How to make gut tubes? - Controlling variability of morphogenetic paths in embryo-like models

Embryos of a given species follow a single morphogenetic trajectory, from zygote to fully developed organs. Variability is largely quantitative (length of limbs, number of cells per organ) with no qualitative differences. For example, all mouse embryos develop a single gut tube, stretching along their antero-posterior axis, and a fixed number of bilaterally arranged somites arranged symmetrically along this axis. This robustness stands in contrast to in-vitro embryo-like models, which, like most organoids, display a high degree of variability. What makes embryonic morphogenesis that robust is unclear.
We use extended gastruloids, or Trunk Like Structures, to study the morphogenetic progression of definitive endoderm (DE) and its divergence. We first catalog the different morphologies and characterize their statistics. We then learn predictive models for the lineage morphotype based on earlier expression and morphology measurements. Finally, we analyze these models to identify key drivers of morphotype variability, and devise “personalized” (organoid-specific) as well as global interventions that will lower this variability and steer morphotype choice. In the process we identify two types of coordination that are lacking in the organoid system, but are required for robust gut tube formation.
We expect the insights obtained here will improve the quality and usability of 3D embryo like models, chart a methodology extendable to other organoids for controlling variability, and will also shed light on the factors that provide the embryo its morphogenetic robustness.