The pandemic flu of 1918-19 raced around the globe after jumping from being a bird-to-bird flu to a human-to-human virus. That leap across the genetic firewall made it possible for the bug to kill an estimated 50 million people.
But that small leap is a huge challenge for a flu virus.
First, it begins with wild birds, where it may or may not pose a threat to humans, depending on the type of fowl. It then migrates into domestic birds, where it is more deadly because it can infect people who handle those birds.
This is the current stage for H5N1, the avian flu strain that so far has killed millions of chickens and other fowl in 45 countries. It's also infected about 200 people who have been in close contact with infected birds, and at last count 108 of those people had died.
But so far no human victim has passed the virus to another person.
H5N1 has infected people who contacted the feces or bodily fluids of infected birds. The virus also has infected various mammals, including tigers, domestic cats and pigs.
The real danger is when the virus makes the genetic leap that allows it to be transmitted human to human. This happens through either genetic drift or genetic shift.
Drift is a random mutation of the genome, with the virus generally remaining within the affected species. Drift happens continuously, and is why the human flu virus changes from year to year, requiring new vaccines for each flu season.
Genetic shift involves a more fundamental change in the virus' genetic code that makes it possible for it to enter a new species. When that happens, the new pathogen is highly virulent because the body has not built up any defenses against the bug.
And this is what has health officials and medical researchers so concerned. There is no telling when or where that jump will happen, said Dr. Larry Jecha, health officer for the Benton-Franklin Health District.
"We don't know for sure how this will happen," said Julie Gerberding, director of the Centers for Disease Control and Prevention, in an interview with public television's Charlie Rose last week. "You need (to know) the biology of the virus and the biology of the specific species affected."
Super bug fear
Some people believe that because H5N1 has been known to exist for more than 10 years without having developed the ability to make the genetic jump, chances are it won't happen.
But if the virus does become a new super bug through genetic shift, the resulting pandemic would hit humans hard.
The deadly virus invades cells in the respiratory passages. Its genetic RNA then replicates itself in the host cell, expanding to the point where the cell bursts, exploding more viruses into the body and exponentially repeating the process. Viral pneumonia is the result.
There is currently very little defense available from antiviral medicines or a flu vaccine.
The antivirals Tamiflu and Relenza are effective in reducing severity of the disease, say experts. The medicines help block an enzyme the virus needs to escape from an infected cell to another. But antiviral supplies are limited.
Having a vaccine is the best line of defense, but there is no effective vaccine for H5N1 yet. And there is always the possibility that genetic shift of the virus could occur before researchers can develop a silver bullet vaccine - which would then likely make it ineffective.
It normally takes six months or more to perfect a flu vaccine once the pandemic virus has been identified, and by then it can infect millions.
Some people who have had a pandemic flu survived without ill effects.
Geneva Murray, 82, of Richland, got sick with the Asian flu in 1957 while living in Ventura, Calif., where she was a cafe waitress trying to raise three girls on her own.
"I was pretty sick for several days," said Murray, who remembers a doctor making a house call to her bedside.
"He didn't know what it was at first, but thought it might be diphtheria," she said. "He didn't tell me it was the Asian flu until later."
Murray recovered, although she didn't have the benefit of a vaccine or flu-specific medication. But she went through the flu while pregnant with her first son, who was born seven months later in 1958 with brain damage. Doctors suspected the damage was caused by the flu virus.
Her son never talked, walked and gradually lost the ability to eat. He died in 1961.
Owen Kruger, 73, of Richland also is a pandemic flu survivor, along with his wife, Patricia.
They and their two young children were stricken while living in Park Forest, Ill., where Kruger worked as a materials science engineer at the Argonne National Laboratory.
"It was very devastating for us," Kruger said. The entire family was laid low for nearly a week while the flu ran its course.
Kruger said they each took cold-water baths to combat fevers that raged up to 104 degrees. "In those days, people just suffered through it," he said.