Risks and Benefits of Gain-of-Function Experiments with Pathogens of Pandemic Potential, Such as Influenza Virus: a Call for a Science-Based Discussion

Casadevall, Arturo; Imperiale, Michael J.

At the heart of the scientific debate over influenza virus GOF experiments are different perceptions of the risk-benefit ratio of such experiments. Proponents of continued GOF experiments emphasize the benefit and downplay or even deny the risk, while opponents do the converse. Since both risk and benefit involve quantitative assessments, in this case with limited information, the debate is fueled by the reality that weighing risks and benefits involves judgment calls. The risks fall into two general categories that are separate but related: namely, biosecurity and biosafety. Biosecurity risk is the likelihood that someone would use products or information gained from GOF experiments that led to a more pathogenic virus to carry out intentional damage in the form of bioterrorism. Biosafety risk is the likelihood of accidental escape that could trigger an outbreak and epidemic. When the National Science Advisory Board for Biosecurity (NSABB) considered the H5N1 GOF papers, the original discussions were focused on biosecurity, which was the charge of the NSABB, but as time passed, the concern evolved from biosecurity to biosafety. Biosecurity estimates are difficult, because they involve a calculation of the risk of deliberate nefarious action, and such information is simply not always available. In fact, these assessments are so difficult that we have called for the formation of a national board to handle questions related to dual-use research of concern (11). On the other hand, biosafety estimates can rely on historical data. Prior experience with lab accidents was used by Lipsitch and Bloom to suggest that there is a significant likelihood that a major lab accident could occur with GOF influenza virus strains (12) . In fact, there is strong circumstantial evidence that the reintroduction of H1N1 into human circulation in 1977 after its disappearance in 1950 began with Editorial the accidental release of a laboratory strain (13) . Calculations of risk must also consider that researchers have learned from mistakes in the past, that the biosafety precautions being taken today have improved over historical standards, and that new regulations were recently put in place for the laboratory of HPAIV (4), with the important caveat that the recent problems at the CDC show that even the most advanced laboratories are vulnerable to serious mishaps. While no one appears to have been harmed by the lapses at the CDC laboratories, there have been recent cases in which laboratory workers were infected with Yersinia pestis (14) and Brucella sp. (15) , among others, highlighting the fact that laboratory accidents with virulent pathogens continue to occur despite knowledge of their potential danger and modern biosafety practices. Calculating the benefits of GOF research is also a somewhat challenging task, since the history of science shows that unexpected results can be more important than those that were originally anticipated when the experiment was designed. The importance of scientific findings is often not apparent at the time of discovery (16) . Hence, the argument from GOF opponents that such experiments have little value due to their risk must be considered with caution, given historical precedents showing that the value of scientific information cannot always be judged with current understanding or knowledge.