Spillover: Animal Infections and the Next Human Pandemic (23 page)

By the middle of July, when the last SARS patient left Tan Tock Seng Hospital, more than two hundred cases had been recognized. Thirty-three of those people died, among whom were Esther Mok’s father, her pastor, her mother, and her uncle, in that order of demise. Esther herself survived.

35

D
ead or recovered, they had all been infected—but infected with
what
?

As the disease spread internationally, scientists on three continents worked in their laboratories with samples of tissue, blood, mucus, feces, and other vital, unsavory materials taken from one patient or another, trying to isolate and identify a causal agent. The very name coined during that early period, SARS, reflects the fact that this thing was known only by its effects, its impacts, like the footprints of a large, invisible beast. Ebola is a virus. Hendra is a virus. Nipah is a virus. SARS is a syndrome.

The search for the SARS pathogen proceeded urgently in those laboratories, but it was hampered by some confusing signals and false leads. For starters, the symptoms looked a little bit too much like influenza—or, more precisely, like influenza at its worst. One form of influenza at its worst is the so-called bird flu, caused by a virus designated as H5N1, with which Hong Kong in particular had had fearful experience just half a dozen years earlier, when eighteen people became infected by spillovers from domestic poultry. Eighteen doesn’t sound like a large number of patients; the fearful aspect was that six of those eighteen died. Health authorities had responded quickly, ordering the closure of live poultry markets and the destruction of every chicken in Hong Kong—amounting to 1.5 million doomed, squawking birds—followed by a seven-week hiatus for decontamination. This draconian response, combined with the fact that H5N1 didn’t transmit well from human to human, only from bird to human, had succeeded in ending the 1997 Hong Kong outbreak. But in February 2003, just when
alarming rumors about “a strange contagious disease”
began to emerge by email and text message from Guangdong, avian flu struck again in Hong Kong. It was entirely distinct from the SARS outbreak, but that couldn’t easily be seen at the time.

The flu killed a thirty-three-year-old man and sickened (but didn’t kill) his eight-year-old son. It probably also killed the man’s seven-year-old daughter, who had died two weeks earlier of a pneumonia-like illness during a family visit to Fujian, the Chinese province just northeast of Guangdong. Possibly the little girl had consorted too closely with Chinese chickens; her brother had definitely done that, according to his own later testimony. Samples of nasal mucus from both the father and the son showed positive for H5N1, which seemed to suggest that the wider flurry of case reports from Guangdong might likewise pertain to avian flu. So the scientists tested their SARS samples for H5N1. But that was a false lead.

Another wrong notion was that SARS might be caused by some form of chlamydia, a diverse group of bacteria that includes two kinds associated with respiratory disease in humans (as well as another, more famous among teenagers, that’s sexually transmitted). One of the respiratory chlamydias is zoonotic, leaping from birds (notably, pet parrots) into humans. During late February, a very senior Chinese microbiologist found what looked like chlamydia
in some SARS specimens and, based on his tenuous evidence—also, his august standing in the respectful milieu of Chinese science—the chlamydia hypothesis was embraced overconfidently by high health officials in Beijing. At least one other eminent Chinese researcher dissented, arguing that, if a chlamydia was the cause, SARS cases should have responded to treatment with antibiotics—which they did not. But that fellow was down in Guangdong, at the Institute for Respiratory Diseases, and Beijing didn’t want to hear him.

The laboratory scientists meanwhile explored other possibilities too, quite a list: plague, spotted fever, Legionnaires’ disease, typhus, several kinds of bacterial pneumonia, seasonal influenza,
E. coli
in the blood, Old and New World hantaviruses, and more. Part of what made the task difficult was that, in pursuing the SARS agent, they didn’t know whether they were looking for something familiar, something newish but closely resembling something familiar, or something entirely new.

And there was one other possible category: something familiar to veterinarians but entirely new as an infection of humans. In other words, an emerging zoonosis.

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.

At the University of Hong Kong, high on the side of a peak overlooking the downtown neighborhoods, a team led by Malik Peiris took this approach to its fruitful conclusion. Peiris is an Oxford-educated microbiologist, born and raised in Sri Lanka, soft-spoken and judicious, with fine dark hair that hugs his skull roundly. He is known primarily as an influenza researcher and, having come to Hong Kong in 1995, just before the big bird-flu scare, he had reason to consider avian influenza as a leading hypothesis for what was now coming out of Guangdong. “
The first thing going through our minds
was that the H5N1 virus had possibly acquired the ability to transmit from human to human,” he told a reporter in 2003. But after testing their SARS samples for H5N1, as well as for a roster of the usual suspects, and finding no evidence of any, his team moved toward the idea that they were dealing with a new virus.

They focused then on trying to culture it. This meant, first of all, giving the mystery creature an environment of living cells in which it was able to replicate, until it grew abundant enough in the culture, and caused enough damage to the cells, that its presence could be seen. The living cells of the culture had to be one or another “immortalized” lineage (such as the famous HeLa cells from an unfortunate woman named Henrietta Lacks), so that they would continue replicating indefinitely until something killed them. Peiris’s team began by offering the new bug five different cell lines that had variously proven hospitable to familiar respiratory pathogens: cells from a dog’s kidney, cells from a rat’s tumor, cells from the lung of an aborted human fetus, and others. No luck. There was no sign of cell damage and therefore no evidence of viral growth. Then they tried another line, derived from kidney cells of a fetal rhesus monkey.
Yes
luck. By the middle of March, they could see “cytopathic effect” in their monkey-cell culture, meaning that something had begun to replicate within those cells and destroy them, spilling from one cell to another and creating a visible zone of devastation. 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.

So the culturing work had established that an unknown coronavirus was present in SARS patients—some of them, anyway—but that didn’t necessarily mean it had caused the disease. To establish causality, Peiris’s team tested blood serum from SARS patients (because it would contain antibodies) against the newfound virus in culture. This was like splashing holy water at a witch. The antibodies recognized the virus and reacted strongly. Less than a month later, based on that evidence plus other confirming tests, Malik Peiris and his colleagues published a paper cautiously
announcing this new coronavirus as “a possible cause”
of SARS.

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.

Several other teams, working independently to isolate a SARS causal agent, had gotten the same answer at about the same time. In the United States, it was a group based at the CDC in Atlanta, with a long list of international partners. In Europe, it was a set of collaborators spread among research institutions in Germany, France, and the Netherlands. In China, it was a small squad of earnest, adept, and deferential researchers who had isolated a coronavirus and photographed it weeks before Peiris’s group did the same. These unfortunate Chinese scientists, based at the Academy of Military Medical Sciences, let themselves be cowed by the chlamydia theory and its august promoter in Beijing, passing up their opportunity to announce the real discovery first. “
We were too cautious,
” one of them said later. “We waited too long.”

The next logical step for Malik Peiris and his gang, after having identified the virus, sequenced a portion of its genome, and placed it within a family tree of other coronaviruses, was to wonder about its origin. The thing hadn’t come out of nowhere. But what was its usual habitat, its life history, its natural host? One scientist involved in the work, a young biologist named Leo Poon, touched on that during a conversation with me in Hong Kong.

“The data that we found in human samples,” said Poon, “suggested that this virus is novel to humans. What I mean is that humans had not been infected by this virus before. So it must have been coming from some kinds of animals.”

But which animals, and how did they happen to transmit the infection to people? Those questions could only be answered by going into the forests, the streets, the markets, the restaurants of southern China to gather evidence. Nudging him toward that subject, I wondered: “Were you part of the fieldwork?”

“No, I’m a
molecular
scientist,” he said. It had been like asking Jackson Pollock if he painted houses, I suppose, but Leo Poon didn’t take my question amiss. He was happy to give credit where due. No, another of their colleagues, a wildcat fellow named Guan Yi, with the instincts of an epidemiologist and the balls of a brass macaque, had crossed into China and, with cooperation from some local officials, taken swabs from the throats, the anuses, and the cloacae of animals on sale in the biggest live market in Shenzhen. Those samples were what first led Leo Poon (who did the molecular analysis), Malik Peiris, Guan Yi himself—and, eventually, scientists and health officials all over the world—to cast their suspicious attentions upon a mammal called the civet cat.

36

I
n a crowded country with 1.3 billion hungry citizens, it should be no surprise that people eat snake. It should be no surprise that there are Cantonese recipes for dog. Stir-fried cat, in such a context, seems sadly inevitable rather than shocking. But the civet cat (
Paguma larvata
) is not really a cat. More accurately known as the masked palm civet, it’s a member of the viverrid family, which includes the mongooses. 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.

One of those observers is Karl Taro Greenfeld, who served as editor of
Time Asia
in Hong Kong during 2003, oversaw the magazine’s coverage of SARS, and soon afterward wrote a book about it,
China Syndrome
. Before his editing role, Greenfeld had covered “the new Asia” as a journalist for some years, giving him opportunity to see what people were putting in their stomachs. According to him:

Southern Chinese have always noshed more widely
through the animal kingdom than virtually any other peoples on earth. During the Era of Wild Flavor, the range, scope, and amount of wild animal cuisine consumed would increase to include virtually every species on land, sea, or air.

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.

These eateries drew their supplies from the “wet markets” of Guangdong province, vast bazaars filled with row after row of stalls purveying live animals for food, such as the Chatou Wildlife Market in Guangzhou and the Dongmen Market in Shenzhen. Chatou began operating in 1998 and within five years had become one of the largest wild-animal markets in China, especially for mammals, birds, frogs, turtles, and snakes. Between late 2000 and early 2003, a team of researchers based in Hong Kong conducted an ongoing survey of wild animals on sale at Chatou, Dongmen, and two other big Guangdong markets. Compared to an earlier survey done in 1993–1994, the team found some changes and new trends.