LA TIMES OFFERS THIS OPINION ON BIRD FLU

What Darwin has to say about bird flu
Can the disease mutate into a widespread threat to humans? Possibly, but it won't happen overnight.

By Wendy Orent, WENDY ORENT is the author of "Plague: The Mysterious Past and Terrifying Future of the World's Most Dangerous Disease."May 28, 2006

THERE'S A LOT OF bird flu virus out there. Despite encouraging news from Vietnam and Thailand, neither of which has reported any bird or human cases of the lethal H5N1 strain this year, the situation in Indonesia continues to worsen. Eight members of a family contracted the disease, and seven of them died this month. The timing suggests person-to-person transmission. Although not the first instance of such transmission, it's the single largest cluster that has been seen, according to virologist Earl Brown of the University of Ottawa. Indonesia appears to lack the resources to combat the disease.The virus is also active in Egypt and has spread to Israel, Jordan and the territories where Palestinians live. Africa has a wide belt of infection. With the disease spread over so much of the world, more people in contact with sick birds means more opportunities for humans to catch the virus. This appears how human influenza pandemics have begun — through human contact with sick birds.

But the factors that set off a pandemic remain unknown. No one has ever tracked the evolution of a new pandemic. All we have seen — in 1918, 1957 and 1968 — is the aftermath of that evolution. Still, we are told that all it would take for H5N1 to become a pandemic would be for the virus to mutate so it could spread in a sustained way from person to person. This is known as "mutation to transmissibility." This phrase has appeared countless times in news reports. It's a warning. It's also boilerplate. What does it really mean?Part of the problem is that "mutate to transmissibility" means different things to different people. To Peter Palese, chairman of the department of microbiology at Mount Sinai School of Medicine, who has studied influenza viruses for 35 years, the phrase makes sense. "These mutations [to make the disease transmissible from human to human] could happen in a chicken. It's not likely, but it cannot be excluded."Palese recognizes that many mutations would be necessary for a virus to switch from a chicken virus to a human one. But, he adds, the genetics of transmission are "one of the black boxes of human influenza research."The H5N1 virus faces several barriers in jumping to and transmitting among humans. The most important is its ability to replicate in and adapt to human tissues, specifically the upper respiratory tract (not in deep lung tissue, where it now seems to grow). In the windpipe, the virus would be more likely to spread in a cough or sneeze, infecting other humans.Palese thinks that bird flu mutations are sitting in the evolutionary driver's seat — that a combination of the right host switches in this most mutable of viruses could set things off. Still, that's a long way from a single mutational switch — say, from chicken to human — triggering a pandemic. But things may be more complicated.To Brown, H5N1 mutations are not enough. They have to occur in the right context. "It's hard to get infected with this [H5N1] virus," he said. "You need a large dose of it to ensure the presence of some mutant strains suitable for growing in mammals." According to Brown, several different mutations on different genes seem to be involved in a virus moving from one host to another. Bird flu strains he's passed through laboratory mice have changed in ways similar to what has been seen in certain cases of the human H5N1 virus, suggesting that the changes may be significant for the strain's adaptation to mammals. Some mutant strains have appeared repeatedly and independently in different humans infected with the bird flu virus. In one patient in Turkey, about half the H5N1 strains detected appeared to be viruses that had adapted to humans. But, as Brown points out, the changes were a dead end — the victim died without passing on the disease.Brown recognizes what seems to elude most people who worry about pandemic outbreaks: What's necessary to produce a human-adapted virus is humans — a series of person-to-person infections. Without that chain of transmission, any human adaptation of H5N1 is difficult to imagine. Here is where communication between those who fear an overnight pandemic and those who believe the process will be longer, slower and more controllable breaks down. If we think H5N1 mutations alone drive escalation to a human-adapted virus, all that's necessary for a pandemic is for the right combination of genes to line up in a sort of viral slot machine.IN A CASINO, the house usually wins, but occasionally someone hits the jackpot. It's the law of large numbers — given enough time and enough opportunity, viral mutation will toss up a deadly combination. No one wants to win the bird flu slot-machine game. If the genes happen to line up and a vulnerable human happens to be the host in the right place, the disease takes off and a pandemic explodes. Given how mutable the H5N1 virus is, the thinking goes, at some point this is inevitable.But as Brown knows, evolution doesn't work this way. Gene mutation isn't in the driver's seat. Rather, it's Darwin's charioteer — natural selection — that drives evolution. Mutations are the raw material of evolutionary change. They don't determine which direction the chariot will go.Any successful H5N1 mutation must interact with other viral genes in a human host to improve its ability to infect the host. This is an adaptive process — and it is true whether the new virus arises directly through mutation or even through recombination with a common flu strain. H5N1 is beautifully, tragically adapted to chickens and has proved a monstrous predator. It evolved this way by preying on chickens packed into huge commercial chicken farms in Asia.The bird flu virus is still at the starting gate when it comes to humans. But should any strain of H5N1 manage to survive many sequential transmissions, Darwin's charioteer may drive off. The best transmitters will be favored by selection, as evolutionary biologist Paul W. Ewald of the University of Louisville contends. The process will continue, human by human, until a fully human-adapted, explosive strain emerges.This process of adaptation is probably how pandemics begin. The World Health Organization recently proposed a plan to move experts and resources to any area afflicted with clusters of viral infection; a plan that, given this evolutionary logic, makes eminent sense. At the beginning, viral adaptation to a host is slow. A disease just beginning to transmit is controllable. Surveillance, flexibility, willingness to impose or undergo quarantines, along with international cooperation, will be necessary to stop pandemic flu — or any other disease moving from animals to humans — before Darwin's driver gets ahead of us and nothing can be done.