Spillover: Animal Infections and the Next Human Pandemic

by David Quammen

A zoonosis is an animal infection transmissible to humans. There are more such diseases than you might expect. AIDS is one. Influenza is a whole category of others. Pondering them as a group tends to reaffirm the old Darwinian truth (the darkest of his truths, well known and persistently forgotten) that humanity is a kind of animal, inextricably connected with other animals: in origin and in descent, in sickness and in health.

Predators are relatively big beasts that eat their prey from outside. Pathogens (disease-causing agents, such as viruses) are relatively small beasts that eat their prey from within. Although infectious disease can seem grisly and dreadful, under ordinary conditions it’s every bit as natural as what lions do to wildebeests and zebras, or what owls do to mice.

This form of interspecies leap is common, not rare; about 60 percent of all human infectious diseases currently known either cross routinely or have recently crossed between other animals and us.

Smallpox could be eradicated because that virus, lacking ability to reside and reproduce anywhere but in a human body (or a carefully watched lab animal), couldn’t hide.

These pathogens aren’t consciously hiding, of course. They reside where they do and transmit as they do because those happenstance options have worked for them in the past, yielding opportunities for survival and reproduction. By the cold Darwinian logic of natural selection, evolution codifies happenstance into strategy.

Viruses are the most problematic. They evolve quickly, they are unaffected by antibiotics, they can be elusive, they can be versatile, they can inflict extremely high rates of fatality, and they are fiendishly simple, at least relative to other living or quasi-living creatures.

Antibodies are molecules manufactured by the immune system of a host in response to the presence of a biological intruder. They are custom-shaped to merge with and disable that particular virus, or bacterium, or other bug. Their specificity, and the fact that they remain in the bloodstream even after the intruder has been conquered, make them valuable as evidence of present or past infection.

Similarity of one kind of host animal to another is a significant indicator of the likelihood that a pathogen can make the leap.

How do such diseases leap from nonhuman animals into people, and why do they seem to be leaping more frequently in recent years? To put the matter in its starkest form: Human-caused ecological pressures and disruptions are bringing animal pathogens ever more into contact with human populations, while human technology and behavior are spreading those pathogens ever more widely and quickly. There are three elements to the situation. One: Mankind’s activities are causing the disintegration (a word chosen carefully) of natural ecosystems at a cataclysmic rate.

Two: Those millions of unknown creatures include viruses, bacteria, fungi, protists, and other organisms, many of which are parasitic.

Viruses can only replicate inside the living cells of some other organism. Commonly they inhabit one kind of animal or plant, with whom their relations are intimate, ancient, and often (but not always) commensal.

Three: But now the disruption of natural ecosystems seems more and more to be unloosing such microbes into a wider world.

A parasitic microbe, thus jostled, evicted, deprived of its habitual host, has two options—to find a new host, a new kind of host . . . or to go extinct. It’s not that they target us especially. It’s that we are so obtrusively, abundantly available.

Viruses, especially those of a certain sort—those whose genomes consist of RNA rather than DNA, leaving them more prone to mutation—are highly and rapidly adaptive.

Any such spillover in the reverse direction—from humans to a nonhuman species—is known as an anthroponosis.

One factor making the hunt for Ebola’s reservoir especially difficult, especially hard to focus, is the transitory nature of the disease within human populations. It disappears entirely for years at a time. This is a mercy for public health but a constraint for science. Viral ecologists can look for Ebola anywhere, in any creature of any species, in any African forest, but those are big haystacks and the viral needle is small. The most promising search targets, in space and in time, are wherever and whenever people are dying of Ebola virus disease. And for a long interlude, no one was dying of that illness—no one whose death came to the attention of medical authorities, anyway.

But the chain of ebolavirus infection, at least so far, has never continued through many successive cases, great distances, or long stretches of time.

Brutal

A few patients do bleed to death, Rollin said, but “they don’t explode, and they don’t melt.” In fact, he said, the often-used term “Ebola hemorrhagic fever” is itself a misnomer for Ebola virus disease, because more than half the patients don’t bleed at all. They die of other causes, such as respiratory distress and shutdown (but not dissolution) of internal organs.

She took deep interest, for instance, in the fact that such a simple organism can be so potently lethal. It contains only a tiny genome, enough to construct just ten proteins, which account for the entire structure, function, and self-replicating capacity of the thing. (A herpesvirus, by contrast, carries about ten times more genetic complexity.) Despite the minuscule genome, Ebola virus is ferocious. It can kill a person in seven days. “How can something that is so small and so simple just be so darn dangerous?”

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.

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.

Another implication was that epidemics don’t end because all the susceptible individuals are either dead or recovered. They end because susceptible individuals are no longer sufficiently dense within the population.

Snake on the menu wasn’t unusual in Guangdong. It’s a province of ravenous, unsqueamish carnivores, where the list of animals considered delectable could be mistaken for the inventory of a pet store or a zoo.

An atypical pneumonia can be any sort of lung infection not attributable to one of the familiar agents, such as the bacterium Streptococcus pneumoniae.

The sorts of lab methodology I’ve described earlier, involving PCR to screen for recognizable fragments of DNA or RNA, combined with molecular assays to detect antibodies or antigens, are useful only in searching for what’s familiar—or, at least, for what closely resembles something familiar. Such tests essentially give you a positive, negative, or approximated answer in response to a specific question: Is it this? Finding an entirely new pathogen is more difficult. You can’t detect a microbe by its molecular signature until you know roughly what that signature is. So the lab scientist must resort to a slightly older, less automated approach: growing the microbe in a cell culture and then looking at it through a microscope.

He found his match among a group known as the coronaviruses, characterized by a corona of knobby proteins rimming each viral particle.

But even if they arrived healthy and robust from the farm, conditions in the markets weren’t salubrious. “The animals are packed in tiny spaces and often in close contact with other wild and/or domesticated animals such as dogs and cats,” the survey team wrote. “Many are either sick or with open wounds and without basic care. Animals are often slaughtered inside the markets in several stalls specialising in this.” Open wire cages, stacked vertically, allowed wastes from one animal to rain down onto another. It was zoological bedlam. “The markets also provide a conducive environment,” the team noted, almost passingly, “for animal diseases to jump hosts and spread to humans.”

The scenario could have been very much worse. SARS in 2003 was an outbreak, not a global pandemic. Eight thousand cases are relatively few, for such an explosive infection; 774 people died, not 7 million.

If the virus had arrived in a different sort of big city—more loosely governed, full of poor people, lacking first-rate medical institutions—it might have escaped containment and burned through a much larger segment of humanity.

One further factor, possibly the most crucial, was inherent to the way SARS-CoV affects the human body: Symptoms tend to appear in a person before, rather than after, that person becomes highly infectious. The headache, the fever, and the chills—maybe even the cough—precede the major discharge of virus toward other people.

With influenza and many other diseases the order is reversed, high infectivity preceding symptoms by a matter of days. A perverse pattern: the danger, then the warning. That probably helped account for the scale of worldwide misery and death during the 1918–1919 influenza: high infectivity among cases before they experienced the most obvious and debilitating stages of illness.

And that infamous global pandemic, remember, occurred in the era before globalization. Everything nowadays moves around the planet faster, including viruses. If SARS had conformed to the perverse pattern of presymptomatic infectivity, its 2003 emergence wouldn’t be a case history in good luck and effective outbreak response. It would be a much darker story. The much darker story remains to be told, probably not about this virus but about another. When the Next Big One comes, we can guess, it will likely conform to the same perverse pattern, high infectivity preceding notable symptoms. That will help it to move through cities and airports like an angel of death.

The unchanging fact is that Borrelia burgdorferi infection doesn’t pass vertically between blacklegged ticks. In plainer language: It is not inherited. Of those million baby ticks, all derived from the female ticks that fed on a single deer, none will be carrying B. burgdorferi when they hatch—not even if every mother tick was infected and the deer was too. The youngsters will come into the world clean and healthy. Each generation of ticks must be infected anew.

Although it’s an intricate system, as Ostfeld warned in his title, certain points about Lyme disease emerge plainly. “We know that walking into a small woodlot,” he wrote, “is riskier than walking into a nearby large, extensive forest. We know that hiking in the oak woods two summers after a big acorn year is much riskier than hiking in those same woods after an acorn failure. We know that forests that house many kinds of mammals and birds are safer than those that support fewer kinds. We know that the more opossums and squirrels there are in the woods, the lower the risk of Lyme disease, and we suspect that the same is true of owls, hawks, and weasels.” As for white-tailed deer: They’re involved, yes, but far from paramount, so don’t believe everything you’ve heard.

A virus won’t grow in a medium of chemical nutrients because it can only replicate inside a living cell.

Viruses face four basic challenges: how to get from one host to another, how to penetrate a cell within that host, how to commandeer the cell’s equipment and resources for producing multiple copies of itself, and how to get back out—out of the cell, out of the host, on to the next. A virus’s structure and genetic capabilities are shaped parsimoniously to those tasks.

Across the outer surface of the envelope, the virion may be festooned with a large number of spiky molecular protuberances, like the detonator stubs on an old-fashioned naval mine. Those spikes serve a crucial function. They’re specific to each kind of virus, with a keylike structure that fits molecular locks on the outer surface of a target cell; they allow the virion to attach itself, docking like one spaceship to another, and they open the way in. The specificity of the spikes not only constrains which kinds of host a given virus can infect but also which sorts of cell—nerve cells, stomach cells, cells of the respiratory lining—the virus can most effectively penetrate, and therefore what sort of disease it may cause. Useful as they are to a virus, though, the spikes also represent points of vulnerability. They are the primary targets of immune response by an infected host. Antibodies, produced by white blood cells, are molecules that glom onto the spikes and prevent a virion from grabbing a cell.

It doesn’t function the way a cell functions; it doesn’t share the same capacities or frailties. That’s reflected in the fact that viruses are impervious to antibiotics—chemicals valued for their ability to kill bacteria (which are cells) or at least impede their growth. Penicillin works by preventing bacteria from building their cell walls. So do its synthetic alternatives, such as amoxicillin. Tetracycline works by interfering with the internal metabolic processes by which bacteria manufacture new proteins for cell growth and replication. Viruses, lacking cell walls, lacking internal metabolic processes, are oblivious to the effects of such killer drugs. Inside the viral capsid is usually nothing but genetic material, the set of instructions for creating new virions on the same pattern. Those instructions can only be implemented when they’re inserted into the works of a living cell. The material itself may be either DNA or RNA, depending on the family of virus. Both types of molecule are capable of recording and expressing information, though each has its advantages and its drawbacks.

The different attributes of DNA and RNA account for one of the most crucial differences among viruses: rate of mutation. DNA is a double-stranded molecule, the famed double helix, and because its two strands fit together by way of those very specific relationships between pairs of nucleotide bases (adenine linking only with thymine, cytosine only with guanine), it generally repairs mistakes in the placement of bases as it replicates itself. This repair work is performed by DNA polymerase, the enzyme that helps catalyze construction of new DNA from single strands. If an adenine is mistakenly set in place to become linked with a guanine (not its correct partner), the polymerase recognizes that mistake, backtracks by one pair, fixes the mismatch, and then moves on. So the rate of mutation in most DNA viruses is relatively low. RNA viruses, coded by a single-strand molecule with no such corrective arrangement, no such buddy-buddy system, no such proofreading polymerase, sustain rates of mutation that may be thousands of times higher.

RNA viruses mutate profligately.

Mutation supplies new genetic variation. Variation is the raw material upon which natural selection operates. Most mutations are harmful, causing crucial dysfunctions and bringing the mutant forms to an evolutionary dead end. But occasionally a mutation happens to be useful and adaptive. And the more mutations occurring, the greater chance that good ones will turn up. (More mutations also mean more chance of harmful ones, lethal to the virus; this puts a cap on the maximum sustainable mutation rate.) RNA viruses therefore evolve quicker than perhaps any other class of organism on Earth. It’s what makes them so volatile, unpredictable, and pesky.

“Infection” need not always entail any significant damage; the word merely means an established presence of some microbe. A virus doesn’t necessarily achieve anything by making its host sick. Its self-interest requires just replication and transmission. The virus enters cells, yes, and subverts their physiological machinery to make copies of itself, yes, and often destroys those cells as it exits, yes; but maybe not so many cells as to cause real harm. It may inhabit a host rather quietly, benignly, replicating at modest levels and getting transmitted from one individual to another without producing any symptoms.

Moral: If you’re a thriving population, living at high density but exposed to new bugs, it’s just a matter of time until the NBO arrives. Note that most of these big ones but not all of them (plague the exception) were viral. Now that modern antibiotics are widely available, vastly reducing the lethal menace of bacteria, we can guess confidently that the Next Big One will be a virus too.

Transmission is travel from one host to another, and transmissibility is the packet of attributes for achieving it. Can the virions concentrate themselves in a host’s throat or nasal passages, cause irritation there, and come blasting out on the force of a cough or a sneeze? Once launched into the environment, can they resist desiccation and ultraviolet light for at least a few minutes? Can they invade a new individual by settling onto other mucous membranes—in the nostrils, in the throat, in the eyes—and gaining attachment, cell entry, another round of replication? If so, that virus is highly transmissible. It goes airborne from one host to another. Fortunately, not every virus can do that. If HIV-1 could, you and I might already be dead. If the rabies virus could, it would be the most horrific pathogen on the planet. The influenzas are well adapted for airborne transmission, which is why a new strain can circle the world within days. The SARS virus travels this route too, or anyway by the respiratory droplets of sneezes and coughs—hanging in the air of a hotel corridor, moving through the cabin of an airplane—and that capacity, combined with its case fatality rate of almost 10 percent, is what made it so scary in 2003 to the people who understood it best.

The oral-fecal route sounds disgusting but is really quite common. It works well for some viruses because host creatures (including humans) are often forced, especially when living at high densities, to consume food or water contaminated by excrement from other members of their population. This is one of the reasons why children die of dehydration in rainy refugee camps. The virus goes in the mouth, replicates in the belly or the intestines, causes gastrointestinal distress, may or may not spread to other parts of the body, and comes gushing out the anus. Diarrhea, for such a virus, is part of an effective strategy for dispersal. Viruses transmitted this way tend to be fairly hardy in the environment, because they may need to linger in that polluted sump for a day or two before some desperate person comes to drink from it. There’s an entire group of such viruses, known as the enteroviruses, including polio and about seventy others, that attack us in the gut. Most of those enteroviruses are uniquely human infections, not zoonoses. Evidently they don’t need other animal hosts for maintaining themselves in a crowded human world. For blood-borne viruses, transmission is more complicated. Generally it depends on a third party, a vector. The virus must replicate abundantly in the blood of the host to produce severe viremia (that is, a flood of virions). The vector (a blood-sucking insect or some other arthropod) must arrive for a meal, bite the host, slurp up virions along with ...

Sexual transmission is a good scheme for viruses with low hardiness in the external environment. It’s a mode of passage that doesn’t require them to go outside. They’re virtually never exposed to daylight or dry air. The virions pass from one body to another by way of direct, intimate contact between host cells lining delicate genital and mucosal surfaces. Rubbing (not just pressing) those surfaces together probably helps. Transmission during coitus is a conservative strategy, reducing risk to such viruses, sparing the need for hardening against desiccation or sunlight. But it has a downside too—notably, that opportunities for transmission are fewer. Even the most lubricious humans don’t have sex as often as they exhale. So the sexually transmitted viruses tend toward patience. They cause persistent infections and endure long periods of latency, punctuated by recurrent outbreaks (like herpesviruses); or else they replicate slowly (like HIV-1 and hepatitis B) up to a critical point at which things get bad. Such patience within a host gives the virus more time and therefore more sexual encounters by which to get itself passed along. Vertical transmission, meaning mother-to-offspring, is another slow, cautious mode. It can occur during pregnancy, during birth, or (in the case of mammals) by way of milk while an infant nurses. HIV-1, for instance, can be transmitted from mother to fetus across the placenta, or to a newborn in the birth canal, or through breastfeeding; but each...

Evolution lowers virulence, tending toward that “more perfect mutual tolerance” between pathogen and host.

The first rule of a successful parasite? Myxoma’s success in Australia suggests something different from that nugget of conventional wisdom I mentioned above. It’s not Don’t kill your host. It’s Don’t burn your bridges until after you’ve crossed them.

Acute infection also means lots of viral shedding—by way of sneezing or coughing or vomiting or bleeding or diarrhea—which facilitates transmission to other victims. Such viruses try to outrace the immune system of each host, taking what they need and moving onward before a body’s defenses can defeat them. (Lentiviruses, including the HIVs, are exceptional here, following a different strategy.) Their fast replication and high rates of mutation supply them abundantly with genetic variation. Once an RNA virus lands in another host—maybe even another species of host—that abundant variation serves the virus well, giving it many chances to adapt to the new circumstances, whatever those circumstances might be. In some cases it fails to adapt; in some it succeeds well.