Scientists track swine flu virus for tiny changes that would cause big problems

Their lab at the University of California-San Francisco holds a growing international collection of viral samples, including some from San Jose swabbed from the noses of sick people, since the first days of the swine flu epidemic. Genetic analysis of each sample will alert researchers to any tiny change that would create a giant problem.

So far, the swine flu virus seems to be evolving slowly. But a small mutation could create resistance to drugs.

The scientific sleuths are most worried about a big genetic leap -- such as in 1918, when a mild virus turned deadly, killing 20 million to 40 million people. If such a leap does happen, the lab hopes to detect it early, triggering more aggressive treatment, quarantining and prevention measures.

Locked inside a large, $14,000 freezer, kept at 110 degrees below zero, are trays of plastic vials holding specimens of the H1N1 virus from California, Canada and Mexico. Some of the viruses came from dead patients; others caused merely an annoying cough.

"So far, we have no evidence that this virus is any more virulent than seasonal flu," said Dr. Charles Chiu, director of the Viral Detection and Discovery Center.

Instead, what seems to matter is the immune response of the infected person; while some people shrug it off, others go into lethal overdrive. There is also new evidence suggesting that co-infection with another virus, such as the common cold, may worsen illness.

"What we're worried about is the possibility, because it is a fundamentally new virus, that it may mutate into a strain that is more virulent," Chiu said.

The ambition of the new center is to hunt down viruses whose identities and origins baffle doctors. And its team wants to understand these mystery viruses at the most essential level: the sequence of its genes.

Upon opening in January, one of the center's first projects was to study H1N1. Its first specimen, from a young girl in Mexico, is now known to be one of the first cases of swine flu. Since then, the virus has spread to 190 countries.

But its researchers have also detected a new virus linked to a rare type of prostate cancer and another virus that causes diarrheal disease in children. In yet another project, they are collecting unusual strains of HIV from Cameroon, Africa.

While at least 20 other labs are studying the genetic structure of the flu virus through conventional sequencing, the San Francisco lab is one of two in the entire nation engaged in viral discovery and "deep sequencing," seeking mutations that occur at very low frequencies. The other is the Center for Infection and Immunity at Columbia University in New York City.

"They're doing a great job. What they do is very important," said molecular virologist Paul Luciw of the University of California-Davis.

"The technology enables analysis of strain variation. If you find something very different, then you have to pay more attention -- isolating that patient and looking at the patient's contacts."

The collection now includes about 100 samples sent from the California Department of Health Services, 100 from Canada and 100 from various sites in Mexico.

More specimens arrive every day.

Long ago, scientists had to peer through microscopes to figure out what was killing people -- a process that could take 10 to 20 years.

Modern surveillance is improved not only through use of "deep sequencing," but another novel detection tool called the virochip, designed by the center's Joseph DeRisi.

The technology uses tiny glass slides dotted with thousands of fragments of DNA from 2,500 known viruses. The tool can study an entire genome at once -- so experiments that used to be impossible are now being performed in days or hours.

All the viral sequences are stored in a huge computer database.

A flu virus is thought to reproduce about every eight hours. Within one day, it's spawned several generations. As it breeds, it mixes and morphs.

By comparing H1N1's genetic code with other influenzas, scientists have found a new combination of elements of previously known viruses. Three flu strains -- from pigs, birds and humans -- combined in one animal to create an unusual "triple re-assortment."

It's not known how, when or where this happened. Then it jumped into humans.

Chiu's team is watching its continued evolution, a gradual accretion of minor mutations called genetic "drift."

"There are changes," he said. "Not a lot of changes -- but there are changes. Now we're investigating the significance of these changes."

What he's worried about is a big change called genetic "shift," when there's a dramatic re-assortment and exchange of strands of genetic material that trigger hard-to-predict epidemic trajectories.

Such a shift could build a virus that is fast-growing, adept at infecting lungs, unfamiliar to the immune system -- and highly contagious.

"That would be a big deal," he said.

For now, they're waiting and watching, so that a catastrophe like 1918 need never happen again.
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