COVER STORY

Flu Fighters

A team of young Columbia scientists discovered the genetic origins of H1N1 swine flu this spring. Now they’re racing to determine its deadly potential.

by David J. Craig Published Fall 2009
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Slippery subject

Rabadan is one of many scientists today parsing the genetic structure of swine H1N1 for clues as to why it has caused mild illness so far. Researchers have discovered that several proteins whose presence is well known to increase the deadliness of influenza are absent in the new swine flu. Most notably, these include the protein PB1-F2, which makes flu viruses especially adept at destroying white blood cells in the nose, lungs, stomach, and intestines. This protein was present in the virus that caused the 1918 Spanish flu and it is present in H5N1 bird flu.

Rabadan and his Columbia colleagues recently examined a century’s worth of flu viruses for the presence of PB1-F2. They demonstrate in a forthcoming paper that the tiny gene section that controls the production of this protein is more likely than others to join a newly reassorted virus. That’s bad news. On a brighter note, Rabadan argues in another forthcoming paper that PB1-F2 serves little useful function. It may frequently appear, he says, only because it is part of a larger gene section that is essential to the flu virus. “This means that when PB1-F2 is broken, as it is in the swine H1N1,” he says, “nature may still favor the proliferation of this mild version of the virus.”

What are the implications of this knowledge? Most of Rabadan’s discoveries, including those involving PB1-F2, are valuable today primarily as basic science, as stepping-stones for research projects that might develop new vaccines or antiviral drugs many years from now. Rabadan acknowledges that he can’t reliably estimate the likelihood that the H1N1 swine flu virus will begin producing PB1-F2, for example. Nor can he predict the likelihood that swine flu will undergo another genetic reassortment, say, with H5N1 bird flu, thereby producing a virus that is both contagious and deadly, or with a flu strain resistant to Tamiflu.

“But that’s my ultimate goal,” Rabadan says. “I believe there are rules to how evolution works and that computational biology is beginning to reveal them.”

Rabadan’s most important discovery toward this end, he says, pertains to all flu viruses that have jumped from animals into humans and circulated among us. His research shows that since 1918 flu viruses in humans have steadily increased their production of the nucleotide uracil. “We believe we can reliably chart future uracil presence in human flu viruses,” says Rabadan, “like a red line pointing upward.” His team is currently working with immunologists at New York University in hopes of explaining this phenomenon; one hypothesis is that uracil helps the virus elude the human immune system.

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