Jeff Miller/University of Wisconsin, Madison

Yoshihiro Kawaoka

A Central Researcher in the H5N1 Flu Debate Breaks His Silence

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In the heated debate about two labs that engineered a variant of the deadly H5N1 avian flu virus that for the first time easily transmits between mammals, one critical voice has been missing: Yoshihiro Kawaoka. But today, Kawaoka speaks his mind in a Nature commentary and in a detailed response to questions from ScienceInsider.

A virologist at the University of Tokyo and the University of Wisconsin, Madison, Kawaoka led one of the studies that has sparked alarm around the world that these lab creations might escape or give ideas to bioterrorists. In a commentary published online by Nature today, he offers intriguing details about his study, a report of which has been accepted by the journal but remains unpublished. Kawaoka also discusses his thoughts about the recommendation from the U.S. government's National Science Advisory Board for Biosecurity (NSABB) that Nature and Science, which has accepted but not published a paper by the second lab that did these studies, redact key portions of the experiments to prevent the widespread dissemination of the recipe for a potential bioweapon.

As Kawaoka explains, his experiment differs in several keys ways from one led by the lab of Ron Fouchier at Erasmus MC in Rotterdam, the Netherlands. Both teams did their experiments in ferrets, a favorite laboratory model for studying transmission of influenza viruses as they mimic viral spread in humans. Until now, H5N1 has never efficiently transmitted between humans or ferrets, although it decimates flocks of chickens and often kills the mammals it infects. Fouchier, who has discussed his work at scientific meetings and with the media, concocted a transmissible H5N1 in ferrets by both manipulating viral genes and repeatedly passaging the virus through the animals to help it adapt to that host. This virus was highly lethal.

Kawaoka, in contrast, stitched the hemagglutinin gene from the avian virus—the H5—into a H1N1 virus that easily spreads between humans and caused the relatively mild 2009 pandemic. His mutant, like Fouchier's, readily transmitted between ferrets housed in different cages, but it was not lethal. "And, importantly, current vaccines and antiviral compounds are effective against it," writes Kawaoka in his commentary.

Although Kawaoka joined Fouchier and others last week in signing an agreement to suspend studies for 60 days on H5N1 viruses that can transmit in mammals, he emphasizes in both his commentary and to ScienceInsider that he strongly disagrees with efforts to limit this work and its full publication. "As the risks of such research and its publication are debated by the community, I argue that we should pursue transmission studies of highly pathogenic avian influenza viruses with urgency," he writes in Nature. "Because H5N1 mutations that confer transmissibility in mammals may emerge in nature, I believe that it would be irresponsible not to study the underlying mechanisms."

Kawaoka emphasizes that the benefits of conducting and fully publishing this work outweigh the perceived risks. He contends that "there is already enough information publicly available to allow someone to make a transmissible H5 HA-possessing virus," highly trained researchers have conducted the work under stringent biosafety standards, the findings can help inform surveillance efforts, and the proposed mechanisms for restricting access to the data are "unwieldy." He further stresses that the work may well attract other investigators to help answer critical questions. He notes, for example, his lab's surprising finding that the mutations connected to transmission do not simply involve the way influenza's hemagglutinin protein binds to cellular receptors, as many researchers assume. "The redaction of our manuscript, intended to contain risk, will make it harder for legitimate scientists to get this information while failing to provide a barrier to those who would do harm," he writes.

Fouchier, who has been in close contact with Kawaoka during this controversy, welcomed his colleague going public with his thoughts about the issues. "I think it is a very powerful statement about the factual benefits of this type of work that by far outweigh the theoretical risks," says Fouchier. "By following the NSABB advice, the world will not get any safer, it may actually get less safe."

In an e-mail response to questions submitted by ScienceInsider, Kawaoka explains that he has not spoken out until now in part because of his discussions with Nature. "The journal advised me to avoid talking to the media until the paper was published," he wrote. "Without being able to describe our findings, I cannot address fully the issues the media want to discuss." He said he decided to break his silence because of the decision to delay publication of his study. "I felt that now, especially with publication of the statement that we would pause the transmission studies, it was time to comment," he said.

Kawaoka appeared unruffled by assertions that this type of research itself is irresponsible and should never have been conducted. "Actually, I don't let this type of criticism bother me," he wrote. "I acknowledge the public anxiety about research with highly pathogenic avian influenza. But, despite what the headlines say, I know our research has the potential to provide significant public health benefits."

In Japan, which unlike the United States has had several outbreaks of H5N1 in birds, "not much" controversy has surrounded this study, he said, as "the public has concerns about a genuine risk that exists in nature rather than a potential risk by bioterrorism." He added that "people wonder why we are pausing the research—they think it is important that we continue."

Kawaoka agreed to the 60-day moratorium because he hoped it would lead to a more thoughtful discussion about the issues. "I realized the controversy about these experiments had provoked a very serious situation and that discussions about regulating and publishing our research were taking place without the input of scientists," he said. "And we were losing the support of the public, those who we meant to benefit from our findings."

He said he is confident that 60 days is enough time to resolve many of the issues raised by the work. "We should be able to find solutions if people are willing to listen to one another and make decisions based on data, not fear," he concluded.

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