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Lack of mathematical theory limits our predictive understanding of the ecological and evolutionary dynamics of symbiotic communities, and that is affecting our ability to successfully understand, manage, and conserve them. In this February 10, 2026 seminar at a workshop at the Banff International Research Station for Mathematical Innovation and Discovery, biologists and mathematicians came together to discuss the current challenges and opportunities for the mathematical modelling of symbiotic systems. Participants developed new ‘eco-evolutionary’ models that explicitly account for host-symbiont intertwined ecology and evolution, and for the consequences of this interdependence. In this talk, Dr. Bordenstein summarized over two decades of research on the layers in which the reproductive and gut microbiome shape the fate of new host species formation, and the opportunities to model the "mystery of mysteries" process that Darwin discussed in the Origin of Species.