Spillover: Animal Infections and the Next Human Pandemic

by David Quammen

William Brebner was dead at the age of twenty-nine. What killed him? Was it polio? Was it rabies? A fellow researcher in the same NYU lab, just out of medical school but bright and ambitious, assisted at Brebner’s autopsy and then made a further investigation, using bits of Brebner’s brain, spinal cord, lymph nodes, and spleen. This man was Albert B. Sabin, decades before his fame as creator of an oral polio vaccine.

Herpes B is a very rare infection in humans but a nasty one, with a case fatality rate of almost 70 percent among those few dozen people infected during the twentieth century (before recent breakthroughs in antiviral pharmaceutics) and almost 50 percent even since then.

The most recent case occurred at the Yerkes National Primate Research Center, in Atlanta, in late 1997. On

National regulations specified that any animals infected with a level-4 agent had to be either handled under BSL-4 containment (meaning space suits, triple gloves, airlock doors, and all the rest, not quite practicable at a tourist attraction for viewing wildlife) or destroyed.

Enterprising local photographers run a brisk trade in photos of tourists posed with macaques. And here’s me in Bali, with a monkey on my head. Cute little guy, just wanted that Snickers bar. But the cute little guys sometimes bite and scratch.

Whether the plague bacterium or another, more mysterious pathogen caused the Black Death (as several historians have recently argued), there’s no question of its bigness. Between the years 1347 and 1352, this epidemic seems to have killed at least 30 percent of the people in Europe.

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.

To understand why some outbreaks of viral disease go big, others go really big, and still others sputter intermittently or pass away without causing devastation, consider two aspects of a virus in action: transmissibility and virulence.

Along with a few other factors, they largely determine the gross impact of any outbreak. Neither of the two is an absolute constant; they vary, they’re relative. They reflect the connectedness of a virus to its host and its wider world. They measure situations, not just microbes. Transmissibility and virulence: the yin and yang of viral ecology.

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?

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 the blood, and carry them away. The vector itself must be a hospitable host, so that the virus replicates further within it, producing many more virions that make their way back to the mouth area and stand ready for release.

The yellow fever virus, West Nile, and dengue transmit this way. It has an upside and a down. The downside is that vector transmission requires adaptations for two very different sorts of environment: the bl...

Blood-borne viruses can also spread to new hosts by way of hypodermic needles and transfusions. But those opportunities are adventitious addenda, recent and accidental, patched onto ancient viral strategies shaped by evolution. Ebola and HIV-1,

Ordinary transmission is however Ebola gets from one individual to another within whatever animal host—identity still unknown—serves as its reservoir. Ordinary transmission allows the virus to perpetuate itself. Extraordinary transmission gives it a burst of high replication, high notoriety, but soon brings it to a dead end.

Whatever mode of transmission a virus favors—airborne, oral-fecal, blood-borne, sexual, vertical, or just getting itself passed along in the saliva of a biting mammal, like rabies—the common truth is that this factor doesn’t exist independently. It functions as half of that ecological yin-yang.

In fact, virulence is such an iridescent, relativistic concept that some experts refuse to use the word. They prefer “pathogenicity,” which is nearly a synonym but not quite. Pathogenicity is the capacity of a microbe to cause disease. Virulence is the measurable degree of such disease, especially as gauged against other strains of similar pathogen.

But if “virus” hearkens back to “poisonous slime,” the point of virulence is to ask, How poisonous?

The first rule of a successful parasite is Don’t kill your host.

It does seem logical, at first consideration, and it’s still often taken as dogma—at least by people who don’t happen to study the evolution of parasites.

Some very successful viruses do kill their hosts. Lethalities of 99 percent, and persisting at that level over time, aren’t unknown. Case in point: rabies virus. 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.” McNeill was right, and the key word in that statement is “quickly.” Timing is all. A disease organism that kills its host slowly but inexorably faces no such crisis.

A virus can succeed nicely in the long term, despite killing every individual infected, if it manages to get itself passed onward to new individuals before the death of the old.

In the meantime, the virus has traveled to the salivary glands as well as the brain, and therefore achieves transmission into the bitten victims, even though the original host eventually dies or is killed with an old rifle by Atticus Finch.

I love the wit of the author

The story began in the mid-nineteenth century, when a misguided white landholder named Thomas Austin had the bright idea of introducing wild European rabbits to the Australian landscape.

Decades passed, with the situation only getting worse. By 1950 there were about 600 million rabbits in Australia, competing with native wildlife and livestock for food and water, and Australians were desperate for action.

Within a decade, though, two things happened: The virus became inherently less virulent and the surviving rabbits became more resistant to it. Mortality fell and the rabbit population began climbing back. This is the short, simple version of the story, with its facile lesson: Evolution lowers virulence, tending toward that “more perfect mutual tolerance” between pathogen and host.

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.

Then in 1991 they put it all, and more, into a thick tome titled Infectious Diseases of Humans.

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.” Bosh

The best measure of evolutionary success, they figured, was the basic reproductive rate of the infection—that cardinal parameter, R0.

R0 = βN/(α + b + v) In English: The evolutionary success of a bug is directly related to its rate of transmission through the host population and inversely but intricately related to its lethality, the rate of recovery from it, and the normal death rate from all other causes. (The clunky imprecision of that sentence is why ecologists prefer math.) So the first rule of a successful parasite is slightly more complicated than Don’t kill your host. It’s more complicated even than Don’t burn your bridges until after you’ve crossed them. The first rule of a successful parasite is βN/(α + b + v).

Edward C. Holmes. Unlike them, he’s a specialist in viral evolution, one of the world’s leading experts. He sits in a bare office at the Center for Infectious Disease Dynamics, which is part of Pennsylvania State University, in a town called State College,

or to bacteria, or to any other type of parasite. He didn’t need to cite the particulars about RNA viruses because I already had that list in my mind: Hendra and Nipah, Ebola and Marburg, West Nile, Machupo, Junin, the influenzas, the hantas, dengue and yellow fever, rabies and its cousins, chikungunya, SARS-CoV, and Lassa, not to mention HIV-1 and HIV-2. All of them carry their genomes as RNA.

To say Eddie Holmes wrote the book on this subject wouldn’t be metaphorical. It’s titled The Evolution and Emergence of RNA Viruses, published by Oxford in 2009,

A glance at his virosphere poster, which portrayed the universe of known viruses as a brightly colored pizza, was enough to support that point.

Most DNA viruses embody the opposite extremes. Their mutation rates are low and their population sizes can be relatively small. Their strategies of self-perpetuation “tend to go for this persistence route,” Eddie said. Persistence and stealth. They lurk, they wait. They hide from the immune system rather than trying to outrun it. They go dormant and linger within certain cells, replicating little or not at all, sometimes for many years. I knew he was talking about things like varicella zoster virus, a classic DNA virus that begins its infection of humans as chickenpox and can recrudesce, decades later, as shingles.

The enzyme employed by RNA viruses, on the other hand, is “error prone,” according to Eddie. “It’s just a really crappy polymerase,” which doesn’t proofread, doesn’t backtrack, doesn’t correct erroneous placement of those nucleotide bases, A, C, G, and U. Why not? Because the genomes of RNA viruses are tiny, ranging from about two thousand nucleotides to about thirty thousand, which is much less than what most DNA viruses carry.

It’s sort of a chicken-and-egg problem, he said. RNA viruses are limited to small genomes because their mutation rates are so high, and their mutation rates are so high because they’re limited to small genomes. In fact, there’s a fancy name for that bind: Eigen’s paradox. Manfred Eigen is a German chemist, a Nobel winner, who has studied the chemical reactions that yield self-organization of longer molecules, a process that might lead to life. His paradox describes a size limit for such self-replicating molecules, beyond which their mutation rate gives them too many errors and they cease to replicate.

What do you do if you’re a virus that’s stuck, with no long-term security, no time to waste, nothing to lose, and a high capacity for adapting to new circumstances? By now we had worked our way around to the point that interested me most. “They jump species a lot,” Eddie said.

The influenzas jump from wild birds into domestic poultry and then into people, sometimes after a transformative stopover in pigs.

But a large fraction of all the scary new viruses I’ve mentioned so far, as well as others I haven’t mentioned, come jumping at us from bats. Hendra: from bats. Marburg: from bats. SARS-CoV: from bats. Rabies, when it jumps into people, comes usually from domestic dogs—because mad dogs get more opportunities than mad wildlife to sink their teeth into humans—but bats are among its chief reservoirs. Duvenhage, a rabies cousin, jumps to humans from bats. Kyasanur Forest virus is vectored by ticks, which carry it to people from several kinds of wildlife, including bats. Ebola, very possibly: from bats. Menangle: from bats. Tioman: from bats. Melaka: from bats. Australian bat lyssavirus, it may not surprise you to learn, has its reservoir in Australian bats. And though the list already is long, a little bit menacing, and in need of calm explanation, it wouldn’t be complete without adding Nipah, one of the more dramatic RNA viruses to emerge within recent decades, which leaps into pigs and via them into humans: from bats.

The debut appearance of a new zoonotic disease is often confusing as well as alarming, and Nipah was no exception. In September 1998, people began getting sick in a northern district of peninsular Malaysia, near the city of Ipoh. Their symptoms included fever, headache, drowsiness, and convulsions. The victims were pig farmers or somehow associated with pig processing.

One of those victims had been a fifty-one-year-old pig farmer from a village called Sungai Nipah. This man had come to the hospital feverish, confused, with a twitchy left arm. Six days later he was dead.

Chua tucked some frozen samples into a bag and got on a plane for America. Many hours later, he was in Fort Collins, Colorado. At the CDC’s satellite center there, which houses its Division of Vector-Borne Diseases, he and CDC scientists examined the Sungai Nipah samples under a topnotch electron microscope. What they saw wasn’t Japanese encephalitis virus. It looked more like a scrum of paramyxovirus, containing long filaments with a sort of herringbone structure. Malaysian measles? Murderous porcine mumps? Based on that tentative identification, Chua was redirected to CDC headquarters in Atlanta, where his new contacts were paramyxovirus researchers.

By the end of the outbreak, at least 283 humans had been infected and 109 had died, for a case fatality rate of almost 40 percent. Nobody wanted to eat pork, or to handle it, or to buy it. Pigs were left starving in their pens. Some broke out to roam the roadways like feral dogs, foraging for food. Malaysia at that time contained 2.35 million pigs, half of them from Nipah-affected farms, so this could have become an almost medieval problem, like a scene from the Black Death: herds of infected pigs stampeding ravenously through empty villages.

It’s almost impossible to screen your pigs, cows, chickens, ducks, sheep, and goats for a virus of any sort until you’ve identified that virus (or at least a close relative), and we have only begun trying.

R0 = βN/(α + b + v) In that formulation, β represents the transmission rate. β is the letter beta, in case you’re not a mathematician or a Greek. Here it’s a multiplier in the single expression that stands as numerator of the fraction, a strong position. What that means is, when β changes muchly, R0 changes muchly. And R0, your good memory tells you, is the measure of whether an outbreak will take off.

Have you noticed the persistent, low-level buzz about avian influenza, the strain known as H5N1, among disease experts over the past fifteen years? That’s because avian flu worries them deeply, though it hasn’t caused many human fatalities.

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.