Genetic coding posted online helps decipher new flu

By Faye Flam
The Philadelphia Inquirer

WASHINGTON — Within days of recognizing that a flu virus might be killing healthy young people in Mexico, scientists were able to decipher its genetic fingerprint and post it on the Web.

The unprecedented speed of that decoding showed early on that the world was confronting a new virus — one for which humans might have little or no immunity. The genetic sleuthing is starting to reveal where this virus came from and is guiding the race to create a vaccine.

Government scientists made the first genetic sequences public last Monday. By Thursday, genetic information was available on viruses from 17 different cases, said University of Pennsylvania virologist Paul Bates.

Multiple samples helped confirm that these all were part of the same outbreak, he said. They also may show how fast the virus is evolving - something scientists are rushing to figure out.

One thing that was clear right away was that this flu virus had undergone major changes called "shifts."

Ordinary seasonal flu changes slowly through "drift" — minor mutations that alter the viruses just enough to require new vaccines each year. Shifts are much more dramatic, said Hildegund Ertl, a virus expert at the Wistar Institute in Philadelphia, and often lead to new viruses with hard-to-predict trajectories.

"Shifting viruses are the types that can start pandemics," Ertl said.

That doesn't mean the new virus will cause widespread devastation, she said. It's much too soon to know. But the fact that this flu is both easily spread and novel helps explain the seriousness with which health officials are responding.

At Columbia University, biologist Raul Rabadan downloaded the genetic sequence last Monday and has been busy using it to trace the convoluted history of the virus.

"We're trying to understand the science — how these viruses mix, why they're dangerous, and what makes them dangerous," he said. He lauded the World Health Organization and the Centers for Disease Control and Prevention for releasing the sequences promptly.

Like a crime lab with a large DNA file on past offenders, the WHO maintains a massive database of known flu viruses.

"All around the world, WHO has surveillance stations, listening posts where they collect flu specimens from different species — ducks, geese, pigs, and people," Bates said.

Scientists can read the genetic codes of these samples within a day or so, using a technology called high throughput sequencing that was developed during the 1990s as part of the Human Genome Project.

Influenza viruses don't carry DNA, but a related genetic-code carrier called RNA. Indeed, viruses are not technically considered organisms in themselves, but carry bits of coded RNA that are good at replicating themselves.

Flu viruses are all little packages of RNA, divided into eight distinct segments. They can replicate this RNA only inside the cells of an animal.

By comparing this flu's genetic code with others in the database, Rabadan found that it had elements of two previously known swine viruses, one from Europe or Asia, the other from North America. The combination probably was created when two strains infected the same pig at the same time.

It's not clear how this happened. But any time two viruses get into the same cell, they can start to swap some of their eight pieces of RNA.

New viruses can then emerge with different combinations of these eight segments — two parts from one and six from the other, say, or five from one and three from the other. More than 100 combinations are possible.

"It's like a puzzle with eight pieces," Rabadan said.

Most of the new combinations will die out, but one may turn out to be good at spreading itself around.

This new virus, (A)H1N1, assembled itself from two segments from the Eurasian virus and six from the North American one.

There's still more to the story, Rabadan said. The North American strain of swine flu alone has a complicated history. Discovered in 1998, it appears to have come from what he calls a triple reassortment, a mixing of segments from a previously known swine flu with a human and bird virus.

Included in the database of genetic sequences is one from the 1918 pandemic flu. Scientists managed to get this by reconstituting the virus from a woman who had been infected and then frozen in the Alaskan tundra.

Sequencing the genes showed that all eight segments of the 1918 flu came from birds, Bates said.

Despite its very different genetics, (A)H1N1 may be a distant echo of the 1918 pandemic, said David Morens, an epidemiologist at the National Institute of Allergy and Infectious Diseases.

"All pig H1N1 viruses ultimately can be traced to the 1918 human virus," he said, the prevailing wisdom being that pigs caught that virus from humans and that since then it has been coursing through the pig population, mutating and combining with other viruses.

Morens said flu pandemics have been happening at least since 1510, but there were no recorded outbreaks among pigs until after 1918. Previous pig outbreaks could have gone unrecorded, he said, but swine flu also might have emerged only after the introduction of high-intensity pig farming.

"The opportunity for epizootics [animal epidemics] to occur was limited before the days pig farmers had thousands of pigs crammed together," he said.

One of the goals for scientists now is to watch how the new flu is evolving, Bates said.

Other genes may give clues to how virulent this flu will turn out to be, and whether it will develop resistance to antiviral drugs such as tamiflu.

Bates and others also will be watching to see if the new flu combines with an existing human flu known to be resistant to antiviral drugs. A resistant flu was one of the seasonal strains last year.

If those two viruses combine, the situation could get much more serious. But the viral sleuths will be working to crack the case.

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