A single clump of mouse stem cells in a dish has begun spontaneously producing the early precursors to eggs and sperm—without ever forming an actual embryo. This matters because scientists have long been unable to watch germ cells develop from start to finish outside a living body. Current embryo-like models can generate early germ cell precursors, but those precursors stall before becoming mature gametes. The researcher suspects the missing ingredient is the surrounding gonad tissue—the niche that normally nurtures germ cells to maturity. By engineering that niche directly from the same stem cell aggregate, she aims to complete the full journey from stem cell to functional egg or sperm in a dish. If successful, this would be a fundamental advance in developmental biology—closing a loop that has remained theoretical for decades. It would provide an experimentally tractable system to answer basic questions about how germ cells first arise, how they migrate, and what signals they need to mature. The work is curiosity-driven fundamental science with no immediate medical or agricultural application. But similar fundamental research on stem cell models has already reshaped how scientists study early human development, and a complete in vitro gametogenesis system could eventually open paths to studying infertility, genetic inheritance, and developmental disorders that are currently impossible to explore.
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To misquote Samuel Butler, "the mouse is the egg's way of making another egg". But what if we didn't need to go through the stage of 'making a mouse' to make an egg? Stem cell-based embryo-like models have revolutionised the developmental biologist's toolbox, providing a suite of powerful, experimentally tractable models of development in vitro. Using one such embryo-like model, known as mouse gastruloids, I have observed the spontaneous emergence of Primordial Germ Cell-like cells (PGCLCs), the early precursors to gametes. Like their in vivo counterparts, these gastruloid PGCLCs are specified early, migrate directionally along the endodermal tract, form discrete clusters, and mature transcriptionally and epigenetically to reach a pre-gametogenesis state equivalent to ~E12.5 germ cells in the embryo. However, the real test of developmental authenticity would be the formation of a functional, mature cell type: a gamete. Here, I propose to use bioengineering principles to elicit the development of an organised gonad-like tissue (a 'gonadoid') directly from gastruloids. This will enable the further maturation of gastruloid PGCLCs to gametes. This makes use of the unique property of self-organised gastruloids to mirror the dynamic and developmentally-faithful PGC niche. Together, gastruloids and gonadoids will allow me to answer long-standing questions in the field, including identifying the early PGC founding population, exploring the mechanisms of migration, and investigating niche-dependency in germ cell maturation. Finally, the mouse gastruloid-to-gonadoid technique has the potential to 'close the loop', implicit in Butler's adage, of embryogenesis-to-gametogenesis in a dish; deriving functional gametes entirely from a single, self-organised aggregate of pluripotent stem cells.
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