Experts continue to clash over NSABB recommendation

Jan 31, 2012 (CIDRAP News) – As more details emerged today on an advisory group's recommendation for scientific journals to withhold key details of H5N1 transmission studies, another round of discussion on both sides of the controversy played out today on the pages of a major microbiology journal.

Three viewpoints on the topic appeared in mBio, the online open access journal of the American Society for Microbiology (ASM). Two supported the recommendation to withhold details about the study methodology and mutations due to bioterror concerns, which have been raised by the National Science Advisory Board for Biosecurity (NSABB), a panel of independent experts that advises the National Institutes of Health (NIH) on dual-use research issues. The third commentary argued for releasing the full details of the studies.

In an editorial introducing the three commentaries, Arturo Casadevall, MD, PhD, editor-in-chief of mBio, and Thomas Shenk, PhD, who chairs the ASM's publications board and is a professor of molecular biology at Princeton University in Princeton, N.J., wrote that their goal in commissioning and publishing the three views is to provide a forum for differences of opinion that will inform debate on the topic. Casadevall, a microbiologist at Albert Einstein College of Medicine in Bronx, N.Y., is also a member of the NSABB.

They said scientists find themselves in unfamiliar territory in addressing the controversy, because of the scientific uncertainty that swirls around some of the issues central to the debate, such as whether infection patterns in ferrets would parallel those in humans or what is the true case-fatality rate of H5N1 infections. Hence, arguments on both sides of the issue mix hard science with opinions and judgments.

Participants in the controversy are well-informed, well-intentioned people who hope to help and protect society and science by airing their viewpoints, Casadevall and Shenk wrote. "We believe that a healthy debate will lead to the best decisions and help avoid great mistakes," they said.

Paul Keim, PhD, acting chairman of the NSABB and director of pathogen genomics in the Translational Genomics Research Institute at Northern Arizona University, revealed that although the NSABB's recommendation had broad agreement from its members during earlier discussions, individual members sometimes had different rationales in arriving at the same conclusions.

He added that the NSABB has formalized tools for considering dual-use research issues, but uncertainties and contradictory information sometimes require subjective decisions, such as weighing the negative consequences and positive benefits of the research results.

In his commentary, Keim spelled out his own rationale for concluding that some of the study results should be withheld. He emphasized that he was speaking for himself and not the rest of the NSABB. Earlier today the NSABB as a group explained its rationale in a statement that appeared in Nature and Science, the two journals that are slated to publish the H5N1 transmission studies (see related CIDRAP News story). Nature also published a question-and-answer piece with Keim.

Keim said information from the influenza research community and a review of data from the World Health Organization (WHO) raised the specter of combining he high mortality of the H5N1 virus with a highly transmissible human-adapted phenotype. "A pandemic by such a pathogen could reasonably be concluded to cause such devastation that it should be prevented at all costs," he wrote.

Though the mammal-to-mammal transmission adaptation findings are a benefit of the research, which will motivate public health officials, vaccine makers, and drug developers to improve strategies and tools for fighting influenza, Keim added that the details of the studies would add little to short-term efforts while allowing someone to replicate the work in a short amount of time.

He also doubted that the details of the study would benefit flu surveillance and response, given how quick the 2009 H1N1 virus spread globally and that the virus was impossible to contain.

The NSABB's recommendations have stirred wide debate about issues such as academic freedom, censorship, and biosecurity, with actions and plans already underway by scientists, the journals, and the US government, Keim said. Global discussions now will pay research and public policy benefits that should increase the public's confidence in science research and ethics and in a more transparent research environment.

In a commentary supporting publication of the full studies, Vincent Racaniello, PhD, a Columbia University virologist who hosts a popular virology blog and has been an outspoken critic of the NSABB recommendation, wrote that the NSABB's request to remove key details to reduce the bioterror potential is wrong, because it is based on weak scientific grounds and hamstrings research that can benefit rather than harm the world.

He proposed that the NSABB's concerns about the highly lethal nature of the H5N1 virus are not supported by a firm grasp on the how many less serious illnesses it causes. "Extensive serological studies must be done to determine the extent of human infection with avian H5N1 influenza viruses," he wrote.

Racaniello said the H5N1 transmissibility the researchers saw in ferrets doesn't mean the virus will be equally transmissible in humans and that it's possible that passage of H5N1 virus in ferrets could attenuate its virulence in humans.

Questions about the lethality of the ferret-adapted H5N1 virus makes the pathogen an unlikely tool for terrorists, he said, adding that simply knowing the amino acid changes involved in the mutations doesn't pose an immediate risk. People wanting to replicate the virus would need to take other sophisticated steps, such as recovering the virus from cloned DNA.

He wrote that with an incomplete picture of what the virus needs for efficient replication, pathogenicity, and transmission, human modifications are less likely to result in a virus that can cause widespread disease. "To think that we can duplicate the enormous diversity and selection pressures that occur in the wild is a severe case of scientific hubris," he added.

Science is at its best when information is freely available, and publishing studies without complete methods and data, "is to abandon a system that brought us to the modern age of medicine," Racaniello wrote.

Robert Webster, PhD, who has led many H5N1 research studies and is with St. Jude's Children's Research Hospital in Memphis, wrote that he doesn't believe the full details of the studies should be published.

He said the risks outweigh the benefits because the H5N1 virus is more lethal than the 1918 pandemic virus, the H5N1 virus circulates in natural settings, and humans have a nearly universal susceptibility to infection from the virus. "This combination of factors creates an unacceptably high level of risk to humanity should mammalian-transmissible H5N1 virus be accidentally or intentionally released."

He urged scientists not to disregard data from ferrets. Though researchers don't know how well ferrets model human flu virus infection, H5N1 illness is typically milder in ferrets than in humans.

Panels that advised the National Institute of Allergy and Infectious Diseases and the WHO on the need for pandemic flu research never addressed the question of dual-use research, but now that scientists have generated transmissible H5N1, the time has come for a full discussion, Webster said.

Webster said the two manuscripts are major contributions that pave the way for a new era in life sciences. "The question before the scientific community is how to preserve scientific openness while minimizing risk to the public," he wrote.

Establishing a higher biosecurity level for future work on transmissible H5N1 viruses might hamper vaccine and antiviral research in countries—several of them with endemic H5N1 in poultry—that don't have biosafety level 4 (BSL 4) facilities might be counterproductive, Webster wrote.

But he added that enhancing BSL 3 safeguards with electronic surveillance and other measures might be a possibility to consider.

Casadevall A, Shenk T. The H5N1 manuscript redaction controversy. (Editorial) mBio 2012 Jan 31;3(1) [Full text]

Keim PS. The NSABB recommendations: rationale, impact, and implications. (Commentary) mBio 2012 Jan 31;3(1) [Full text]

Racaniello V. Science should be in the public domain. (Commentary) mBio 2012 Jan 31;3(1) [Full text]

Webster RG. Mammalian transmissible H5N1 influenza: the dilemma of dual-use research. (Commentary) mBio 2012 Jan 31;3(1) [Full text]

See also:

Jan 31 CIDRAP News story "NSABB: Studies show how H5N1 can jump natural barrier"

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