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Man Who Sequenced Spanish Flu Virus Seeks More Clues About the Killer Bug

Posted on: Saturday, 15 April 2006, 15:00 CDT

By HELEN BRANSWELL

(CP) - Influenza experts trying to forecast the future path of the worrisome H5N1 avian flu virus do so in the face of an unsettling number of unknowns.

What little is understood about influenza pandemics - and it is by no means sure H5N1 will cause one - has been puzzled out in recent years based on viral and epidemiologic excavations of the three pandemics of the last century.

Even less is known about how the viruses that caused those pandemics emerged from their natural hosts, aquatic birds, and adapted to become efficient human pathogens.

Dr. Jeffery Taubenberger is hoping to add new pieces to the biggest pandemic puzzle of the three, the 1918 Spanish Flu, by tracing how the virus evolved in the years before 1918 and then through the various waves of disease that pandemic provoked.

"There's a lot of work to do," says Taubenberger, the scientist who led the historic project to tease tiny fragments of the 1918 virus from preserved lung tissue of long-dead victims, using those precious traces to chart the full genetic blueprint of a virus believed to have killed upwards of 40 million people worldwide.

"I'm really, in a sense, very tired of this arche-virology, because it's just so slow and painful," admits Taubenberger, who is chair of molecular pathology at the U.S. Armed Forces Institute of Pathology in Rockville, Md.

"But I feel that it's absolutely essential to answer a lot of the questions that we want to know about 1918. And then extend those answers or apply what we learn to the more generalizable rules about how it is pandemics form and how they evolve."

Years of work by Taubenberger and colleagues in his laboratory culminated last fall in the publication of an analysis of the final three genes of the 1918 virus to be sequenced.

Completion of the work allowed researchers from the U.S. Centers for Disease Control in Atlanta and Mt. Sinai School of Medicine in New York to reconstruct each of the eight genes and reassemble the deadly H1N1 virus in a bid to coax from it the secrets of its virulence. That work is progressing at high security labs at the CDC.

But Taubenberger is continuing the search for additional virus samples that could provide strong clues as to how the 1918 H1N1 became so deadly. New findings could help researchers spot emerging pandemic menaces in the future.

He also hopes the process will answer the mystery of whether H1N1 jumped directly from birds to people, or adapted first in some other mammalian host.

The Spanish flu virus that Taubenberger's team sequenced was drawn from the second, most lethal wave of that pandemic, which occurred in North America in the fall of 1918.

Comparing it to viruses from the years preceding the pandemic, the milder first and third waves as well as others from the years immediately after the pandemic could bring into focus mutations that allowed the hyper-virulence to develop and then wane.

"If it's really true that its loss was due to a change in the virus, if we find say a 1923 case and sequence across, any differences could be really important," Taubenberger says.

Infectious disease expert Dr. Michael Osterholm thinks pre-pandemic study may be more fruitful as the decrease in virulence may have had more to do with expanding immunity in people than with mutations.

"If I had a choice of knowing the front side or the back side changes (in the virus) I'd want to know the front side," he says. "That would be more powerful (proof)."

Taubenberger expects preserved tissue samples from the Royal London Hospital will offer up some of these viruses for study.

In fact, his lab has already managed to snag a fragment of an influenza A virus - all known pandemics have been caused by influenza A viruses - from a sample preserved in 1915.

"We know for sure that we have a pre-1918 case that has at least a tiny, tiny - underline tiny - fragment of influenza RNA," he says.

It remains to be seen whether Taubenberger's team has enough material to do more in-depth genetic analysis of the virus. "It's a difficult problem. But we're trying that right now. We're working on that."

Even if that effort should fail, Taubenberger has identified another 200 cases from the hospital's preserved tissue bank he thinks were likely influenza deaths.

"And I feel confident that when we screen these 200 cases that we will find (influenza) cases."

In tandem with this work his team will investigate ways to sequence more quickly any viral samples found.

"All of this is incredibly painful. It's not like saying: Oh, I have a viral isolate from a patient's nose today and next week we can have the full genomic sequence," Taubenberger says of the work his team undertakes.

"So we're also trying to look at the possibility of some new approaches to sequencing that might be faster . . . so we don't have to wait another nine years before we know that there's a difference."

Source: Canadian Press

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