The pandemic's most contentious question: Did SARS-CoV-2 emerge through natural spillover from animals to humans, or through a laboratory incident tied to research intended to anticipate the next outbreak? A flashpoint in that debate has been DEFUSE " a 2018 grant proposal submitted to DARPA, the Defense Department's advanced research agency. DEFUSE outlined plans to test spike-protein swaps and cleavage-site insertions in bat coronaviruses. Newly obtained NIH records suggest that the experimental concepts later spotlighted in DEFUSE " tuning bat coronavirus infectivity through spike swaps, receptor-binding changes, and cleavage-site insertions" were already embedded in multiple U.S.-funded coronavirus research projects years before the pandemic. NIH ... reviewers saw potential risk. In an internal "biohazard comment," a grants manager warned that recombinant coronaviruses engineered to enhance spike cleavage or strengthen ACE2 binding "may have novel and unexpected virulence phenotypes" " or, new and unpredictable traits that could make the virus more dangerous. NIH reviewed " and frequently approved " experiments designed to alter receptor-binding domains, swap spike proteins between viruses, or modify cleavage sites that influence how coronaviruses infect cells. American and Chinese researchers shared sequences, experimental ideas and preliminary findings in real time.