The Flu Hunters: Racing to Outsmart a Pandemic
By Eben Harrell / London Monday, Aug. 10, 2009
On April 25, Rod Daniels, the Deputy Director of the World Influenza Center in London, was at a meeting in Germany when he received a call from a co-worker: an influenza outbreak had been reported in Mexico and the first samples of the virus were on their way to London for examination. A virologist who has studied flu for over 30 years, Daniels knew exactly what he was looking for. Influenza A viruses ? the type that can cause pandemics ? use a protein called hemagglutinin to bind to the cells of their animal hosts. When a virus jumps from animals to humans, its contagiousness is largely determined by what is called the "binding specificity" of this protein. An Alpha-2,3 binding specificity means the virus is well suited to the cells in an animal respiratory tract, but probably not human cells. An Alpha-2,6 binding specificity, on the other hand, means the virus can easily bind to human cells.
"I got back to the lab and as soon as we saw a sequence of the hemagglutinin, we looked at the receptor binding site and found indications of an Alpha-2,6 binding specificity," Daniels, 54, remembers. "I knew then ? we have a problem."
Four months later, and the human race is entrenched in a battle with the H1N1 2009 pandemic virus, with infections reported in 168 countries. In this mortal contest, it's the job of Daniels and his fellow virologists to decode the opponent's playbook. Working in a grim, 1930s building in London's northern suburbs (its exterior was used to portray an insane asylum in the blockbuster Batman Begins), scientists at the World Influenza Centre receive virus samples from around the world and use sophisticated machinery to map out their genetic structures. During normal years, the scientists concoct the recipe that the World Health Organization (WHO) uses for seasonal flu vaccines. But in a pandemic year, they become vigilantes looking for any changes in the virus that could alter the course of the pandemic.
"Right now this pandemic would appear to be a mild one," says the center's director Alan Hay, 65. "But influenza viruses can change quite suddenly. And there's no reason another, more dangerous, virus couldn't emerge with pandemic potential. It's crucial that we keep our eye on the ball."
Flu's hardiness as a human scourge is the result, paradoxically, of the instability of its genetic structure. One flu virus can easily swap genetic information with another, or mutate as it reproduces. The World Influenza Centre is one of five WHO centers (there are others in Atlanta, Tokyo and Melbourne, and a lab specializing in animal influenza in Memphis) that form the hub of a global influenza surveillance network. The center receives samples taken from ill patients in over 100 countries. By examining the genetic makeup of the viruses in these samples, scientists can make educated guesses about how lethal and contagious a pandemic will be. But they are only guesses. While exhaustive, 21st-century virology can explain and illustrate what's already happened ? and help health officials react ? the only valid, real-time laboratory is the human population itself.
"If we get reports of a more severe infection with higher mortality rates, we can map the changes that made the virus more severe and monitor its spread. That could help health officials formulate policies," says Hay. "But we are always playing catch-up with flu. It's impossible to stay ahead of this virus."
According to WHO figures, the H1N1 virus has so far proved to be mild, causing only 1,200 deaths in 160,000 confirmed cases. Hay says his team is watching for several changes in the virus' genome that could make the pandemic more severe. The first involves the H1N1 vaccine that is currently in production. The batch is based on a recipe that Hay's team helped put together in April. As it takes six months to produce a vaccine, virologists must be on the lookout for an "antigenic drift" ? changes in the virus that would allow it to escape the immune responses induced by the vaccine. (Because the flu virus can mutate so easily, antigenic drift is not unusual.)
Hay's team is also on the lookout for changes in the virus that might make it resistant to the antiviral drug Tamiflu, which has been shown to reduce the severity of the disease caused by many flu viruses. Tamiflu works by inhibiting the Neuraminidase enzyme (that's the N in H1N1) and preventing it from doing its job of helping the virus replicate once inside a human cell. But certain amino acid changes in the Neuraminidase can render Tamiflu ineffective. This usually happens over time following extensive prescribing of the drug, but it can occur spontaneously. In the winter of 2007-08, a seasonal H1N1 variant circulating in Europe did just that, catching scientists by surprise. "We really didn't see that coming," says Daniels, who was one of the first scientists to identify the change. "Suddenly, an increasing number of H1N1 isolates were Tamiflu-resistant and the resistant strains have persisted such that over 95% of H1N1 virus in America was [Tamiflu] resistant in the 2008-09 season. And it doesn't appear to have had anything to do with over-prescription of the drug. It was just a spontaneous mutation."
Hay says the nightmare scenario would involve the pandemic appearance of the highly pathogenic H5N1 avian influenza. With a mortality rate of over 60%, the virus is so dangerous to humans that his team can only work with it in biosecurity level 4 laboratories, the highest level of biological containment available. So far, H5N1 is only passed to humans from birds, and is not transmissible between humans. But if it were to swap genes with another influenza virus, possibly H1N1 (through, for example, a patient who contracts the two illnesses simultaneously), a new, more lethal pandemic strain could emerge with a high rate of contagion. "I would say that is an unlikely scenario," Hay says. "But the point is you don't know what's going to happen. You have to remain alert to all possibilities."
Hay and Daniels have spent the bulk of their working lives searching for a virus that could cause a pandemic. Now they are watching a pandemic unfold in front of their eyes. When he talks about influenza, Daniels tends to use his hand as a visual aid, cupping his palm to mimic the virus' spherical structure and pretending his curled fingers are the sphere's protein spikes. As he looks down at his hand, his face breaks into a wry smile. "Forget the pandemic strain for a second and consider seasonal flu," he says. "How this virus can continue to evolve, maintain its viability no matter what we throw at it, and cause us problems on an annual basis ? it's just mind blowing. I'll say this about it ? it's a worthy adversary."
http://www.time.com/time/world/article/0,8599,1915516,00.html
By Eben Harrell / London Monday, Aug. 10, 2009
On April 25, Rod Daniels, the Deputy Director of the World Influenza Center in London, was at a meeting in Germany when he received a call from a co-worker: an influenza outbreak had been reported in Mexico and the first samples of the virus were on their way to London for examination. A virologist who has studied flu for over 30 years, Daniels knew exactly what he was looking for. Influenza A viruses ? the type that can cause pandemics ? use a protein called hemagglutinin to bind to the cells of their animal hosts. When a virus jumps from animals to humans, its contagiousness is largely determined by what is called the "binding specificity" of this protein. An Alpha-2,3 binding specificity means the virus is well suited to the cells in an animal respiratory tract, but probably not human cells. An Alpha-2,6 binding specificity, on the other hand, means the virus can easily bind to human cells.
"I got back to the lab and as soon as we saw a sequence of the hemagglutinin, we looked at the receptor binding site and found indications of an Alpha-2,6 binding specificity," Daniels, 54, remembers. "I knew then ? we have a problem."
Four months later, and the human race is entrenched in a battle with the H1N1 2009 pandemic virus, with infections reported in 168 countries. In this mortal contest, it's the job of Daniels and his fellow virologists to decode the opponent's playbook. Working in a grim, 1930s building in London's northern suburbs (its exterior was used to portray an insane asylum in the blockbuster Batman Begins), scientists at the World Influenza Centre receive virus samples from around the world and use sophisticated machinery to map out their genetic structures. During normal years, the scientists concoct the recipe that the World Health Organization (WHO) uses for seasonal flu vaccines. But in a pandemic year, they become vigilantes looking for any changes in the virus that could alter the course of the pandemic.
"Right now this pandemic would appear to be a mild one," says the center's director Alan Hay, 65. "But influenza viruses can change quite suddenly. And there's no reason another, more dangerous, virus couldn't emerge with pandemic potential. It's crucial that we keep our eye on the ball."
Flu's hardiness as a human scourge is the result, paradoxically, of the instability of its genetic structure. One flu virus can easily swap genetic information with another, or mutate as it reproduces. The World Influenza Centre is one of five WHO centers (there are others in Atlanta, Tokyo and Melbourne, and a lab specializing in animal influenza in Memphis) that form the hub of a global influenza surveillance network. The center receives samples taken from ill patients in over 100 countries. By examining the genetic makeup of the viruses in these samples, scientists can make educated guesses about how lethal and contagious a pandemic will be. But they are only guesses. While exhaustive, 21st-century virology can explain and illustrate what's already happened ? and help health officials react ? the only valid, real-time laboratory is the human population itself.
"If we get reports of a more severe infection with higher mortality rates, we can map the changes that made the virus more severe and monitor its spread. That could help health officials formulate policies," says Hay. "But we are always playing catch-up with flu. It's impossible to stay ahead of this virus."
According to WHO figures, the H1N1 virus has so far proved to be mild, causing only 1,200 deaths in 160,000 confirmed cases. Hay says his team is watching for several changes in the virus' genome that could make the pandemic more severe. The first involves the H1N1 vaccine that is currently in production. The batch is based on a recipe that Hay's team helped put together in April. As it takes six months to produce a vaccine, virologists must be on the lookout for an "antigenic drift" ? changes in the virus that would allow it to escape the immune responses induced by the vaccine. (Because the flu virus can mutate so easily, antigenic drift is not unusual.)
Hay's team is also on the lookout for changes in the virus that might make it resistant to the antiviral drug Tamiflu, which has been shown to reduce the severity of the disease caused by many flu viruses. Tamiflu works by inhibiting the Neuraminidase enzyme (that's the N in H1N1) and preventing it from doing its job of helping the virus replicate once inside a human cell. But certain amino acid changes in the Neuraminidase can render Tamiflu ineffective. This usually happens over time following extensive prescribing of the drug, but it can occur spontaneously. In the winter of 2007-08, a seasonal H1N1 variant circulating in Europe did just that, catching scientists by surprise. "We really didn't see that coming," says Daniels, who was one of the first scientists to identify the change. "Suddenly, an increasing number of H1N1 isolates were Tamiflu-resistant and the resistant strains have persisted such that over 95% of H1N1 virus in America was [Tamiflu] resistant in the 2008-09 season. And it doesn't appear to have had anything to do with over-prescription of the drug. It was just a spontaneous mutation."
Hay says the nightmare scenario would involve the pandemic appearance of the highly pathogenic H5N1 avian influenza. With a mortality rate of over 60%, the virus is so dangerous to humans that his team can only work with it in biosecurity level 4 laboratories, the highest level of biological containment available. So far, H5N1 is only passed to humans from birds, and is not transmissible between humans. But if it were to swap genes with another influenza virus, possibly H1N1 (through, for example, a patient who contracts the two illnesses simultaneously), a new, more lethal pandemic strain could emerge with a high rate of contagion. "I would say that is an unlikely scenario," Hay says. "But the point is you don't know what's going to happen. You have to remain alert to all possibilities."
Hay and Daniels have spent the bulk of their working lives searching for a virus that could cause a pandemic. Now they are watching a pandemic unfold in front of their eyes. When he talks about influenza, Daniels tends to use his hand as a visual aid, cupping his palm to mimic the virus' spherical structure and pretending his curled fingers are the sphere's protein spikes. As he looks down at his hand, his face breaks into a wry smile. "Forget the pandemic strain for a second and consider seasonal flu," he says. "How this virus can continue to evolve, maintain its viability no matter what we throw at it, and cause us problems on an annual basis ? it's just mind blowing. I'll say this about it ? it's a worthy adversary."
http://www.time.com/time/world/article/0,8599,1915516,00.html