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Despite the advent of several novel, synthetic gene drive mechanisms andtheir potential to one-day control a number of devastating diseases, amongother applications, practical use of these systems remains contentious andrisky. In particular, there is little in the way of empirical evidence of thelong-term robustness of these synthetic systems against mutational breakdown.Rather, most existing systems are either known or predicted to be susceptibleto rapid inactivation, though methodological designs continue to be refined.Here we evaluate a currently existing synthetic, underdominance-based genedrive system 200+ generations after it was first established in a laboratorycolony of Drosophila melanogaster. Not only do we find that the system is stillfunctioning as designed, we also show evidence that disruptions to the geneticconstruct are highly likely to be removed by natural selection, contributing tothe system's robust, long-term stability. This stability appears to be a resultof a fundamental relationship between ribosomal proteins (a novel target of thesystem) and natural cellular defenses that protect against cancer development.As far as we are aware, this is the longest continually functioning syntheticgene drive system thus verified, making it highly appropriate for additionalresearch into its eventual suitability for field trials. Due to inherentproperties of this gene drive, it is also likely to be adaptable for use inmany different species. The insect lines established and used to test thissystem have been deposited at a Drosophila stock center, and are available tolabs for further, independent testing.

RPM-Drive: A robust, safe, and reversible gene drive system that remains functional after 200+ generations