Newsday - September 7, 2001
Laurie Garrett

Using a revolutionary technique, University of Wisconsin researchers also have managed to build and manipulate their own flu viruses.

And another research team from Australian National University in Canberra says it has figured out what made the 1918 influenza the deadliest ever seen - a virus that killed at least 20 million people.

These reports appear in today's issue of the journal Science, along with a call for a $45-million investment in creation of a flu surveillance system that could use such genetic discoveries to identify deadly strains worldwide and prepare vaccines with greater precision.

"Technologies to create the first global lab against influenza are available," writes a team of the world's top flu experts. "All that remains is their integration. The key questions are: Who will invest in the first global lab? Governments? Trusts? Foundations? Should the international health community wait until the next pandemic?"

The innovation developed by University of Wisconsin biologists Yoshi Kawaoka and Masato Hatta is called "reverse genetics" and allows the scientists to build a virus, one piece at a time. With the viral genetic blueprint in hand, Kawaoka and Hatta could manufacture flu viruses of any kind.

"This technology of reverse genetics was first developed in 1989, but Yoshi ... streamlined it, taking it to a new level," said Linda Lambert, head of influenza programs at the National Institutes of Health. "It's a proof of principle that you can . .. make your vaccine virus using this technology. And make it a safer vaccine, much, much faster."

Kawaoka used the technique to dissect a flu strain that surfaced in chickens in Hong Kong in 1997. That outbreak caused global concern because the virus jumped directly from birds to people, with lethal outcomes. It had previously been thought that influenza could not hurt humans until it passed through intermediary mammals, such as pigs or horses.

"So in 1997, when an avian virus was transmitted directly to humans, it was surprising," Kawaoka said in an interview.

In his latest experiment Kawaoka discovered that the Hong Kong viruses made one simple mutation, on a gene called PB2. As a result, the virus changed an amino acid building block of a key viral protein from a highly acidic form into a basic one, called lysine.

The lysine-containing protein allows the virus to rapidly produce millions of copies of itself inside human cells. And it somehow affects the virus' ability to infect a broader range of human cells - not just nasal and lung tissue, but also cells in the bloodstream and brain.

Kawaoka examined 10 samples of flu from the 1997 Hong Kong epidemic and found that three bore this mutation. In an accompanying editorial in the journal, flu expert Robert Webster of St. Jude Children's Research Hospital in Memphis, Tenn., argues that Kawaoka's discovery proves that the flu was evolving rapidly in Hong Kong, and a global catastrophe could have erupted if local authorities hadn't responded rapidly. Thousands of potentially flu-infected chickens and chick embryos were destroyed, bringing an abrupt halt to that epidemic.

"What we learned from Yoshi's paper is that these viruses were rapidly adapting to humans," Lambert added, "and thank God we slaughtered those chickens."

An Australian research team, led by biologist Mark Gibbs, used advanced computer techniques to analyze the genetic blueprints of all known strains of influenza that were circulating immediately before, and during, the devastating 1918 pandemic. It concludes that the world's worst-known flu had evolved well beyond the single lysine mutation stage that Kawaoka described and had almost no avian-like RNA. Rather, it seems to have been made from two viruses - one in pigs living in the American Midwest, and another found in humans in Scotland. The two viruses commingled, resulting in a recombined super- virus.

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