Spillover: Animal Infections and the Next Human Pandemic

by David Quammen

In any case the dead ape was usually covered with scavenging insects—ants, tiny flies, even bees. Ondzie told of one occasion when three bees from a carcass ran up his arms, under his hood flap, down across his bare body, and commenced to sting him as he worked on the samples. Can Ebola virus travel on the stinger of a bee? No one knows.

❌❌❌

So the good news about Reston virus, derived both from the 1989 US scare and from retrospective research on Luzon, is that it doesn’t seem to cause illness in humans, only in monkeys. The bad news is that no one understands why.

Didn’t realize no people died in Reston

One animal died and, after it tested positive for Reston virus, forty-nine others housed in the same room were euthanized as a precaution. (Most of those, tested posthumously, were negative.) Ten employees who had helped unload and handle the monkeys were also screened for infection, and they also tested negative, but none of them were euthanized.

Is this... humor?

Advisory: If your husband catches an ebolavirus, give him food and water and love and maybe prayers but keep your distance, wait patiently, hope for the best—and, if he dies, don’t clean out his bowels by hand. Better to step back, blow a kiss, and burn the hut.

Big yikes

When I mentioned the descriptions in Preston’s book, Rollin mockingly said, “They melt, splash on the wall,” and gave a frustrated shrug. Mr. Preston could write what he pleased, Rollin added, so long as the product was labeled fiction. “But if you say it’s a true story, you have to speak to the true story, and he didn’t. Because it was much more exciting to have blood everywhere and scaring everywhere.” 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.

Johnson also concurred with Pierre Rollin that the bloodiness angle has been oversold. If you want a really bloody disease, he said, look at Crimean-Congo hemorrhagic fever. Ebola is bad and lethal, sure, but not bad and lethal precisely that way.

During the Kikwit outbreak, 59 percent of all patients didn’t bleed noticeably at all, and bleeding in general was no indicator of who would or wouldn’t survive. Rapid breathing, urine retention, and hiccups, on the other hand, were ominous signals that death would probably come soon. Among those patients who did bleed, blood loss never seemed massive, except among pregnant women who spontaneously aborted their fetuses. Most of the nonsurvivors died stuporous and in shock. Which is to say: Ebola virus generally killed with a whimper, not with a bang or a splash.

The tininess of Platt’s wound, in light of subsequent events, testifies that even a minuscule dose of an ebolavirus is enough to cause infection, at least if that dose gets directly into a person’s bloodstream. Not every pathogen is so potent. Some require a more sizable foothold. Ebolaviruses have force but not reach. You can’t catch one by breathing shared air, but if a smidgen of the virus gets through a break in your skin (and there are always tiny breaks), God help you. In the terms used by the scientists: It’s not very contagious but it’s highly infectious.

Unlike your average young convenience-store clerk, Kelly herself had a strong early aptitude for science.

🧐

In particular, she gained expertise in a line of vaccine development using viruslike particles (VLPs), rather than the more conventional approach, which uses live virus attenuated by laboratory-induced evolution. VLPs are essentially the outer shells of viruses, capable of inducing antibody production (immune readiness) but empty of functional innards, and therefore incapable of replicating or causing disease. VLPs seem to hold high promise for vaccines against viruses, such as Ebola, that might be too dangerous for live-virus vaccination.

(BSL-3 comprises the laboratory suites in which researchers generally work on dangerous but curable diseases, many caused by bacteria, such as anthrax and plague. BSL-4 is reserved for work on pathogens such as Ebola, Marburg, Nipah, Machupo, and Hendra, for which there are neither vaccines nor treatments.)

Picture those circumstances for Kelly Warfield. Customarily she worked in the BSL-4 suite known as AA-5, off a cinderblock corridor in the most secure wing of USAMRIID, behind three pressure-sealed doors and a Plexiglas window. She wore a blue vinyl protective suit (she and her colleagues simply called them “blue suits,” not space suits or hazmats) with a fully enclosed hood, a clear face shield, and a ventilation hookup. Attached to her hookup was a yellow hose, coiling down from the ceiling to bring filtered air. She wore rubber boots and two pairs of gloves—latex gloves beneath heavier canners gloves, sealed to her suit at the wrists with electrical tape. Even with canners gloves over latex, her hands were the most vulnerable part of her body; they couldn’t be protected with vinyl because they had to be delicately dexterous. Her workbench was a stainless steel cart, like a hospital cart, easy to clean, easy to move. If you didn’t love the work, you wouldn’t put yourself in this place.

After that, Warfield had her choice each evening among Frederick’s best: Chinese, Mexican, pizza. And she could share with her visiting friends, such as Negley, who would sit in the blind spot beneath the security camera, flip up her face shield, and eat.

Wait, what?! She ate in the room with her?!

But she could cite its attractions in scientific terms. 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.

(Ebola)

But there exists a grim circularity: Gathering more data requires more outbreaks.

The plague bacterium had shot its wad.

oh

So said the great malaria man, Ronald Ross, in a 1916 paper presenting his own mathematical approach to epidemics.

Don’t think that’s a title you want

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 ou...

Or a past in biology 🤓👩🏻‍🔬

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.

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, 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.

Mathematics to me is like a language I don’t speak though I admire its literature in translation.

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.

Lol

If you read the recent scientific literature of disease ecology, which is highly mathematical, and which I do not recommend unless you are deeply interested or troubled with insomnia, you find the basic reproduction rate everywhere.

Knowles and Gupta also injected it into three human volunteers (that is to say, “volunteers,” their freedom to decline having been a dubious matter),

(Passaging was necessary for replenishing a supply of the parasite, since it couldn’t be cultured in a dish or a tube; but passaging it directly through humans liberated the parasite from whatever different evolutionary pressures had been entailed in completing its life cycle within mosquitoes. It became like the protist equivalent of a designated hitter—very capable of batting, and freed from the responsibility to play outfield.)

We are a relatively young kind of primate, we humans, and therefore our diseases are young too. We have borrowed our troubles from other creatures. Some of those infections, such as Hendra and Ebola, visit us only occasionally and, when it happens, arrive soon at dead ends. Others do as the influenzas and the HIVs have done—take hold, spread from person to person, and achieve vast, far-flung, enduring success within the universe of habitat that is us.

This seafood merchant was a man named Zhou Zuofeng. He holds the distinction of being the first “superspreader” of the SARS epidemic.

Another title you don’t want

Zhou himself would eventually become known among medical staff in Guangzhou as the Poison King.

Back in Singapore, health officials and government authorities cooperated to stanch further transmission. They enacted firm measures that reached far beyond the hospitals—such as enforced quarantine of possible cases, jail time and fines for quarantine breakers, closure of a large public market, school closures, daily temperature checks for cab drivers—and the outbreak was brought to an end. Singapore is an atypical city, firmly governed and orderly (that’s putting it politely), therefore especially capable of dealing with an atypical pneumonia, even one so menacing as this. On May 20, 2003, eleven people were taken to court and fined $300 each for spitting.

Moving to Singapore

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.

Within a few more days, the team had electron microscope images of round viral particles, each particle encircled by a corona of knobs. This was so unexpected that one microscopist on the team had recourse to what amounted to a field guide; he browsed through a book of viral micrographs, looking for a match, as you or I might do for a new bird or a wildflower. He found his match among a group known as the coronaviruses, characterized by a corona of knobby proteins rimming each viral particle.

*ominous music*

They were right, and the virus became known as SARS coronavirus, inelegantly abbreviated as SARS-CoV. It was the first coronavirus ever found to inflict serious illness upon humans. (Several other coronaviruses are among the many viral strains responsible for common colds. Still others cause hepatitis in mice, gastroenteritis in pigs, and respiratory infection in turkeys.) SARS-CoV has no ominous ring. In older days, the new agent would have received a more vivid, geographical moniker such as Foshan virus or Guangzhou virus, and people would have run around saying: Watch out, he’s got Guangzhou! But by 2003 everyone recognized that such labeling would be invidious, unwelcome, and bad for tourism.

The culinary trade in such unusual wild animals, especially within the Pearl River Delta, has less to do with limited resources, dire necessity, and ancient traditions than with booming commerce and relatively recent fashions in conspicuous consumption. Close observers of Chinese culture call it the Era of Wild Flavor.

Wild Flavor (yewei in Mandarin) was considered a way of gaining “face,” prosperity, and good luck. Eating wild, Greenfeld explained, was only one aspect of these new ostentations in upscale consumption, which might also involve patronizing a brothel where a thousand women stood on offer behind a glass wall. But the food vogue arose easily from earlier traditions in fancy cuisine, natural pharmaceuticals, and exotic aphrodisiacs (such as tiger penis), and went beyond them. One official told Greenfeld that two thousand Wild Flavor restaurants were now operating within the city of Guangzhou alone. Four more received licenses during the hour Greenfeld spent in the man’s office.

The real point, according to Guan and his colleagues, was that the wet markets such as Dongmen and Chatou provided a venue for SARS-like coronaviruses “to amplify and to be transmitted to new hosts, including humans, and this is critically important from the point of view of public health.”

Clearly that was taken very seriously! 🙄

Eradication teams from the Forestry Department (which regulates the wild animal trade) and the Health Department went out to civet farms. During the days that followed, more than a thousand captive civets were suffocated, burned, boiled, electrocuted, and drowned.

Jfc ELECTROCUTED?!

But disappointment, in science, is sometimes a gateway to insight.

After the SARS outbreak and the civet publicity, local governments (presumably with some pressure from Beijing) had tightened down, enacting new restrictions against wildlife in the markets. The Era of Wild Flavor hadn’t ended but it had been driven underground. “There’s still a lot of people in China that believe eating fresh, wild animals is good for your respiratory system, it’s good for sexual potency, whatever,” Aleksei said.

After a brief traverse, we came to a hole in the slope, not much larger than an old cellar door. Guangjian and Jian climbed down into it and disappeared; Aleksei and I followed. Beyond the hole was a small foyer and, on the far side of that, a low slot, like a mountain’s smirk, leading onward. We belly crawled through and came up dirty in a second small chamber. Not for the claustrophobic. We crossed that chamber and then butt skidded through another low gap, down another rabbit hole into a third chamber (this all felt a little like being swallowed through the multiple stomachs of a cow), which opened out wider and deeper.

Panicking just from reading this 🙅🏻‍♀️🙅🏻‍♀️🙅🏻‍♀️

It was a shrug back toward our dinner discussions and the tangled matter of categorical lines: edible animals versus sacrosanct animals, safe animals versus infected animals, dangerous offal versus garbage. His point again was that such lines of division, especially in southern China, are arbitrarily and imperfectly drawn.

Mr. Wei Shangzheng eventually pulled up in a white van. He was a short, stocky, amiable man who laughed easily and often, especially after his own statements, not because he thought he was funny but from sheer joy at life’s curious sweetness.

Apart from the aftershock cases in early 2004, SARS hasn’t recurred . . . so far.

damnit

Much has been written about SARS in the scientific literature since spring of 2003. Most of those papers are narrowly technical, addressing the details of molecular evolution, reservoir relationships, or epidemiology, but some take a broader view, asking What is it that makes this virus unusual? and What have we learned from the SARS experience? One thought that turns up in the latter sort is that “humankind has had a lucky escape.” 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.

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. Even among some of the superspreaders, in 2003, this seems to have been true. That order of events allowed many SARS cases to be recognized, hospitalized, and placed in isolation before they hit their peak of infectivity. The downside was that hospital staff took the first big blasts of secondary infection; the upside was that those blasts generally weren’t emitted by people still feeling healthy enough to ride a bus or a subway to work. This was an enormously consequential factor in the SARS episode—not just lucky but salvational. 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. The bug traveled ahead of the sense of alarm. 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 p...

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.

🚨🚨🚨

tobacco mosaic

Sir Peter Medawar, an eminent British biologist who received a Nobel Prize the same year as Macfarlane Burnet, defined a virus as “a piece of bad news wrapped up in a protein.”

A plate of Ebola virions mixed with Hendra virions would resemble capellini in a light sauce of capers.

...why

Viruses, from the beginning of virology, have been defined in the negative (not captured by a filter, not cultivable in chemical nutrients, not quite alive), and the most fundamental negative axiom is that a virion is not a cell.

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. (For the record, there’s also a smaller group of DNA viruses that code their genetics on single strands of DNA and suffer high mutation rates, as in RNA. And there’s a little group of double-stranded RNA viruses. To every rule, an exception. But we’re going to ignore those minor anomalies because this stuff is already complicated enough.) The basic point is so important I’ll repeat it: RNA viruses mutate profligately.