'Genetically altered virus may help develop drugs and vaccines'

'Genetically altered virus may help develop drugs and vaccines'

Recent reports that two teams of scientists had genetically altered a deadly flu virus to make it more contagious have provoked fear, even outrage, in some quarters.

Biosecurity advisers to the US government, which paid for the research, have urged that full details not be published for fear that terrorists could make use of them. The World Health Organization warned Friday that while such studies were important, they could have deadly consequences.

Some scientists argue that the research should not even have been done, since the modified virus could slip out of a lab and spark a lethal epidemic. Others contend that such experiments are essential to learning what naturally occurring changes in flu viruses are the most dangerous. The results could help inform efforts to predict epidemics, they say, and to develop antiviral drugs and vaccines.

There is one point on which the factions agree: the ability of a virus to spread easily from person to person is the key to determining whether it can cause a pandemic. There is much scientists do not know about what makes a virus transmissible – and much they must learn before they are able to prevent another flu pandemic.

Contagion depends on a complex interplay between a virus and its victim, including where it enters the body, the types of cells in which it can reproduce and whether it can then escape to reach another human.

The virus that scientists made more contagious was the A(H5N1) avian flu. In its natural form, it is known to have infected only about 600 people since its discovery in 1997, but it killed more than half of them. Humans almost never transmit it to one another. But if that ever were to change, bird flu could become one of history’s worst pandemics.

The work to make the virus more transmissible was done by two separate groups, one at Erasmus Medical Centre in Rotterdam, in the Netherlands, and the other at the University of Wisconsin. The experiments were performed on ferrets, because flu behaves in them almost exactly as it does in humans.

In Rotterdam, a team led by Dr. Ron Fouchier made a strain of bird flu that could drift through the air into nearby cages and infect other ferrets. Although that result has set off worldwide concern, some researchers say the modified virus might not behave the same way in people, because ferrets are not a perfect model for human transmission.

The new virus does not seem as contagious as either the 1918 Spanish flu or the 2009 swine flu, Fouchier said. To become airborne, the virus required a range of genetic modifications – “a combination of everything,” he said.

Upper airways

In humans, bird flu viruses live best in the lower lungs, he said, which makes it harder for them to escape in sneezes and coughs. If one could replicate in the upper airways, it would be more likely to be released as an aerosol and might be more transmissible.

If the virus were shed, or expelled, as individual particles instead of in clumps, said Fouchier, it would be more easily spewed out in the tiny droplets of a cough. “It also may help if the virus induces coughing or sneezing,” Fouchier added.

Modifications to any of these viral traits may help make the bird flu virus more contagious. And in fact, it took only a few mutations to make the new virus, he said.
Fouchier declined to describe them in detail. But other scientists said increased transmissibility usually depends on changes in at least two of eight genes: one that helps the virus invade cells, and one that helps it copy itself. In birds, flu is primarily a gut disease, shed in feces, whereas in people it is primarily a nose, throat and lung disease, shed in saliva and mucus.

Ram Sasisekharan, a Massachusetts Institute of Technology researcher on a team that did a 2009 study that made a bird flu more transmissible in ferrets, said another crucial mutation was in the HA gene, which codes for the hemagglutinin spike that attaches the virus to cells. The mutation slightly changed the shape of the spike, making the virus more transmissible. Sasisekharan’s study did not involve A(H5N1) bird flu. Instead, the researchers started with a type of duck flu and spliced in genes from the highly contagious 1918 Spanish flu.

To invade cells, viruses need to latch onto structures on the surface called receptors. In people and ferrets, cells in the nose mostly carry receptors called alpha 2,6, whereas birds have alpha 2,3 receptors in their guts. Normally the A(H5N1) virus prefers the bird receptors, but the HA mutation changes the shape of the spike.

Sasisekharan argued that, at least in theory, humans could get the virus by ingesting it, since human gut cells also have alpha 2,3 receptors. From there, he said, the virus could travel throughout the body; it could reach the brain and cause fatal encephalitis, for example. But Dr Joseph Bresee, chief of epidemiology at the flu division of the Centers for Disease Control and Prevention, argued that the virus must enter humans through the nose, throat or lungs.

In any case, Sasisekharan cautioned, the mutations that enable a virus to jump species would vary for each type and strain of flu virus. Mutations that worked to make one more contagious might not have the same effect in another. There is one reassuring note in the unsettling findings from Rotterdam and Wisconsin. Fearsome though it may be, the new virus appears to be vulnerable to existing vaccines and flu drugs.