Thursday, June 21, 2012

Science Publishes The Fouchier Ferret Study



BSL-4 Lab Worker - Photo Credit –USAMRIID  


# 6398


Just over 9 months ago, at the 2011 ESWI Influenza Conference in Malta, Dutch researcher Ron Fouchier described the results of a groundbreaking – and later, ground shaking – experiment he’d conducted with the H5N1 avian flu virus and ferrets.


Katherine Harmon’s piece in Scientific American (see SciAm: What Will The Next Influenza Pandemic Look Like?) briefly touched on his work, but it was Debra MacKenzie’s article a week later (see New Scientist: Five Easy Mutations) that really called attention to this experiment.


Fouchier was quoted as saying that he’d `mutated the hell’  out of the H5N1 virus in the lab, and then passed it serially through 10 ferrets, during which time it mutated further to become easily transmissible among the lab animals while retaining virulence.


Halfway across the world, Yoshihiro Kawaoka, a highly respected virologist at the University of Wisconsin-Madison School of Veterinary Medicine announced the creation of a comparable H5N1 super flu at roughly the same time.


Quietly at first, and then rising to a crescendo, a number of biosecurity experts began to openly question the wisdom of publishing details of (and in some cases, even conducting) these types of experiments.


Their concerns included the potential for an accidental lab release of the virus, and the possibility that someone could use this knowledge – if published – to create a bio-weapon.


The debate within the scientific community was both lengthy and visceral. A recommendation from the NSABB to redact portions of Fouchier’s study for publication was met with heavy criticism.


Those wishing to review that process (some might call it an ordeal) can select this link which will return more than two dozen blog posts on that intense debate.


After much discussion, it was decided that both Kawaoka’s and Fouchier’s (revised) studies should be published in full, and six weeks ago, the first paper appeared (see Nature Publishes The Kawaoka H5N1 Study).



Today the Journal Science publishes the long-awaited Fouchier study in a special section that includes an treasure trove of other H5N1 research-related reports, perspectives, news stories, and even an audio podcast.


To great credit to the editors and publishers of Science, all of these articles are being made available – in their entirety – to the public. 




With well over 100 pages of reports and supporting material, there’s a lot here to read and absorb (and a lot of it, particularly for non-scientists – is admittedly tough sledding).


Luckily, I’m sure we’ll be hearing a good deal of expert dissection and analysis emerging over the next few days.


Under the latest H5N1 news, you’ll find the following offerings:


Public at Last, H5N1 Study Offers Insight Into Virus's Possible Path to Pandemic M. Enserink

For Young Scientists, A Wild Ride - M. Enserink
How Much Longer Will Moratorium Last? - D. Malakof

Read all of Science's News coverage of the H5N1 controversy.

A Science Podcast brings us an Interview with Bruce Alberts; Science's Editor-in-Chief.


From Fouchier and his team we get the main event; an 8-page, highly technical report on how they created a genetically modified, mammalian-transmissible, version of the H5N1 virus:


Airborne Transmission of Influenza A/H5N1 Virus Between Ferrets

Sander Herfst, Eefje J. A. Schrauwen, Martin Linster,
Salin Chutinimitkul, Emmie de Wit, Vincent J. Munster, Erin M. Sorrell, Theo M. Bestebroer, David F. Burke, Derek J. Smith, Guus F. Rimmelzwaan, Albert D. M. E. Osterhaus, Ron A. M. Fouchier


Highly pathogenic avian influenza A/H5N1 virus can cause morbidity and mortality in humans but thus far
has not acquired the ability to be transmitted by aerosol or respiratory droplet (“airborne transmission”) between humans. To address the concern that the virus could acquire this ability under natural conditions, we genetically modified A/H5N1 virus by site-directed mutagenesis and subsequent serial passage in ferrets. The genetically modified A/H5N1 virus acquired mutations during passage in ferrets, ultimately becoming airborne transmissible in ferrets.





Fouchier also includes 34 pages of supporting material.


Erasmus Medical Center, where these experiments were conducted, at the same time (2pm ET today)  released a new Bird Flu Research Q&A that responds to several important questions, including:

  • What was the purpose of the work?
  • What experiments were done?
  • What are the main conclusions?
  • How does this help public health?



Along with the publication of Fouchier’s study, we also get a major report from C.A. Russell et al., that looks at the potential for these mutations to occur naturally in the wild.  The report’s pedigree also includes Albert Ostershaus, Ron Fouchier, and Yoshiro Kawaoka.



The Potential for Respiratory Droplet– Transmissible A/H5N1 Influenza Virus to Evolve in a Mammalian Host

Colin A. Russell, Judith M. Fonville,  AndréE.X.Brown, David F. Burke, David L. Smith, Sarah L. James, Sander Herfst, Sander van Boheemen, Martin Linster, Eefje J. Schrauwen, Leah Katzelnick, Ana Mosterín, Thijs Kuiken, Eileen Maher, Gabriele Neumann, Albert D. M. E.  Osterhaus, Yoshihiro Kawaoka, Ron A.M.Fouchier, Derek J. Smith


Avian A/H5N1 influenza viruses pose a pandemic threat. As few as five amino acid substitutions, or four with reassortment, might be sufficient for mammal-to-mammal transmission through respiratory droplets. From surveillance data, we found that two of these  substitutions are common in A/H5N1 viruses, and thus, some viruses might require only three additional substitutions to become transmissible via respiratory droplets between mammals.


We used a mathematical model of within-host virus evolution to study factors that could increase and decrease the probability of the remaining substitutions evolving after the virus has infected a mammalian host. These factors, combined with the presence of some of these substitutions in circulating strains, make a virus evolving in nature a potentially serious threat. These results highlight critical areas in which more data are needed for assessing, and potentially averting, this threat.


Again, you’ll find copious supplementary information available for this paper as well.


Also included in this special section are related commentaries, policy forum papers, and perspectives, including:


Statement by Science Editor‐in‐Chief Dr. Bruce Alberts Regarding Publication of H5N1 Avian Influenza Research


Regulating the Boundaries of Dual-Use Research - Mark S. Frankel


Influenza: Options to Improve Pandemic Preparation -Rino Rappuoli and Philip R. Dormitzer


Benefits and Risks of Influenza Research: Lessons Learned - Anthony S. Fauci and Francis S. Collins


Evolution, Safety, and Highly Pathogenic Influenza Viruses - Marc Lipsitch, Joshua B. Plotkin, Lone Simonsen, Barry Bloom


Securing Medical Research: A Cybersecurity Point of View - B. Schneier



Like many of you, I’m sure I’ll be spending a good amount of time over the next few days trying to absorb, and understand, this avalanche of new information.