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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Birds before swine

Prior to this spring, the practical implications of Rabadan’s work were not obvious. Then on Monday, April 27, 2009, just three days after the World Health Organization (WHO) announced the outbreak of an unfamiliar flu in Mexico, the U.S. Centers for Disease Control and Prevention released the genetic sequences of the new virus samples. Scientists working for the U.S. and Canadian governments had concluded already that the influenza belonged to a family of viruses known as H1N1. They hoped that others could identify its origins and perhaps determine how dangerous it was.

“We dropped everything else we were doing,” says Rabadan. His team first downloaded the genetic sequences of the few dozen flu samples that had been identified by other labs as the novel form of H1N1. They entered these sequences into computer programs, some of which Rabadan’s team had designed, and compared the new H1N1 sequences against the older flu sequences that were publicly available, which included hundreds of swine flu viruses and thousands of human and bird flu viruses.

“The math was actually quite simple in this case,” says Hossein Khiabanian, a postdoctoral researcher in Rabadan’s lab who earned his PhD in astrophysics from Brown. “Basically, we made long lists showing the 13,000 nucleotides of each flu sequence and then determined which viruses shared the largest numbers of nucleotides.” They mapped the new flu strain’s convoluted ancestral lineage this way back several decades. If two viruses matched closely on some of their eight genes but bore little resemblance on other genes, the researchers concluded that one of the two viruses was the product of a genetic reassortment.

“For four days that’s all we did, around the clock,” says Vladimir Trifonov. Another postdoctoral researcher in Rabadan’s lab, he was trained in computer science at the University of Texas at Austin. “It helped that we knew from experience which genes tend to mutate once a virus has jumped from a pig into humans. When we looked at the new samples, we had some idea of what they might have looked like several generations earlier.”

The group’s findings, published the following week in the online journal Eurosurveillance and later in the New England Journal of Medicine, revealed that this new version of H1N1 resulted from a recent genetic reassortment, and an odd one, at that, to have jumped into humans — not a combination of a human flu with a pig flu, but a mix of two flu strains endemic to pigs. Each of the parent strains had infected humans on rare occasions in the past, usually causing mild illness, but neither had been known to spread from person to person.

“That two swine viruses unable to spread between people would combine to form a virus that is contagious is amazing,” says Rabadan. “It would seem to demonstrate the role that chance plays in these events. Influenza is incredibly diverse, which makes it very adaptable and also difficult to anticipate.”

Rabadan’s discovery eventually put to rest debate about what the new illness should be called. Pork industry representatives, soon after the flu outbreak in Mexico was announced, urged scientists, public officials, and journalists to refrain from calling the novel influenza strain “swine flu.” They pointed out that one of the virus’s parent strains itself stemmed from a reassortment that took place among bird, human, and pig influenzas several years ago. They also emphasized that the new virus hadn’t yet been detected in any pigs, only in humans.

Rabadan says it’s true that one of the parent strains contained trace amounts of genetic material from bird and human flus, but that it had been circulating in pigs exclusively for the last 10 years. “If you could follow the ancestral history of any flu virus back far enough, you’d find that it once circulated in other animals,” says Rabadan, adding that all forms of influenza developed originally in birds. “But this new flu, in any meaningful manner of speaking, is from pigs.”

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