A scientist's hunch from 40 years ago about the spread of influenza could provide the basis for a defence against a new pandemic. David Brown reports
Robert 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, 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 south-east 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 killed to keep the viruses from spreading. But what worries Webster and other experts 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 per cent 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.
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.
Since 1968, Webster (73), has been based at a cancer hospital, St Jude Children's Research Hospital in Memphis, Tennessee, where he heads his own lab of four principal investigators, a dozen graduate students and post-doctoral researchers, and a $7 million annual budget.
Webster thinks an avian flu pandemic "is just inevitable. One of these is just going to blow".
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 three 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.
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 behaviour 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 (€ million) campaign to do so.
The highly lethal H5N1 viruses isolated from last year's human cases of avian flu were genetically 99 per cent identical to each other. The slightly less lethal - but perhaps more transmissible - virus taken from patients in Vietnam early this year is only 98 per cent 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.
H5N1 strains with slightly different traits have appeared several times in east Asia since the first one emerged in southern China in 1996. Last autumn, while analyzing a strain circulating after an outbreak in Hong Kong in 2002, one of Webster's 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.
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 of 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.
Those countries, which collectively are the likely ground zero of pandemic flu, also need to improve their disease surveillance.
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.