How simple physics drives the earliest stages of embryogenesis

The initial stages of mammalian embryo development involve a single fertilised egg that repeatedly divides to create a solid ball of cells called a morula. Despite the apparent simplicity of this process, which involves only one cell type and a few tens of cells, there are still a host of unanswered questions, particularly around the underlying biophysical mechanisms that are at play. To address this, we here develop a novel type of vertex model that includes cortical tension, cell-to-cell adhesion, membrane curvature and cell volume forces, along with a zona pellucida, cell division and the effect of noise. We fit our model to both mouse and human experimental data, which allows us to address a number of key questions including the relative roles of adhesion and tension, how the cortical tension varies around the cell, the purpose of the zona pellucida, and the rules governing the first few cell divisions. We also determine the biophysical effects responsible for compaction and internalisation, including addressing why the morula does not typically decompact during internalisation. Next, we investigate the position-versus-polarisation debate during trophectoderm differentiation, how the division axis is determined during later divisions, and the role of noise. Finally, we compare human and mouse, focussing on the key similarities that may span all mammals. Our use of a force-based computational model allows us to address fundamental questions relating to mammalian development, particularly the underlying biophysical rules governing early embryogenesis, with important applications to stem cell models such as blastoids, conservation efforts of endangered species and embryo grading during IVF. Significance Statement The very first stages of embryogenesis are a vital but still poorly understood part of development, with important applications to fertility, fertility lifespan and assisted conception such as IVF. Most research in this area has focussed on experimental approaches, ignoring the potential for biophysical modelling. Here, we address this by developing a novel computer simulation of the first thee-to-four cell divisions of the fertilised egg, resulting in a compact bunch of cells called a morula. In particular, we develop a new type of vertex model for the early embryo that for the first time includes contributions from a range of realistic biophysical forces. By analysing real mouse and human embryo data through our model, we reveal how simple physics drives crucial early developmental processes, including compaction, internalisation, cleavage, noise and species-specific differences.