Concern as revived 1918 flu virus kills monkeys

The 1918 influenza virus, which killed some 50 million people worldwide, has proved fatal to macaques infected in a laboratory. The study follows Nature's controversial publication¹ of the virus's sequence in 2005, alongside a paper in Science that described the recreation of the virus from a corpse and its potency in mice².

Some scientists question the wisdom of reconstructing such a deadly virus. Do the benefits outweigh the risks?

Those who carried out the macaque study say yes, as a better understanding of how it acts in a system similar to humans' will help scientists treat future pandemics. The study was carried out in the biohazard level 4 labs of the Public Health Agency of Canada in Winnipeg. Yoshihiro Kawaoka of the University of Wisconsin-Madison and his colleagues infected macaques with the 1918 virus or a contemporary flu strain³. Whereas the contemporary virus caused mild symptoms in the lungs, the 1918 flu spread quickly throughout the respiratory system and the monkeys died within days. The damage parallels reports of human patients in 1918.

The team reports that the 1918 virus caused the monkeys' immune systems to go into overdrive, causing immune proteins to be expressed at abnormally high levels and attack the body — what immunologists call a cytokine storm.

The research suggests that 1918 flu might work in a similar way to other viruses, such as West Nile, that can also cause a massive auto-immune reaction. This suggests a route towards treatment, says Michael Gale, a virologist at the University of Texas Southwestern Medical Center. Drugs that target over-zealous immune responses, such as those that control an immune protein called interleukin-6, are being developed for other diseases. Tweaked versions might work for pandemic flu.

But despite the promise of treatments, the results echo what had already been found in mice, and Gale feels there is a more important issue to be addressed. "The pathogenesis is interesting," he says. "But the key question is: how was it spread so efficiently?"

A team at the Mount Sinai School of Medicine has already started to investigate. Peter Palese is working with Adolfo Garcia-Sastre and Jeffery Taubenberger, who first reconstructed the virus, to find out how it spreads. Working with ferrets, they have found that a change of only one or two amino acids in the flu sequence is enough to stop transmission. They will publish the result in Science. Identifying which sections of the genome are responsible for transmission "has huge predictive value for whether strains will become pandemic or not", says Guus Rimmelzwaan at the World Health Organization's National Influenza Centre in Rotterdam, the Netherlands.

The next move for Kawaoka's team is along similar lines — they will be swapping sections in and out of the virus to establish exactly which bits make it so lethal.

But the latest results haven't assuaged everyone's concerns. Richard Ebright, a bacteriologist at Rutgers University, New Jersey, believes the virus should never have been recreated. "The key implication is that the material is now present in at least two locations," he says. The new study, he argues, increases the risk that the virus could escape and sets "a dangerous precedent" for other labs to follow.

Ebright argues that publishing the study in Nature, when similar research on more mundane pathogens regularly appears in lower-impact journals, could in itself increase the proliferation risk, if it tempts research groups to work on high-risk pathogens simply to get more recognition. Similar views were expressed off the record by other scientists. Ritu Dhand, Nature's chief biological sciences editor, defends the decision to publish, arguing that because the 1918 virus is not like other flu viruses, gaining insight into what makes it is so virulent in humans is of scientific interest.

Gale agrees that understanding the 1918 flu strain better could have huge public-health benefits. But he says there might be better ways to study this, and admits that some research might be driven as much by historical interest as by the potential health benefits.

Jens Kuhn, a virologist at Harvard Medical School who advises on arms control, also feels divided. "Everything I say, I make 'enemies' on one or the other side," he says. "I am torn sometimes between the two worlds."

A Flu Hope, Or Horror?

By Charles Krauthammer
Friday, October 14, 2005; A19

While official Washington has been poring over Harriet Miers's long-ago doings on the Dallas City Council and parsing the byzantine comings and goings of the Patrick Fitzgerald grand jury, relatively unnoticed was perhaps the most momentous event of our lifetime -- what is left of it, as I shall explain. It was announced last week that U.S. scientists have just created a living, killing copy of the 1918 "Spanish" flu.

This is big. Very big.

First, it is a scientific achievement of staggering proportions. The Spanish flu has not been seen on this blue planet for 85 years. Its re-creation is a story of enterprise, ingenuity, serendipity, hard work and sheer brilliance. It involves finding deep in the bowels of a military hospital in Washington a couple of tissue samples from the lungs of soldiers who died in 1918 -- in an autopsy collection first ordered into existence by Abraham Lincoln -- and the disinterment of an Alaskan Eskimo who died of the flu and whose remains had been preserved by the permafrost. Then, using slicing and dicing techniques only Michael Crichton could imagine, they pulled off a microbiological Jurassic Park: the first-ever resurrection of an ancient pathogen. And not just any ancient pathogen, explained virologist Eddie Holmes, but "the agent of the most important disease pandemic in human history."

Which brings us to the second element of this story: Beyond the brilliance lies the sheer terror. We have brought back to life an agent of near-biblical destruction. It killed more people in six months than were killed in the four years of World War I. It killed more humans than any other disease of similar duration in the history of the world, says Alfred W. Crosby, who wrote a history of the 1918 pandemic. And, notes New Scientist magazine, when the re-created virus was given to mice in heavily quarantined laboratories in Atlanta, it killed the mice more quickly than any other flu virus ever tested .

Now that I have your attention, consider, with appropriate trepidation, the third element of this story: What to do with this knowledge? Not only has the virus been physically re-created, but its entire genome has also now been published for the whole world, good people and very bad, to see.

The decision to publish was a very close call, terrifyingly close.

On the one hand, we need the knowledge disseminated. We've learned from this research that the 1918 flu was bird flu, "the most bird-like of all mammalian flu viruses," says Jeffery Taubenberger, lead researcher in unraveling the genome. There is a bird flu epidemic right now in Asia that has infected 117 people and killed 60. It has already developed a few of the genomic changes that permit transmission to humans. Therefore, you want to put out the knowledge of the structure of the 1918 flu, which made the full jump from birds to humans, so that every researcher in the world can immediately start looking for ways to anticipate, monitor, prevent and counteract similar changes in today's bird flu.

We are essentially in a life-or-death race with the bird flu. Can we figure out how to preempt it before it figures out how to evolve into a transmittable form with 1918 lethality that will decimate humanity? To run that race we need the genetic sequence universally known -- not just to inform and guide but to galvanize new research.

On the other hand, resurrection of the virus and publication of its structure open the gates of hell. Anybody, bad guys included, can now create it. Biological knowledge is far easier to acquire for Osama bin Laden and friends than nuclear knowledge. And if you can't make this stuff yourself, you can simply order up DNA sequences from commercial laboratories around the world that will make it and ship it to you on demand. Taubenberger himself admits that "the technology is available."

And if the bad guys can't make the flu themselves, they could try to steal it. That's not easy. But the incentive to do so from a secure facility could not be greater. Nature, which published the full genome sequence, cites Rutgers bacteriologist Richard Ebright as warning that there is a significant risk "verging on inevitability" of accidental release into the human population or of theft by a "disgruntled, disturbed or extremist laboratory employee."

Why try to steal loose nukes in Russia? A nuke can only destroy a city. The flu virus, properly evolved, is potentially a destroyer of civilizations.

We might have just given it to our enemies.

Have a nice day.

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