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At least 40 million died of the 1918-19 "Spanish flu," the most deadly disease episode in history. Influenza cases were treated at places including this army ward in Kansas in 1918. (National Museum of Health and Medicine, Armed Forces Institute of Pathology)

The Flu Hunter

For years, Robert Webster has been warning of a global influenza outbreak. Now governments worldwide are finally listening to him

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Editor’s Note, April 27, 2009: The Center for Disease Control and World Health Organization confirmed the existence of over 40 human cases of swine flu in the United States after a more severe outbreak in Mexico claimed the lives of 149 people. In 2006, Smithsonian magazine profiled Robert Webster, a scientist who researches modern influenza viruses and how they spread from animals to humans.

Robert Webster was in the backyard of his home in Memphis doing some landscaping. This was in the early winter of 1997, a Saturday. He was mixing compost, a chore he finds enchanting. He grew up on a farm in New Zealand, where his family raised ducks called Khaki Campbells. Nothing pleases him more than mucking around in the earth. He grows his own corn, then picks it himself. Some of his friends call him Farmer Webster, and although he is one of the world’s most noted virologists, he finds the moniker distinguishing. He was going about his mixing when his wife, Marjorie, poked her head out the back door and said, “Rob, Nancy Cox is on the phone.” Cox is the chief of the influenza division at the Centers for Disease Control and Prevention, in Atlanta. Webster went to the phone. He has a deep voice and a thick accent, which people sometimes confuse with pomposity. “Hello, Nancy,” he said.

Cox sounded distressed. She told him there had been a frightening development in Hong Kong—more cases, and another death.

Oh my God, Webster recalls thinking. This is happening. It’s really happening this time.

Some months before, a 3-year-old boy in Hong Kong had developed a fever, a sore throat and a cough. The flu, his parents thought. But the boy grew sicker. Respiratory arrest set in, and he died. The case alarmed doctors. They could not recall seeing such a nasty case of the flu, particularly in a child so young. They sent off samples of his lung fluid for testing, and the results showed that he did indeed have the flu, but it was a strain that had previously appeared only in birds. H5N1, it’s called. Webster is the world’s preeminent expert on avian influenza, and it was only a matter of time before the test results made their way to him. But he was not yet troubled. He thought there must have been some sort of contamination in the lab. H5N1 had never crossed over into humans. Had to be a mistake, he thought.

That was until Cox interrupted his gardening to tell him about the new cases.

It immediately occurred to Webster that he should be on an airplane. “I had to go into the markets,” he told me recently. “I had to get into the markets as fast I could.” He meant the poultry markets, where chickens are bought and sold by the hundreds of thousands. The little boy who died a few months before had been around some chickens, as have most little boys in that part of the world, where families often live side by side with their chickens, pigs, ducks and dogs. If H5N1 was, in fact, in the markets, as Webster suspected, that was the beginning of his worst-case scenario: the virus could mutate in the chickens and perhaps other animals, and then acquire the know-how to pass from person to person, possibly initiating a pandemic that, he thought, might kill as many as 20 million people.

Webster has been predicting and preparing for such an event for his entire career as a scientist. His lab at St. Jude Children’s Research Hospital in Memphis is the world’s only laboratory that studies the human-animal interface of influenza. It was Webster who discovered that birds were likely responsible for past flu pandemics, including the one in Asia in 1957 that killed about two million people. He has spent a good part of his life collecting bird droppings and testing them for signs of influenza. Some of that collecting has taken place while he and his family were on vacation. One evening in Cape May, New Jersey, his school-age granddaughter ran toward him on the way to dinner saying that she had discovered some poop for him. He was so pleased.

A couple of days after Cox’s phone call, Webster stepped off a plane in Hong Kong. He stopped at the University of Hong Kong to drum up some help to sample chicken droppings in the market. He also phoned his lab in Memphis and some scientists in Japan whom he had trained. He told them to pack their bags.

It occurred to Webster that there was a problem. The problem was H5N1. Neither he nor any members of his staff had ever been exposed to the virus strain, meaning they did not have any antibodies to it, meaning they had no defense against it. If they became infected, they would likely meet the same fate as the little boy who died.

They needed a vaccine. Four decades before, Webster had helped create the first widespread commercial flu vaccine. Until he came along, flu vaccines were given whole—the entire virus was inactivated and then injected. This caused numerous side effects, some of which were worse than the flu. Webster and his colleagues had the idea to break up the virus with detergents, so that only the immunity-producing particles need be injected to spur an immune response. Most standard flu shots still work like this today.

Before they went to work in Hong Kong, Webster and his colleagues created a sort of crude vaccine from a sample containing the H5N1 virus. They declined to discuss the matter in detail, but they treated the sample to inactivate the virus. Webster arranged for a pathologist in Hong Kong to drip the vaccine into his nose and the noses of his staff. In theory, an-tibodies to the virus would soon form.

“Are you sure this is inactivated?” the pathologist said.

Webster pondered the question for a moment.

“Yes it is. I hope.”

And the fluid began dripping.

“It’s very important to do things for yourself,” Webster told me recently. “Scientists these days want other people to do things for them. But I think you have to be there, to be in the field, to see interactions.” In many ways, Webster’s remarkable career can be traced to a walk along an Australian beach in the 1960s, when he was a microbiology research fellow at Australian National University.

He was strolling along with his research partner Graeme Laver. Webster was in his 30s then, Laver a little older. Every 10 or 15 yards they came across a dead mutton bird that apparently had been washed up on the beach. By that time, the two men had been studying influenza for several years. They knew that in 1961, terns in South Africa had been killed by an influenza virus. Webster asked Laver: “What if the flu killed these birds?”

It was a tantalizing question. They decided to investigate further, arranging a trip to a deserted coral island off Queensland. Their boss was not entirely supportive of the adventure. “Laver is hallucinating,” the boss told a colleague. They were undeterred. “Why there?” Laver once wrote of the trip. “Beautiful islands in an azure sea, hot sand, a baking sun, and warm coral lagoon. What better place to do flu research!” They snorkeled during the day. At night, they swabbed the throats of hundreds of birds. Back at their lab, they had a eureka moment: 18 birds had antibodies to a human flu virus that had circulated among people in 1957. Of course this meant only that the birds had been exposed to the virus, not that they were carrying or transmitting it.

To figure out if they were, Webster and Laver took subsequent trips to the Great Barrier Reef, Phillip Island and Tryon Island. More swimming during the day, sherry parties at dusk, and then a few hours of swabbing birds. They took the material back to their lab at Australian National University, in Canberra. It is standard procedure to grow flu viruses in chicken eggs. So they injected the material from the swabs into chicken eggs, to see if the influenza virus would grow. Two days later the fluid was harvested. In most of the eggs, the virus had not grown. But in one of the eggs, it had grown. That could mean
only one thing: the virus was in the birds.

Webster wanted to know more. Specifically, he wanted to know whether birds might have played a role in the influenza pandemic of 1957. He traveled to the World Influenza Center, in London, which has a large collection of influenza virus strains from birds and also antibody samples from flu victims. His experiment there was rather simple. He gathered antibody samples from victims of the 1957 flu pandemic. He also gathered samples of several avian flu strains. Then he mixed the samples. What did the antibodies do? They attacked the bird flu strains, meaning the human flu virus had some of the same molecular features as avian flu viruses.

How could that be? The answer is something now known as reassortment. The influenza virus, whether it’s carried by birds or humans, has ten genes, which are arranged on eight separate gene segments. When two different influenza viruses infect the same cell, their genes may become reassorted—shuffled, mixed up. The net effect is that a new strain of flu virus forms, one that people have never been exposed to before. Webster refers to the mixing process as “virus sex.” Perhaps Webster’s greatest contribution to science is the idea that pandemics begin when avian and human flu viruses combine to form a new strain, one that people lack the ability to fight off.

After he entered the Hong Kong poultry markets, Webster needed only a few days to turn up enough chicken droppings to show that the H5N1 strain was indeed circulating. Along with many of his colleagues, he recommended that all the chickens in the market area be killed, to prevent spread of the virus. About 1.5 million chickens in Hong Kong met their maker. And that seemed to do the trick. The virus was gone.

But Webster had a hunch it would be back. The reason was ducks. Webster thinks the most dangerous animal in the world is the duck. His research has shown that ducks can transmit flu viruses quite easily to chickens. But while chickens that come down with bird flu die at rates approaching 100 percent, many ducks don’t get sick at all. So they fly off to other parts of the world carrying the virus. “The duck is the Trojan horse,” Webster says.

After the chickens in Hong Kong were killed, wild ducks probably relocated the virus to other parts of Asia, where it continued to infect chickens and shuffle its genetic makeup. When the strain emerged from hiding again, in Thailand and Vietnam in late 2003, it was even stronger. The virus passed directly from birds to people, killing dozens in what the World Health Organization has described as the worst outbreak of purely avian influenza ever to strike human beings.

Webster says the world is teetering on the edge of a knife blade. He thinks that H5N1 poses the most serious public health threat since the Spanish flu pandemic of 1918, which killed an estimated 40 million to 100 million people worldwide. Though the H5N1 strain has so far shown no signs that it will acquire the ability to transmit easily from person to person—all evidence is that flu victims in Vietnam and Thailand acquired the virus from direct contact with infected poultry—that has provided Webster no comfort. It’s only a matter of time before this virus, as he puts it, “goes off.” He has been saying this for several years. The world is finally taking notice. Elaborate plans are now being created in dozens of countries to deal with a pandemic. In November, President Bush requested that $7.1 billion be set aside to prepare for one, with hundreds of millions of dollars to be spent on further developing a new vaccine that was recently hatched in Webster’s lab.

Webster has been advising federal health officials every step of the way. He does so out of fear of this virus and also because it is his job. When the H5N1 strain emerged in the late 1990s, the National Institute of Allergy and Infectious Diseases awarded Webster a major contract to establish a surveillance center in Hong Kong, to determine the molecular basis of transmission of avian flu viruses and isolate strains that would be suitable to develop vaccines. “He’s certainly one of those people in this field who have been way ahead of the curve in bringing attention to this issue,” Anthony Fauci, the institute’s director, told me. “He was out ahead of the pack. He’s one of the handful of people who have not only been sounding the alarm, but working to prevent this thing from turning into something that nobody wants to see happen.”

Webster’s job keeps him out of the country two to three weeks a month. Back in Memphis, his lab analyzes samples of influenza virus strains from around the world, to see how they are mutating. Recently, health officials have reported finding H5N1 avian flu in birds in Turkey, Romania, Croatia and Kuwait. It has not yet been found in birds in North America. If H5N1 makes its way here, Webster will likely be among the first to know.

This past June, I caught up with Webster at a meeting of the American Society for Microbiology, in Atlanta, where he was scheduled to deliver a speech about the threat of bird flu. There were more than 5,000 microbiologists in attendance, which, because I am a recovering hypochondriac, I found strangely comforting. Walking around with Webster at a meeting of scientists is an experience that must be similar to walking around with Yo-YoMa at a meeting of cellists. When Webster walked by, people suddenly stopped speaking, a fact to which he seemed oblivious.

He opened his talk by asking a series of intriguing questions: “Will the H5N1 currently circulating in Vietnam learn to transmit, reproduce, from human to human? Why hasn’t it done so already? It’s had three years to learn how, and so what’s it waiting for? Why can’t it finish the job? We hope it doesn’t.”

He paused. “Is it the pig that’s missing in the story?” Webster explained that the strain is still not capable of acquiring the final ingredient needed to fuel a pandemic: the ability to transmit from person to person. For that to happen, Webster and others believe that a version of the human flu virus, which is easily transmittable between people, and the H5N1 avian virus have to infect the same mammalian cell at the same time and have virus sex. If H5N1 picks up those genes from the human flu virus that enable it to spread from person to person, Webster says that virtually nobody will have immunity to it. If an effective vaccine based specifically on that newly emerged virus isn’t quickly available, and if antiviral drugs aren’t also, many deaths will ensue.

Watching Webster speak, I couldn’t help thinking that animals are not always our friends. It turns out that animals are a frequent source of what ails us. University of Edinburgh researchers recently compiled a rather frightening list of 1,415 microbes that cause diseases in humans. Sixty-one percent of those microbes are carried by animals and transmitted to humans. Cats and dogs are responsible for 43 percent of those microbes, according to the Edinburgh researchers; horses, cattle, sheep, goats and pigs transmit 39 percent; rodents, 23 percent; birds, 10 percent. Primates originally transmitted AIDS to humans. Cows transmit bovine spongiform encephalopathy, or mad cow disease. In their 2004 book, Beasts of the Earth: Animals, Humans and Disease, the physicians E. Fuller Torrey and Robert Yolken cite evidence suggesting that a parasite transmitted by cats, Toxoplasma gondii, causes schizophrenia. Acouple of years ago, the monkeypox virus broke out among several people in the Midwest who had recently had close contact with pet prairie dogs.

And then there are pigs. For many years, Webster has theorized that pigs are the mixing bowls for pandemic flu outbreaks. He has actually enshrined the theory in his house. He has a stained-glass window next to his front door that depicts what he perceives to be the natural evolution of flu pandemics. At the top of the glass, birds fly. Below them, a pig grazes. Man stands off to the left. Below all of them are circles that represent viruses and seem to be in motion. They are set in a backdrop of fever red.

The pig is in the picture because its genome, perhaps surprisingly, shares certain key features with the human genome. Pigs readily catch human flu strains. Pigs are also susceptible to picking up avian flu strains, mostly because they often live so close to poultry. If a human flu strain and an avian flu strain infect a pig cell at the same time, and the two different viruses exchange genetic material inside a pig cell, it’s possible that the virulent avian strain will pick up human flu virus genes that control transmission between people. If that happens with H5N1, that will almost certainly mean that the virus will be able to pass easily from person to person. A pandemic may not be far behind.

During his talk in Atlanta, Webster pointed out that this H5N1 virus was so crafty that it has already learned to infect tigers and other cats, something no avian flu has ever done. “The pig may or may not be necessary” for a pandemic to go off, Webster said. “Anyway, this virus has a chance at being successful.” He said he hoped world health officials “would keep making their plans because they may face it this winter.
We hope not.”

I went hunting with Webster. Hunting for corn. His cornfield is on a patch of land he owns about five miles from his home on the outskirts of Memphis. He grows genetically modified corn that he gets from Illinois. An extra gene component known for increasing sweetness has been inserted into the corn’s DNA, producing some of the sweetest corn in the United States. Three of his grandchildren were with us, visiting from North Carolina. They had come, among other reasons, for Webster’s annual Corn Fest, where members of the virology department at St. Jude Hospital gather in his backyard to sit around eating corn on the cob. The record for the most ears of corn eaten in one sitting at the Corn Fest is 17. The record holder is the teenage son of one of Webster’s protégés. Webster reports the prize was a three-day stomachache. He encouraged me not to beat this record.

“There’s a good one,” Webster said, bending down to pull off an ear. He was wearing long shorts, a plaid blue shirt and a wide-brimmed canvas hat. He had been fussing around among the stalks for a few minutes before he found an ear he liked. He seemed unhappy with the quality of the corn, muttering into his chest. In between picking some ears, I asked why he was down on the crop. “I believe I planted too soon,” he said. “The ground was still too damp.” This caused many of the ears to bloom improperly. I asked why he had planted so early. He said, “I had to be in Asia.” It occurred to me that attempting to stop a global epidemic was a reasonable excuse for a so-so batch of corn.

Webster was home this weekend for the first time in many weeks. He had been to Asia and back nearly a dozen times in the past year. I asked Marjorie Webster how often she sees him, and she replied, “Not much these days.” It is a sacrifice she seems willing to make; Webster has told her plenty about the bug and what it can do.

We picked corn for about half an hour, then went back to Webster’s home to do some shucking. He shucked at a pace nearly double mine. We must have shucked 250 ears of corn. We placed the shucked ears in a cooler of ice. By noon we had finished, so I decided to go do some sightseeing. Beale Street, Elvis impersonators, several barbecue joints. A little before 5 p.m., I wandered into the lobby of the Peabody Hotel, a landmark. I wanted to see the ducks. Since the 1930s, ducks have swum in a fountain in the hotel’s lobby. The ducks live upstairs in a sort of duck mansion. In the morning, they ride down in an elevator. When the elevator doors open in the lobby, the ducks wobble down a red carpet, single file, about 30 yards, in front of hundreds of people who snap photographs as if they were duck paparazzi. When the ducks plop into the fountain, people cheer. At 5 p.m., the ducks are done for the day; they wobble back along the carpet to the elevator, then ride back to their mansion for dinner. One generally has to witness the occasion to believe it.

I wondered whether Webster had ever tested these ducks. That evening, at the corn party, after my third ear, and Webster’s second, I told him that I had gone to see the ducks. “Oh, the Peabody ducks,” he said, the first time I’d seen him visibly happy in days. “The kids loved the ducks when they were little.” I asked whether he liked the ducks too. “Why not? I enjoy the ducks,” he said. I said, “Have you ever swabbed them?” He answered: “No. Sometimes you just don’t want to know. There are some ducks I won’t swab.”

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