Tiptoeing Around Pandora’s Box

Tiptoeing Around Pandora’s Box
By Martin Enserink
Science 2004 305: 594-595

Researchers say crossing avian and human flu viruses is crucial to
understanding the threat of a new influenza pandemic, but they admit that
they might create a monster.

Once again, the world is crossing its fingers. The avian influenza outbreak
in Asia, already one of the worst animal-health disasters in history, has
flared up in four countries; tens of thousands of birds are being killed in
desperate attempts to halt the virus’s spread. And again, the unnerving
question arises: Could the outbreak of the H5N1 strain spiral into a human
flu pandemic, a global cataclysm that could kill millions in a matter of
months and shake societies to their core?

There is a way to find out, flu scientists say–but it’s controversial.
Leaving nature to take its course, a pandemic could be ignited if avian and
human influenza strains recombine–say, in the lungs of an Asian farmer
infected with both–producing a brand-new hybrid no human is immune to. By
mixing H5N1 and human flu viruses in the lab, scientists can find out how
likely this is, and how dangerous a hybrid it would be.

Such experiments can give the world a better handle on the risks, but they
could also create dangerous new viruses that would have to be destroyed or
locked up forever in a scientific high-security prison. An accidental
release–not so far-fetched a scenario given that the severe acute
respiratory syndrome (SARS) virus managed to escape from three Asian labs in
the past year–could lead to global disaster. Given their scientific merit,
the World Health Organization (WHO) is enthusiastically promoting the
experiments. But worried critics point out that there is no global mechanism
to ensure that they are done safely.

Despite the concerns, such studies have already begun. In 2000, the U.S.
Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia,
started experiments to create crossovers between the H5N1 strain isolated
during a 1997 outbreak in Hong Kong and a human flu virus adapted for the
lab. The study was suspended when CDC’s flu researchers became overwhelmed
by SARS and the new H5N1 outbreak, both in 2003, says CDC flu expert Nancy
Cox, who led the work. But the agency plans to resume the work shortly with
the H5N1 strain now raging in Asia.

Others are exploring the options as well. Virologist Albert Osterhaus of
Erasmus University in Rotterdam, the Netherlands, is eager to try not just
H5N1 but also other bird flu strains, such as H7N7. The Netherlands won’t
have the required high-level biosafety lab until late 2005, so Osterhaus is
talking to researchers in France who do. In the United Kingdom, researchers
at the Health Protection Agency, the National Institute for Biological
Standards and Control, and universities are also discussing the idea. There
are no concrete plans yet–in part because of a lack of funds–but there’s a
consensus that the studies are important and that Britain is well suited to
do them, says influenza researcher Maria Zambon of the Health Protection

The aim of reassortment studies, as they’re called, would not be to develop
new countermeasures, says WHO’s principal flu scientist, Klaus Stöhr,
because researchers believe current drugs and an H5N1 vaccine in development
would work against a pandemic strain as well. But the experiments would
provide a badly needed way to assess the risk of a pandemic. If they
indicate that a pandemic virus is just around the corner, health officials
would further intensify their fight in Asia and go full-throttle in stashing
vaccines and drugs; if not, they could breathe a little easier. “It’s an
extremely important question, and we have a responsibility to answer it,”
insists Stöhr.

The safety worries are legitimate, Stöhr concedes, and the work should be
done only by labs with ample flu expertise and excellent safety systems–not
the ones that let SARS out. “We don’t want people just fiddling around,” he
says. He also downplays concerns that the results, when published, might
help those who would unleash a pandemic on purpose. Anyone with the
scientific smarts to do so can already find plenty of ideas in the
literature, Stöhr asserts. Moreover, the studies are unlikely to produce
anything that could not arise naturally, says Osterhaus: “You could create a
monster. But it’s a monster that nature could produce as well.”

But critics beg to differ. “We’ve been debating whether to destroy the
smallpox virus for years–and now we’re planning to create something that’s
almost as dangerous?” asks Mark Wheelis, an arms-control researcher at the
University of California, Davis. Wheelis also points out that there’s no way
to keep countries with poor safety records from getting in on the game. At
the very least, there should be some global consensus on how to proceed,
adds Elisa Harris, a researcher at the Center for International and Security
Studies at the University of Maryland, College Park–although no formal
mechanism for reaching it exists.

Mix and match

The H5N1 strain has been vicious to its human victims, killing 23 of 34
patients in Vietnam and Thailand this year. So far, however, every known
patient had been in contact with infected birds; there’s no evidence that
the virus can jump from one person to the next–for now. But the virus could
evolve inside one of its human hosts, acquiring mutations that make it
possible to infect humans directly, Stöhr says. Another scenario–one
researchers believe sparked several previous influenza pandemics–is
reassortment with a human flu virus in a person infected with both.

Influenza has a peculiar genome that’s divided into eight loose segments,
most of them containing precisely one gene. Each segment is copied
separately in the host cell’s nucleus; at the end of the reproduction cycle,
all eight meet up with one another–and with envelope and membrane
proteins–to form a new virus particle that buds from the host cell membrane
to wreak havoc elsewhere. When a cell happens to be infected with two
different strains, homologous segments can mix and match into new, chimeric

To create a worldwide outbreak, a newcomer must cause disease in humans and
be transmissible between them, and its coat must look so new that no human
immune system recognizes it. This is determined primarily by the two
glycoproteins on the viral surface, hemagglutinin and neuraminidase–the “H”
and “N” in names like H5N1. (Hemagglutinin comes in at least 16 different
types, N in nine.) The current fear is that the Asian flu will keep its
H5–which humans have never seen before–but swap enough of the remaining
seven gene segments with those of a human strain to become more adept at
replication in its new host.

During H5N1’s first major outbreak in Hong Kong poultry in 1997, 18 people
got sick and six died. But the outbreak was stamped out efficiently, and
little was heard of H5N1 for 6 years–until it came roaring back last year.
Given the magnitude of the current outbreak, the riddle is why reassortment
has not yet taken place, says Stöhr. Reassortment studies could help explain
whether the world has simply been lucky, or whether there’s some barrier to
reassortment of H5N1.

The experiments are straightforward. Researchers take a cell line such as
MDCK or Vero cells, often used for virus isolation, and add both H5N1 and a
currently circulating human strain, such as H3N2 or H1N1. Or they can use a
slightly less natural technique called reverse genetics, with which virtually any combination of genes can be put into a flu virus. Any viable hybrid strains would be inoculated into mice; those that cause disease would move on to ferrets, a species very similar to humans in its susceptibility to influenza. Any strain that is pathogenic in ferrets and also jumps, say, from a sick animal to a healthy one in an adjacent cage could be humankind’s next nightmare.

During its first round of experiments with the H5N1 strain, CDC managed to
create several reassortants, Cox says, but it didn’t get around to
characterizing them; they’re still sitting in a locked freezer in Atlanta.

Global risks, global review?

Most agree that such experiments are in a league of their own. Controversial
flu studies were conducted in the past; for instance, researchers sequenced
parts of the genome of the “Spanish flu” strain from 1918 (Science, 21 March
1997, p. 1793) and inserted its genes into other strains to find out why it
was so deadly. But that didn’t amount to a wholesale fishing expedition for
pandemic strains. And because the 1918 strain was an H1 virus, just like one
of the currently active ones, you’d expect at least some immunity to it in
the human population, says Yoshihiro Kawaoka of the University of Tokyo and
the University of Wisconsin, Madison, who studies the 1918 strain. With an
H5 virus, in contrast, everyone would be vulnerable.

Yet although most countries have systems to review the safety and ethical
aspects of run-of-the-mill scientific studies, none have formal panels to
weigh studies that could, say, put the entire world at risk or be of
potential help to bioterrorists. [The U.S. government has announced plans
for a national biosecurity panel and a review system to fill that gap
(Science, 12 March, p. 1595), but they have yet to be implemented.] So
although CDC’s first round of studies cleared all the usual review hurdles
at the agency, Cox says, nothing beyond that was considered necessary.
Since then, “the times have changed,” Cox says. The H5N1 strain now plaguing
Asia, with which CDC wants to work this time, appears to be more virulent
than the 1997 version, and the specter of nefarious use of pathogens looms
much larger. Moreover, the mishaps with SARS have made people jittery about
labs’ abilities to keep bugs on the inside. That’s why Cox says she has
consulted more extensively with colleagues inside and outside CDC, including
experts such as Nobel laureate Joshua Lederberg and WHO. She also plans to
seek approval from colleagues at the U.S. National Institutes of Health and
the U.S. Food and Drug Administration.

But flu researcher Karl Nicholson of the University of Leicester, U.K., says
there should be a more formal, global consensus on the necessity of the
studies, who should conduct them, and how. For any country to undertake them
on its own, he says, “is like a decision to start testing nuclear weapons
unilaterally.” WHO would be the best organization to start such a process,
says Harris: The destruction of the smallpox virus has been debated at WHO,
and an international panel there is overseeing experiments with it at CDC
and in Russia.

But Stöhr believes existing safeguards suffice. The studies have been
discussed widely with scientists in WHO’s global flu lab network and at a
recent flu meeting in Lisbon, he says, and have met with nothing but
“overwhelming agreement.” “If there are other voices, we will take them
seriously,” Stöhr adds–but for now, it’s up to the labs to have their plans
rigorously vetted by national authorities and get started.

Eventually, any strain with pandemic potential should be destroyed, he says.
But there’s no way to enforce this, and skeptics point out that the smallpox
virus was slated for destruction, too–until the threat of bioterrorism
created a movement to keep it alive, perhaps indefinitely, for defensive
studies. In a way this discussion is moot, says Richard Webby of St. Jude
Children’s Research Hospital in Memphis, Tennessee. With flu strains readily
available, anyone with a good knowledge of molecular biology could recreate
a pandemic virus once it’s discovered, he says. “You can destroy this
virus,” Webby says, “but it will never really be gone.”

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