One of the enduring mysteries of COVID-19 is why some people get a severe disease that can be fatal, whereas the majority experience a very mild or even asymptomatic disease. On this episode of the Bio Eats World Journal Club, host Lauren Richardson (@lr_bio) discusses this discrepancy with Dr. Helen Su, Chief of the Human Immunological Diseases Section at the National Institute of Allergy and Infectious Diseases (part of the NIH) and co-leader of the COVID Human Genetic Effort. This international collaboration set out to investigate whether there is a genetic component to severe COVID and published the first of their findings in two articles in Science. The conversation covers these two papers — “Inborn errors of type I IFN immunity in patients with life-threatening COVID-19” and “Autoantibodies against type I IFNs in patients with life-threatening COVID-19” — which both find that dysfunction in a very specific part of the immune system leads to severe COVID, but through distinct mechanisms. We break down these results, how they can inform treatment, and how this collaboration was able to uncover these important findings in record time.