News FocusSARS IN CHINA

China's Missed Chance

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Science  18 Jul 2003:
Vol. 301, Issue 5631, pp. 294-296
DOI: 10.1126/science.301.5631.294

Aggressive public health measures helped bring SARS under control, but Chinese scientists lost a unique opportunity to shine. Now, they're trying to make up

BEIJING—In mid-March, severe acute respiratory syndrome (SARS) began spiraling out of control. A doctor staying in room 911 of the Metropole Hotel in Hong Kong had infected 12 other people, who in turn had sown new cases around the planet. Shaken by the acute danger, officials at the World Health Organization (WHO) in Geneva issued a “global alert” on 12 March; 5 days later, they recruited 11 labs around the world in a joint, feverish hunt for the cause of the new disease.

What almost nobody knew was that in a well-equipped lab in southern Beijing, a group of virologists had already discovered a new virus in samples from some of the earliest patients. They had grown it in cell cultures and suckling mice and taken snapshots using their electron microscope. The virus, they had noticed, had a distinctive halo of spikes that put it in a family not known to kill humans: the coronaviruses. By the first week of March, the group had tentative evidence that the new virus might indeed be linked to the epidemic.

There was just one problem. They didn't dare tell the world.

At the time, the official line in China was that atypical pneumonia, as it was then called, was caused by a Chlamydia bacterium, says Yang Ruifu, a soft-spoken microbiologist and a member of the team at the Academy of Military Medical Sciences (AMMS) that discovered the coronavirus. Promoted by Hong Tao, an esteemed senior microbiologist and member of the Chinese Academy of Engineering, the Chlamydia hypothesis had become so well established that “it would not have been respectful” to challenge it, Yang says. Indeed, others say, the Ministry of Health had effectively banned alternative views.

CREDIT: BEI QING/CHINA FEATURESPHOTOS

And so the team did not seek media attention for its discovery; nor did it alert any of the labs in the WHO network. If the researchers had, they might have accelerated the collective odyssey by days, if not weeks, says Klaus Stöhr, the German virologist coordinating the WHO network. “These scientists were the first ever to see the SARS virus,” says Stöhr, who recently visited AMMS. “And we had no idea.” A call or an e-mail to Stöhr might also have ensured Yang and his colleagues a more prominent place in the history of the disease and perhaps even a publication or two in a prestigious scientific journal. “We were too cautious,” Yang now says ruefully. “We waited too long.”

China's attempts to sweep the SARS epidemic under the rug in the early months have been widely publicized, as has the subsequent all-out battle to rein in the disease—a battle that ended in victory on 24 June, when WHO officially declared the world's hardest hit country to be SARS-free. Less well known, however, is what took place in Chinese research labs as SARS emerged and what scientists plan to do now that the disease appears to be gone. Science talked to more than two dozen researchers, science administrators, and other experts in China in an attempt to piece together the scientific response to the outbreak.

Like the AMMS team, many scientists here are saddened at losing an opportunity to show off China's growing scientific prowess. Chinese scientists could have been the first to nail the pathogen, sequence its genome, and describe how it sickens its victims, they say. But as one researcher put it in a widely read newspaper story, they were “defeated” by foreign competitors. That failure, many note, stems in part from systemic problems in Chinese science: a lack of coordination and collaboration, stifling political influence, hesitation to challenge authorities, and isolation from the rest of the world.

But researchers are also determined to catch up. Today, many institutes are abuzz with SARS research projects, the Chinese government has embraced science as a key weapon against the disease, and science and technology minister Xu Guanhua is personally directing an ambitious research program that runs the gamut from epidemiology to developing drugs and vaccines.

The effort is being closely watched—and to some degree, guided—by WHO. Although SARS has vanished, urgent questions remain about its origins and spread. Some of the answers can be found nowhere but in China.

False leads

Like their peers elsewhere, Chinese scientists had trouble finding out anything about the mysterious disease plaguing the southern province of Guangdong early this year. The media hardly mentioned it, but from phone calls, e-mails, and Internet chat rooms, many suspected that something serious was going on. It wasn't until 11 February that provincial health authorities first announced the outbreak; by then, it had been quietly spreading for 2 months and had sickened more than 300.

Speculation about the cause erupted almost immediately. One local expert blamed a bacterium called Mycoplasma pneumoniae. Others put their money on avian influenza; about the same time, a man and his 9-year-old son from Hong Kong died from a bird flu strain named H5N1 after a trip to Guangdong.

Even the nation's premier public health agency, the Chinese Center for Disease Control and Prevention (CDC—not to be confused with its U.S. namesake in Atlanta) in Beijing, had trouble finding answers. Doctors and hospitals in Guangdong were reluctant to give up samples, says CDC director Li Liming. Nonetheless, a few came in, and a host of diseases—such as Legionnaire's and plague—were ruled out. Then on 18 February, Hong, a senior microbiologist at CDC's Institute for Virology, announced that he had found a suspect: He had seen what looked like Chlamydia bacteria in lung tissue from two deceased patients.

Frustrating wait.

At the Beijing Genomics Institute, Zeng Changqing (left) and Yu Jun were eager to sequence the virus but could not get their hands on it.

CREDIT: DING YIMIN/CHINA FEATURES

Chlamydia is notorious because the trachomatis strain causes a common sexually transmitted disease. Two relatives, however, can cause respiratory infections: C. pneumoniae is transmitted between humans, whereas C. psittaci is zoonotic, meaning that it jumps from animals, usually birds, to humans.

Even so, some people dismissed the Chlamydia idea almost out of hand. Zhong Nanshan, the director of the Institute for Respiratory Diseases in Guangzhou, Guangdong's capital, had fought SARS at the frontlines; he knew that antibiotics didn't work against the disease, so a bacterium seemed highly unlikely. Some virologists within CDC and its provincial counterpart in Guangdong were also skeptical.

The evidence was never very strong. In a paper in the 25 April National Medical Journal of China, Hong reported having found “Chlamydia-like particles” in a total of seven patients. (In two, he also noted the presence of a coronavirus, which by then had been proven to be the cause of SARS.) But he was not able to actually isolate the microbe or characterize it further, and Chlamydia was not found in most SARS patients. Moreover, antibodies to known Chlamydia species did not react with the tissue samples. Hong therefore proposed that the agent was a new type of Chlamydia, but others suggested that it may have been something different altogether.

Nevertheless, Chlamydia became the dominant theory. In hindsight, CDC director Li puts part of the blame on the media, which reported as fact what was just a hypothesis. But others say his agency and the ministry of health effectively shut down the discussion. “They prevented others from expressing their views,” says Chen Zhu, vice president of the Chinese Academy of Sciences (CAS) and vice chair of the national SARS science task force. “They closed the doors and only thought about Chlamydia,” says Henk Bekedam, head of WHO's Beijing office.

As a result, few researchers joined the search, and those who wanted to continued to have a hard time obtaining samples. Researchers at the Beijing Genomics Institute (BGI), for example, who had recently made a name for themselves sequencing the rice genome, were eager to help. BGI's deputy director Wang Jian flew to Guangdong several times during the early outbreak, only to come back empty-handed. “It was pretty hopeless,” says his colleague Yu Jun.

Still, researchers at AMMS—the Chinese equivalent of Walter Reed—did manage to get in early. A team at AMMS's Institute of Microbiology and Epidemiology, led by Zhu Qingyu and Qin Ede, specializes in pathogen detection; team members eagerly told Science the steps they took to try to nail the agent, and when. On 14 February, they say, AMMS researchers returned from Guangdong with a few coveted patient samples they had obtained from military hospitals. By 22 February, they had managed to grow a virus of some sort from the samples in so-called vero cells. And on the 26th—more than 2 weeks before WHO issued its global alert—they observed what looked like coronavirus particles in an electron micrograph.

They saw it first.

Yang Ruifu (left) and Zhu Qingyu had pictures of the new coronavirus (top) on 26 February—but they kept quiet about it.

CREDITS: (TOP) WANG CUIE/AMMS; (BOTTOM) ZHAI JUNHUI/AMMS

That in itself didn't prove anything. Similar hunts turn up all kinds of pathogens, says WHO's Stöhr, because people carry any number of microbes with them. But in the first week of March, weeks ahead of researchers at the University of Hong Kong, Yang says, the team also discovered that serum from SARS patients could inhibit the growth of the virus—a key test to show a correlation between an isolated agent and a disease. But because the AMMS team had serum from only a few patients, it didn't feel confident enough to challenge the accepted wisdom. “We wanted to be very sure,” says Yang. “Dr. Hong Tao is very famous in China. We had to show respect.”

By 17 March, SARS had exploded into a global problem, and teams in Stöhr's network, which at the time didn't include any from mainland China, had started holding daily teleconferences, posting their findings on a secure Web site, and sending each other samples and reagents by overnight delivery. They worked at breakneck speed; by 24 March, they had fingered the coronavirus, and 3 weeks later, they showed that it could cause SARS-like symptoms in monkeys, fulfilling the last criterion for nailing down a new infectious agent. But looking back, says Stöhr, had the AMMS researchers reported their findings immediately, the larger group might have been on the right trail much sooner.

Within China, the international consensus about the coronavirus theory did not receive a warm welcome. In March, bolstered by WHO's daily reports and new, more solid data of their own, AMMS scientists reported their findings to the Ministry of Health. But the department stuck to the Chlamydia theory. When Bi Shengli, a virologist at CDC, announced in an 11 April newspaper story that his work confirmed the implication of the coronavirus, he was rebuked by the department, which set up a working group the next day to control publicity about SARS pathogen studies.

Stamped out.

Doctors and nurses in Beijing celebrate the success of China's battle against SARS, as does a special postage stamp.

CREDITS: (TOP) LIU YU/CHINA FEATURES PHOTOS; (BOTTOM) CHINA FEATURES PHOTOS

The impasse contributed to another lost opportunity. At BGI, scientists were becoming increasingly frustrated at not being able to flex their sequencing muscle on the new pathogen. The official reason was that safety regulations banned transfers of the virus. BGI researchers also suspected other labs of holding on to the virus so they could sequence it themselves. “It's like you have a lawnmower in your hand,” says Yu, “but other people are trying do the job with paper cutters.”

Finally, in the second week of April, researchers say the mood began to shift. On 14 April, the safety regulations were lifted, says BGI director Yang Huanming. That same night, AMMS researchers shipped viral RNA samples to BGI, and at 2 a.m. the sequencers started spitting out genetic letters. But by then, the BGI researchers knew they, too, had already lost the race. A day earlier, a group at the BCCA Genome Sciences Centre in Vancouver, Canada, had posted the entire genome sequence online. BGI spelled out the genomes of four different SARS virus isolates and posted them on GenBank on 16 April.

A new wind

Eventually, researchers at AMMS and BGI were vindicated. On 20 April, health minister Zhang Wenkang and Beijing Mayor Meng Xuenong were fired for their mishandling of the SARS epidemic, and the government pledged an all-out fight against the disease. That morning, Chinese President Hu Jintao visited AMMS and praised the lab's work; in the afternoon, Hu's motorcade headed to BGI to learn about the sequencing project.

On the public health front, the fight has been remarkably successful, and in the research labs, the atmosphere continues to improve. A national SARS science task force, chaired by Xu, has united experts from different ministries and science organizations. Together, they decided to initiate 95 research projects, funded at more than $13 million—which, in China, goes a long way. Many institutes are devoting their own resources as well. “SARS may be gone, but the research is just beginning,” says Liu Qian, executive vice president of the Chinese Academy of Medical Sciences.

Liu's academy, which includes four hospitals in Beijing, is screening drugs, developing vaccines, and trying to develop new animal models. So are many other groups. Also on the research agenda are physical protections against the virus—such as suits and masks—and mathematical models of epidemic.

Some are already getting results. At Tsinghua University in Beijing, Rao Zihe, a structural biologist who returned to China in 1996 after 7 years in Oxford, has temporarily devoted his lab to SARS. (“China had patient number one, death number one,” Rao says, shaking his head. “Publications? Zero.”) To fire up his employees, he divided them into two competing groups. Now Rao, who also heads the CAS Institute for Biophysics, says he has solved the structure of the SARS virus's main protease—a step that could aid the development of SARS drugs.

Focus on the virus.

Rao Zihe solved the structure of a SARS protein.

CREDIT: M. ENSERINK

Many of these studies could be carried out anywhere in the world. But as the cradle of SARS and the hardest-hit country, China also has the potential to answer specific questions crucial in preventing a resurgence. During the past 3 weeks, WHO's Stöhr has been visiting China to help ensure that those answers are found. Among his top priorities is the hunt for an animal reservoir, which has so far yielded confusing results, in part because the two leading teams are barely on speaking terms (see p. 297).

There are key epidemiological riddles as well. How many of the “suspected” and “probable” cases reported really had SARS? Which of the control measures in China—from face masks and “fever clinics” to roadblocks—helped stem the epidemic so effectively? And why was China's mortality rate, at 6.5%, much lower than in other countries? Perhaps the disease was overreported here, Stöhr says, but the Chinese may also have treated patients differently, in which case their experience may save lives if SARS returns.

To answer these questions, Chinese scientists and clinicians will have to collaborate much more than they usually do, Xu says. For example, a new panel led by Zhong will make sure that valuable tissue samples, scattered in hospitals, are properly shared. So far, Chinese scientists—traditionally distrustful of each other—seem to like this new atmosphere, says David Ho, scientific director of the Aaron Diamond AIDS Research Center in New York City, who is cooperating with Chinese scientists on several SARS projects and co-chaired a meeting in Beijing last week. The SARS crisis may also give a boost to the sorely neglected fields of life sciences and public health, says CAS vice president Chen. China needs a central body that sets biomedical research policy and doles out funds, like the U.K. Medical Research Council, says Chen. In addition, “Chinese officials now realize they must reform the CDC,” says Ho, who has met with Xu several times. “It was simply ineffective.”

Hong, meanwhile, says he is still trying to find out whether a Chlamydia infection may have played a role in some SARS patients. But in a brief interview with Science, Hong admitted that the coronavirus is the true villain in SARS.

For Ho, who was born in Taiwan and became a scientific star in the United States, the rise and fall of Hong's theory offers yet another valuable lesson. “The Chinese give way too much respect to the opinion of teachers or elderly individuals,” he says. “Younger scientists should learn to challenge authority a little more when the data do not fit.” That's a lesson China has now learned the hard way.

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