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Scripps' Leap Bolsters Quest for Bird Flu Warning System

Posted on: Sunday, 19 March 2006, 03:03 CST

By STACEY SINGER Palm Beach Post Staff Writer

Scientists at The Scripps Research Institute have broken new ground in the effort to track the evolution of bird flu, developing a technology that offers an early-warning system for the flu's feared transition from bird-slayer to human menace.

It's a rare but deadly event for bird flu to jump the species barrier. So rare that scientists are aware of only a few occurrences: The first was the Spanish flu of 1918. It killed an estimated 30 million to 50 million people worldwide.

The second, the Asian flu, hit in 1957, killing 4 million. The third, in 1968, was the Hong Kong flu, which left 37,000 dead in the United States.

The new bird flu strain sweeping the globe - labeled H5N1 - already has infected 177 people and killed 98 of them. And yet, scientists say, it's not very contagious. For now, H5N1 favors the cells found in birds' intestinal tract.

If and when its preference changes to people, health officials fear a cascade of human-to-human infection will follow, leaving millions dead. Congress in December appropriated $3.8 billion to prepare for and prevent that day.

In a paper released Thursday by the journal Science, the team based at Scripps' La Jolla, Calif., headquarters said they had created mutations in the lab that would probably increase bird flu's attraction to human cells.

The potentially deadly mutation was identified with new technology called a glycan microarray. Developed at Scripps as part of a large international collaborative effort, the technology allows scientists to rapidly spot mutations in a key viral protein.

The Science paper suggests the technology may have an important role to play in mapping out whether bird flu is evolving into a greater threat to humans.

Molecular biologist James Stevens said this type of research can provide health authorities with an early warning system to look for particular mutations that might lead to human adaptation.

"We can plan ahead if we know what we think might happen," Stevens said.

Making a dangerous virus more dangerous might sound counterintuitive, but the Scripps scientists were working with just a small piece of influenza - one that's incapable of causing infection on its own. It came from a strain of H5N1 that killed a 10- year-old boy in Vietnam in 2004.

"The more these viruses interact with the human population, the more likely it is that it could adopt this type of mutation," Stevens said.

The scientists focused on one protein that studs the influenza virus exterior, called hemagglutinin. It's the "H" in H5N1, and it's critical because its job is to recognize and latch on to cells. Viruses cannot replicate on their own - they must hijack healthy cells to do it for them.

Viruses find their cellular victims by looking for the distinctive sugar molecules that coat cells' outer membranes.

The authors of the Science paper were able to change the H5N1 hemagglutinin enough for it to latch more easily onto sugars found on the exterior of cells lining human lungs.

Encouragingly, the mutations' attachment to the cells was weak - suggesting the existing virus cannot easily cross the species barrier outside a lab, Stevens said.

"It's surprising that it wasn't easy to convert," he said. "There may be other factors that prevent it. That's not to say that Mother Nature won't come along and throw us a curve ball."

Dr. Robert Belshe, a physician at St. Louis University's Infectious Diseases and Immunology department, said this research and others gives him hope that there's still time to head off a human pandemic. Belshe is conducting clinical trials on investigational avian flu vaccines.

The current avian flu outbreak was first recognized nine years ago. As it spreads in birds, one of the signs to watch for will be the mutation described in the Science paper, he said.

"If that occurred naturally it would be a very alarming event," Belshe said.

Vaccines and drugs offer the best defense, but it takes time and money to prepare the right attack and then make adequate quantities. Knowing what to watch for will help buy more time, Belshe said.

Scientists at Scripps have traveled this road before. Stevens recently analyzed mutations believed to convert the 1918 flu to a human strain. Twenty years earlier, Scripps' James Paulson helped develop a method to see how flu bonded to sugars on cell membranes. It enabled a team including Wilson to find the amino acid combination that cause Hong Kong flu to bind to human cells.

Scripps' Ian Wilson also played a key role in understanding the Hong Kong flu. Working in the lab of Harvard's Don Wiley, he helped characterize the shape of hemagglutinin in 1981. In La Jolla, in the atrium of the Skaggs Institute for Chemical Biology at Scripps, a 3- foot-tall, three-dimensional model of a hemagglutinin molecule sits on a pedestal.

When Scripps President Richard Lerner managed to recruit Wilson away from Harvard, he marked the occasion by commissioning the enormous model, Wilson said.

That model happens to be of the hemagglutinin found on the deadly Hong Kong flu. Coincidentally, its the source for the mutation that Stevens found gave H5N1 the strongest potential foothold on human cells.

Will a similar change happen in nature?

"It's all down to statistics and chance," Stevens said. "It could happen tomorrow, it could happen 10 years from now, it may never happen."

In addition to Stevens, Wilson and Paulson, the Science paper was authored by Terrence Tumpey of the Centers for Disease Control and Prevention's Influenza Branch, Jeffery Taubenberger of the Armed Forces Institute of Pathology and Scripps molecular biologist Ola Blixt.

Blixt, working with Paulson and the Consortium for Functional Glycomics, designed the glycan microarray that was used to assess how well the bird flu hemagglutinin attached to sugars on the surface of human lung cells.

It's a clever technology, one that grew out of similar automation created for genetic screening.

Glass plates are covered with the ends of sugar molecules found on key cell types - 300 per plate. Fluorescent tagged hemagglutinin is washed across the plate. The spots that light up most brightly are the ones most able to bind the viral protein.

The science of glycomics, and the technology of glycan microarrays, is relatively young, but Paulson predicts it will lead to many more discoveries.

Twenty years after he discovered why Hong Kong flu made the leap to humans, Paulson said, "The questions are the same, but the tools are a lot more sophisticated."

stacey_singer@pbpost.com

Will bird flu jump to humans?

Scripps scientists have made small molecular changes that could enable the bird flu virus to gain a foothold in humans. They hope to develop an early-warning system for when the flu begins to spread.

Bird flu virus and cell:

* Sugars on cell membrane can attract the virus.

* Receptors on virus will bind tightly if they encounter the right type of sugar.

Researchers have introduced mutations to the bird flu virus that help it latch on to human cells.

For now, bird flu receptors prefer the type of sugar found on cells in birds' intestinal tracts.

To infect humans on a large scale, bird flu receptors must mutate to attach easily to cells in the human respiratory tract.

Researchers aren't sure, however, if this small change will ever happen on its own.

Source: The Scripps Research Institute; staff research

How viruses spread

Viruses can't replicate on their own. Here's how they hijack live cells to help them make copies of themselves - and make people sick.

An enzyme helps viruses exit the cell.

A protein allows the virus to attach to a healthy cell.

RNA-segment contains the genetic material of the influenza virus.

1. Animal virus attaches to a healthy human cell.

2. Outer membrane of the virus opens, pouring the viral contents into the cell.

3. Viral genetic material combines with genes in the nucleus.

4. A new virus is created. It exits the cell.

Sources: The Scripps Research Institute; staff research

Source: Palm Beach Post

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