News this Week

Science  15 Mar 2013:
Vol. 339, Issue 6125, pp. 1258
  1. Around the World

    1 - Atacama Desert, Chile
    ALMA Unveiled
    2 - Arlington, Virginia
    Audit Flags Alleged Plagiarism in Funded NSF Proposals
    3 - Naples, Italy
    Calls to Rebuild Burned Science Museum
    4 - Bangkok
    Bid to Restrict Polar Bear Trade Fails

    Atacama Desert, Chile

    ALMA Unveiled

    CREDIT: ALMA (ESO/NAOJ/NRAO), J. GUARDA (ALMA)

    The world's biggest telescope held its inauguration ceremony this week on a high desert plateau in northern Chile. Nearly all the 66 antennas that make up the Atacama Large Millimeter/submillimeter Array (ALMA) are now receiving data at the telescope site 5000 meters above sea level. The telescope, built at a cost of more than $1.3 billion, will help astronomers study the cold universe at wavelengths that fall between microwaves and infrared light. Observing in that part of the electromagnetic spectrum will enable researchers to gain new insights into the origins of stars, galaxies, and planets.

    Funded by the United States, Japan, and Europe, ALMA began delivering science long before its 13 March inauguration ceremony, discovering that certain galaxies in the infant universe went through a phase of intense star birth more than 12 billion years ago. The finding, reported in Nature this week—and based on observations made by only 16 antennas—suggests that the universe became a fertile birthing ground for stars long before when was previously thought.

    Arlington, Virginia

    Audit Flags Alleged Plagiarism in Funded NSF Proposals

    The National Science Foundation (NSF) is investigating nearly 100 cases of suspected plagiarism drawn from a single year's worth of proposals funded by the agency.

    The cases were spotted in an internal examination by NSF's Office of Inspector General (IG) of every proposal that NSF funded in fiscal year 2011. The use of plagiarism software on some 8000 awards made that year resulted in a "hit rate" of 1% to 1.5%.

    Plagiarism is one of three categories, along with fabrication and falsification, recognized as research misconduct by federal research agencies. NSF IG Allison Lerner told a congressional panel recently that the number of "substantive allegations of misconduct associated with NSF proposals and awards … has more than tripled in the past 10 years, as has the number of findings of research misconduct." She said her office has issued 120 findings of research misconduct since 2003 and that "more than 80%" involved plagiarism. http://scim.ag/NSFplag

    Naples, Italy

    Calls to Rebuild Burned Science Museum

    CREDIT: CONTROLUCE/AFP/GETTY IMAGES

    The Città della Scienza (City of Science) complex in Naples, including a 12-year-old interactive museum and an education and conference center, went up in smoke last week. The fire took hours to extinguish; just one of the museum's buildings survived. Calls for rebuilding began almost immediately, and by late last week the Italian Ministry of Economic Development, Infrastructure and Transport, the Ministry for Territorial Cohesion, the local government, and the mayor of Naples agreed on a plan to make available €20 million for its reconstruction, according to an article in Italy's La Repubblica. Several online campaigns for money to rebuild, including a crowdsourcing effort by the social platform DeRev and the online platform Cambiomerci, have received pledges to contribute both money and expertise to help the complex resume its activities. The origin of the fire is now under investigation. The Italian media is reporting growing suspicions of arson as the cause.

    Bangkok

    Bid to Restrict Polar Bear Trade Fails

    CREDIT: KIM HANSEN/WIKIMEDIA COMMONS

    With melting habitats, polar bears are in danger of extinction; hunting and trade in body parts also pose a threat. But last week, delegates to the Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES) meeting in Bangkok voted down a motion, proposed by the U.S. Department of the Interior, to restrict trade in polar bear parts. The motion failed with 38 votes for, 42 against, and 46 abstentions.

    Polar bears are currently listed on CITES's Appendix II, which means that countries that export body parts must vouch that the animals were legally killed and that the deaths will not harm the survival of the species. The United States and Russia, which both already ban sales within their borders, proposed to shift polar bears from Appendix II to I, which is stricter, outlawing commercial trade in the species.

    The other three countries that have polar bears—Canada, Greenland, and Norway—opposed the additional protection. The Canadian delegation argued that the extent of trade does not endanger the species and that banning trade could boost the price of trophies, perhaps leading to illegal hunting. The World Wildlife Fund also did not support the change in listing. http://scim.ag/polbear

  2. Random Sample

    ScienceLIVE

    Join us on Thursday, 21 March, at 3 p.m. EDT for a live chat on emerging diseases. Ten years after SARS, are we better prepared? http://scim.ag/science-live

    You Are What You Like

    Like smart.

    High IQs correlate to "liking" curly fries, Morgan Freeman's voice, The Colbert Report, thunderstorms, Mozart, and science.

    CREDIT: © FACEBOOK; JOSEPH KACZMAREK/AP PHOTO; CHRIS PIZZELLO/AP PHOTO; BRAND X PICTURES/THINKSTOCK; NASA/JPL; WIKIMEDIA COMMONS (2)

    Every day, millions of people click on Facebook "Like" buttons, declaring preferences for books, movies, and cat videos. But likes may reveal much more, including sexual orientation, drug use, and religious affiliation, according to a study that analyzed the online behavior of 58,000 Facebook users.

    To get data on personal attributes for comparison with the likes, a team of psychologists at the University of Cambridge in the United Kingdom created a Facebook app called myPersonality. After agreeing to volunteer as a research subject, app users answer questions and take psychological tests that measure things such as intelligence, competitiveness, extraversion versus introversion, and general satisfaction with life. With those data, and data from the user's Facebook profile and friends network, the researchers built a statistical model that predicted personal attributes based on likes.

    It turns out that likes can predict many private details, the team reported on 11 March in the Proceedings of the National Academy of Sciences. The most accurate predictions were for gender (93%) and race (95%) (Caucasian versus African-American). But likes also accurately predicted more sensitive attributes: homosexuality (88% for men, 75% for women); religion (82%); political party membership (85%); and even use of cigarettes, alcohol, and drugs (73%, 70%, and 65%, respectively). Some predictions for likes make intuitive sense, such as "Jesus" for Christians and "Glee" for gay men. But others are harder to explain, such as the strong association between liking curly fries and having a high IQ. "What was traditionally laboriously assessed on an individual basis can be automatically inferred for millions of people without them even noticing," says lead author Michal Kosinski, "which is both amazing and a bit scary."

    Noted

    What life might lurk in Lake Vostok remains a mystery. Days after Russian scientists announced a new species of bacteria found in water collected from the subglacial Antarctic lake, that discovery was negated—by another member of the team. Geneticist Vladimir Korolyov of the St. Petersburg Nuclear Physics Institute said the bacteria weren't denizens of the lake but were mostly in the drilling fluid.

  3. Newsmakers

    Scientist Enters Italian Senate

    Capua

    CREDIT: E.U.

    Virologist Ilaria Capua, of the Istituto Zooprofilattico Sperimentale delle Venezie in Legnaro, Italy, will enter the Italian parliament this week for the first time as a newly elected deputy for the Civic Choice party. The party is led by outgoing Prime Minister Mario Monti, who asked Capua to join his crew for her commitment to meritocracy and transparency and for her expertise in science and public health.

    The offer came at the right time; Capua had been considering leaving Italy, as her current laboratory space is not sufficiently equipped to continue her group's research projects. "His call came on the sixth of January, after I had spent my Christmas holidays looking for a place abroad where I could go working," Capua says. She hopes her new role as a politician could also help prevent other scientists from going abroad.

    Marrett to Fill in at NSF When Suresh Leaves

    Cora Marrett will become acting director of the National Science Foundation (NSF) when Subra Suresh steps down on 22 March to become president of Carnegie Mellon University.

    Marrett

    CREDIT: PHOTO BY SAM KITTNER/KITTNER.COM FOR NSF

    It's a familiar drill for Marrett, 70, a sociologist and longtime academic administrator. She kept the trains running between the departure of former NSF Director Arden Bement in May 2010 and Suresh's arrival that October, and has held the deputy director's job for nearly 4 years. Before that, she ran NSF's education programs and, in the 1990s, its social and behavioral sciences directorate.

    Several former NSF directors would like to see her considered for the real job. "They couldn't do any better than to nominate Cora," says John Slaughter, an engineer who led NSF in the early 1980s. "She's helped to define the agency's programs in several areas." Neal Lane, a physicist who headed NSF in the mid-1990s, calls her "smart, dependable, and organized. I'm very high on her."

  4. War Stories

    1. Martin Enserink

    In 2003, the world successfully fought off a new disease that could have become a global catastrophe. A decade after the SARS outbreak, how much safer are we?

    CREDIT: CHRISTIAN KEENAN/STRINGER/GETTY IMAGES

    GENEVA, SWITZERLAND—What were they going to call it? That was the final question for a small group of men huddling in a room here at the headquarters of the World Health Organization (WHO) on the morning of Saturday, 15 March 2003. They were about to issue a second global alert on a serious new disease that was spreading rapidly, and it needed a name.

    Three days earlier, WHO had warned about the illness, known simply as "atypical pneumonia," for the first time. Then, it was known to have occurred in mainland China, Hong Kong, and Vietnam. Now, there were suspected cases in Canada, Singapore, Thailand, Indonesia, and the Philippines. And at 2 a.m. that Saturday, WHO epidemiologist Michael Ryan had learned that a Singaporean doctor who was likely infected with the disease was on his way home from New York; he would be taken off the plane during a stopover in Frankfurt. A new statement, in which then-WHO Director-General Gro Harlem Brundtland described the disease as a "worldwide health threat," was about to be sent to the press.

    "We had to give the disease a name," says David Heymann, then WHO's executive director of communicable diseases. "If we hadn't, the media might have come up with something stigmatizing like Chinese flu." Heymann wanted a name that rolled off the tongue easily—something like AIDS.

    Dick Thompson, a former science reporter for Time who joined WHO as a press officer in 2001, says he eventually coined "severe acute respiratory syndrome" based on what they knew so far. It worked well as an acronym, he said. The alert went out later that morning. The first global health threat of the 21st century had a name: SARS.

    In the following months, just over 8000 people in almost 30 countries were infected with SARS, and 774 died. Initially, it seemed that SARS might be unstoppable—that it would sweep the globe and infect millions. But aggressive countermeasures by health care workers, public health officials, and scientists put the genie back into the bottle—not using a drug or a vaccine, but simply by preventing patients from infecting others. By 5 July, it was all over.

    The two alerts were issued a decade ago this week. To mark the occasion, Science asked many of the key players at WHO, as well as public health agencies and research labs, about what happened—and about the lasting lessons they learned from those frightening months. Many said that SARS was the most dramatic episode in their career; a time of 18-hour workdays, anxiety, and the occasional fight—but also of courage, unprecedented collaboration, and scientific excitement. Some said it resembled a war and called the SARS virus "the enemy."

    Umesh Parashar, an epidemiologist at the U.S. Centers for Disease Control and Prevention (CDC) in Atlanta, helped battle SARS in Hong Kong. Parashar had investigated the U.S. anthrax attacks in 2001 and would work on the influenza pandemic in 2009; neither matched SARS "in its intensity and sheer enormity," he says. Among his most vivid memories: entering a meeting room at Hong Kong's Prince of Wales Hospital, which had a big SARS outbreak, and seeing everybody wearing masks. "I had never had that sense of personal vulnerability," he says.

    David Heymann, Centre on Global Health Security at Chatham House

    "We had to give the disease a name. If we hadn't, the media might have come up with something stigmatizing line Chinese flu."

    CREDIT: U.K. HEALTH PROTECTION AGENCY

    As to SARS's legacy, many agree that the world is better prepared today for the emergence of infectious diseases that have the potential to go global. Disease surveillance has improved, and scientific advances make it easier to fish an unknown pathogen from a sample and characterize it. SARS also spurred the introduction in 2005 of new international rules on how to report and handle disease threats. The outbreak drove home that the world is an awfully small place, and collaboration is essential.

    At the same time, many countries lack the ability to detect a breakaway virus early on, and producing new vaccines quickly is still difficult for almost any disease. Although SARS painfully demonstrated that sweeping an epidemic under the rug, as China tried to do, is counterproductive, few people believe that this age-old reflex won't occur again.

    The recent emergence of a distant cousin of SARS on the Arabian Peninsula has highlighted some of the remaining problems. After the first case, it took 3 months for information about the new virus, now named NCoV for novel coronavirus, to come out. Many questions remain about where it came from, how it got into humans, and its potential to spread—and they "probably aren't pursued aggressively enough," says virologist John Mackenzie of Curtin University, Bentley, in Australia, who led a WHO mission to Beijing when SARS was exploding there.

    The SARS outbreak didn't start in March 2003. Scientists later discovered that the first known case, in November 2002, was a 45-year-old man in Foshan, a city in the southern Chinese province of Guangdong. Studies would also show that the virus originated in bats and infected humans most likely through animals traded in China's wild animal markets.

    The provincial government initially banned the press from writing about the disease and downplayed its significance; an official bulletin issued on 11 February finally acknowledged 305 cases, including five deaths, but said the outbreak was under control. In neighboring Hong Kong, experts were "very concerned," says University of Hong Kong virologist Malik Peiris. "If something untoward was happening across the border, it would come to Hong Kong pretty quickly."

    And it did. Hong Kong became the virus's springboard to the globe on 21 February, when a 64-year-old nephrologist from Guangzhou, the capital of Guangdong, checked into room 911 of the Metropole Hotel in Kowloon. He went to a nearby hospital the next day with severe pneumonia. At least 16 other hotel guests and a visitor became infected and they carried the disease to 3 new countries (see sidebar, p. 1272). In Geneva, WHO had an experienced team to respond. Heymann, an American epidemiologist who today heads the U.K. Centre on Global Health Security at Chatham House and is a professor at the London School of Hygiene and Tropical Medicine, had helped eradicate smallpox in India and had battled many diseases in Africa; in 1995, he led WHO's response to the largest Ebola outbreak until then, in Kikwit, in what was then Zaire. Guénaël Rodier, a Frenchman and WHO's then-director of communicable disease surveillance, had an equally international resume and had worked alongside Heymann in Kikwit.

    Now, as they were coordinating a global response from their desks in the tidy city of Geneva, their collective field experience was essential, says Ryan, an energetic Irishman and a junior member of the team. "You're not just sitting there clicking buttons and looking at things on screen," he says. "When you talk to national authorities or to people in hospitals, they know: This person knows my situation. They've been there."

    In several ways, the international health community was only half prepared. Heymann's team was convinced that a new pandemic disease could emerge; to help identify and respond to such threats, they had already set up the Global Outbreak Alert and Response Network, consisting of institutes and labs around the world. Health Canada had set up a system called GPHIN that allowed WHO to monitor a wide range of online sources, including news outlets, for anything suggesting unusual disease patterns. (It was initially called the "rumor list," Rodier says.)

    Malik Peiris, The University of Hong Kong

    "If something untoward was happening across the border, it would come to Hong Kong pretty quickly."

    CREDIT: THE UNIVERSITY OF HONG KONG LI KA SHING FACULTY OF MEDICINE

    At WHO's helm, Brundtland, a former Norwegian prime minister, backed the new, more activist role for the U.N. agency, but it raised hackles among member states, who were used to reporting such information in their own time. "Countries would scream at us," Ryan recalls. "We would pick up an event in the media, and go to a country and say, 'Look, what's happening?' They would ask us: 'What right do you have?' "

    WHO was also hamstrung by the existing legal framework. An agreement last revised in 1969, the International Health Regulations (IHR), spelled out how countries should report and handle diseases that can cross borders, but it was outmoded and ineffective; for one, it only covered plague, cholera, and yellow fever. As a result, there was nothing that compelled China, or any other country, to tell the rest of the world what was happening within its borders early in 2003.

    Henk Bekedam, a tall, outspoken Dutchman who led the WHO office in Beijing at the time, experienced the problem firsthand. At first, WHO believed that the Guangdong outbreak might be the start of a pandemic of the avian flu virus H5N1—a few cases were detected in February in humans in Hong Kong—or it might be something completely different. WHO pressed China to find out more, but little information was forthcoming.

    In late February, Bekedam received help from a three-member mission of foreign experts: Hitoshi Oshitani of WHO's regional office in Manila; Keiji Fukuda, then at CDC in Atlanta; and Masato Tashiro from Japan's National Institute of Infectious Diseases. But the trio couldn't get an appointment with Chinese health officials. After spending 9 days at WHO's Beijing office, Oshitani and Fukuda finally met with the China CDC, Bekedam says, but they learned little and were denied a trip to Guangdong. Even after SARS was acknowledged as a new disease, Chinese officials long downplayed its extent.

    All of that changed when new leadership—Hu Jintao took over as China's president on 15 March—realized the problem was too big to hide or neglect. On 20 April, Chinese Health Minister Zhang Wenkang and Beijing Mayor Meng Xuenong were dismissed. Hu started championing the fight, and China began opening up to WHO. "From that moment, you couldn't work with a better country," Bekedam says. "It was very impressive."

    Ten years on, the world's most populous country has made major strides in public health, improving its surveillance and expanding its laboratory capacity, says Bekedam, who left Beijing in 2007 and now works in WHO's regional office in Manila. Peiris says that China's labs have "improved dramatically over the last 10 years."

    But the most important consequence of SARS, many say, was that it made clear the inadequacies of the IHR. In 2005, the World Health Assembly adopted a revision of the IHR that took effect in 2007, requiring countries to report within 24 hours anything that "may constitute a public health emergency of international concern"—including unknown diseases. Each country must have the ability to detect such threats and assess their risk. The rules also allow WHO to follow up on informal reports about diseases—thus giving the "rumor list" a formal basis.

    But implementation has lagged. More than 100 countries did not meet the June 2012 deadline for establishing the necessary surveillance and lab capacity and had to ask WHO for a 2-year extension. Among the least prepared are poor countries with high biodiversity that are also seen as a likely cradle for new pathogens. Money is a key problem.

    "There was supposed to be a massive investment in national and international public health infrastructure," after the revision of the IHR, Ryan says, "and I don't think we have seen that yet. It's one thing to set in motion a set of rules; it's another thing to create the infrastructure you need." Ryan left WHO in 2011 to become an adjunct professor of international health at University College Dublin, in part because he was frustrated by a shifting culture at WHO that he characterizes as more about "discussion, discussion, and discussion" than about getting things done.

    Pascale Brudon, the French head of WHO's Hanoi office, had more luck convincing the Vietnamese government that SARS was a problem. And the outbreak there, with only 63 cases in total, taught the world some key lessons about the disease early on.

    On 27 February, doctors at the French hospital in Hanoi asked Carlo Urbani, a parasitologist in the WHO office, to look at an unusual case: a Chinese-American businessman who suffered from severe pneumonia with an unknown cause. Within days, hospital staff members were falling ill as well. Urbani—a "very Italian" man, Brudon says, who loved wine, food, music, and life in Hanoi—was worried, and he sent a report to the WHO office in Manila on 3 March.

    Pascale Brudon, Retired from WHO, Hanoi

    "If you want to do something good for Vietnam and the world, you should take this seriously because it may be very important."

    CREDIT: M. A. CIPRUT

    Soon, staff members at the French hospital started falling ill. The Vietnamese government "considered it a private problem in a private hospital," says Brudon, who is now retired and living in Paris. In a 4-hour meeting on Sunday, 9 March, she and Urbani tried to convince Vice-Minister of Health Nguyen Van Thuong that it wasn't. "If you want to do something good for Vietnam and the world, you should take this seriously," Brudon recalls telling him, "because it may be very important." Finally, Nguyen promised to inform the prime minister, set up a task force, and ask for foreign help.

    Urbani became one of the heroes in the SARS story, because he helped raise the alarm at WHO. Until then, the new disease appeared to be confined to Guangdong and Hong Kong; now, it was clear that it had spread further. (The American businessman was one of the guests on the ninth floor of Hong Kong's Metropole Hotel.) "Vietnam was the trigger" for the first alert on 12 March, Heymann says.

    On 12 March, Urbani traveled to Bangkok, where he was scheduled to give a presentation at a parasitology meeting. He called Brudon before boarding a plane in Hanoi to say he wasn't feeling well and was considering canceling the trip. "I told him to go—he had wanted to go to this meeting," Brudon says. "I said he was probably just tired. We were all exhausted." But after Urbani had boarded the plane, she started worrying, and she called the WHO office in Manila, which helped arrange an ambulance to pick him up at the Bangkok airport. It was soon clear that he had the as-yet unnamed new disease.

    Brudon had a few phone calls with Urbani in the following days, but he deteriorated rapidly and died on 29 March. "We were all devastated," she says. Colleagues streamed into WHO's office that Saturday, Brudon says; there were flowers, photos, and music. "We all drank too much."

    SARS was an extraordinarily dangerous disease for health care workers; they accounted for more than one-fifth of all cases. Doctors and nurses weren't used to such high infection risks, and interventions such as intubation of the trachea and the use of drug nebulizers exacerbated them because they set loose virus-laden aerosols. "We learned that health care is part of the solution, but it can also amplify the problem," Ryan says.

    WHO started to advocate the kind of rigorous infection control that it had used during the viral hemorrhagic fever outbreaks in Africa, including strict isolation of the patient and the use of gloves, gowns, surgical masks, and protective eyewear. "We realized quickly that the measures used to stop the spread of Ebola and Marburg worked for SARS as well," Rodier says.

    As the weeks passed, it became clear that other measures could help curtail the virus in the community at large. There were a few so-called superspreading events, such as the Metropole Hotel outbreak and a big outbreak in Amoy Gardens, a Hong Kong apartment complex. But most SARS patients infected few others. If public health systems were able to find and isolate suspected cases early, and if they could quarantine the people they had been in touch with, they might be able to stop the virus.

    Vietnam became the first country to show that this strategy could work; on 28 April, WHO declared it SARS-free, inspiring hope that the virus could be wiped out worldwide. "When Vietnam was able to stop transmission, we knew it was possible," Heymann says.

    Within days after the initial alerts, WHO's modernist headquarters in Geneva became the center of a virtual conference room that spanned the globe. The agency set up networks of doctors treating SARS patients to exchange information and of epidemiologists assembling and analyzing data on the virus's spread. A third network consisted of virology labs that joined hands to find the cause of SARS—a very unusual arrangement for the competitive field (see p. 1269). Led by Klaus Stöhr, a German epidemologist in charge of WHO's influenza network, the effort "was pretty phenomenal," says Larry Anderson, who was at CDC at the time and is now at Emory University in Atlanta. Peiris says it's a model for similar crises in the future.

    Yet in the end, 21st century lab science had little impact on the fight against SARS; the disease was stopped using 19th century hygiene measures. Diagnostic tests developed soon after the virus was isolated weren't needed to manage the outbreak, and the sequence, completed by Canadian scientists on 12 April, had little direct impact. Scientists launched programs to develop antivirals and vaccines against SARS—and some of the work is still going on—but they never came to fruition; the direct need for them disappeared in July 2003, when the epidemic was declared over.

    Today, identifying and characterizing a new agent takes much less time, says virologist Christian Drosten of the University of Bonn in Germany. High-throughput sequencing allows researchers to pull out an infectious agent from a patient sample without culturing it first. Sequencing SARS would now take hours, not weeks, and diagnostic tests can be developed much faster, Drosten says.

    But although the science may be better, many of the social issues remain the same. No country likes to admit having a new health threat within its borders, especially when the economic and political consequences can be huge. The situation with the new NCoV has driven that point home.

    To Maria Zambon, a virologist at the United Kingdom's Health Protection Agency whose lab identified four NCoV cases, the parallels with SARS are striking: Here's another coronavirus that can cause severe disease and can spread from one person to another. So far, it does not appear to do so very efficiently, but Zambon is concerned nonetheless. "It could become as much a threat as SARS," she says.

    And again, similar questions have arisen, starting with the timeliness of the reporting. News about the NCoV virus was reported on ProMED, an internet service providing outbreak news, on 20 September 2012, by Ali Mohamed Zaki, an Egyptian microbiologist working in a hospital in Jeddah, Saudi Arabia. Zaki identified the virus in June in a man who died of pneumonia and shared samples with Ron Fouchier of Erasmus MC in the Netherlands, who sequenced it.

    Accounts differ on why 3 months passed between the discovery and the ProMED report. Fouchier says that Zaki notified the Saudi government of the finding and urged reporting it to WHO; only when Saudi officials refused did he send the e-mail to ProMED, Fouchier says. (Zaki did not respond to questions from Science.) But Ziad Memish, Saudi Arabia's deputy minister for public health, says that Zaki never told the government anything. "We were surprised to hear about this whole thing from ProMED," Memish tells Science.

    The sequence of the virus is closely related to those of other viruses found in bat species, and researchers assume that the new virus also originated in bats. So far, 14 people have been found to be infected with the virus, eight fatally. Seven came from Saudi Arabia, two from Qatar, two from Jordan, and in February, the United Kingdom reported three cases in people residing there. One of them had traveled to the Middle East and Pakistan, but the others had not, suggesting that the virus can spread between humans.

    But many questions remain, and Fouchier says they're not being answered fast enough. The fact that five of the cases were diagnosed in Europe means there must be unrecognized cases in the Middle East, he says; a program of antibody testing could reveal how many and yield more information on how the virus spreads. If bats are indeed the virus's reservoir, it's important to know how it got into humans. Infected bat urine or feces may have ended up in human food, for instance, but it's also possible that there is an intermediate host—for instance some farm animal. Surveys of goats, camels, cattle, and other domestic animals could quickly confirm or rule out these species as carriers.

    Guénaël Rodier, WHO, Copenhagen

    "We realized quickly that the measures used to stop the spread of Ebola and Marburg worked for SARS as well."

    CREDIT: WHO

    Memish says Saudi Arabia is working to answer these questions, but that will take time; for instance, there aren't sufficiently reliable antibody tests at the moment. Fouchier disagrees. "You can answer a lot of these questions within a month," he says. WHO held a meeting in Cairo in January to discuss the new virus with experts from the region and established labs elsewhere; Fouchier, who attended, says the meeting's goal of more international collaboration has not panned out. His own lab has offered technology, expertise, and training free of charge, he says, but there have been no takers. Drosten has had the same experience. WHO is less proactive than it was during SARS, Fouchier adds: "It's all handled much more cautiously."

    Fukuda, who is now WHO's assistant director-general for health, security, and environment, chaired the Cairo meeting. He says that his own experience—including the frustrating 2003 visit to Beijing—has taught him to be patient. "In an ideal world, yes, we would have all the primary questions answered really quickly," Fukuda says. "But I accept it takes time for some of this information to come up." But the time for studies is now, Drosten says: NCoV may be only weakly transmissible between humans, but if it's circulating at low levels, it may evolve to become more adept at jumping from person to person: "For a virus, every day in the human host is a new day full of experiments."

    Stöhr, who left WHO in 2007 and is now vice-president of Novartis Vaccines and Diagnostics, says WHO is in a difficult position. "Do you want to be criticized for overreacting, or do you want to be criticized at the end, when things have gotten out of hand, for not having gone far enough?" Given everything that happened 10 years ago, Stöhr says the former is probably the safer option.

  5. SARS: Chronology of the Epidemic

    1. Martin Enserink

    In 2003, the world successfully fought off a new disease that could have become a global catastrophe. Here's what happened from the first case to the end of the epidemic.

    November 2002–July 2003

    16 November

    CREDIT: ADAPTED FROM WIKIMEDIA COMMONS

    First known case of SARS, not identified until much later in Foshan of Guangdong Province, China.

    23 January

    Guangdong Health Bureau sends official document on atypical pneumonia to provincial health bureaus and medical institutions.

    30 January

    Seafood seller in Guangzhou infects more than 50 hospital staff members and 19 relatives, the first known "superspreading event."

    10 February

    World Health Organization's (WHO's) Beijing office receives e-mail warning of a "strange contagious disease" in Guangdong.

    11 February

    Guangdong officials report 305 cases and five deaths of acute respiratory syndrome between 16 November 2002 and 9 February 2003.

    14 February

    The Chinese Ministry of Health informs WHO that the Guangdong outbreak is under control.

    21 February

    A Guangdong physician falls ill in Hong Kong's Metropole Hotel. Other guests carry SARS to Hanoi, Singapore, and Toronto.

    26 February

    A Chinese-American businessman from New York who stayed at the Metropole Hotel is admitted to the French Hospital in Hanoi.

    3 March

    Carlo Urbani examines the Hanoi case and notifies WHO's regional office in Manila of unusual disease.

    7 March

    Health care workers at Hong Kong's Prince of Wales Hospital start falling ill.

    CREDIT: AP PHOTO/VINCENT YU

    10 March

    Outbreak explodes in Hanoi hospital; at least 22 staff members fall ill with influenzalike symptoms.

    12 March

    WHO issues a rare global alert about a severe form of "atypical pneumonia."

    15 March

    CREDIT: PETER PARKS/AFP/NEWSCOM

    In second alert, WHO names disease SARS, calls it "a worldwide health threat" and issues travel advisories.

    17 March

    WHO sets up network of 11 labs to hunt for the agent causing SARS. Networks for clinicians and epidemiologists will follow.

    24 March

    Scientists in the lab network finger new coronavirus.

    29 March

    WHO's Urbani dies of SARS in Bangkok.

    30 March

    Start of SARS outbreak in Amoy Gardens apartment complex in Hong Kong. More than 300 become infected.

    CREDIT: PETER PARKS/AFP/NEWSCOM

    16 April

    WHO says that macaque study in Rotterdam clinches the case for a new coronavirus as the cause of SARS.

    18 April

    WHO team in Beijing expresses strong concern over inadequate reporting of SARS cases.

    20 April

    Beijing acknowledges 339 previously undisclosed cases. China's minister of health and mayor of Beijing are fired.

    25 April

    Outbreaks in Hanoi, Hong Kong, Singapore, and Toronto show signs of peaking.

    28 April

    Vietnam becomes first country to successfully end SARS outbreak.

    14 May

    Toronto declared SARS-free.

    22 May

    Canada reports new SARS cluster in Toronto.

    23 May

    CREDIT: PAUL HILTON/EPA/NEWSCOM

    Scientists announce detection of SARS-like virus in the Himalayan palm civet and raccoon dog.

    31 May

    Singapore declared SARS-free.

    23 June

    Hong Kong declared SARS-free.

    24 June

    Beijing declared SARS-free.

    CREDIT: MICHAEL REYNOLDS/EPA/NEWSCOM

    2 July

    Toronto declared SARS-free a second time.

    5 July

    Taiwan declared SARS-free. After 8096 cases and 774 deaths, WHO declares the end of the SARS epidemic.

  6. Understanding the Enemy

    1. Dennis Normile

    Research sparked by the SARS outbreak increased the understanding of emerging diseases, though much remains to be learned.

    No touching.

    Patient isolation and staff member protection halted SARS transmission in hospitals.

    CREDIT: STR/EPA/NEWSCOM

    In the end, what made SARS such a threat to human health turned out to be surprisingly and alarmingly simple. Thirty months after the causative agent was found to be a novel coronavirus and 2 years after the disease had been stamped out, scientists determined that what gave the agent the ability to infect and sicken humans came down to two key amino acid changes in a viral protein. More digging has since uncovered still other tricks that SARS and all other coronaviruses have hidden in their genomes to bolster their chances of thriving and causing illness.

    The findings are part of a legacy of an unprecedented scientific effort. The SARS outbreak came and went in just 8 months, infecting almost 8100 people in 29 countries and killing 774 (see p. 1264). But as soon as it emerged, dozens of labs around the world jumped into the fray. Working on parallel tracks, they tried to figure out the causative agent, where it came from, what made it so deadly, and how to stop it. Their effort and the work it spawned are continuing to increase our understanding of how zoonotic diseases emerge and spread and how they might be contained, if not prevented.

    "SARS was the first pandemic of the 21st century and one of the best studied as it was ongoing and in retrospect," says Kathryn Holmes, a coronavirus specialist at the University of Colorado, Denver. "Over 3000 papers were published on the SARS coronavirus in the last 10 years," adds Kwok-yung Yuen, a microbiologist at the University of Hong Kong (HKU). Researchers have identified dozens of new coronaviruses in nature that could also threaten human health.

    The understanding of the SARS virus and other coronaviruses came together piece by painstaking piece. Almost like a mystery writer planting misleading clues in a story, nature delivered a number of false leads. Even today, many aspects of the virus, the disease, and the epidemic remain a puzzle. That leaves nagging worries about how well prepared the world is if SARS or something like it stages a comeback.

    An unexpected culprit

    Shortly after the World Health Organization (WHO) issued its alerts about SARS in mid-March 2003, scientists at 11 labs in nine countries joined forces to try to understand the new threat. Putting aside their rivalries, they agreed to daily teleconferences to share their findings. Job one was to identify the cause of the disease, as that would lead to diagnostic tests and, possibly, treatments and vaccines.

    Several groups in Asia had started hunting for the causative agent soon after rumors surfaced of an unusual pneumonia circulating in China's southern Guangdong Province in January 2003. Scientists at the Chinese Center for Disease Control and Prevention in Beijing suspected chlamydia infection, as traces of that bacterium were found in lung tissue recovered from early SARS victims. Others focused on the avian influenza virus H5N1. When it had first emerged in Hong Kong in 1997, H5N1 killed six of 18 victims. The H5N1 hypothesis got a boost in mid-February, when it caused one death and one illness in a Hong Kong family that had visited Fujian Province, which neighbors Guangdong. But when clusters of atypical pneumonia cases surfaced in Hong Kong in early March, HKU researchers found no evidence of H5N1 infection. Then "we knew we were dealing with something completely out of the blue," HKU virologist Malik Peiris told Science in 2003 (9 May, p. 886).

    Uncaged.

    Guangdong's live animal markets provided an ideal environment for a SARS precursor to mutate and adapt to humans.

    CREDIT: AP PHOTO/STR

    The first breakthrough came on 24 March when WHO confirmed that three labs had independently concluded that a new coronavirus was the cause of SARS. "It was a surprise. Coronaviruses were considered quite harmless to humans," says Christian Drosten, a virologist then at the Bernhard Nocht Institute for Tropical Medicine in Hamburg, Germany, who led one of the groups. The other groups were at HKU and at the U.S Centers for Disease Control and Prevention (CDC) in Atlanta. Although they had long posed a threat to livestock health, "in humans, coronaviruses were common cold agents, nobody had them on their list" of suspects for SARS, explains Drosten, now at the University of Bonn.

    Before SARS, Drosten says, few human virologists worked on coronaviruses, which are named for the crownlike spikes on their surface. But that quickly changed.

    Out of the wild

    Several groups, including Drosten's, set about developing diagnostic tests. Others began looking for the virus's origins. It was natural to assume there was an animal reservoir "because 70% of emerging infections come from animals," Yuen says. The Hong Kong group, which was already monitoring flu viruses circulating in poultry in southern China, was perfectly positioned for the hunt.

    Early epidemiological evidence suggested that many of the first suspected SARS cases had connections to the trade in wild mammals in Guangdong Province, which is home to distinctive culinary traditions. In addition to vegetables, poultry, fish, and reptiles of all kinds, wild beavers, rabbits, badgers, and other small animals were sold at live animal markets and either butchered on the spot or at restaurants specializing in exotic dishes. In early May 2003, Yi Guan, another HKU virologist, and his field team collected samples from animals at a large market in Shenzhen, just over the border from Hong Kong, and retrieved a virus similar to the SARS coronavirus from Himalayan palm civets (Paguma larvata) and a raccoon dog (Nyctereutes procyonoides). The group also found that 12 of 55 market workers carried antibodies to the SARS virus, with the highest rates in those who handled wild animals. None of them reported having had any SARS-like symptoms within the previous 6 months. Guan and his colleagues concluded that the precursor to the human SARS virus had been circulating asymptomatically among the animals and market workers. "The markets provided an environment for the virus to circulate and adapt," Guan says.

    But Guan's team was unable to find the virus in civets in the wild, which suggested that the animals were an intermediary. So the hunt for the natural reservoir continued.

    In September 2005, two groups simultaneously reported finding "SARS-like" viruses in Chinese horseshoe bats in Guangdong. One group, led by Australian researchers, had made an inspired guess that bats might be involved, knowing that bats harbor both Nipah and Hendra viruses, which had both recently caused human outbreaks. Similarly, a Chinese group had set its sights on fruit bats and got lucky when a young researcher grabbed and tested samples from horseshoe bats by mistake. The coronaviruses found in the bats were related to but still different from both the human and civet SARS viruses; their sequences were between 88% and 92% identical to the human coronavirus.

    This means there is either a closer SARS progenitor virus lurking in nature or the virus found in the horseshoe bats underwent extensive mutation in unidentified intermediate hosts either in the wild or in Guangdong's animal markets.

    The first 11 documented human cases of SARS came from different cities in a region within Guangdong Province. The patients had not been in contact with each other; seven of them had connections to the wild game trade, according to a 12 March 2004 Science paper (p. 1666) by a Chinese SARS consortium led by Guo-Ping Zhao of the Chinese National Human Genome Center in Shanghai. These initial cases likely contracted a virus from live animals in the markets. After that, the evidence suggests that with one or two exceptions, virtually all later patients were infected through human-to-human transmission. Apparently, one or more final changes had given the virus the ability to spread efficiently between humans, making it a truly global threat.

    In sequence

    But exactly what had changed in the virus during this exquisite adaptation to the human host? A new generation of faster and cheaper DNA sequencing technology gave researchers unprecedented power to find out.

    The genomes of the human and civet coronaviruses turned out to be 99.8% identical. One glaring difference was a 29-nucleotide stretch that was present in samples from civets but missing in the human samples available then, which mostly came from patients in Hong Kong, who were infected at a later stage of the outbreak than those in Guangdong. Scientists initially thought this 29-nucleotide deletion might be involved in making the virus transmissible among and infectious in humans.

    Crowned.

    The SARS coronavirus (pictured) has nucleocapsid (N), membrane (M), envelope (E), and crownlike spike (S) proteins.

    CREDIT: (INSET) K. SUTLIFF/SCIENCE; HAZEL APPLETON/HEALTH PROTECTION AGENCY CENTRE FOR INFECTIONS/SCIENCE SOURCE

    But that hypothesis was soon proven wrong. In the 12 March 2004 issue of Science, the Chinese SARS Consortium reported that some samples retrieved from early human cases in China did contain the suspect 29 nucleotides after all. And samples isolated from patients who became ill late in the outbreak had deletions in the same genomic region, but these were far larger—89 or even 415 nucleotides. The significance of the lost nucleotides, which all turned out to be in what is known as open reading frame (ORF) 8, is still not understood.

    Mutations that changed the virus's spike, or S, glycoprotein turned out to be more important. Coronaviruses use their spike protein to attach to host cells, and if a cell does not have compatible receptors then the virus cannot infect it efficiently. Several groups started focusing on how the spike differed between the civet and human viruses and how it changed as the virus circulated among humans. Zhao's group found that the sequence of the spike protein changed rapidly as the virus moved from person to person early in the outbreak, but stabilized as it went on, presumably because the spike had become well adapted to human-to-human transmission.

    Zhao's team and a second group from Harvard Medical School in Boston and other institutions narrowed their focus to differences in amino acids between the animal and human viruses at two key locations on the spike protein. At one, the civet S protein encoded for a serine, while the human virus encoded a threonine. And at the other position, the civet's asparagine became a lysine in the spike protein of the human virus.

    Then, a 16 September 2005 Science paper, by Fang Li of Harvard Medical School et al., reported crystallizing both the spike protein binding domain and the human receptor, clarifying the significance of the amino acid changes (p. 1864). In the spike of the animal virus, the residues at the two key locations inhibited binding to human receptors. But the human SARS virus had a loop structure that could nestle snugly against human angiotensin-converting enzyme 2 (ACE2), a protein found on lung epithelial cells that the virus used as its entry point. The two key changes in the viral spike increased the binding affinity a thousandfold.

    Those two adaptations were enough to give the virus the ability to infect humans and spread from person to person and cause lethal disease.

    Accessories to the crime

    Once the virus made the leap to humans, it caused serious disease. A better understanding of how it did so emerged only years later as researchers continued studying SARS and other coronaviruses.

    All coronaviruses share four "core" genes—the spike, envelope, membrane, and nucleocapsid genes. They also have so-called accessory genes that are scattered through the genome between the core genes.

    The accessory genes are not essential to viral survival and replication, but they do benefit the virus. Take the bit of extra genetic material designated ORF6 in the human SARS virus. In a series of experiments, Ralph Baric, a virologist at University of North Carolina, Chapel Hill, and colleagues found that ORF6 helps the virus escape detection by the human immune system. "Infect a cell with flu, and you have [an immune response] within 6 hours. In the case of SARS virus, it takes 36," Baric says. That delay gives the virus a head start on replicating and causing more serious disease. Accessory genes vary in number, location, and function among the different coronavirus groups. How coronaviruses acquired and adapted this genetic material is a mystery.

    Lucky break

    When the first clusters of SARS cases occurred in quick succession in cities around the world, public health experts feared this new disease would quickly circle the globe and threaten millions. Several alarming events—such as a cluster of more than 300 infections at an apartment complex and the spread of infection through guests at a hotel, both in Hong Kong—heightened those fears (see sidebar, 1272). But in retrospect, "SARS was nowhere near as infectious as influenza," Holmes says. Both flu and SARS spread through respiratory droplets that usually travel within about a 1-meter circumference of a person. But flu patients start producing and expelling virus through sneezing and coughing before they start feeling feverish. This means that they are likely to continue normal activities and come into contact with strangers.

    However, SARS patients did not start shedding virus until the onset of symptoms, 7 to 10 days after infection. By that time, they tended to be so sick that they stayed home or checked into a hospital, which is one reason why secondary infections occurred mostly among household members and health care workers.

    Early on, before the virus was identified and its transmission dynamics understood, hospital practices unwittingly aided its spread. On 4 March, a patient was admitted to Hong Kong's Prince of Wales Hospital with severe pneumonia. A week later, more than 112 health care workers and patients came down with SARS. It turns out the patient was given a nebulizer to deliver antibiotics to his lungs. But nebulizers can atomize respiratory droplets, enabling them to waft about the room. In other early cases, patients suffering from advanced pneumonia were intubated, a procedure in which a tube is passed through the mouth into the trachea to force air into the lungs. This also exposed health care workers to infectious respiratory droplets. Hospital infections—including staff members, other patients, and visitors—accounted for more than 70% of SARS cases in Toronto and Singapore.

    Hospitals soon recognized the problem. "But in the beginning, it was an uphill battle, it was very difficult to prevent hospital infections," says Joseph Sung, who is now university president and who was then chief of medicine and therapeutics at Prince of Wales Hospital, which is affiliated with the Chinese University of Hong Kong. Sung explains that wards were congested and didn't have proper isolation facilities; the staff members were not familiar with protection procedures; and there was a shortage of basic equipment such as masks.

    "Hospital-based infections were hugely important in the expansion of SARS, and shutting them down through good infection control was essential to stamping out the outbreak," says James Lloyd-Smith, an epidemiologist and disease ecologist at University of California, Los Angeles.

    For controlling infections outside hospitals, "We were a bit lucky," Baric says. The 7- to 10-day gap between infection and the onset of viral shedding gave officials a window of opportunity to trace contacts and quarantine them, even though there was spotty compliance with some quarantine regimes.

    Can it return?

    SARS may be the second human pathogen, after smallpox, to ever be eradicated. But is it gone for good? "Coronaviruses are important emerging pathogens," Baric says. "They are highly mobile, can jump between species by recombination or mutation, and when they do, they cause micro-outbreaks with the potential to drive additional mutations that enhance person-to-person transmission," he adds.

    Recent research suggests that most, if not all, of the known human coronaviruses originated in animals, sometimes in the not too distant past. In the February 2005 Journal of Virology, virologist Marc Van Ranst and colleagues at the Catholic University of Leuven in Belgium concluded that the human coronavirus OC43, which causes the common cold, likely resulted from an adaptation of a bovine coronavirus around 1890. Drosten's group claimed in Emerging Infectious Diseases in September 2009 that human coronavirus 229E, another common cold culprit, likely diverged from a bat coronavirus between 1686 and 1800.

    Last September, a group at the University of Maryland, Baltimore, and other institutions reported, also in the Journal of Virology, that the human coronavirus NL63 likely diverged from a common ancestor in bats 563 to 822 years ago. Just discovered in 2004, NL63 causes a type of lung inflammation common in infants.

    Researchers and public health officials are now closely watching the latest new human coronavirus to make the jump, alternately called EMC or NCoV. First discovered in Saudi Arabia last June, the virus has sickened 14 people and killed eight. This virus, too, seems to have originated in bats. So far "it is not as transmissible as SARS," says Drosten, who was involved in identifying the virus and in developing a diagnostic test. He and colleagues reported in the 11 December 2012 issue of mBio that the new virus does not latch onto the ACE2 receptor that provided such efficient entry for the SARS virus. In a letter in this week's issue of Nature, the group identifies dipeptidyl peptidase 4 as a receptor for the new virus. "It remains to be seen how important the disease will be epidemiologically," Holmes says.

    Meanwhile, few researchers rule out a repeat performance by the SARS virus or something very close to it. Indeed, it almost came back. During the winter of 2003 to 2004 , four people in Guangdong contracted a SARS-like illness. They had no contact with one another, and each developed mild disease. Sequence analysis by Zhao and his collaborators revealed that all four were infected with the same coronavirus—and it had one of the two key mutations found in the lethal SARS virus that caused the global epidemic. The group also found civets carrying a nearly identical virus with the same mutation. They concluded in a 15 February 2005 paper in the Proceedings of the National Academy of Sciences that the precursor to the SARS virus had continued to circulate in animals in the province, and in late 2003, one of the two key proteins mutated again, allowing it to infect humans and cause illness, but not with the same transmissibility or virulence of the 2002 to 2003 strain. Scientists convinced authorities to ban wild game from the markets. Aside from a few incidents of laboratory infections, no further human cases of SARS have ever been found.

  7. The Metropole, Superspreaders, and Other Mysteries

    1. Dennis Normile

    For all that has been learned about SARS in the past 10 years, mysteries still endure. What happened at the Metropole Hotel in Hong Kong the night of 21 February 2003? How did SARS spread at the Amoy Gardens, a high-rise apartment building complex? And how do "superspreaders" emerge?

    For all that has been learned about SARS in the intervening 10 years, some mysteries endure. Foremost is what happened at the Metropole Hotel in Hong Kong the night of 21 February 2003. A physician from Guangdong Province in southern China who worked at a hospital treating patients suffering from what was then called atypical pneumonia stayed in room 911 at the Metropole that night. He checked out the next morning but was admitted to a local hospital, where he died several days later.

    Links of contagion.

    One-hundred-forty-four of Singapore's 206 probable SARS cases were traced to a chain of five individuals that included four "superspreaders."

    CREDIT: WHO/WPRO

    Sixteen other guests who stayed at the hotel that night and one visitor contracted what was later identified as SARS and carried the novel coronavirus to Hanoi, Singapore, and Toronto, sparking outbreaks in those cities. Epidemiologists later traced close to half of the 8100 cases of SARS worldwide back to the Metropole Hotel. Whatever happened on the ninth floor turned what might have been a local outbreak of a new disease into an alarming global threat, underscoring just how quickly a new virus can spread with modern air travel.

    But how the other guests were infected is not clear. It is unlikely they all met in the hallway or elevator. And, strangely, no hotel staff members became sick.

    A World Health Organization (WHO) investigative team from Canada visited the hotel, which has since changed its name, in late April 2003 and collected samples from numerous surfaces in rooms on the ninth floor, the hallway, and even the vacuum cleaner used in that wing and analyzed them for genetic material from the SARS virus. They tested the flow of air through the ventilation system and seals in the plumbing and ruled them out as avenues of transmission. The team made one surprising discovery: copious amounts of viral remnants on the carpet in front of room 911 but, curiously, not in the room itself. In a report dated July 2003, they speculate that the man vomited on the floor in front of his room and then, embarrassed perhaps, cleaned it up himself. Subsequently, other guests could have been exposed by walking through the contaminated area. While "there is no definite proof for the … outlined scenario," as the July 2003 report concludes, many say it's as good a guess as any.

    Another peculiar event at the Amoy Gardens, a high-rise apartment building complex in Hong Kong, in late March and early April 2003 also sent confusing signals about how easily the virus was spreading in the community. At the time, it was not clear if the causative agent was being transmitted by airborne particles, as measles and tuberculosis spread, or by infected respiratory droplets, which carry most flu viruses, for example, only a short distance. It was later determined that a man who lived in Guangdong possibly became infected at Hong Kong's Prince of Wales Hospital where he was being regularly treated for a chronic renal condition. Already ill and suffering diarrhea, he spent the nights of 14 and 19 March with his brother, who lived in Amoy Gardens. Over the next month, more than 300 Amoy Gardens residents contracted SARS.

    Lingering mystery.

    A man who spent one night at Hong Kong's Metropole Hotel (left) spread SARS to other ninth floor guests who later sparked outbreaks in Hanoi, Toronto, and Singapore.

    CREDITS (LEFT TO RIGHT): AP PHOTO/ANAT GIVON; WHO/WPRO

    Studies and experiments by the Hong Kong government later identified a possible scenario. The bathrooms of the Amoy Gardens apartments had drains in the floors with standard water traps of the kind seen in plumbing throughout the world. However, investigators found that few residents relied on the drains, mopping bathroom floors instead of hosing them. This allowed the water traps to dry out. The same piping was connected to the toilets. Investigators concluded that the diarrhea from the patient flushed into the system and produced aerosols that traveled through the piping and into bathrooms, where the moist environment allowed the virus to survive. This transmission route likely spread the infections through one block of apartments and from there, through person-to-person contact.

    The Amoy and Metropole index cases remain at the center of another unsolved puzzle: They were among what came to be called "superspreaders," who accounted for a disproportionate number of further infections, in some cases passing the virus on to more than a dozen other people (see graphic). "SARS made superspreading impossible to ignore," says James Lloyd-Smith, an epidemiologist at the University of California, Los Angeles. But he adds that his own investigations and modeling, reported in a 17 November 2005 Nature letter, have shown that the superspreader phenomenon occurs with other infectious diseases, including measles and smallpox. He says superspreading likely results from a combination of biological factors, transmission routes, contact rates, and travel patterns of the infected people. Kwok-yung Yuen, a microbiologist at the University of Hong Kong who was heavily involved in understanding the SARS outbreak, agrees that superspreading "is still a mystery." Like Lloyd-Smith, he suspects a confluence of factors. For instance, superspreaders could have been suffering from another illness at the same time that caused coughing and sneezing that helped spread the SARS virus. Lloyd-Smith says that in epidemiology, it is important to be wary of averages: Many infected with disease don't pass it on at all, but some become superspreaders.

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