1. On the verge of disaster?

2. Mixing and matching genes

3. Responding to infection

4. Science fights flu

An emergency hospital during the 1918 influenza epidemic in Camp Funston, Kan. Could an avian flu cause a repeat of this nightmarish pandemic? Courtesy National Museum of Health and Medicine, Armed Forces Institute of Pathology, Washington, D.C.

The influenza virus contains eight interior "genetic segments." The outside is lined with H and N receptors that vary from strain to strain. Diagram: Los Alamos National Laboratory.

Driftin' and shiftin': An unstable virus
Viruses are tiny bits of genetic code housed inside a capsule. Unlike the much larger bacteria, viruses are not really alive, since they can only reproduce inside a "host" cell. Often, while more virus particles are being made, the virus or the host immune system kills the cell. These cell deaths are, obviously, a major source of disease in viral illnesses.

Viruses are in continual battle with animal immune systems: a process that is simply evolution -- survival of the fittest -- but on a microscopic scale and an accelerated schedule. Like HIV, the AIDS virus, flu virus is built of RNA, which lacks the apparatus that DNA reproduces.

The genetic "proofreading" apparatus reduces the rate of mutations. Without it, the genetic material of influenza is unstable. While reproducing, the virus forms many non-working virus particles. Some particles, however, are just different enough to evade the immunity that animals have gotten from vaccines or previous infections.

It is this viral instability that requires the design of a new flu vaccine each year, says Peter Shult, a communicable disease expert at the Wisconsin State Laboratory of Hygiene.

Usually, flu virus changes through "antigenic drift," which makes subtly different strains that, while infectious, are familiar enough to eventually be defeated by most human immune systems. "If a change occur within a subtype that has been circulating, there is always some residual immunity," Shult says.

Much more serious than antigenic drift is "antigenic shift," which creates entirely new strains of virus. These strains are identified by two molecules on the surface: hemagglutinin (H) and neuraminidase (N).

Choose 1 from column H and 1 from column N
Combining the various forms of these two antigens gives flu enormous genetic variability, Shult adds. "In the population of wild waterfowl [which normally host the influenza virus], there are potentially 15 different subtypes of hemagglutinin, and nine subtypes of neuraminidase. There is a large genetic repertoire of viruses that is normally in other animal hosts, but potentially can get into the human population."

Such a leap of species is what makes flu docs nervous, since new-to-us subtypes are dangerous. In 1997, a new subtype called H5N1 arose in Hong Kong, killing birds - and six people among 18 confirmed cases.

Why worry about six deaths? Because the virus was able to infect people at all, it "raised the concern that it could be next pandemic strain," says Shult.

Why didn't the 1997 strain cause more disease? Because -- and this is key -- it lacked the ability to transmit from one person to the next. In general, avian flus are poor at jumping from one person to another.

Now, H5N1 is back in Asia, again infecting people, but also infecting a vastly greater number of domestic birds. And while preliminary estimates are unreliable, in Vietnam, 13 of 18 confirmed cases have died.

Making the leap
Could avian flu get better at infecting people? Unfortunately, yes. As a result of being genetically unstable, flu can mix, or reassort, its genes while reproducing inside a human cell. Here's the scenario: If a person was infected with both H5N1 and a strain that easily jumps between people, Shult says, "You can get an intermixing of the genetic components, can have a novel virus that arises with the transmission characteristic of a human virus and the acquired lethality of H5N1 from the avian virus."

And the result could make 1918 look tame. Recall that flu is among the most infectious of all viruses, spread easily and effectively through the coughs and sneezes it sparks among its victims.

So how does society respond to the threat of a pandemic?

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