Spillover: Animal Infections and the Next Human Pandemic (38 page)

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.” Bosh and nonsense, said Anderson and May. In reality the virulence of a parasite “is usually coupled with the transmission rate and with the time taken to recover by those hosts for whom the infection is not lethal.” Transmission rate and recovery rate were two variables that Anderson and May included in their model. They noted three others: virulence (defined as deaths caused by the infectious agent), deaths from all other causes, and the ever-changing population size of the host. The best measure of evolutionary success, they figured, was the basic reproductive rate of the infection—that cardinal parameter,
R
0
.

So they had five crucial variables and they wanted to understand the net effect. They wanted to trace the dynamics. This led them to a simple equation. There will be no math questions in the quiz at the end of this book, but I thought you might like to cast your eyes upon it. Ready? Don’t flinch, don’t worry, don’t blink:

R
0
=
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
β
N/
(α
+ b + v
).

The other thing that makes Anderson and May’s 1982 paper vivid is its discussion of myxoma in Australian rabbits. That brought their modeling to an empirical case and allowed them to test theory against fact. They described Frank Fenner’s five grades of virulence. They saluted his methodical combination of field sampling and lab experiments. They mentioned the mosquitoes and the open sores. Then, using Fenner’s data and their own equation, they plotted a relationship between virulence and success. Their result was a model-generated prediction: Given
this
rate of transmission, given
that
rate of recovery, given
those
unrelated mortalities, then . . . an
intermediate
grade of virulence should come to predominate.

Son of a gun, it matched what had happened.

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.” Their italics:
not
necessarily
. On the contrary,
it depends
. It depends on the specifics of the linkage between transmission and virulence, they explained. It depends on ecology and evolution.

66

A
nderson and May were theoreticians who worked much with other people’s data. So is 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, amid the rolling hills and hardwoods of central Pennsylvania, and discerns patterns of viral change by scrutinizing sequences of genetic code. That is, he looks at long runs of those five letters, A, C, T, G, and U, strung out in unpronounceable streaks as though typed by a manic chimpanzee. Holmes’s office is tidy and comfortable, furnished sparsely with a desk, a table, and several chairs. There are few bookshelves, few books, few files or papers. A thinker’s room. On the desk is a computer with a large monitor. That’s how it all looked when I visited, anyway.

Above the computer hung a poster celebrating “the Virosphere,” meaning the unplumbable totality of viral diversity on Earth. Beside that, another poster showed Homer Simpson as a character in Edward Hopper’s famous painting “Nighthawks.” I’m not sure what that one was celebrating, unless perhaps donuts.

Edward C. Holmes is an Englishman, transplanted to central Pennsylvania from London and Cambridge. His eyes bug out slightly when he discusses a crucial fact or an edgy idea, because good facts and ideas impassion him. His head is round and, where not already bald, shaved austerely. He wears wiry glasses with a thick metal brow, as in old pictures of Yuri Andropov. Though shaved, though brilliant, though Andropovian at first glance, Edward C. Holmes isn’t austere. He’s lively and humorous, a generous soul who loves conversation about what matters: viruses. Everyone calls him Eddie.

“Most emerging pathogens are RNA viruses,” he told me, as we sat beneath the two posters. RNA as opposed to DNA viruses, he meant, 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. The category does seem to encompass much more than its share of dastardly zoonoses, including most of the newest and the worst. Some scientists have begun asking why. 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, and that’s what had brought me to his door. Now he was summarizing some of the highlights.

Granted, Eddie said, there are an
awful
lot of RNA viruses generally, which might seem to raise the odds that many would come after humans. RNA viruses in the oceans, in the soil, in the forests, and in the cities; RNA viruses infecting bacteria, fungi, plants, and animals. It’s possible that every cellular form of life on the planet supports at least one RNA virus, he had said in the book, though we don’t know for sure because we’ve just begun looking. 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.

Two reasons for that, he explained. It’s not just the high mutation rates but also the fact that their population sizes are huge. “Those two things put together mean you’ll produce more adaptive change.”

RNA viruses replicate speedily, generating their big populations (high titers) of virions within each host. Stated another way, they often produce acute infections, severe for a short time and then gone. Either they soon disappear or they kill you. Eddie called it “this kind of boom-bust thing.” 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.

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 downside for DNA viruses, Eddie said, is that they can’t adapt so readily to a new species of host. They’re just too stable. Hidebound. Faithful to what has worked in the past.

The stability of DNA viruses derives from the structure of the genetic molecule and how it replicates, using DNA polymerase to assemble and proofread each new strand. 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 takes more nucleotides,” Eddie said—a larger genome, more information—“to make a new enzyme that works.” One that works as neatly as DNA polymerase does, he meant.

And why are RNA genomes so small? Because their self-replication is so fraught with inaccuracies that, given more information to replicate, they would accumulate more errors and cease to function at all. 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. They die out. RNA viruses, thus constrained, compensate for their error-prone replication by producing huge populations and achieving transmission early and often. They can’t break through Eigen’s paradox, it seems, but they can scoot around it, making a virtue of their instability. Their copying errors deliver beaucoup variation, and beaucoup variation allows them to evolve fast.

“DNA viruses can make much bigger genomes,” Eddie said. Unlike the RNAs, they’re not limited by Eigen’s paradox. They can even capture and incorporate genes from the host, which helps them to confuse a host’s immune response. They can reside in a body for longer stretches of time, content to get themselves passed along by slower modes of transmission, such as sexual and vertical. Most crucially, they can repair copying errors as they replicate, thus lowering their mutation rates. “RNA viruses can’t do that.” They face a different set of limits and options. Their mutation rates can’t be lowered. Their genomes can’t be enlarged. “They’re kind of stuck.”

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.

VII

CELESTIAL HOSTS

67

F
rom where do these viruses jump? They jump from animals in which they have long abided, found safety, and occasionally gotten stuck. They jump, that is, from their reservoir hosts.

And which animals are those? Some kinds are more deeply implicated than others as reservoirs of the zoonotic viruses that jump into humans. Hantaviruses jump from rodents. Lassa too jumps from rodents. Yellow fever virus jumps from monkeys. Monkeypox, despite its name, seems to jump mainly from squirrels. Herpes B jumps from macaques. The influenzas jump from wild birds into domestic poultry and then into people, sometimes after a transformative stopover in pigs. Measles may originally have jumped into us from domesticated sheep and goats. HIV-1 has jumped our way from chimpanzees. So there’s a certain diversity of origins. 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.

68

T
he 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 was a pork seller, who died of a brain inflammation. In December, after the northern outbreak seemed to be tapering off, a new cluster of cases appeared southwest of the capital, Kuala Lumpur, in a pig-farming area of the state of Negri Sembilan. By the end of the year, ten workers had fallen ill, gone comatose, and died. The government reacted quickly but with imperfect comprehension. At first it was all about mosquitoes and pigs.

Mosquitoes were implicated as the presumed vectors; pigs, as the presumed reservoir hosts. But vectors and reservoirs of what? Japanese encephalitis virus was the presumed cause.

Japanese encephalitis (JE) is an endemic disease in Malaysia and much of southeastern Asia, tallying upward of thirty thousand human cases (mostly nonfatal) throughout the region each year. The JE virus belongs to the same family as West Nile, dengue, and yellow fever virus. It’s vector-borne, traveling by mosquito from its reservoirs in domestic pigs and wild birds. Antibodies found in some of the sickened Malaysian pig workers seemed to confirm its responsibility for the 1998 outbreak, and so Japanese encephalitis became the object of rising public concern and government action. Health officials started pondering how many people—or how many pigs—they should vaccinate against it.

In early January, a story ran in the
New Straits Times,
Malaysia’s leading English-language newspaper, under the headline:
GIRL IS FOURTH PERSON IN NEGRI TO DIE OF ENCEPHALITIS.
The girl in question, thirteen years old and unnamed in the article, had been helping her family with their pig business. Below the piece about her was another, a small item, reporting that Malaysia’s Health Minister had ordered a campaign of fogging to kill mosquitoes. Kill mosquitoes, eliminate the vector, stop JE transmission, yes? Yes but no. One day later, in the same newspaper:
GIRL DIES OF SUSPECTED JE IN IPOH.
That brought the death count, between Negri Sembilan in the south and Ipoh in the north, to thirteen. This child was only a toddler. She expired at her family home, a half mile from the nearest pig farm. “
Pigs are a common host for the virus
,” the story added—meaning the JE virus, of course. Was there any other?

Maybe. While the news media flamed over Japanese encephalitis, and the government took steps to control it, scientists in the Department of Medical Microbiology at the University of Malaya (not “Malaysia,” because it has preserved its historical name), in Kuala Lumpur, grew increasingly skeptical. They knew JE about as well as anyone, and some aspects of what was happening now just didn’t seem to fit the pattern. Apart from the two young girls so conspicuously mourned in the newspapers, almost all other recent victims had been adult males, men with hands-on involvement in the farming, transport, or butchery of pigs. In fact, most of them were not only male and adult but ethnic Chinese, a group that dominated the Malaysian pig industry. Japanese encephalitis as previously known, on the other hand, was notorious for affecting mainly children. Professor Sai Kit Lam (“Ken” Lam, to his Anglophone friends), then head of Medical Microbiology at the university, stated publicly that this outbreak was killing too many adults to fit the normal profile of JE. The case fatality rate of the current outbreak, too, seemed weirdly high. It was running at more than 54 percent. Maybe this was a new strain of the JE virus, more virulent than usual, more aggressive against adults, less widely spread to the general populace by its insect vector.

Or a different virus altogether, with a different mode of transmission. Mosquito vectoring didn’t seem to fit. What sort of mosquito chooses to bite only adult male Chinese pig farmers?

Meanwhile the pigs of Malaysia were sick too, suffering their own epizootic outbreak of something or other. Again, the familiar form of Japanese encephalitis didn’t explain it, since pigs usually tolerate that infection without showing clinical signs like this. They can be amplifier hosts as well as reservoirs of JE, in that their prevalence of infection may help increase the prevalence of the virus in mosquitoes, which then may bite humans. Pregnant sows infected with JE may also abort or deliver stillborn young; but it doesn’t cause conditions such as were now being seen in Malaysia. And there were other problems with the JE hypothesis. Whereas the new human disease among pig-industry workers was neurological, causing encephalitis and other problems of the nervous system, the pig ailment was both neurological and respiratory. It seemed very contagious from pig to pig, evidently moving by airborne transmission. One after another, first in the big sties of the Ipoh region and then down into Negri Sembilan, animals started coughing, shuddering, barking, wheezing piteously, collapsing off their feet, and in some cases dying.

The lethality among pigs, though, was much lower than the rate among human cases. Their symptoms at first suggested something called classical swine fever, a viral infection also known as hog cholera. But that guess was soon dismissed. Hog cholera, which isn’t zoonotic, couldn’t account for the human illnesses. Then maybe Japanese encephalitis of a nasty new sort? The outbreak spread from one pig farm to another in almost a rolling chorus of porcine hacking—people could hear it coming and wait with dread. “
It became known as a one-mile barking cough
,” according to a visiting expert from Australia, “because you could hear it a mile away. People would know that the disease had arrived in their area.” It traveled on the sneeze of a pig. It traveled too by truck, when animals were moved from one farm to another. And it traveled across borders, as in early 1999, when Malaysian pigs were exported to Singapore and the disease struck abattoir workers there. Eleven Singaporeans got sick. In the excellent medical facilities of the city-state, only one died.

Still no one knew what this thing was. Most of the early laboratory diagnostics, in Malaysia, had been done either by the Ministry of Health or, for the pig samples, by the national veterinary research institute up in Ipoh. Scientists at the University of Malaya, especially in Ken Lam’s Department of Medical Microbiology, followed the crisis closely but quietly. Paul Chua was the department’s chief clinical virologist. His work involved wet-lab methods, such as viral culturing and microscopy. Sazaly AbuBakar was the molecular virologist, meaning that he looked at viral genomes as Eddie Holmes does: in blurps of dry code, ACCAAACAAGGG, letter by letter. For a while, neither Chua nor AbuBakar could do much more than read the newspaper accounts, talk with colleagues, and speculate, because they didn’t have samples of blood, tissue, or cerebrospinal fluid, the raw evidence for lab diagnostics.

And then suddenly they did. As the outbreak continued in Negri Sembilan, not far from the capital, patients began arriving at the University of Malaya Medical Center. These patients were treated, some died, and Paul Chua received samples taken from three of the bodies. 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 and his trusted lab technician isolated virus from the Sungai Nipah sample, growing it in a line of tame laboratory cells derived originally from the kidney of an African monkey. Immediately the virus in culture started causing damage. The damage didn’t look like JE. Individual cells were enlarged, merging into big membranous bubbles peppered with multiple nuclei. Chua called in his colleague AbuBakar to look.

“Really unusual,” AbuBakar said, recalling the sight of those cells, when I stopped by his office in Kuala Lumpur. I had met him at a Nipah conference and he’d welcomed further chat. Paul Chua by then had left for a job in the Ministry of Health, but AbuBakar (his young students called him Prof. Sazaly) was now chair of Medical Microbiology himself. “We all concluded it is something unusual that we see in the cell culture.”

The logical next step, Prof. Sazaly told me, was to get a look at this virus under a good electron microscope. Although cell cultures reveal the collective action of the virus, visible to the naked eye as reflected in ravaged cells, it takes electron microscopy to show individual virions. “But unfortunately, at that time, we don’t have good electron microscopes anywhere in the country.” The one at the university was old and bleary. Malaysia is an Asian tiger, with many keen and well-educated scientists, but still short on certain technological resources.

So the department head, Ken Lam, called on old contacts in the United States, making arrangements for Paul Chua to visit. 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. They doused his samples with various assays, testing for antibody reaction, and got a provisional positive from the assay for Hendra antibodies. Sequencing part of the viral genome, though, they found that this was an entirely new bug: not Hendra, something similar but distinct. Paul Chua and his colleagues named it Nipah virus, after that little village of the fifty-one-year-old farmer. The disease eventually became known as Nipah virus encephalitis.

69

T
here’s a convergence of stories here. Once the Malaysian microbiologists knew that their outbreak was caused by a virus closely resembling Hendra, Ken Lam phoned another colleague, this time in Australia. “Look, we’ve got something,” he said. That was an understatement. The worrisome part was that he didn’t know where this “something” had come from or where it might go. He wanted expert help. No one was an expert on Nipah virus, not yet, but an expert on Hendra might be the next best thing. Through an intermediary, Lam’s request reached Hume Field, the lanky former veterinarian who had discovered Hendra in fruit bats. Field saddled up quickly. He got the call on a Thursday, to the best of his recollection, and by Monday he was on a plane to Kuala Lumpur.

Field joined an international team, led by a senior man from the CDC, which had convened from Atlanta and elsewhere to help the Malaysian professionals deal with the crisis. Their first task was to halt the immediate risk to people. “At that time, the human case rate was escalating,” Field told me later, during one of our talks in Brisbane. “Something like fifty new cases a week. So there was huge pressure—social, political—to stop the source of infection.” To do that, he added, the team had to understand the virus and learn how it behaved in pigs.

They began at what he called “hot farms,” where the infection was still burning its way through resident pigs. You could tell a hot farm by ear; it was Field whom I quoted above, describing the “one-mile barking cough.” He and the rest of the team wanted sick pigs from which to collect samples, hoping those samples might yield a virus matching the one Paul Chua had isolated from his pig farmer. “And that’s what happened,” Field said. They dispatched samples to the Australian Animal Health Laboratory, in Geelong, where colleagues isolated a virus that matched Paul Chua’s. Final proof of that match came from AbuBakar’s team in Kuala Lumpur. All this confirmed pigs as an amplifier host of the same Nipah virus that was killing humans. But it said nothing about where Nipah might ultimately reside.

The Malaysian government in the meantime had ordered a mass culling—that is, the extermination of every pig, infected or uninfected, on every farm that the outbreak had touched. Some of those piggeries had been abandoned by their operators, panicky and bewildered, even before the discovery of the new virus. People in certain areas even fled their homes; Sungai Nipah became a ghost town. 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. A phalanx of cullers, including soldiers from the army as well as police and veterinary officers, moved into the countryside wearing protective suits, gloves, masks, and goggles. Their assigned task was to shoot, bury, or otherwise dispose of more than a million animals, and to do it quickly, without splashing virus everywhere. Despite all precautions, at least half a dozen soldiers did get infected. Hume Field noted: “There’s no easy way to kill a million pigs.”