Might SARS-CoV-2 Have Arisen via Serial Passage through an Animal Host or Cell Culture?: A potential explanation for much of the novel coronavirus' distinctive genome.

Despite claims from prominent scientists that SARS-CoV-2 indubitably emerged naturally, the etiology of this novel coronavirus remains a pressing and open question: Without knowing the true nature of a disease, it is impossible for clinicians to appropriately shape their care, for policy-makers to correctly gauge the nature and extent of the threat, and for the public to appropriately modify their behavior. Unless the intermediate host necessary for completing a natural zoonotic jump is identified, the dual-use gain-of-function research practice of viral serial passage should be considered a viable route by which the novel coronavirus arose. The practice of serial passage mimics a natural zoonotic jump, and offers explanations for SARS-CoV-2's distinctive spike-protein region and its unexpectedly high affinity for angiotensin converting enzyme (ACE2), as well as the notable polybasic furin cleavage site within it. Additional molecular clues raise further questions, all of which warrant full investigation into the novel coronavirus's origins and a re-examination of the risks and rewards of dual-use gain-of-function research.

Complex Autoinflammatory Syndrome Unveils Fundamental Principles of JAK1 Kinase Transcriptional and Biochemical Function.

Autoinflammatory disease can result from monogenic errors of immunity. We describe a patient with early-onset multi-organ immune dysregulation resulting from a mosaic, gain-of-function mutation (S703I) in JAK1, encoding a kinase essential for signaling downstream of >25 cytokines. By custom single-cell RNA sequencing, we examine mosaicism with single-cell resolution. We find that JAK1 transcription was predominantly restricted to a single allele across different cells, introducing the concept of a mutational "transcriptotype" that differs from the genotype. Functionally, the mutation increases JAK1 activity and transactivates partnering JAKs, independent of its catalytic domain. S703I JAK1 is not only hypermorphic for cytokine signaling but also neomorphic, as it enables signaling cascades not canonically mediated by JAK1. Given these results, the patient was treated with tofacitinib, a JAK inhibitor, leading to the rapid resolution of clinical disease. These findings offer a platform for personalized medicine with the concurrent discovery of fundamental biological principles.