Is Gain of Function a Reliable Tool for Establishing Sars-Cov-2 Origin?

The present opinion article, while dealing with the debated origin of “Severe Acute Respiratory Syndrome-Coronavirus-2” (SARS-CoV-2), the betacoronavirus responsible for “Corona Virus Disease-2019” (COVID-19), provides a speculative insight into the so-called “gain of function” (GOF), a process resulting in the acquirement of new phenotypic features on behalf of the viral pathogen. More in detail, a GOF-related phenomenon leading to increased SARS-CoV-2 virulence and/or transmissibility—as clearly exemplified by the “delta” and the “omicron” as well as by other “variants of concern”—would not necessarily imply that viral genetic manipulations made in the laboratory are its exclusive drivers, provided that GOF may also occur as a consequence of a natural selection process. In order to gain a better understanding of SARS-CoV-2 GOF and GOF-associated phenomena, an in-depth knowledge of the complex viral-host interaction dynamics is absolutely needed, while also paying special attention to the human-animal-viral ecological interfaces within an “ad hoc” multidisciplinary, “holistic”, scientific evidence-based and “One Health”-based approach.