Chapter 2
Investigating SARS

Long before SARS was an international epidemic—when it was still a mysterious disease affecting people in Guangdong Province, doctors around the world were hearing rumors by way of the Internet. Always concerned about the emersion of a new illness, WHO researchers around the world were keeping track of any information they could get about the pneumonia-type illness.

Six Percent

Any new disease causes worry, and there have been a number of killers that have emerged in the past quarter century—from AIDS to Ebola. In addition, WHO doctors around the world have monitored oubreaks of well-known but dangerous diseases such as malaria and cholera. In many cases, the disease can be identified and contained in one area before it spreads out of control. However, the most frightening of all scenarios, say experts, is that a highly contagious disease that is unknown to doctors reaches an international airport, thus spreading it to other nations before anyone is even aware of it. That is just what happened with SARS.

Of course, no one knew then how deadly the disease might be or how contagious. The numbers of people dying of SARS were very small compared with, say, the numbers dying from AIDS in a single year—which totaled 3 million worldwide in 2002. With the data they had, doctors estimated that the death rate of SARS was about 6 percent—in other words, of every one hundred people infected with SARS, six died.

Six percent is a fairly low death rate as long as the disease is relatively contained in a particular area and not extremely contagious. However, with a disease that spreads easily from person to person, it is an extremely worrisome rate. Researchers point to a strain of flu in 1918 with a death rate of less than three percent, but which was so highly contagious that it killed between 25 million and 40 million people worldwide in eighteen months.

As time went on and more people became infected with SARS, doctors became more alarmed. One aspect of the new disease that worried WHO researchers was the high infection rate among health professionals. In Hanoi, Vietnam, for example, 56 percent of the doctors and nurses who came into contact with the disease became infected. Says Julie Gerberding, director of the CDC, "We never see that kind of rate."²⁴

WHO officials alerted the CDC in Atlanta, informing them that as soon as WHO doctors were able to get tissue and blood samples from patients with the disease, they would send them to the CDC's Building 15, where the most feared diseases on the planet are studied. From what doctors knew about SARS thus far, it seemed to fit in the category of what are known as special pathogens—germs that are both contagious and deadly, with the potential to kill a great many victims.

Guessing Wrong

Tissue and blood specimens were delayed, however. For one thing, autopsies are quite rare in most Asian hospitals, and doctors at first were reluctant to authorize the taking of lung tissue samples. When some hospitals were finally persuaded to begin releasing specimens, their transport to the research facilities was delayed because many international shippers refused to carry such hazardous material. By March 10, 2003, specimens were brought to various research facilities—including Building 15 in Atlanta—by U.S. military planes, and doctors began to inspect the vials of blood, sputum, and bits of tissue from patients' lungs or throats.

One of the early assumptions about SARS was that it would prove to be a new type of influenza, or flu virus. After all, many strains of flu have originated in rural areas of China, where people and livestock often live very close to one another. Epidemiologists, doctors who study the transmission of diseases, say that many viruses that cause disease in humans actually originate with animals. Ducks, because they have weak immune systems, seem to be breeding grounds for new viruses. In a duck's body, such viruses can mutate and then are able to jump to pigs, and from pigs to people. Many strains of flu have originated this way in southern China, where the living conditions of ducks, pigs, and people create what one researcher termed "a toxic stew."²⁵

Other news gave researchers even more support for their theory of a new strain of flu. They heard of a new bird flu in China that had made some people sick. Perhaps, doctors reasoned, the strange new SARS disease was another mutation of the bird virus, but this time more virulent and contagious than usual. "We put one and one together," explains one researcher, "and thought this was the [bird flu virus] beginning its trip around the world."²⁶

A Difficult Job for a Crisis Team

The scramble to learn about the mystery disease began in mid-March, when WHO doctors were alerted that a Toronto woman had become infected. Apparently, SARS had hopped continents. WHO issued its first global warning, alerting travelers that what appeared to be a very dangerous contagious disease had become a worldwide health threat.

On March 17, 2003, WHO officials called the top epidemiologists throughout the world to form a crisis team that would tackle the problem of identifying the cause of the disease. Doctors in China had easily ruled out bacteria as the cause of SARS. Bacteria would have been visible under their microscopes, and antibiotics, which are powerful killers of bacteria, would have had an effect on the disease. The prevailing theory was that it was a virus, but even for the best researchers in the world, identifying the virus would be difficult. After all, it had taken more than three years for researchers to isolate and identify the AIDS virus.

Identifying viruses is far more difficult than identifying bacteria. Bacteria are living organisms and can be observed with a fairly standard microscope. Viruses, however, are very tiny—some are a million times smaller than bacteria. In addition, viruses act in different ways than bacteria, since they can survive only when inside a living cell. In fact, scientists believe that viruses are not true living things, since they cannot survive or reproduce on their own. Seeing and identifying one extremely tiny virus within a cell, when scientists are not aware of what they are looking for, is difficult, time-consuming work.

"The Medical Equivalent of Shock and Awe"

There are other factors that often slow work for scientists. Laboratories are exceptionally expensive places to run, and scientists are often in competition with one another to find a new medicine or vaccine that can bring in funds for research. For that reason, research facilities are rarely willing to consolidate or share information, since they view one another as rivals. And because there is no greater achievement for a scientist than discovering a pathogen or its cure, the scientists themselves are often competitors.

The director of WHO's crisis team, Dr. Klaus Stohr, says that because of the immediate threat of the new disease, it was not difficult to convince the doctors to lay aside the competitiveness. They agreed to work together, sharing patient data, lab results, and other information. "These are all famous microbiologists whose life's dream is to discover a virus, put their name on it and win the Nobel Prize," says Stohr. "But they understand that our only chance to put this thing back in the bottle is if we all work together."²⁷

Stohr set up a website with a secure password for the participating epidemiologists. He also arranged twice-a-day conference calls so the team could discuss any new theories or ideas, results of lab tests, and so on. The results were beyond anything Stohr could have anticipated. Not only did the team identify the cause of the disease, but it did so in less than seven weeks. The speed at which the battle against SARS was waged, says one researcher, was "the medical equivalent of shock and awe [the phrase President George W. Bush had used to describe the U.S. attack on Baghdad in March 2003]."²⁸

A Surprising Culprit

The first significant step in the process was to drop infected tissue or blood into flasks of cells containing a culture of monkey kidney cells, called Vero cells. Vero cells are especially good for breeding viruses, and scientists often use a Vero cell solution to indicate the presence of a virus. One scientist at the CDC in Atlanta noticed that one of the flasks that contained a mixture of Vero cells and throat tissue from a patient had turned from cloudy to clear. The clear areas meant that something was killing the Vero cells.

The flask material was processed so that it could be viewed under a special electron microscope, which magnified it over eighty thousand times. Many researchers believed that the microscopic view would show a pathogen from the family of viruses that cause various strains of flu. What they saw, however, was something they never expected: a coronavirus.

Coronaviruses are easily identifiable by their round shape crowned with what look like spikes under an electron microscope. (The viruses get their name from the Latin word corona, meaning "crown.") One reporter who viewed the viruses in a Hong Kong lab notes that "magnified 100,000 times, the organisms are fuzzy little balls that fill the screen and look like the burrs that stick to your pants during a hike through the woods.… You can just make out tiny hooks poking out of the spherical bodies."²⁹

But while coronaviruses can make animals very sick and are often seen in livestock infections, in humans they had never been known to cause anything more serious than a cold. Never had scientists seen anything in the coronavirus family that could cause pneumonia or anything as deadly as this new disease.

Trying Out a New Tool

The next step was to find out more about this particular coronavirus. To do that, WHO researchers sent samples of the virus to a laboratory at the University of California in San Francisco. Doctors there have a new tool called a DNA microarray, with which they can pinpoint a virus by examining a fragment of its genetic makeup.

The DNA microarray contains a slide spotted with fragments from over one thousand viruses known to science. If the WHO sample has any fragments that match up with the samples on the slide, spots will light up on a special scanning device. Then the army of spots is displayed on a computer monitor, and when a technician slides a cursor over any lit up spot, the name of the virus will pop up.

In this case, researchers were excited to see several spots light up on the microarray. The good news was that there were genetic similarities to three known coronaviruses that infect animals. The bad news was that the mystery virus was not identical to any of them. It was a new virus, never seen or studied.

"Suddenly They're Rock Stars"

The scientific community realized that the dangerous unknown coronavirus was a problem. While there are many researchers who study viruses, there were not many who specialized in coronaviruses. One doctor says that because coronaviruses had never been a serious threat to people and were difficult to grow or study in a laboratory, the topic had become "a sleepy little corner of virology."³⁰ Far more researchers were interested in studying viruses that cause Ebola, West Nile disease, or AIDS—all of which are known killers. With the discovery of this particular virus, however, coronaviruses became a hot topic, and anyone who specialized in them was in great demand. "Suddenly," laughs one virologist, "they're rock stars."³¹

After adding such specialists to the WHO team, researchers concentrated their efforts on the puzzling new coronavirus. Like others in its family, the SARS virus has spikes coated with proteins, which are designed to latch onto the cell of an organism—in this case, most likely an animal victim. The surfaces of an animal's cells have receptors, which are designed to link up with important body chemicals, such as insulin. A virus whose spikes match up with a cell's receptors can then latch onto the cell and infect the animal.

Once a cell is invaded by a coronavirus, the virus takes over the reproductive system of the cell and uses it to replicate itself—up to one thousand times per cell. This process eventually kills the cells, and the animal becomes sick. The key, says coronavirus expert Kathryn Holmes, is to find out how the SARS virus—whose genetic material most resembles an animal, not a human, virus—began infecting people in the first place. "We know the people getting SARS now are catching it from people, not from being exposed to unusual animals," said Holmes. "But where did it come from?"³²

Frustrating Mutations

Holmes and other experts believe it is likely that an animal virus mutated, and its protein spikes changed in such a way that they could latch onto human cells. Perhaps the barbs on the spikes altered in mutation, enabling them to be more of a threat to a human host. Researchers working on mapping the virus's genetic makeup support that theory, for in twelve different laboratories, twelve genetic profiles have been noted.

Researchers believe that the variety of genetic profiles is due to the primitive nature of coronaviruses. All known coronaviruses are composed of single strands of genetic material which has no built-in system to spot errors as it reproduces, as other viruses do. That means that every time the virus replicates itself, it changes in a very slight way. Notes one virologist, "Coronaviruses mutate for a living."³³

This constant mutation is frustrating to scientists who are searching for a reliable tool for doctors to diagnose patients. In some diseases, doctors can perform blood tests to look for antibodies—the body's response to a particular germ that contains the genetic code of the virus. With an ever changing code, however, the coronavirus makes diagnosis tricky, for the antibodies in one patient may look different from those of another patient. "You look for symptoms like a cough, fatigue, a low-grade fever," says one doctor. "But that pretty much sums up a case of the flu, doesn't it? It's no wonder that so many SARS patients have been hospitalized in [regular hospital] wards, when they should have been isolated."³⁴

Returning to Guangdong

To find answers to the virus's beginnings, some researchers went to Guangdong Province, where the first cases of SARS occurred. Scientists noted that the first victims of the disease were people who worked in the many live animal markets throughout the province. A visit to a market just an hour south of the province's capital showed reporter Elizabeth Rosenthal a place that seemed rife with germs:

In hundreds of cramped stalls that stink of blood and guts, wholesale food vendors tend to veritable zoos that will grace Guangdong Province's tables: snakes, chickens, cats, turtles, badgers, frogs. And, in summertime, sometimes rats, too. They are all stacked in cages one on top of another—which in turn serve as seats, card tables for the poor migrants who work there.³⁵

Scientists found it easy to imagine how a virus could move from such animals to people in the crowded and filthy conditions of the market stalls, where sick and dying animals were cramped together in filthy cages in close proximity to stall workers. To test that theory, researchers collected specimens from eight different wild animals sold at the market and found varied strains of the coronavirus in all eight animals, including civet cats and rats being butchered in the stalls.

From Person to Person

As some researchers concentrated on the beginnings of the virus and its probable jump from animals to people, others tried to understand how it spread from person to person. At first doctors believed that for someone with SARS to infect another person required fairly close proximity, with the infected person sneezing or coughing and those droplets coming into contact with an uninfected person.

However, as doctors began seeing more patients with SARS, they noticed that in all cases, the disease affects the lower part of a patient's lungs. That means that close contact is not necessary. Viruses that arise from the lower lungs tend to come out in a fine aerosol, rather than heavy droplets from sneezes and bronchial coughs. The aerosol is so light that it can linger for a much longer time in the air.

In addition, scientists found that the SARS virus can live outside the body for up to twenty-four hours, which means that it might be possible for an infected person who touches a doorknob or elevator button, for example, to leave an active virus for someone who touches those same objects hours later. That may explain, say scientists, how so many people were infected by one person at the Hong Kong hotel in March 2003.

A Puzzle

But even that theory could not account for the situation at the Amoy Gardens, a thirty-three-floor housing project in Hong Kong. In March 2003 clusters of people who had never met one another became infected. By the end of that month, three hundred people had become infected with SARS, and researchers scrambled to find an explanation for the rapid transmission of the disease. Said one WHO researcher in mid-March, "There is something going on—a form of transmission we don't understand."³⁶

Some doctors in Hong Kong were frustrated by their inability to pinpoint the method of infection. They worried that the disease might even be spread through heating and cooling vents from one apartment to another. If that disturbing theory were true, it would be almost impossible to protect oneself from SARS if anyone in the building had it.

A more plausible theory was put forward in April. Researchers learned that a kidney patient left a Hong Kong hospital and visited his brother at the Amoy Gardens. Without realizing it, the kidney patient had become infected with SARS at the hospital, where many early SARS patients were treated. While at his brother's apartment, the infected man suffered from bouts of diarrhea, and used the toilet frequently. Researchers believe that it is possible that the SARS virus was spread throughout the Amoy Gardens by the man's feces.

Once flushed in the toilet, the virus-infected waste could have contaminated the sewage system through faulty plumbing. Rats, roaches, or other vermin could have come into contact with the virus in the leaky sewer pipe and carried it throughout the building, where hundreds of people unknowingly became infected. The theory is plausible, but residents of the Amoy Gardens remained nervous. "We don't really think [the doctors] know themselves what the method of transmission is," says one woman. "How do they know? It's just a theory, and no one is sure, and that is what makes me frightened."³⁷

Superspreaders?

Another puzzling aspect of the SARS epidemic are those people known as "superspreaders"—those who seem to be able to infect large numbers of people. From the beginning, scientists have been baffled at how one infected person can infect ninety people, while another can be ill without spreading the virus at all. Some researchers believe that people are superspreaders because of the way they cough—perhaps forcing more of the contaminated phlegm or spray from their lungs than do most patients. Others believe that some people have far more of the virus in their systems for some reason, and that makes them more likely to contaminate others.

On the other hand, researchers believe that some people who have had SARS have been able to fight off the virus without becoming ill. "I'm quite convinced that some people might have contracted the infection but not the disease," says one Hong Kong researcher. "Some may develop mild symptoms, like a little bit of cough and no fever; some may just feel a little tired for a day or two."³⁸

This phenomenon is a mystery, just as the existence of superspreaders. Having people with the virus who do not become ill, however, is far more beneficial to the public. Scientists know that mild cases of SARS, where people do not exhibit any serious symptoms, are a good thing, because they act as natural vaccines. People lucky enough to get only a mild infection will have immunity from the virus in the future.

No Cure in Sight

But for the majority of people, a case of SARS is a very serious threat—and one for which scientists have yet to find an effective cure. Treatment or prevention of the disease is an ongoing challenge, but doctors admit that there is much to be learned about the virus before cures are found. Until then, researchers hope that an existing drug for a different virus might give some relief.

In Hong Kong, for example, doctors have been giving some patients a combination of steroids and an antiviral drug called Ribavirin. Though they say it has had promising results in some cases, other researchers are doubtful because the drugs do not have an effect on the SARS virus in their labs. In other labs, researchers are testing other drugs, such as those for hepatitis, AIDS, asthma, and some cancers. They hope that the same enthusiasm and spirit of cooperation the international science community showed in identifying the virus will cure the disease as well.