Hunting for Clues in the Swine Flu Genetic Code

Within days of confirming fresh cases of the new swine flu in California and Texas last week, scientists at the Centers for Disease Control (CDC), in Atlanta, had sequenced the entire genome of the virus. By Monday, much of that genomic information was loaded into a publicly available database, allowing the world’s scientists to begin searching for clues to the origins of the mysterious virus and the severity of the threat it poses.

The World Health Organization (WHO) raised its alert to level 5 on Wednesday, signaling that a pandemic is imminent, and making the search for new information even more urgent. “The biggest question now is, how severe will the pandemic be?” said Margaret Chan, WHO director-general, at a press conference on Wednesday evening. Currently, symptoms appear to range from mild to lethal.

Researchers hope that the genome will shed light on the pathogen’s power, as well as on its origins. Clusters of cases around the world already suggest that it is highly transmissible between humans. But it’s not yet clear how deadly the virus is–namely, whether it’s significantly more lethal than the seasonal flu virus, which kills an average of 36,000 people in the United States each year.

It’s also unclear whether the high mortality rates of the swine flu observed to date in Mexico, as compared to in the United States, reflect differences in the virus itself, or are linked to environmental factors such as differences in treatment, or an underestimate of infection rates in Mexico. There have been about 160 suspected swine flu deaths among approximately 2,500 people treated with severe pneumonia in Mexico since the outbreak began (Mexico’s National Institute for Public Health reports 49 confirmed infections and seven deaths). As of Wednesday afternoon, the CDC reported 91 confirmed cases in the United States and one death.

“Right now, we don’t have any evidence of a difference in virulence, but that’s one possibility we’re looking at,” said Richard Besser, acting director of the CDC, at a press conference on Tuesday. As of Wednesday afternoon, sequence information from virus samples isolated from patients in Mexico was not available through the public database, but there was data from samples collected in California, Texas, New York, Kansas, Ohio, and Germany. Neither the WHO nor the CDC could explain why.

“Given that this is still a rapidly evolving story, we need to get a handle on the first gene sequences from California, and hopefully from Mexico and others, to see how this virus has evolved,” says Ram Sasisekharan, a professor of biological engineering at MIT. “Where does it really come from? And can we explain the observed differences in what has happened in Mexico, which seems much more severe than what has happened in the U.S.?”

Virus genomes constantly mutate and can easily swap genes with other viruses, sometimes endowing a pathogen with the power to infect different species or to trigger more serious disease in their hosts. The new swine flu virus appears to have done more swapping than usual, with genetic segments from four different sources: North American swine influenza viruses, North American avian influenza viruses, one gene segment from a human influenza virus, and two gene segments that are normally found in swine influenza viruses in Asia and in Europe.

“Parts of it are from the original 1918 virus, parts are similar to the current circulating H1N1 strain from seasonal flu,” says Sasisekharan. “We are still trying to understand what that means.” The 1918 Spanish flu triggered a pandemic that killed millions around the globe.

The new swine flu is of a subtype called H1N1, the class of influenza that is responsible for the majority of seasonal flu. (The 1918 virus was also an H1N1 strain.) But humans have no existing immunity to the novel swine flu virus. “We want to look and see how the [surface proteins] differ from current circulating H1N1 strains,” says Ian Wilson, a scientist at Scripps Research Institute, in La Jolla, CA.

One such protein, called hemagglutinin, sits on the outside of the influenza virus and determines which cells it can infiltrate. Preliminary analysis of the hemagglutinin gene for the new swine virus “has the telltale signatures for human receptor binding,” says Sasisekharan. “But until we make the protein and confirm whether it binds to receptors in human airways or deep lung,” we won’t know for sure. He adds that the gene for the hemagglutinin protein has close to 90 changes in the amino acids that make up the protein. “That’s significant from a vaccine-development point of view,” says Sasisekharan, since it suggests that existing seasonal flu vaccines will not be effective against it.