Stan had discovered and coined the term prions in 1982, and when I established my own laboratory in 1989, I wanted to address two related questions: First, why do neurons degenerate in neurodegenerative diseases such as Creutzfeldt-Jakob disease and Alzheimer’s disease? Second, is the neurodegenerative process mediated by developmentally-related, physiological signaling, or is it mediated by purely pathological, non physiological processes? To address these questions, we needed a simple, rapidly iterative, genetically manipulable yet disease-relevant model, and unfortunately, no such model existed in 1989 (which made me envy the oncology researchers, who had well characterized cell culture phenotypes, readily transfectable cells, and remarkable in vitro-in vivo correlations in their model systems). Furthermore, there was resistance to developing and utilizing such a model: at neurodegenerative meetings in the early 1990s it was argued that any process that occurred rapidly in an in vitro system was unlikely to have much relevance for processes that occurred over years in vivo in chronic neurodegenerative conditions. It seemed like a rational argument at the time, but fortunately it turned out to be incorrect.