Kolata: Looking for Bugs in All the Wrong Places

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Hazard in Hunt for New Flu: Looking for Bugs in All the Wrong Places

By GINA KOLATA

Science moves in mysterious ways, and sometimes what seems like the

end of the story is really just the beginning. Or, at least, that is

what some researchers are thinking as they scratch their heads over

the weird genetic sequence of the 1918 flu virus.

Dr. Jeffery Taubenberger, a molecular pathologist at the Armed Forces

Institute of Technology who led the research team that reconstructed

the long-extinct virus, said that a few things seemed clear.

The 1918 virus appears to be a bird flu virus. But if it is from a

bird, it is not a bird anyone has studied before. It is not like the A

(H5N1) strain of bird flus in Asia, which has sickened at least 116

people, and killed 60. It is not like the influenza viruses that

infect fowl in North America.

Yet many researchers believe that the 1918 virus, which caused the

worst infectious disease epidemic in human history, is a bird flu

virus. And if so, it is the only one that has ever been known to

cause a human pandemic.

That, Dr. Taubenberger said, gives rise to a question. Are scientists

looking for the next pandemic flu virus in all the wrong places? Is

there a bird that no one ever thought about that harbors the next

1918-like flu? And if so, what bird is it, and where does it live?

" I can't even assign a hemisphere, " he said. " It just came from

somewhere else. Maybe it's in pigeons. Or in songbirds. "

" It's weird, it's really weird, " he added. " My view is to be

undogmatic as possible and just try to follow the data. This is the

result we get. The question is, What does it mean? "

Dr. Taubenberger's question emerged from the science fiction-like

search for the 1918 virus that eventually led to its reconstruction.

A decade ago, Dr. Taubenberger and his colleagues found shards of the

extinct virus in two fingernail-size snippets of formaldehyde-soaked

lung tissue from two soldiers and from the frozen lung of an Inuit

woman who died of the flu in 1918 and was buried in permafrost.

Slowly and painstakingly, they fished out the tiny fragments of viral

genes and began reconstructing them.

The first gene they sequenced was the one that codes for the

hemagglutinin protein on the virus's surface. Immediately, Dr.

Taubenberger and his colleagues were struck by an oddity: the chain

of nucleotides that coded for the amino acids in the protein were

arranged differently from those found in any other bird flu.

The genetic code is flexible; there is more than one way that a group

of three nucleotides can be arranged to code for the same amino acid.

But every bird flu virus ever studied used the same spellings for the

hemagglutinin amino acids. Not the 1918 flu.

There were two possibilities, Dr. Taubenberger thought. One was that

bird flus have evolved over the decades and that back in 1918, the

amino acids in bird viruses were simply coded differently.

Another was that if the 1918 flu virus came from a bird, it was no

bird that anyone had considered before.

" We decided there was no way to address this, " Dr. Taubenberger said.

After all, the birds from 1918 were long gone, and their viruses had

died with them.

Then Dr. Fanning, a scientist in Dr. Taubenberger's group,

mentioned that he had a friend at the sonian who worked at the

National Museum of Natural History in Washington. It had several

thousand preserved birds from the early 20th century that were

floating in Mason jars of alcohol.

From there, they reached P. Dean, a supervisor in the division

of birds at the museum, who sent Dr. Taubenberger a computer printout

of the birds in the museum's collection - hundreds of birds, with

notes telling the species and the exact times and places where they

were collected. But which to choose?

Dr. Taubenberger consulted with one of the leading experts on bird

flus, Slemons of Ohio State, who chose 40 birds on the

museum's list, all waterfowl collected around 1918. The museum found

25 of them.

The scientists took tiny pinches of tissue from passages of the

birds' excretory tracts, or cloacas, and Dr. Taubenberger looked for

flu viruses in the tissue. Six of the birds had a flu virus. The

genetic coding for the amino acids in those viruses was exactly like

that in bird flu viruses today, Dr. Taubenberger found.

In fact, the viruses had not even evolved. Human influenza viruses

change every year, mutating slightly so they can reinfect people who

had just had the flu and developed antibodies against it. But birds,

Dr. Slemons said, do not have much of an immune response to

influenza, and so there is no particular pressure for the virus to

mutate.

Another reason the viruses stay the same, he said, is that some birds

live for only a couple of years and so, every year, the viruses have

a new bird population to infect. Finally, he said, birds are

chronically infected with lots of flu viruses at once, and all the

viruses coexist peacefully.

" There are so many that there is no selective pressure on any virus, "

he said.

But if bird viruses do not evolve and if the waterfowl viruses in

1915 and 1916 look just like bird viruses today, where did the 1918

virus come from? Or was it really a bird virus?

After all, at the time that he looked at the sonian birds, Dr.

Taubenberger had reconstructed only part of the virus's genetic

sequence. Maybe when he had the whole thing, the picture would change.

It did not. The entire sequence, published last month in Nature, had

the distinctive protein structures of a bird virus, he said. And it

had that same peculiar way of spelling its amino acids.

When he compared the 1918 virus with today's human flu viruses, Dr.

Taubenberger noticed that it had alterations in just 25 to 30 of the

virus's 4,400 amino acids. Those few changes turned a bird virus into

a killer than could spread from person to person.

Dr. Taubenberger noticed that, so far, the A(H5N1) viruses in Asia

have just a few of those changes. They do not, however, have the

unusual ways of coding the amino acid instructions that the 1918

virus had. So are the Asian bird viruses on their way to becoming

pandemic viruses, or not?

Some experts like Dr. Palese of the Mount Sinai School of

Medicine in New York say the A(H5N1) flu viruses are a false alarm.

He notes that studies of serum collected in 1992 from people in rural

China indicated that millions of people there had antibodies to the A

(H5N1) strain.

That means they had been infected with an H5N1 bird virus and

recovered, apparently without incident.

Despite that, and the fact that those viruses have been circulating

in China more than a dozen years, almost no human-to-human spread has

occurred. " The virus has been around for more than a dozen years, but

it hasn't jumped into the human population, " Dr. Palese said. " I

don't think it has the capability of doing it. "

Dr. Taubenberger said he could argue it either way.

" It's a nasty virus, " he said. " It is highly virulent in domestic

birds and wild birds. The fact that it has killed half the humans it

has infected makes it of concern, and the fact that it shares some

features with the 1918 virus makes it of concern.

" But the fact that it has circulated in Asia for years and hasn't

caused a pandemic argues against it. Maybe there are some biological

barriers we don't understand. "

So where will the next pandemic come from? Dr. Taubenberger says he

wonders if it may be from a bird no one has thought of, a bird with a

flu virus that has the same funny coding of amino acids that he saw

in the 1918 flu.

He has teamed up with scientists in Alaska to get swabs from the

cloacas of migrating birds, and he is looking in those samples for

flu viruses that look like the one from 1918.

" Probably nobody else has thought much about this, " Dr. Taubenberger

said. " But we've been staring at the sequence of the virus for the

last 10 years, and we've been thinking about it. " For him, the story

is not over; it has just taken another turn.

http://www.nytimes.com/2005/11/08/science/08flu.html