovirus converts its RNA into DNA within a host cell; its viral DNA then penetrates the cell nucleus and gets itself integrated into the genome of the host cell, thereby guaranteeing replication of the virus whenever the host cell reproduces itself.

First, the incidence of AIDS among homosexuals linked by sexual interactions suggested that it was an infectious disease. Second, the incidence among intravenous drug users suggested a blood-borne infectious agent. Third, the cases among hemophiliacs implied a blood-borne agent that escaped detection in processed blood products such as clotting factor. So: It was infinitesimal, contagious, blood-borne. “AIDS could not be caused by a conventional bacterium, a fungus, or protozoan,” Montagnier wrote, “since these kinds of germs are blocked by the filters through which the blood products necessary to the survival of hemophiliacs are passed. That left only a smaller organism: the agent responsible for AIDS thus could only be a virus.”

Now here’s the part that, as it percolates into your brain, should cause a shudder: Scientists think that each of those twelve groups (eight of HIV-2, four of HIV-1) reflects an independent instance of cross-species transmission. Twelve spillovers. In other words, HIV hasn’t happened to humanity just once. It has happened at least a dozen times—a dozen that we know of, and probably many more times in earlier history. Therefore it wasn’t a highly improbable event. It wasn’t a singular piece of vastly unlikely bad luck, striking humankind with devastating results—like a comet come knuckleballing across the infinitude of space to smack planet Earth and extinguish the dinosaurs. No. The arrival of HIV in human bloodstreams was, on the contrary, part of a small trend. Due to the nature of our interactions with African primates, it seems to occur pretty often.

Several years later, it was Worobey who detected evidence of HIV in a certain Congolese biopsy specimen from 1960. Worobey amplified fragments of the viral genome, pieced the fragments together, recognized them as an early version of HIV-1, and named the sequence DRC60. Comparing his sequence with ZR59, the other earliest known strain, he reached a dramatic conclusion: that the AIDS virus has been present in humans for decades longer than anyone thought. The pandemic may have gotten its start with a spillover as early as 1908.

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. To me he said: “This wasn’t a new virus in humans.” Worobey’s work directly refuted the OPV hypothesis. If HIV-1 existed in humans as early as 1908, then obviously it hadn’t been introduced via vaccine trials beginning in 1958.

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.” In fact, Gao and his colleagues did more than trace HIV-1 to the chimp; their analysis of viral strains linked it to individuals of a particular subspecies known as the central chimpanzee (Pan troglodytes troglodytes), whose SIV had spilled over to become HIV-1 group M. That chimpanzee lives only in western Central Africa, north of the Congo River and west of the Oubangui. So the 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.

So much for where as well as when. AIDS began with a spillover from one chimp to one human, in southeastern Cameroon, no later than 1908 (give or take a margin of error), and grew slowly but inexorably from there. That leaves our third question: how?

Drori gave me a LAGA newsletter describing the efforts to stem poaching of chimps and gorillas, and he warned me against the myth that ape hunting is a problem because local people are hungry. The reality, he said, is that local people eat duikers or rats or squirrels or monkeys—if they eat meat at all—whereas the fancy stuff, the illicit delicacies, the chimpanzee body parts, the gobs of elephant flesh, the hippopotamus steaks, get siphoned away by upscale demand from the cities, where premium prices justify the risks of poaching and illegal transport. “What brings the money are the protected species,” he said. “Things that are rare.” It sounded like the Era of Wild Flavor back in southern China.

A study of bushmeat traffic in and around Ouesso, done in the mid-1990s by two expat researchers and a Congolese assistant, had found about 12,600 pounds of wild harvest passing through this market each week. That total included only mammals, not fish or crocodiles. Duikers accounted for much of it and primates were second, though most of the primate meat was monkey, not ape. Eighteen gorillas and four chimps were butchered and sold during the four-month study.

Studying the evolutionary history of HIV-1 is more than an idle exercise. The point is to understand how one strain of the virus (group M) made itself so deadly and widespread among humans. Such understanding, in turn, may lead toward better measures to control the devastation of AIDS, possibly by way of a vaccine, more likely by way of improved treatments.

All those injections, according to Pepin, might account for boosting the incidence of HIV infection beyond a critical threshold. Once the reusable needles and syringes put the virus into enough people—say, several hundred—it wouldn’t come to a dead end, it wouldn’t burn out, and sexual transmission could do the rest. Some experts, including Michael Worobey and Beatrice Hahn, doubt that needles were necessary in any such way to the establishment of HIV in humans—that is, to its early transmission from one person to another. But even they agree that injection campaigns could have played a role later, spreading the virus in Africa once it was established.

Tested retrospectively, those samples revealed that 7.8 percent of the women had been HIV-positive. 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.

This study by Gilbert and Worobey and their colleagues delivered one other piquant finding. Their data and analysis indicated that just a single migration of the virus—one infected person or one container of plasma—accounted for bringing AIDS to America. That sorry advent occurred in 1969, give or take about three years.

Ecologists have a label for such an event. They call it an outbreak. This use of the word is more general than what’s meant by an outbreak of disease. You could think of disease outbreaks as a subset. Outbreak in the broader sense applies to any vast, sudden population increase by a single species.

Two of those molecules become spiky protuberances from the outer surface of the viral envelope: hemagglutinin and neuraminidase. Those two, recognizable by an immune system, and crucial for penetrating and exiting cells of a host, give the various subtypes of influenza A their definitive labels: H5N1, H1N1, and so on. The term “H5N1” indicates a virus featuring subtype 5 of the hemagglutinin protein combined with subtype 1 of the neuraminidase protein. Sixteen different kinds of hemagglutinin, plus nine kinds of neuraminidase, have been detected in the natural world. Hemagglutinin is the key that unlocks a cell membrane so that the virus can get in, and neuraminidase is the key for getting back out.

The steady incidence of mutations yields incremental change in how the virus looks and behaves. Ergo you need another flu shot every autumn: This year’s version of flu is different enough from last year’s. Reassortment yields big changes. Such major innovations by reassortment, introducing new subtypes, which may be infectious but unfamiliar to the human population, are what generally lead to pandemics.

Burke’s third criterion was “intrinsic evolvability,” meaning readiness to mutate and to recombine (or reassort), which “confers on a virus the potential to emerge into and to cause pandemics in human 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.”

These scientists are on alert. They are our sentries. They watch the boundaries across which pathogens spill. And they are productively interconnected with one another. When the next novel virus makes its way from a chimpanzee, a bat, a mouse, a duck, or a macaque into a human, and maybe from that human into another human, and thereupon begins causing a small cluster of lethal illnesses, they will see it—we hope they will, anyway—and raise the alarm. 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.

Everything I’ve just mentioned is encompassed within this rubric: the ecology and evolutionary biology of zoonotic diseases. Ecological circumstance provides opportunity for spillover. Evolution seizes opportunity, explores possibilities, and helps convert spillovers to pandemics.

During the early twentieth century, disease scientists from the Rockefeller Foundation and other institutions conceived the ambitious goal of eradicating some infectious diseases entirely. They tried hard with yellow fever, spending millions of dollars and many years of effort, and failed. They tried with malaria, and failed. They tried later with smallpox, and succeeded. Why? The differences among those three diseases are many and complex, but probably the most crucial one is that smallpox resided neither in a reservoir host nor in a vector. Its ecology was simple. It existed in humans—in humans only—and was therefore much easier to eradicate.

That’s the salubrious thing about zoonotic diseases: They remind us, as St. Francis did, that we humans are inseparable from the natural world. In fact, there is no “natural world,” it’s a bad and artificial phrase. There is only the world. Humankind is part of that world, as are the ebolaviruses, as are the influenzas and the HIVs, as are Nipah and Hendra and SARS, as are chimpanzees and bats and palm civets and bar-headed geese, as is the next murderous virus—the one we haven’t yet detected.

“If you hold mean transmission rate constant,” he told me, “just adding heterogeneity by itself will tend to reduce the overall infection rate.” That sounds dry. What it means is that individual effort, individual discernment, individual choice can have huge effects in averting the catastrophes that might otherwise sweep through a herd. An individual gypsy moth may inherit a slightly superior ability to avoid smears of NPV as it grazes on a leaf. An individual human may choose not to drink the palm sap, not to eat the chimpanzee, not to pen the pig beneath mango trees, not to clear the horse’s windpipe with his bare hand, not to have unprotected sex with the prostitute, not to share the needle in a shooting gallery, not to cough without covering her mouth, not to board a plane while feeling ill, or not to coop his chickens along with his ducks. “Any tiny little thing that people do,” Dwyer said, if it makes them different from one another, from the idealized standard of herd behavior, “is going to reduce infection rates.”

“There’s only so many ways gypsy moths can differ,” he said finally. “But the number of ways that humans can differ is really, really huge. And especially in their behavior. Right. Which gets back to your question, which is, How much does it matter that humans are smart? And so, I guess I’m actually going to say that it matters a whole lot. Now that I stop to think about it carefully. I think it will matter a great deal.”