Recombinomics Commentary 11:30
Recombinomics Commentary 04:40
In Steven Soderbergh's new bio-thriller, Contagion, the audience is kept guessing about the killer's identity until the final frame. Is it the mu shu pork that Gwyneth Paltrow consumed in a Kowloon diner or is it, as Laurence Fishburne, playing the deputy director of the Centres for Disease Control and Prevention, suggests, all the fault of the birds? "Someone doesn't have to weaponise the bird flu," he intones at one point. "The birds are doing that."
In the end, Soderbergh appears to have it both ways, suggesting that the culprit is a combination of bird flu and nipah, a bat-borne virus prevalent on Malaysian pig farms. In real life, however, there is little doubt about where the true threat lies.
"I haven't seen the film yet but bird flu is the real killer lurking in the shadows," says Robert Webster, the world's pre-eminent expert on bird flu, when I catch up with him en route from Oxford to Malta where he has back-to-back influenza conferences. "Nature has already shown us that there is a virus out there that kills 50% of the people it infects. We ignore it at our peril."
It is a warning that Webster, a virologist known as the "pope of bird flu", has been sounding for more than 50 years, initially to the scepticism of his peers but to growing respect more recently. The virus that keeps Webster awake at night is H5N1.
The bird flu virus first emerged as a public health risk in 1997 when it caused 16 human infections and six fatalities in Hong Kong, prompting Margaret Chan, Hong Kong's then director of public health and now director-general of the World Health Organisation, to close the territory's wet markets and initiate a mass poultry cull.
However, it was the resurgence of human infections in Thailand and Vietnam in 2003, followed by outbreaks on chicken farms across Asia, the Middle East and eastern Europe in 2005 that made H5N1 a household name, while the H1N1 swine-flu outbreak of 2009 prompted the World Health Organisation to declare a pandemic. "We were extremely lucky in 2009," he says.
"Nature didn't put in the killer genes, that's all."
At the same time, Webster insists, the threat from H5N1 has not gone away. On the contrary, if the latest the scientific data are to be believed, a new "mutant" strain of the virus, codenamed 2.3.2., has already moved from China and Vietnam to central Asia and eastern Europe, spread by migratory waterfowl.
Meanwhile, in H5N1 "hotspots" such as Egypt, where another variant is endemic in the poultry industry, the virus continues to kill people in significant numbers.
As Webster told an international gathering of flu experts at St Hilda's College, Oxford, earlier this month: "Highly pathogenic H5N1 avian influenza appears to be spreading into Eurasia again, most likely carried by wild bird migrations. It's only a matter of time before it comes to the Americas."
Webster, who is 79 and was raised on a farm in New Zealand, has spent half his life on the trail of bird flu. Based at the Department of Infectious Diseases at St Jude Children's Research Hospital in Memphis, where he presides over the world's only laboratory studying the human-animal interface in flu, Webster has incubated thousands of chicken's eggs in search of life-saving vaccines and has fostered the careers of scores of researchers.
"The world owes a huge debt to Bob," says Ilaria Capua, the director of the World Animal Health Organisation's national reference laboratory for avian influenza in Padua, Italy. "In many ways, he is both the father and mother of influenza."
These days, Webster spends much of the year in the field, travelling to bird flu hotspots such as China, Bangladesh and Indonesia. Together with his former colleague, the Australian flu researcher Graeme Laver, who died in 2008, Webster was the first to recognise that migratory waterfowl are the natural host of influenza viruses in the wild.
He and Laver began to develop the idea in the 1960s when they were walking along a beach on the southeastern coast of Australia and found the shoreline littered with dead mutton birds. In 1961, researchers had isolated an influenza virus – H5N1 as it happens – from dead terns in South Africa. They wondered whether the flu had also killed these birds.
With the aid of a $500 grant from the WHO, and backing from their department at the Australian National University in Canberra, Webster and Laver travelled to the Great Barrier Reef. There, accompanied by their wives and young children, they snorkelled by day and at night took swabs from the trachea and cloaca of hundreds of birds. Eighteen had antibodies to the Asian flu, the human virus that sparked the 1957 pandemic.
The question was: had the birds merely been exposed to the virus or were they also responsible for transmitting it? It was a question that would take Webster from Peru's guano islands to the lakes of north Canada, the Arctic Circle and other locations where birds migrated in large numbers. But the Eureka moment came in his own backyard. "We had travelled the world and got nothing," Webster recalls. "Then someone in my lab mentioned it was duck hunting season in Memphis."
Webster and a colleague took their swabbing equipment to a bait shop by the Mississippi river and sat beside two women whose job it was to pluck the birds. By the end of the hunting season, they had found the missing link: 5% of the ducks were carrying the flu virus. The following year, they travelled to the ducks' migratory grounds in Alberta and found that up to a quarter of the birds were infected.
But though it was killing the mutton birds and terns, the virus was not affecting the ducks. On the contrary, they appeared perfectly healthy.
Webster had found his "Trojan duck". Ducks, he explains, harbour and replicate the virus in the wild, transmitting it to chickens and other poultry whenever they defecate in open water. But while H5N1 and other wild viruses, such as H9N2 and H7N7, are deadly to farmed poultry, most ducks do not get sick at all. To date, researchers have identified 16 haemagglutinin (HA) subtypes in aquatic bird populations. These subtypes are constantly circulating and altering their genetic make-up via a mechanism known as antigenic drift..
However, perhaps Webster's greatest contribution to science lies in his insight that pandemics begin when avian and human flu virus "reassort" or exchange genes to form a new strain, one that people lack the ability to fight. Webster, a fellow of the Royal Society, calls this process "viral sex".
In the last 100 years, it has happened five times. The first and most calamitous occasion was in 1918-19 when an H1N1 virus caused a pandemic that killed an estimated 50 million people. In 1957 and 1968, it happened again, resulting in 1 million to 4 million deaths.
The most recent reassortment event was in 2009, when a virus distantly related to the 1918 pandemic strain caused a worldwide alert, triggering the activation of international pandemic response plans and the production of billions of pounds' worth of drugs and vaccines.
Scientists are still uncertain what prompted the reassortment and why Mexico was the centre – H1N1 was what scientists call a "triple reassortant", containing genes from a human flu, and genes from both north American and Eurasian strains of swine flu.
Despite having invested millions in disease surveillance since the 1990s, Webster says the virus caught flu-watchers with their "pants down". "In 2009, we were focused on H5N1. We just did not imagine that a variant of H1N1 would suddenly appear because the virus had been stable for years. It was in its monogamous phase. The view was that it couldn't mate with other viruses."
But if the 2009 swine-origin virus forced flu researchers to reassess their knowledge of flu and gave them a new appreciation of its shape-shifting abilities, the broader public remains for the most part uninformed.
With around 18,000 deaths from swine flu worldwide to date – about half the number who die from seasonal flu in the US every winter – scepticism over the threat of a flu pandemic is at an all-time high.
"At the moment, politicians have no interest in flu and you can't blame them. No one is dying," says Webster. "When bird flu gets to the US, however, I predict people will wake up to the need for vaccination pretty quickly."
For Webster, that is only a matter of time. Since 2003, H5N1 has infected 565 people and killed 331, a mortality rate of close to 60%. It has also killed or forced the culling of more than 400 million domestic poultry and cost an estimated $20bn.
Last month, the UN's Food and Agriculture Organisation (FAO) urged renewed vigilance after reports that a six-year-old Cambodian girl had died from bird flu, the eighth person to die from H5N1 in the country this year. At the same time, the FAO reported that wild birds appeared to have reintroduced H5N1 to countries that had been virus-free for several years, including Israel, the Palestinian territories, Bulgaria, Romania, Nepal and Mongolia.
However, the agency said its biggest concern was the appearance of the new 2.3.2. group of viruses in China and Vietnam, and the associated risk that migratory waterfowl could carry the virus further afield, leading to a resurgence of "backyard" poultry infections across the Middle East and Europe, as had occurred in 2005-6.
Webster believes the focus on 2.3.2. is premature. He is more worried about the related 2.2.1 strain that is endemic in Egypt's poultry industry (there have already been 32 human infections and 12 deaths this year, the highest of any country in the world). Concern is mounting in Bangladesh over the prevalence of another virus – H9N2 – that is endemic to live bird markets.
Webster argues that we need to know more about the duck's role in perpetuating viruses in the wild. "These viruses could be coming out of chickens and the ducks are just picking it up in the water or it could be that the duck is transferring the virus to its young when it breeds. We just don't have a good answer to that."
In the absence of better data, the only way to be safe is to vaccinate ducks too, but in China, where backyard poultry farms are vital to the rural economy and ducks range freely in paddy fields, vaccination is anathema to most farmers. Characteristically, Webster, who grew up raising Khaki Campbell ducks on his parents' New Zealand farm, finds this "perfectly understandable".
"If my ducks are healthy and laying eggs, why should I spend money on vaccines?" he asks. "The Trojan duck is really the key to controlling the problem."
Capua and others are not so sure. At the influenza conference in Oxford, concerns centred on the lack of targeted vaccine programmes and what many speakers saw as the faltering resolve of Asian governments. "We ought to have eradicated these viruses by now, at least in farmed poultry," argues Capua. "That we haven't speaks to the need for closer co-operation between the medical and the animal health community."
In the immediate instance, however, Soderbergh's film may prove the best way of galvanising action. With its lingering shots of viruses attaching to seemingly innocent objects, such as bus stops and cocktail glasses, and its apocalyptic scenes of societal breakdown, Contagion has been hailed as a "grown-up bio-thriller for modern times". And Webster acknowledges that "to the extent that it may scare people, it could be useful".
"What people don't appreciate is that H5N1 has already been the cause of a chicken apocalypse. Once it learns to go human to human there'll be no stopping the damn thing."
Recombinomics Commentary 19:11
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