by Dan Vergano,
January 25, 2011

from USATODAY Website

It was a public health nightmare:

A deadly flu bug spread like wildfire around the world, killing tens of millions of people.

That was nearly a century ago.

Fears that the nightmare could return today - perhaps with even more terrifying consequences - have set off a heated debate among scientists and, for the first time, delayed the publication of scientific flu research in two professional journals.

The object of those fears:

a threatening new version of the bird flu virus that didn't emerge from nature but was born out of experiments in a lab.

Researchers in the Netherlands and at the University of Wisconsin-Madison, who were trying to determine what genes might mutate and make bird flu attack humans, created a strain that can pass easily among ferrets.

Why should we care that ferrets get the bird flu?

Ferrets are the closest lab animal models to humans for flu vaccine studies. Until now, cases of bird flu passing from infected birds to humans were limited to people - farmworkers usually - who worked closely with the birds. And bird flu almost never passes from person to person.

So creation of a strain easily transmissible between mammals poses frightening scenarios:

What if the strain escaped from the lab and spread among humans?

David Nabarro, a World Health Organization expert, estimated that such a pandemic could kill 20 million to 150 million people worldwide.

What if terrorists intent on doing harm learned enough from the published scientific work to reproduce the strain on their own? They could release it to start a pandemic.

The National Science Advisory Board for Biosecurity (NSABB) reviewed the work, and last month, it requested for the first time ever that two scientific journals, Science and Nature, withhold from the public details of the two potentially dangerous bird flu studies.

Journal editors, sensitive to the security issues, have delayed publication of the studies.

"We have to protect the public by making sure the critical information doesn't get into the hands of those who might misuse it," says Science editor-in-chief Bruce Alberts.

On the other hand, he says,

"This knowledge could be essential for speeding the development of new treatments to combat this lethal form of influenza."

Last week, leaders of the two labs involved announced a two-month halt to research on bird flu viruses engineered to pass among mammals, citing "perceived fears" that the microbes may escape from the lab.

They called for the World Health Organization to discuss the risks and benefits of their research.

"I think it is a reasonable first step," says University of Michigan virologist Michael Imperiale, a member of the federal NSABB group.

The strains are securely locked down in labs in the Netherlands and Wisconsin, but the episode raises questions about whether such experiments should be done in the first place.

"I'm not convinced a 'doomsday' strain is what we have here," says NSABB chief Paul Keim, an anthrax researcher at Northern Arizona University in Flagstaff, "but now at this point, we can see the trajectory creating something of very grave concern."

A high rate of death

Why the concern?

Bird flu, or H5N1 avian flu, has killed 342 people in the past decade out of 581 who were infected, a death rate of almost 60%, according to the World Health Organization.

That percentage is much debated by researchers, who argue it's skewed because many milder cases aren't reported. That rate is about 120 times higher than for the 1918 flu, and roughly 600 times greater than for the 2010 seasonal flu.

The 1918 flu virus strain that killed perhaps 50 million people, including 675,000 Americans, according to the federal Centers for Disease Control and Prevention (CDC), hangs heavy over the debate.

That bug, emerging near the end of World War I, had new genetic features and wreaked havoc on the unprepared immune systems of people at the time.

The nightmare for scientists today is that the mutation-prone bird flu virus - which they say is similarly foreign to the human immune system - could evolve into a strain that could be transmitted from person to person and trigger a similar deadly outbreak.

In the ferret flu studies, biologists may have completed that step in the laboratory. The researchers reinfected ferrets with bird flu until a strain evolved that seemed able to move from ferret to ferret by sneeze, raising fears it could travel the same way among people if it escaped.

Outside the lab, some question the wisdom of putting the world at this kind of risk.

Bioterror expert Michael Osterholm of the University of Minnesota asks what good it is to identify threatening new flu genes in a lab when no way exists to monitor Asia's poultry cages for an outbreak.

"We have worried about this for a long time," says microbiologist Ronald Atlas of the University of Louisville.

Atlas was a member of the 2004 National Academy of Science panel that described this very scenario - a lab creation aimed at combating a disease triggering pandemic fears - and called for the creation of the NSABB.

"My sense is the scientific community is really divided on this," Atlas says.

'Tickling the dragon's tail'

At the dawn of the atomic era, weapons scientists tried "tickling the dragon's tail," in the words of Manhattan Project physicist Richard Feynman, handling radioactive blocks just close enough together to gauge where nuclear chain-reactions start, at considerable risk to themselves and everyone in the vicinity.

Today's biological equivalent comes from "dual-use" microbes, grown in labs to be strong enough to test vaccines but running the risk the microbes could accidentally escape or be hijacked for bioterrorism.

Case in point: the anthrax attacks in 2001, which killed five people. The strain of Ames anthrax bacteria used in the attacks was specifically grown for vaccine testing.

FBI investigators concluded the culprit was a lab insider, researcher Bruce Ivins, who committed suicide in 2008 while the investigation was underway.

Over the past decade, a litany of other microbe reports have drawn concern:

• In 2002, Stony Brook (N.Y.) University researchers reported the re-creation of polio virus from stitched-together DNA fragments. The study raised concerns that bioterrorists could patch together attack bugs from gene scraps alone, not even needing the bugs themselves in a Petri dish.
   

• In 2005, federally funded researchers published a reconstructed gene map of the 1918 flu virus after a review by Keim's panel. Then-CDC chief Julie Gerberding called the research "critically important in our efforts to prepare for pandemic influenza."
   

• Last year, the National Research Council reported that the FBI and the "U.S. intelligence community" had inspected a suspected al-Qaeda bioterror lab during the anthrax murder investigation. Critics of the FBI case, such as Rep. Rush Holt, D-N.J., worried that terrorists were growing microbes for bioterror purposes.

Much like the knowledge that atomic bombs were possible spurred nuclear proliferation during the Cold War, news that bird flu can be made transmissible to mammals could suggest ideas to a well-trained, would-be bioterrorist, Keim says.

"The research is out there," he says.

Scientific disagreement

The pages of one journal in the middle of the debate, Nature, reveal the wide disagreement among scientists about whether publishing the lab-made bird flu strain represents a step too far.

"I believe that the risk of future outbreaks in humans is low," wrote flu genetics expert Peter Palese of the Mount Sinai School of Medicine in New York in a Jan. 12 opinion piece.

Bird flu has had millions of chances in tightly packed chicken coops of evolving the capability of transmitting among people, he argues, a natural experiment showing there is little chance of the bug triggering a pandemic.

"Slowing down the scientific enterprise will not 'protect' the public - it only makes us more vulnerable," Palese said.

Palese and some other researchers question the high mortality rate ascribed to bird flu, saying it more likely reflects deaths among the very sickest patients, ones who headed for the hospital.

Mild cases never showed up in records, they suggest. The death rate from the dreaded 1918 flu was about 0.5% (still very high for the flu - that's one in 200 patients), according to a U.S. Armed Forces Health Surveillance Center review.

On the other hand, smallpox researcher D.A. Henderson of the University of Pittsburgh's Center for Biosecurity in Baltimore wrote in Nature's Jan. 19 edition,

"We should not publish a blueprint for constructing such an organism."

The lab creation, in his estimation, produced "the ultimate biological threat."
 

Looking for middle ground

"The real question is, where do we find some middle ground, to make a system that preserves scientific openness but also safety?" Atlas says.

 

"The irony is that we do have the bones of a biosafety system already in place. Everyone seems to forget that."

Under federal law, bird flu must be investigated within a "Biosafety Level 3" lab, requiring special training, equipment, ventilation and oversight.

Related regulations require that labs register "select agents," including bird flu.

"Obviously, it went through that process," says spokesman Terry Devitt of the University of Wisconsin-Madison, who notes that the National Institutes of Health approved the research in the first place.

However, Atlas points out the 2004 National Academy of Sciences report that called for the creation of the NSABB also said extra "biosafety" reviews should be conducted at the university level.

Devitt acknowledges this wasn't part of the school's review process.

Some researchers, such as chemical biologist Richard Ebright of Rutgers University, have called for assigning the ferret study virus strains to Biosafety Level 4, the highest level of security.

Worldwide, at least 42 labs investigate bird flu, or bugs just as deadly, according to Lynn Klotz of the Center for Arms Control and Non-Proliferation in Washington, and Ed Sylvester of Arizona State University.

Looking at the history of lab infections, such as the SARS death in 2004 of a student in Beijing who caught the disease from two graduate students infected in a lab, they put the odds of a lab "escape" at 80% within four years. An escape doesn't mean a pandemic, but it does offer one an avenue.

Federal officials, according to Keim, have asked the NSABB to review the safety of communication of similar bird flu infection studies.

"We had a debate a decade ago and decided that this science was too important to restrict," Atlas says. "The real responsibility for control has to come from the scientific community."