Robert G. Webster is watching his 40-year-old hunch about the origin of pandemic influenza play out before his eyes. It would be thrilling if it were not so terrifying.
Four decades ago, Webster was a young microbiologist from New Zealand on a brief sojourn in London. While he was there, he did an experiment that pretty much set the course of his scientific career. In just a few hours, he showed that the microbe that swept the globe in 1957 as "Asian flu" bore an unmistakable resemblance to strains of virus carried by certain birds in the years before.
Webster's observation was a surprise -- and a troubling one. It suggested an origin of the unusually virulent strains of influenza virus that appear two or three times each century. His hunch, that at least some of these pandemic strains were hybrids of bird and human flu viruses, was correct.
Since then, Rob Webster has become arguably the world's most important eye on animal influenza viruses. These days, he is deeply worried about what he's seeing.
Strains of influenza virus known as A/H5N1 have been spreading in wild and domestic birds across Southeast Asia and China since 1996. In recent weeks, the virus has apparently struck poultry in Siberia and Kazakhstan.
Since late 2003, about 100 million domesticated birds -- mostly chickens and ducks -- either have died of the virus or have been intentionally killed to keep the viruses from spreading. But what has Webster and other experts so worried are the 112 people who have been infected with the H5N1 "bird flu," more than half of whom have died. The fatality rate of 55 percent outstrips any human flu epidemic on record, including the epochal Spanish flu of 1918 and 1919 that killed at least 50 million people.
Why this new virus is so deadly is not entirely understood, although scientists have hints.
Influenza viruses invade cells lining the throat and windpipe, where they replicate and cause inflammation but are eventually suppressed by the immune system. In some cases, the microbe invades the lungs and leads to viral or bacterial pneumonia. Some H5N1 strains, however, have two features that make them even more dangerous.
Normally, the flu viruses can replicate only in the throat and lungs. With H5N1, however, the protein that triggers replication can be activated in many other organs, including the liver, intestines and brain. What is usually a respiratory infection can suddenly become a whole-body infection. Simultaneously, a second "defect" in the virus unleashes a storm of immune-system chemicals called cytokines. In normal amounts, cytokines help fight microbial invaders. In excessive amounts, they can cause lethal damage to the body's own tissues.
The trait H5N1 has not acquired is the ability to spread easily from person to person. The 112 human cases since late 2003 may turn out to be simply rare events in a bird epidemic that will eventually subside, as all epidemics do.
What is worrisome, though, is evidence pointing the other way.
Working Full Tilt
Webster's insight about the origins of pandemic flu led to an unavoidable conclusion. If scientists had any hope of preventing the pandemics, they had to keep watch on influenza in many species, not just human beings.
Learning how the virus is changing in birds, and what it may need to get real traction in people, are what keep Webster, 73, working full tilt at an age when many people are slowing down or have retired.
"I probably have more energy than is good for me," he says, sitting in his glass-walled corner office that looks out over green suburbs.
Since 1968, he has been at St. Jude Children's Research Hospital in Memphis, a cancer hospital established by the late actor and comedian Danny Thomas in gratitude to the patron saint of hopeless causes, whom Thomas credited with rescuing his career. It's an unlikely landing spot for Webster, who grew up on a 240-acre farm on New Zealand's South Island. But then, he came to the object of his scientific work mostly by chance, too.
After getting a doctorate in microbiology at the Australian National University in Canberra, he went to work in the laboratory of Frank Fenner, an expert on pox viruses. (Fenner would later help lead the 10-year campaign that successfully eradicated smallpox.) Webster expected to work on that family of microbes.
"On the day I arrived, Frank had me into his office and said so-and-so needs help in influenza virus. That's where you're going to go," he recalled.
Today, Webster heads his own lab of four principal investigators, a dozen graduate students and post-doctoral researchers, and a $7 million annual budget. The lab has chambers for handling high-risk pathogens and uses nearly 3,000 fertile chicken eggs a week for growing influenza viruses. Elsewhere on the St. Jude campus is a small plant licensed by the Food and Drug Administration to make experimental vaccines. The "seed strain" of virus used to make an H5N1 vaccine now in human trials in the United States was made at St. Jude by one of Webster's colleagues, Erich Hoffmann.
Since 1997, Webster has also spent three months a year as a visiting professor at the University of Hong Kong. That gets him closer to the historical breeding ground of new flu strains: China. With H5N1 steadily gaining momentum this year, he has returned to Asia twice since his Hong Kong stint ended in March. One trip was to brief prime ministers of the Association of Southeast Asian Nations (ASEAN) about what they can to do to stanch the spread of H5N1.
The World Health Organization "will help in the initial outbreak," he says he told them. "But if it breaks through, guys, you're on your own."
On this day, Webster is back in Memphis. Pointed ears and a puckish smile give him the look of a superannuated pixie, perhaps a character out of "The Lord of the Rings," which was filmed on his native ground. But his words these days are dark, his outlook grim.
He thinks an avian flu pandemic "is just inevitable. One of these is just going to blow."
A Question of Opportunity
H5N1's potential as the next pandemic virus is all a matter of probability and opportunity.
Influenza A is a simple virus. That is one of the things that makes it so adaptable and potentially dangerous. It flourishes in hundreds of animal species with only 10 genes and a genome of 13,600 nucleotides, or "letters." (The human genetic code, in comparison, has about 25,000 genes and 3 billion nucleotides.) Of course, influenza virus needs more than 10 genes to replicate itself and spread. Like all viruses, it gets what it needs from the cells it invades, hijacking their molecular machinery.
Influenza A's adaptability arises, in part, because its genes are carried on eight unconnected strands, called "gene segments."
The segments can be traded like cards in a game of hearts, producing new strains of flu, the equivalent of new hands of cards. But that can happen only if two different viruses find themselves in the same cell, which is a very rare event. However, when millions of people, chickens and pigs -- the last animal can be infected by both human and bird influenza viruses -- live close together, as they do in China, rare events happen.
This gene-trading is called "reassortment." In the 1960s, Webster hypothesized that something like reassortment -- the process had not yet been discovered -- must explain the really big changes that appeared every once in a while in human flu viruses. This is the theory he tested in his London experiment decades ago.
There he asked for a little space at the National Institute for Medical Research at Mill Hill and access to the famous lab's collection of human serum and influenza viruses.
He mixed antibody-rich serum from victims of the 1957 flu pandemic with samples of avian flu viruses. In a matter of hours, he saw the human antibodies attack some of the microbes. This showed that the 1957 human virus shared features with some of the bird viruses.
"It's the only paper I've ever done based on just one day of experiments," he recalled recently, still both proud and amazed.
It turns out that of the Asian flu's eight gene segments, three had recently arrived from birds, according to an analysis of the genes' molecular fingerprints that was done much later. Two of the bird genes were for surface proteins that give a flu virus its immunological identity -- hemagglutinin and neuraminidase (denoted "H" and "N").
Something similar happened in 1968, when the Hong Kong flu strain got a new "H" from birds through reassortment, as well as a bird version of another, less important, gene segment. That strain, too, caused a pandemic.
Small Changes Add Up
The other way avian flu viruses can adapt to become human viruses is by slowly acquiring mutations. As small changes pile up, the virus's behavior can evolve. One trait that can appear is the capacity to enter human cells easily. That, and the ability to replicate efficiently once inside, are the two requirements for contagiousness.
Evolution of flu viruses is inevitable because the microbe is prone to making mistakes as it copies its genes. The more times a virus replicates, the more opportunity there is for a new mutation to arise that allows easy person-to-person transmission. For that reason, suppressing H5N1 outbreaks in birds -- where the microbe is replicating trillions of times a day -- is a crucial tool in preventing a human outbreak. China and Indonesia have vaccinated poultry flocks against H5N1, and Vietnam this month is starting a two-year, $35 million campaign to do so, too.
The highly lethal H5N1 viruses isolated from last year's human cases of avian flu were genetically 99 percent identical to each other. The slightly less lethal -- but perhaps more transmissible -- virus taken from patients in northern Vietnam early this year is only 98 percent identical to last year's; more important, it isn't completely inhibited by antibodies to last year's strain. It may be on its way to becoming a new, human-adapted strain.
But H5N1 flu isn't evolving just in human hosts. It's also changing in birds in a dangerous way.
Decades ago, Webster demonstrated that waterfowl are the true "home range" of influenza A viruses -- another of his key scientific contributions. For nearly 30 years, he and his colleagues have annually sampled wild ducks in the birds' nesting grounds in Alberta, looking for new flu strains. Since 1985, they have also sampled the feces of more than 5,000 migrating shorebirds along Delaware Bay.
H5N1 strains with slightly different traits have appeared several times in East Asia since the first one emerged in southern China in 1996. Last fall, while analyzing a strain circulating after an outbreak in Hong Kong in 2002, one of Webster's post-doctoral researchers, Diane Hulse, made an unusually important observation.
Many ducks experimentally infected with the virus didn't die, even though the strain was highly lethal to chickens. But one of the duck viruses was highly lethal to ferrets, the animal whose susceptibility mirrors that of people. This meant that killing infected chickens wasn't going to be enough to stop the spread of the microbe. Ducks could serve as a permanent reservoir of H5N1 virus.
Webster immediately informed officials at the WHO, who in turn sounded the alarm. They announced that ducks -- there are 2 billion domestic ones in East Asia -- might be "silent carriers" of H5N1 influenza strains potentially fatal to people.
The discovery by Hulse and Webster led, in part, to an extreme program Thailand mounted last November. About 70,000 investigators went into every village in the country looking for sick ducks and sampling the feces of healthy-looking ones. Flocks carrying H5N1 influenza virus were killed.
The strategy appears to have worked. Last year, Thailand had 12 human deaths from H5N1 flu. So far this year, it has had none.
Stretching out before Webster and public health experts is a long list chores the world must complete if it is to abort the bird-to-man transfer of disease he long ago proved could happen.
Last month, two teams of scientists based in China, one assisted by Webster, proved that H5N1 is now circulating in several species of migratory birds capable of carrying the virus to India, Australia and Central Asia. Tests announced last week suggest that some of those long-distance fliers have already carried H5N1 into Mongolia, where it hadn't been seen before.
A task equal in importance to charting the spread of H5N1 is developing and distributing a good duck vaccine for the billions of those birds in East Asia.
Those countries, which collectively are the likely ground zero of pandemic flu, also need to improve their disease surveillance. In particular, they need to develop laboratories capable of safely isolating and testing influenza viruses.
And while they are doing that, they -- and the rest of the world, Webster believes -- would be well advised to draw up a plan to limit human movement and distribute vaccine and antiviral drugs should a pandemic flu strain emerge despite the efforts to prevent it.
It's a long list with an uncertain deadline, and it's enough to keep Rob Webster at work.