Tuesday, November 29, 2011


Published Date: 2011-11-28 16:54:21
Subject: PRO/AH/EDR> Avian influenza (73): ferret experiment controversy
Archive Number: 20111128.3474
AVIAN INFLUENZA (73): FERRET EXPERIMENT CONTROVERSY***************************************************

A ProMED-mail post
ProMED-mail is a program of the
International Society for Infectious Diseases
Date: Wed 23 Nov 2011
Source: Science Insider, American Association for the Advancement of
Science (AAAS) [edited]

Scientists brace for media storm around controversial flu studies
Locked up in the bowels of the medical faculty building [in Rotterdam]
and accessible to only a handful of scientists lies a man-made flu
virus that could change world history if it were ever set free.

The virus is an H5N1 avian influenza strain that has been genetically
altered and is now easily transmissible between ferrets, the animals
that most closely mimic the human response to flu. Scientists believe
it's likely that the pathogen, if it emerged in nature or were
released, would trigger an influenza pandemic, quite possibly with
many millions of deaths.

In a 17th floor office in the same building, virologist Ron Fouchier
of the Erasmus Medical Centre calmly explains why his team created
what he says is "probably one of the most dangerous viruses you can
make" -- and why he wants to publish a paper describing how they did
it. Fouchier is also bracing for a media storm. After he talked to
'ScienceInsider '[Science Journal] yesterday [22 Nov 2011], he had an
appointment with an institutional press officer to chart a
communication strategy.

Fouchier's paper is one of 2 studies that have triggered an intense
debate about the limits of scientific freedom and that could portend
changes in the way US researchers handle so-called dual-use research:
studies that have a potential public health benefit but could also be
useful for nefarious purposes like biowarfare or bioterrorism.

The other study -- also on H5N1, and with comparable results -- was
done by a team led by virologist Yoshihiro Kawaoka at the University
of Wisconsin, Madison, and the University of Tokyo, several scientists
told 'ScienceInsider'. (Kawaoka did not respond to interview
requests.) Both studies have been submitted for publication, and both
are currently under review by the US National Science Advisory Board
for Biosecurity (NSABB), which on a few previous occasions has been
asked by scientists or journals to review papers that caused worries.

NSABB chair Paul Keim, a microbial geneticist, says he cannot discuss
specific studies but confirms that the board has "worked very hard and
very intensely for several weeks on studies about H5N1
transmissibility in mammals." The group plans to issue a public
statement soon, says Keim, and is likely to issue additional
recommendations about this type of research. "We'll have a lot to
say," he says.

"I can't think of another pathogenic organism that is as scary as this
one," adds Keim, who has worked on anthrax for many years. "I don't
think anthrax is scary at all compared to this."

Some scientists say that's reason enough not to do such research. The
virus could escape from the lab, or bioterrorists or rogue nations
could use the published results to fashion a bioweapon with the
potential for mass destruction, they say. "This work should never have
been done," says Richard Ebright, a molecular biologist at Rutgers
University in Piscataway, New Jersey, and the Howard Hughes Medical
Institute who has a strong interest in biosecurity issues.

The research by the Kawaoka and Fouchier teams set out to answer a
question that has long puzzled scientists: Does H5N1, which rarely
causes human disease, have the potential to trigger a pandemic? The
virus has decimated poultry flocks on 3 continents but has caused
fewer than 600 known cases of flu in humans since it emerged in Asia
in 1997, although those rare human cases are often fatal. Because the
virus spreads very inefficiently between humans it has been unable to
set off a chain reaction and circle the globe.

Some scientists think the virus is probably unable to trigger a
pandemic, because adapting to a human host would likely make it unable
to reproduce. Some also believe the virus would need to reshuffle its
genes with a human strain, a process called reassortment, that some
believe is most likely to occur in pigs, which host both human and
avian strains. Based on past experience, some scientists have also
argued that flu pandemics can only be caused by H1, H2, and H3
viruses, which have been replaced by each other in the human
population every so many decades -- but not by H5.

Fouchier says his study shows all of that to be wrong. Although he
declined to discuss details of the research because the paper is still
under review, Fouchier confirmed the details given in news stories in
New Scientist and Scientific American about a September [2011] meeting
in Malta where he first presented the study. Those stories describe
how Fouchier initially tried to make the virus more transmissible by
making specific changes to its genome, using a process called reverse
genetics; when that failed, he passed the virus from one ferret to
another multiple times, a low-tech and time-honored method of making a
pathogen adapt to a new host.

After 10 generations, the virus had become "airborne": healthy ferrets
became infected simply by being housed in a cage next to a sick one.
The airborne strain had 5 mutations in 2 genes, each of which have
already been found in nature, Fouchier says; just never all at once in
the same strain.

Ferrets aren't humans, but in studies to date, any influenza strain
that has been able to pass among ferrets has also been transmissible
among humans, and vice versa, says Fouchier. "That could be different
this time, but I wouldn't bet any money on it."

The specter of an H5N1 pandemic keeps flu scientists up at night
because of the virus's power to kill. Of the known cases so far, more
than half were fatal. The real case-fatality rate is probably lower
because an unknown number of milder cases are never diagnosed and
reported, but scientists agree that the virus is vicious.

"These studies are very important," says biodefense and flu expert
Michael Osterholm, director of the Center for Infectious Disease
Research and Policy [CIDRAP] at the University of Minnesota, Twin
Cities. The researchers "have the full support of the influenza
community," Osterholm says, because there are potential benefits for
public health. For instance, the results show that those downplaying
the risks of an H5N1 pandemic should think again, he says. Knowing the
exact mutations that make the virus transmissible also enables
scientists to look for them in the field and take more aggressive
control measures when one or more show up, adds Fouchier. The study
also enables researchers to test whether H5N1 vaccines and antiviral
drugs would work against the new strain.

Fouchier says he consulted widely within the Netherlands before
submitting his manuscript for publication. The US National Institutes
of Health (NIH), which funded the work, has agreed to the publication,
says Fouchier, including officials at the National Institute of
Allergy and Infectious Diseases. (The NIH declined to answer questions
for this story.) Now, Fouchier is eagerly waiting for NSABB's

Osterholm says he can't discuss details of the papers because he's an
NSABB member. But he says it should be possible to omit certain key
details from controversial papers and make them available to people
who really need to know. "We don't want to give bad guys a road map on
how to make bad bugs really bad," he says.

But some scientists say the board's debate comes way too late, because
the studies have been done and the papers are written. "This is a good
example of the need for a robust and independent system of PRIOR
review and approval of potentially dangerous experiments," retired
arms control researcher Mark Wheelis of the University of California,
Davis wrote to 'ScienceInsider' in an e-mail. "Blocking publication
may provide some small increment of safety, but it will be very modest
compared to the benefits of not doing the work in the 1st place."

Scientists have long discussed whether to have mandatory reviews of
dual-use studies before they begin, and given the global risks, some
have even argued for some international risk assessment system for
pandemic viruses. For instance, a proposal by 4 researchers from the
Center for International and Security Studies at Maryland would have
classified Fouchier's work as an "activity of extreme concern" that
would have required international pre-approval.

But NSABB advised against such mandatory systems in 2007, and most
countries don't have formal mechanisms in place to review studies
before they start. (In the United States, it's "recommended" that
researchers ask an institutional review board for advice if they think
a study raises concerns.) Fouchier's study was green-lighted in
advance by the Dutch Commission on Genetic Modification (COGEM), but
that only means the panel is satisfied with safety procedures at
Fouchier's lab, explains chair Bastiaan Zoeteman; it's not COGEM's job
to decide whether a study is desirable. NIH didn't give the funding
proposal a special review either, says Fouchier. "The creation of a
pandemic virus has been the classical example of dual use research of
concern the past decade," says Ebright. "It's remarkable that the
NSABB is discussing it in 2011."

Keim agrees about the need for reviews up front. "The process of
identifying dual use of concern is something that should start at the
very 1st glimmer of an experiment," he says. "You shouldn't wait until
you have submitted a paper before you decide it's dangerous." Keim
says. "Scientists and institutions and funding agencies should be
looking at this. The journals and the journals' reviewers should be
the last resort."

NSABB does not have the power to prevent the publication of papers,
but it could ask journals not to publish. Even Ebright, however, says
he's against efforts to ban the publication of the studies now that
they have been done. "You cannot post hoc suppress work that was done
and completed in a non-classified context," he says. "The scientific
community would not stand for that."

[Byline: Martin Enserink]

Communicated by:
Martin Enserink
Contributing news editor, Europe
Science magazine (www.science.com)
Paris / Amsterdam

[ProMED-mail thanks Martin Enserink for making this information
available for the benefit of our subscribers. Readers can make their
own assessment of the situation. This moderator inclines to the view
that any form of censorship would be undesirable and ineffective.
Conceptually this research is uncomplicated and probably within the
capabilities of several laboratories. - Mod.CP]


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