The origin of life remains among the most compelling and debated scientific mysteries. Traditional hypotheses, such as the RNA World and Metabolism-First models, emphasize nucleic acids or metabolic cycles as life’s earliest foundations. However, both approaches inherently assume the existence of structured, stable compartments to maintain molecular interactions; yet do not fully explain their emergence. In this paper, we propose the Membrane-First Hypothesis, asserting that a plausible pathway toward life may have begun with spontaneously forming amphiphilic boundaries that enabled protocellular microenvironments that actively resisted entropy, maintained stable internal environments, and provided primitive localized gradients that bias reaction fluxes. Other prebiotic organizing structures, such as mineral surfaces and coacervate-like droplets, are considered alongside membranes, and their respective advantages and limitations are evaluated. Drawing insights from systems science, including dissipative structures, autopoiesis, hierarchical complexity, and cybernetics, we argue that membranes were not passive containers, but the drivers of differential persistence (‘proto-selection’) and complexity. By systematically comparing existing origin-of-life theories, we propose that membrane-based compartments uniquely integrate metabolic and genetic emergence, offering robust experimental pathways for validation. This systems-science-informed model fundamentally reshapes our understanding of life’s defining origin. We argue that membranes represent one plausible route by which localized, energy-coupled protocellular systems could have emerged prior to fully Darwinian evolution.
Yiannis Laouris (Thu,) studied this question.