Controversy Continues After Engineered-Bird-Flu Study Published

Mutant H5N1 virus binds to human trachea (left) and lung (right) tissue samples, provoking an antibody response (green). Image: Imai et al./Nature

After months of controversy, an experiment describing how H5N1 avian influenza can be modified into potentially human-contagious forms was published today.

The study was originally submitted to the journal Nature in 2011. Concern that its details, along with those in a similar, as-yet-unpublished experiment, could be turned to malevolent ends delayed its publication.

Subsequent public controversy resulted in a temporary moratorium on such research that is still ongoing. The uproar, however, is far from over: Flu researchers and biodefense experts continue to argue over the findings’ safety and scientific value.

“Given the possibility of accidental escape from the lab — a not too uncommon event — the risks seem to me enormous, while the benefits are very small,” said Richard Roberts, a Nobel Prize-winning geneticist who now works at New England Biolabs.

Amino acid structure of the mutant H5N1′s modified protein; the positions of four key virulence-increasing mutations are noted. Image: Imai et al./Nature

In the study, researchers led by virologist Yoshiro Kawaoka of the University of Wisconsin introduced random genetic mutations to one of the flu virus’ eight genes.

The mutations changed the shape of the protein the gene produced, allowing H5N1 — which until now had great difficulty infecting mammals, including humans — to infect and pass easily between ferrets, an animal commonly used to model human flu pathology. The viruses also attached more easily to human respiratory-tract cells.

The resulting strains were non-lethal to ferrets, and it’s thought they’d be non-lethal to humans as well, though this is obviously untested. Experimental vaccines against naturally occurring H5N1 appeared activated by exposure to the new strains, suggesting a protective effect, though this too remains unproven.

According to the study’s authors and many flu experts, the findings are important in several ways: They prove that it’s indeed possible for H5N1 to evolve to infect humans, they flag several genetic mutations to watch for in naturally evolving strains, and they underscore the need for continued research. The potential hybridization of H5N1 with the H1N1 swine flu of 2009 is especially troubling.

“These findings do not only provide further indication that such a virus may arise naturally; they also pave the way for improved influenza surveillance and pandemic preparedness,” wrote University of Hong Kong virologists Hui-Ling Yen and Malik Peiris, the scientist who first identified SARS, in a commentary accompanying the study.

Over the last several months, objections to the research have frequently been called uninformed or overblown. “Fear needs to be put to rest with solid science and not speculation,” wrote microbiologist Peter Palese of the Mount Sinai School of Medicine in a January commentary in the Proceedings of the National Academy of Sciences.

Hints of that tone remain in an “independent risk assessment” commissioned by Nature, describing how the findings “could be misrepresented by a willful media, in the absence of a knowledgeable public.”

Many prominent virologists are afraid to criticize the findings publicly.

Many experts do, however, remain skeptical of the findings’ value.

The mutations identified are indeed interesting, but thousands of other as-yet-unknown mutations may have the same effect, potentially limiting this work’s relevance. It’s uncertain whether naturally occurring mutations would even behave the same way.

Global flu surveillance is also piecemeal and grossly underfunded, making it unlikely that the identity of these experimental mutations can be put to use in the near future.

“I find it rather unlikely that these experiments would have resulted in the discovery of anything useful other than the knowledge that aerosolic transmission was possible,” said Richard Roberts of New England Biolabs.

Virologist Michael Osterholm of the University of Minnesota expressed a similar sentiment in a January editorial in the journal Science. ”The desire to disseminate the entirety of the methods and results of the two H5N1 studies in the general scientific literature will not materially increase our ability to protect the public’s health from a future H5N1 pandemic,” he wrote. Osterholm declined to comment this week.

According to Roberts, many prominent virologists are afraid to criticize the findings publicly for fear of retribution from the National Institutes of Health and other funders that promised the strategy of experimentally making dangerous pathogens more virulent would be safe and valuable.

“That’s certainly not the case,” said Anthony Fauci, director of the National Institutes of Allergy and Infectious Disease, the NIH division that funded the research. “We’re driven by a philosophy of open scientific discourse. Disagreements are one of the fundamental positive aspects of science.”

Images: Imai et al./Nature

Citations: “Experimental adaptation of an influenza H5 HA confers respiratory droplet transmission to a reassortant H5 HA/H1N1 virus in ferrets.” By Masaki Imai, Tokiko Watanabe, Masato Hatta, Subash C. Das, Makoto Ozawa, Kyoko Shinya, Gongxun Zhong, Anthony Hanson, Hiroaki Katsura, Shinji Watanabe, Chengjun Li, Eiryo Kawakami, Shinya Yamada, Maki Kiso, Yasuo Suzuki, Eileen A. Maher, Gabriele Neumann & Yoshihiro Kawaoka. Nature, Vol. 785 No. 7396, May 3, 2012.

“Bird flu in mammals.” By Hui-Ling Yen and Malik Peiris. Nature, Vol. 785 No. 7396, May 3, 2012. Nature, Vol. 785 No. 7396, May 3, 2012.

“Framework for Assessing the Risks and Benefits of Communicating Dual Use Information That May Have Biosecurity Implications.” Nature, Vol. 785 No. 7396, May 3, 2012.