The Race To Contain A Virus

By Karl Taro Greenfeld/Guangzhou

In recorded history, no disease has jumped the species barrier to infect humans, caused an epidemic and then never threatened us again--not without the discovery of a vaccine or cure to curtail the microbe. Some diseases, such as chicken pox, gradually become endemic to man and eventually result, if we are lucky, in nothing more than a mild childhood illness. Others, such as Ebola, retreat back to whatever animal reservoir they came from, stalking humanity from their hidden lair, only occasionally lashing out to bloody a village or crash a rural hospital. But diseases do not, as a rule, just go away.

In the past two weeks, with two new cases in China's Guangdong province and suspected cases turning up in Manila and Hong Kong, it seems that severe acute respiratory syndrome (SARS) is re-emerging too. The brutal culling of masked palm civets from Guangdong wildlife markets and farms that commenced last week has only exacerbated the sense that matters had been spiraling out of control. Forestry officials incinerated some civets, boiled others to death and drowned still more in disinfectant. Also called a civet cat, the small, furry mammal with big innocent-looking eyes is unrelated to real cats, being more of a first cousin to the mongoose. Nevertheless, it was as if China was sacrificing thousands of animals to ward off the Fourth Horseman of the Apocalypse.

The inside story of how that decision to cull civets came to be made, however, is one of aggressive public health, great courage and, most important, good science. It is very possible that research led by one virologist, Dr. Yi Guan, 42, and the extraordinary measures he took to make officials aware of his work may lead scientists to new ways to contain a fresh SARS outbreak.

Almost every week for the past year, Yi, a microbiology associate professor at the University of Hong Kong, has traveled by rail up to Shenzhen and Guangzhou to carry out fieldwork. It was Yi, along with the Shenzhen Centers for Disease Control, who in May took samples from Shenzhen's Dongmen Market and made the discovery that the masked palm civet, as well as the raccoon dog and hog badger, carried a virus remarkably similar to the SARS coronavirus. That research, initially hailed as a breakthrough in establishing the zoonotic origins of SARS, resulted in the Guangdong government temporarily banning the sale of civets. For Yi this should have been a crowning moment.

Instead, subsequent research by a mainland Chinese team challenged Yi's research, finding no evidence of the coronavirus in civets. Meanwhile, other scientists murmured that Yi's data was based on too narrow a range of samples drawn from just one market. Perhaps those civets, some argued, had been infected by humans in that market rather than the other way around. For Yi, a hot-tempered, chain-smoking workaholic, this was an unbearable impugning not just of his research but also of his genuine desire to apply his science to public health. Even more worrying was China's decision in August lifting the ban on sales of civets. By September, the markets were again crawling with them. One dealer in Shenzhen, when asked if he could procure a thousand civet cats, replied, "That's hard." He paused, then added, "It may take me a day to get that many."

Despite the doubts cast by other scientists, Yi was still sure there was SARS coronavirus in wildlife markets. Taking into account the possibility that seasonality was a factor in the replication of the coronavirus, he waited until October--about a year since the first cases appeared--and began returning to the Guangdong wild-animal markets every week with his black satchel full of syringes, swabs and sample vials. Working with the Guangzhou CDC and the Shenzhen CDC, he paid $6 for each animal he tested to an animal trader who supplied Dongmen Market. In Guangzhou's Xinyuan Market, Yi would buy animals and haul them away in cages to the Guangzhou CDC labs, where he would gather samples before sending the creatures to be destroyed. Occasionally, when he was in a hurry, he would sedate the animal right there in the market, drawing blood and swabbing for feces.

When Yi brought those samples back to Hong Kong, a frightening picture started to emerge. Not only was he again finding the SARS coronavirus in a host of animals--the civet cat, as well as various types of badger--he was astonished, when he did the genomic sequencing, to observe that these coronaviruses had actually mutated to become more similar to the SARS coronavirus samples taken from humans during the outbreak one year ago. All this confirmed that the disease that had infected humans was again at large. The animals that showed the highest infection rate by far were the civet cats, with 16 positive cases out of 21 animals tested. These civets had come from several different markets and traders, which meant the disease was lurking in wild-animal markets throughout Guangdong--and maybe the rest of China. Roasted whole, braised or added to soups, the animal is considered a delicacy among many Chinese. One reason: civets are said to be full of yang, a heat-giving energy source that, according to traditional belief, helps people stay warmer in cold weather.

In late December, Yi was sitting in his apartment in Hong Kong, smoking and wondering about his way forward. It was only a matter of time before another outbreak would occur, he now believed. There was simply too much interaction between humans and civets for this virus not to make the leap. But it could take months to get a paper peer-reviewed and published so it would impact public health by encouraging the Guangdong government to curtail the civet population--or at least limit contact between humans and the animal. In that time, the disease could again gain a foothold among humans. But as long as there were no new cases then perhaps Yi had time to fast-track his paper and get it published in a few weeks. Then his wife called from work with news: there was a suspected SARS case in Guangdong. At that moment, "I felt like I had to do something," Yi explains. "I mean, why do you do science? To write papers? Or to make a difference in the real world?"

Yi believes deeply in the future of the People's Republic and is forgiving of its occasional foibles, dismissing malfeasances, such as last year's early cover-up of the outbreak, with a shrug. The many top officials he has met, he believes, will always do what is right if they have the relevant information. The problem is getting that data in front of them.

So Yi framed a simple letter to Beijing's Hong Kong and Macau Affairs Office, which he also sent to the Ministry of Health and the China CDC. "With winter coming, the wildlife markets have reopened, providing the perfect conditions for another outbreak of SARS," he wrote. He went on to list his findings that the civet is the major carrier of the SARS coronavirus, that the SARS coronavirus exists in different animals from different regions, that this virus can infect humans and, most frightening, that the "transmitting mechanism for the resurgence of SARS is in place." He enclosed four pages of genetic sequences taken from civets and had the letter hand-delivered on Jan. 2. Within hours the Ministry of Health in Beijing passed the letter to the Guangdong Department of Health. Yi's reputation as a virologist was such that the Guangdong government invited him to Guangzhou on Jan. 3 to make his case.

At noon that day, Yi met with some of the province's highest health officials. Every person in that room had lived and worked through the first-ever SARS outbreak, and many were clinicians who had watched patients wither, suffocate and die from the disease. Of these physicians, the most powerful was Dr. Zhong Nanshan, 67, director of the Guangzhou Institute of Respiratory Disease. Famous for having been a physician to China's late leader Deng Xiaoping, Zhong had also pioneered the earliest clinical treatments of SARS, emerging as the doctor most associated with fighting, and eventually defeating, the disease. He is the best-known doctor in the mainland--and the most intimidating. One World Health Organization (WHO) official described him as being "like a god."

Zhong was willing to hear Yi out, but where was his evidence? All they had, another public-health official explained, was this letter of warning, which, frankly, seemed a little hysterical. As the letter had been passed down from the Ministry of Health, somehow the four pages of genetic sequences, which provided the evidence backing up his assertions, had been lost. Yi called his laboratory in Hong Kong and had the documents e-mailed.

Yi's hosts were skeptical of the impetuous virologist, remembering that it had been Yi, in the early days of the first epidemic, who kept incorrectly insisting that SARS was a novel form of avian influenza. Even after the genetic sequences had arrived, his peers were unconvinced. "When someone is showing you raw data, you have to be careful," said Dr. Xu Ruiheng, deputy director of the Guangdong CDC. "You have to ask yourself, is this real or is this fabricated?" In turn, Yi asked his counterparts if they had the sequences for the human patient now recovering in Guangzhou No. 8 People's Hospital. They produced their documents. It turned out they had not yet analyzed this virus' phylogenetic origins, the RNA road map that would offer some understanding of how this particular strain would be related to those previously gathered. Yi suggested they send their sequences to his lab in Hong Kong, where his technicians and assistants were standing by to use their computer modeling programs to analyze the amino-acid sequences to reconstruct the evolutionary origins of this year's virus. That way, they would be able to compare the two and determine more precisely the real risk level. If the two phylogenetic trees were similar, Yi explained (and Zhong concurred), it would confirm that the disease was again afoot and, in this case, was certainly related to the wild-animal markets. The Guangzhou officials agreed. The new case's sequences were sent and the men drank tea and smoked while waiting for Yi's lab to complete the computer modeling.

The data that returned just an hour later revealed that the two viruses were more than similar: they were almost identical. The 14 amino-acid sequences concurred, which meant that the viruses not only belonged to the same phylogenetic tree, they were also both on the same branch--and practically on the same leaf. The virus that was in those wild-animal markets had somehow infected a human being. The data were so compelling that the committee resolved that afternoon to phone the provincial governor and recommend a culling of civets.

Zhong was the only one in that room with the clout to make the call. The situation was simple: the wild-animal business in Guangdong was estimated to be worth anywhere from $100 million to $200 million a year; the economic impact of another SARS outbreak, however, was immeasurable. Zhong called on Jan. 4 and later that day an order was issued to launch a campaign to eradicate civets from the province's farms and markets. By the next morning, said Peng Shangde, deputy director of the Guangdong Forestry Department, "we were staffed and the trucks were rolling."

Officials at the Guangdong CDC, while confident that culling the civets was necessary, are not totally convinced that it will curtail an outbreak. They have ordered a further extermination of rats--a much more elusive target--because of evidence that they carry a similar virus. Dr. Rob Breiman, an epidemiologist from the U.S. Centers for Disease Control and Prevention, is leading the WHO team currently tracing the origins of last year's epidemic in Guangdong. Breiman observes, "Everyone certainly thinks this is meaningful. But where is the civet cat in the chain? Are they getting it from another animal? Are civet cats infecting rodents as well as humans? We just don't know exactly where civet cats fit in." But he concedes, "From a political and public-health standpoint, it was a reasonable step in response to the re-emergence of SARS this year to act on the most likely source."

Yi's American mentor, Dr. Robert Webster of St. Jude's Children's Research Hospital in Memphis, Tenn., a pioneer in establishing the zoonotic origins of many influenzas, says, "The research is solid, but still, Yi has certainly stuck his neck way out there on this one." Yi, as usual, is dismissive of any doubts. Back in Hong Kong, he explains how the virus found in other animals such as badgers is genetically less similar to the strains found in humans, before vowing that culling civets "will break the chain of infection."

The incubation period for SARS is 14 days. The last civets were taken from the wild-animal markets on Jan. 6. By Jan. 20, if no new human cases emerge, we will have a very good indication if Yi, and the Guangdong government, made the right call. --With reporting by Jodi Xu/Guangzhou

With reporting by Jodi Xu/Guangzhou