PROJECT SUMMARY Relics of mobile DNA make our genomes look like the aftermath of a mob scene. Even worse, some endogenous retrotransposons did not die out, but rather still swarm our cells early in ontogeny. Their actions can seriously damage the genome of the nascent embryo and cause sporadic diseases and infertility. Recently, we discovered a mechanism by which neighboring cells actively remove pluripotent cells that fail to undergo silencing of their endogenous retrotransposons. Our hypothesis is that there is a conditional policing mechanism reminiscent of a primitive immune system. We propose that pluripotent stem cells sense the endogenous retroviral load of their neighboring cells and, if it is higher than their own, act to kill and remove the overloaded cells. Upon completion of the outlined work, we will have (i) probed a previously unexplored sensing mechanism that involves cells “sniffing” one another for endogenous retroviruses and the removal of cells that failed to silence their genetic parasites (Aims 1 and 2) and (ii) tested whether this system is tunable and subject to immune modulation (Aim 3). These outcomes will have a positive impact because they will force us to shift our attention away from solely cell-intrinsic defense strategies towards considering a much more nuanced system in which cells constantly monitor one another for endogenous retrotransposon-related health. Our line of investigation will provide new targets for genetic diagnosis and interventions targeting pregnancy loss and infertility.