Cells in Negative Space


This paper by Israel et al published in Nature on the use of induced pluripotent stem cells to generate models of familial and sporadic Alzheimer’s has received some attention. There are significant questions yet-to-be-answered about the validity of this cell model, and questions about the effects of the reprogramming itself. But particularly in comparison to the circular thinking that begat the wildly overhyped transgenic mouse models of AD, this is intriguing, and the authors have sterling credentials (Salk, Scripps, UCSD, and more). The emergence of an Alzheimer’s phenotype (elevated AB1-40, tau, GSK3b) in the cells generated by both familial AD patients and one of the two sporadic AD patients is striking, and at least allows one to contemplate the use of such cells in compound screening (which the authors did with both beta and gamma secretase inhibitors). But just as visual art triggers the consideration of negative space as well as positive space, we are struck by what did not happen, the fact that reprogrammed cells from one of the two sporadic AD patients did not show an Alzheimer’s phenotype. It speaks to the heterogeneity of sporadic AD,  but one must wonder what variable(s) in that second sporadic AD patient led to the absence of the AD phenotype. Is it developmental, where longer incubation might have seen the phenotype arise? Does it reflect some relatively greater impact of environmental factors in that patient’s etiology? At the very least, it requires that the iPSC model not be embraced as impetuously as were its transgenic antecedents.

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