From engineered embryos to animal models: the structure-regulation gap in synthetic mammalian reproduction

Alternative approaches to mammalian reproduction have made remarkable progress with the combination of genome engineering, stem cell technologies and synthetic embryos, allowing the study of molecular and cellular processes during germline development and early development. These models offer insightful platforms to investigate in vivo inaccessible molecular and cellular processes. Yet, while these advances have been made, the current models are still limited to partial reconstitution of development. A major limitation of these approaches is their inability to orchestrate diverse regulatory pathways, such as genetic, epigenetic, and environmental cues, in a temporally regulated and physiologically mimetic fashion. This is linked to decreased developmental potential, epigenetic drift and limited translational potential. Recent advances in multi-omics, bioengineered culture platforms, and modeling studies allow molecular states to be mapped in detail, cellular microenvironments to be reconstituted, and processes to be simulated in dynamic detail. But such technological advances may not be sufficient without complementary consideration of biological regulatory processes. This review highlights the disconnect between structural reconstruction and regulatory integration, and its implications for the current state of synthetic reproduction. It also discusses the need for systemic, integrated approaches for better developmental outcomes. Continued advances will require multi-level approaches that integrate genetic, epigenetic, and environmental regulatory control to enable more predictive and clinically relevant reproductive models. The limitation is reflective of a fundamental limitation in attempting to recapitulate regulatory synchrony as opposed to structural complexity alone, and a critical structure-regulation gap that limits developmental fidelity and translational potential.