A quick update on gain-of-function; I’m between papers (one submitted, one back from a coauthor with edits), and gain-of-function is back in the news.
Ron Fouchier and Yoshihiro Kawaoka have responded to a new paper on gain-of-function, which appeared in PLoS Medicine last week. The paper, by Marc Lipsitch and Alison P. Galvani, takes three popular conceptions of GOF research to task: 1) that it is safe; 2) that it is helpful in the development of vaccines; and 3) that it is the best option we have for bettering our understanding of flu viruses. I’m going to concentrate, here, on Fouchier’s reply to concerns about safety when performing gain-of-function research.
For context, Lipsitch and Galvani argue that
a moderate research program of ten laboratories at US BSL3 standards for a decade would run a nearly 20% risk of resulting in at least one laboratory-acquired infection, which, in turn, may initiate a chain of transmission. The probability that a laboratory-acquired influenza infection would lead to extensive spread has been estimated to be at least 10%.
A result that Fouchier calls “far fetched.” His reason?
The data cited by Lipsitch and Galvani include only 11 laboratory-acquired infections in the entire USA in 7 years of research, none of which involved viruses, none of which resulted in fatalities, and—most importantly—none of which resulted in secondary cases.
But Fouchier’s objection misses a couple of key points. The data Lipsitch and Galvani use comes from a 2012 paper in Applied Biosafety, which looked that the reported number of thefts, losses, or releases (TLR) of pathogens in American labs from 2004–2010. What they found was that TLRs have been increasing steadily, from 57 in 2007, to 269 in 2010. One reason given by Lipsitch and Galvani is that in 2008, significant investment was made in outreach and education about the need for accurate reporting about TLRs.
The other likely culprit? The proliferation of BSL–3 and BSL–4 laboratories.
Between 2004 and 2010, the number of BSL–3 laboratories in the USA—that we know of—more than tripled, from 415 to 1,495. This is likely an underestimate, however, because there is no requirement to track the number of BSL–3 labs that exist. The number of BSL–4 labs has also increased to 24 worldwide; 6 of these are in the USA. When you get an explosion of labs, you are likely to get a corresponding increase in laboratory accidents. That there have only been eleven laboratory acquired infections reported from hundreds of releases should cause us relief; but it doesn’t show that gain-of-function research is safe.
The problem, unacknowledged by Fouchier, is one of scale—as the number of labs increases, the number of experiments with dangerous pathogens (including H5N1) is likely to increase. Laboratory accidents are not a matter of if, but a matter of when. Significantly increasing the number of labs adds significantly to that “when.” And, in the words of Lipsitch and Galvani,
Such probabilities cannot be ignored when multiplied by the potential devastation of an influenza pandemic, even if the resulting strain were substantially attenuated from the observed virulence of highly pathogenic influenza A/H5N1.
More problematic is that Fouchier fails to note that laboratory containment failures have killed in the last decade—just not in the USA. In 2004, a researcher from the Chinese National Institute of Virology fell ill with SARS. She, while ill, infected both a nurse, who infected five others; and her mother, who died.
This represents, contrary to Fouchier’s claim, a laboratory containment failure that was a virus, did cause secondary (and tertiary) infections, and that killed. The study on which Lipsitch and Galvani base their estimate only covered the USA. A worldwide view is likely to be more concerning, not less. That’s why Lipsitch and Galvani refer to their estimate as “conservative,” and why for years there have been calls for heightened security when it comes to pandemic influenza studies.
Fouchier is right that scientific research has never caused a virus pandemic. But it’s a glaring logical error, to say nothing of hubris, to use that claim to dismiss the concern that it could happen.
There are other issues to be had with the responses of Fouchier and Kawaoka, but the overall message is clear: they continue to dismiss concerns that gain-of-function studies are risky, and provide little in the way of tangible benefits in the form of public health outcomes. I’m hoping for a more thoroughgoing reply from Lipsitch, who earlier this morning expressed some interest in doing so. This is an important debate, and needs to be kept open to a suitable range of voices.