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.

In recent years, some members of the scientific community have been involved in a vigorous debate over so-called "gain-offunction" (GOF) experiments involving pathogens with pandemic potential (PPP), such as influenza virus. Proponents and opponents of GOF work engaged in extensive discussion about the value, safety, ethics, and validity of this type of research. The debate was initially catalyzed by research experiments published in 2012, which reported that serial passage in ferrets rendered variants of the highly pathogenic avian influenza virus (HPAIV) H5N1 transmissible in a mammalian species (1, 2) . These experiments were performed, in part, because there was debate in the field as to whether H5N1 could become transmissible in humans. The result was accompanied by publication of the specific mutations associated with this new function, which was essentially a "species jump" to mammalian transmission. Although influenza virus has historically demonstrated the capacity to move across species, in this particular experiment, the GOF was the acquisition of mammalian transmissibility for a virus that previously lacked it. The debate over this type of experimentation (i.e., that which changes the transmissibility of an influenza virus to include a mammalian species) resulted in a temporary moratorium on GOF experiments involving HPAIV, followed by continuation of the work with additional biosafety precautions and regulations (3, 4) . There followed a period of relative quiescence as the new status quo established itself. However, several papers describing similar experiments with other influenza virus strains have subsequently been published (5-7), along with accompanying editorials that explain the decision for publication (8, 9) . In recent months the controversy over GOF experiments has been rekindled by reports of the generation of new viruses that are similar to the 1918 strain (6) and further fueled by two laboratory accidents at the Centers for Disease Control that heightened concern about accidental escape of laboratory strains with pandemic potential. With this backdrop, GOF experiments have been severely criticized in the general media, and 18 individuals, including both authors of this editorial, signed a statement of concern involving influenza virus GOF experiments (http://www.cambridgeworkinggroup.org/). The essence of this statement from the Cambridge Working Group (CWG) was a call for curtailment of such experiments, during which time there could be a risk-benefit analysis of future work and the convening of a conference to discuss the many issues involved in this developing situation. The CWG statement has been criticized, but there appears to be some agreement on the need for an Asilomar-type conference to explore the many issues involved in GOF experiments (http://www.twiv.tv/2014/07/20/ twiv-294/). Most recently, a group called Scientists for Science posted its own statement emphasizing the importance of research on potentially dangerous pathogens and also calling for a conference to discuss the issues (http://www.scientistsforscience.org/). We note that both statements share many points of agreement, which provides a promising base for constructive dialog. In the past, mBio has provided a forum for discussion and debate on the merits of this work. Here we take up the pen (or keyboard) to highlight some issues pertinent to the ongoing debate and promote further discussion, our major goal in signing the CWG statement.