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.

Given that symbolic language is the basis for much of human communication, we begin with terminology and dissect the phrase "gain of function," or GOF. When applied to influenza virus research, the term GOF has taken on the meaning of something dangerous, risky, and possibly nefarious. However, GOF means exactly what it says, that the entity in question has gained a new property. In the case of influenza virus, the concern regarding GOF has been associated with the acquisition of a new function, such as mammalian transmissibility, increased virulence for humans, or evasion of existing host immunity. For example, passage of H5N1 virus in ferrets allowed selection for variants with ferretto-ferret transmissibility, and the GOF was the acquisition of mammalian transmission. However, the same type of experiment can be beneficial to humanity, since the principle of passage in a nonnative host can be used to generate attenuated vaccines. For example, some human-pathogenic viruses, such as poliovirus, were attenuated by passage in cells of another species, such as monkey cells. In those experiments, the GOF was replication in another species, and this property reduced the efficiency of replication in human cells, thus resulting in a new attenuated strain that could be used as a vaccine. Indeed, those attenuated viruses manifested a GOF, namely, attenuation. One of us recently published a GOF experiment with BK polyomavirus, in which mutation of a regulatory microRNA (miRNA) greatly enhanced replication (10) . Hence, GOF is a powerful experimental tool that is routinely used in biomedical research, and the concern with influenza virus research is not gain of function per se but rather the selection of variants with increased mammalian transmissibility and virulence that could affect human populations if there were deliberate or accidental release. It is clear that GOF is a problematic phrase, and this term has acquired a particular meaning in the ongoing debate and particularly in the lay media. Unfortunately, the term GOF has come to only represent something that can be used to confer dangerous properties to a microbe. Despite these problems in terminology, we use the expression GOF in this essay with the understanding that we are referring to the narrow category of experiments that involve primarily changes to the virulence and transmissibility of PPP, such as influenza virus. Although influenza virus is the subject of the ongoing debate, it is important to note that these issues extend to other PPP, such as severe acute respiratory syndrome (SARS) coronavirus.