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Playing With Viruses

Replicating This Flu Strain Could Get Us Burned

By Wendy Orent
Sunday, April 17, 2005; Page B01

Flu used to be the "Rodney Dangerfield of diseases," as Tim Uyeki puts it. Uyeki is a flu epidemiologist at the Centers for Disease Control and Prevention (CDC) in Atlanta, and he's been concerned that for years people didn't give influenza the respect it deserved.

But now flu has all the attention any germ can get. First, there was a flu vaccine shortage over the winter, prompting long lines and provoking rage from people who couldn't get their shots. Later, bird flu mesmerized the world, with the CDC and the World Health Organization (WHO) keeping up a steady drumbeat: A flu pandemic -- overdue for decades -- would be upon us at any moment. Finally, it was announced that a pandemic flu strain had been accidentally sent to influenza labs around the world as part of a testing kit by Meridian Bioscience, a contractor for the College of American Pathologists.

Battling the bug: Victims of the 1918 flu crowd into an emergency hospital ward at Camp Funston, a subdivision of Fort Riley in Kansas, where the so-called Spanish flu is believed to have originated. (AP)

Viral Spirals

Estimated death tolls from the three major flu pandemics of the 20th century:

Spanish flu, 1918-19

Worldwide: More than 20 million

United States: 500,000-600,000

Asian flu, 1957-58

Worldwide: More than 1 million

United States: 72,000

Hong Kong flu, 1968-69

Worldwide: 750,000

United States, 34,000

SOURCE: Centers for Disease Control and Prevention

The jittery WHO, poised for catastrophe, insisted on the immediate destruction of the strain, for fear of accidental release. And while the threat posed by Meridian's error is far less than initial reports suggested, the reality is that lab accidents do happen. What's more, the feverish anxiety of public health officials to head off a new influenza pandemic may be generating the greatest influenza threat we face.

The threat is man-made. Scientists in the United States and Great Britain are studying the deadliest flu epidemic of the last century, the 1918 pandemic. In order to learn what made it kill so many, they are working on producing artificial viruses that replace common human flu genes with 1918 genes. An accidental release of one of their constructs could make the Meridian error look as menacing as a cauliflower.

The flu strain sent out by Meridian is known as H2N2/Japan. H2N2 strains first appeared in 1957, causing a world-wide pandemic. But H2N2/Japan is what virologists call a "reference reagent," regularly used in laboratory tests. It's already in the freezers of every serious flu researcher, says virologist Earl Brown of the University of Ottawa. Furthermore, calling the H2N2/Japan strain a "killer" -- as news reports across the globe have done -- makes little sense. It is no deadlier than any other new strain, and may actually be less so. According to microbiologist and pathologist Jared N. Schwartz, of the College of American Pathologists, H2N2/Japan has been through lab processes that typically weaken the virus. No one has contracted H2N2/Japan from these lab kits. This is not surprising. As flu researcher Adolfo Garcia-Sastre of the Mount Sinai School of Medicine in New York puts it, you'd have to aerosolize the virus in some way in order to catch it -- not something that is likely to be done with a reference strain.

Following the pandemic of 1957, which killed perhaps a million people, most of them elderly, H2N2 became the dominant human flu virus for 11 years. In 1968, a new strain, called H3N2, caused a new pandemic, and H2N2 mysteriously vanished. People born after 1968 may have partial immunity because of the N2 component of the virus, common also to the currently circulating H3N2 strain. Still, no one born after 1968 has full immunity, so WHO flu experts are concerned that a lab accident could cause another pandemic. But H2N2, like most flu strains, is disproportionately deadly to the elderly -- precisely the group most likely to have some immunity.

The WHO's frenzied demands that laboratories destroy this strain seem like an overreaction. Apparently, WHO wants to show a nervous world that it is taking action. But this mania to do something -- anything -- to stave off a pandemic has been building for years and led to the imprudent decision to re-create the dangerous 1918 strain.

The 1918 flu evolved its lethality on World War I's Western Front. This was no accident. According to Carol Byerly, a historian of military medicine and author of a new book, "Fever of War: The Influenza Epidemic in the U.S. Army During World War I," the 1918 flu built up its unique virulence in the trenches and the hospitals, the trains and trucks of the front, where the deathly ill lay beside the uninfected, allowing lethal strains to be easily passed on.

Tissue samples that prescient World War I Army physicians stored away, combined with flu RNA taken from the partially frozen corpse of an Inuit woman in Brevig Mission, Alaska, have yielded enough genetic information to allow the sequencing of all eight genes in the 1918 influenza virus genome. Molecular pathologist Jeffery Taubenberger and his colleagues from the Armed Forces Institute of Pathology have brought these lost genes from 1918 back from the dead; they've sequenced five of the genes, and are close to completing the last three as well.

These sequences by themselves are harmless: They are strings of information. As Garcia-Sastre puts it, "There's no smoking gun in the 1918 sequences. So we really want to find out what made it kill, so that if it emerges again in the future, we'd be able to recognize a virus with virulence characteristics like 1918." Through a technique Garcia-Sastre and colleagues developed, these sequences -- symbols on paper -- can be translated into actual viral RNA. Since the whole genome hasn't yet been published, scientists can't re-create the entire 1918 flu. But they can combine some 1918 genes either with laboratory strains that have been adapted to grow in mice, which don't normally catch human flu, or with ordinary human flu strains to yield new artificial strains. Then the researcher infects mice with his new strain. Strains using three of the 1918 genes are already known to kill mice.

These techniques are fascinating. But the work is also dangerous. Peter B. Jahrling, chief scientist at the National Institute of Allergy and Infectious Diseases, compares the research to "looking for a gas leak with a lighted match." What concerns Jahrling and Brown, among others, is that experiments involving 1918 genes are not being carried out under the highest biosafety level, BSL-4. While most of the scientists use what is known as BSL-3 plus, or enhanced, conditions, they do not use space suits, chemical showers or gas-tight cabinets in their work.

Still, it's hard to say how much difference a higher biosafety level would make: Work on dangerous agents is, by definition, dangerous. Even in BSL-4 labs mistakes can happen, and some of these mistakes have been fatal -- to the experimenter. In addition to three laboratory escapes of the SARS virus in 2003 and several resultant fatalities, a number of Russian researchers at the Vektor laboratories in Siberia have died of Ebola, and several scientists at Boston University contracted tularemia, or rabbit fever, in recent years.

The 1918 flu is a particularly potent agent, and it isn't only the lives of experimenters at risk if one of them contracts one of the artificial constructs. As Brown puts it, "These are tried and true virulence strains for humans. This virus and its genes have to be given a bit more respect. You don't want it out in nature where it could cause serious disease." While the antiviral drug oseltamivir, or Tamiflu, seems to protect against the 1918 constructs, Jahrling says "you'd really want a belt to go with those suspenders." And Richard Ebright, a microbiologist at Rutgers University, says that "using Tamiflu as a prophylactic makes it more likely that if a strain is accidentally released, it's going to be a Tamiflu-resistant strain."

There's an added danger. The scientists now known to be working on these strains are all respected by their peers; no one expects them to be careless. But the five published sequences are in the public domain, and there is simply no way to know who else may be working on them at any given time. Even more disturbing is what may happen when Taubenberger publishes the remaining three gene sequences. Then the entire 1918 flu could be built from scratch by anyone, anywhere, who has sufficient resources and skill. It is quite conceivable that resurrected 1918 flu could someday be used as a bioterrorist agent.

Clearly, if these genes had never been dug up, we wouldn't have to worry about any of this. And how necessary is this admittedly remarkable work in the first place? Evolutionary biologist Paul Ewald of the University of Louisville points out that influenza is normally a relatively mild disease: It keeps its hosts up and moving in order for it to spread. But the precise conditions of the Western Front allowed the virus to evolve unprecedented virulence. Without those conditions, lethal pandemic flu cannot evolve. Says Byerly, "The 1918 flu epidemic most likely will not happen again because we won't construct the Western Front again."

If Ewald and Byerly are right, then the principal rationale for this research -- protection from another lethal pandemic -- blows away, though the research remains a useful tool to show how lethal flu kills.

Indeed, if they are right, the greatest danger of lethal pandemic flu may lie in some slip, some failure of lab protocol or Tamiflu, or even in someone's malice. Then the vaunted cure may prove worse than the disease .

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Wendy Orent, an Atlanta-based freelance writer, is the author of "Plague: The Mysterious Past and Terrifying Future of the World's Most Dangerous Disease" (Free Press).

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