Division of labour in a matrix, rather than phagocytosis or endosymbiosis, as a route for the origin of eukaryotic cells.

Two apparently irreconcilable models dominate research into the origin of eukaryotes. In one model, amitochondrial proto-eukaryotes emerged autogenously from the last universal common ancestor of all cells. Proto-eukaryotes subsequently acquired mitochondrial progenitors by the phagocytic capture of bacteria. In the second model, two prokaryotes, probably an archaeon and a bacterial cell, engaged in prokaryotic endosymbiosis, with the species resident within the host becoming the mitochondrial progenitor. Both models have limitations. A search was therefore undertaken for alternative routes towards the origin of eukaryotic cells. The question was addressed by considering classes of potential pathways from prokaryotic to eukaryotic cells based on considerations of cellular topology. Among the solutions identified, one, called here the "third-space model", has not been widely explored. A version is presented in which an extracellular space (the third-space), serves as a proxy cytoplasm for mixed populations of archaea and bacteria to "merge" as a transitionary complex without obligatory endosymbiosis or phagocytosis and to form a precursor cell. Incipient nuclei and mitochondria diverge by division of labour. The third-space model can accommodate the reorganization of prokaryote-like genomes to a more eukaryote-like genome structure. Nuclei with multiple chromosomes and mitosis emerge as a natural feature of the model. The model is compatible with the loss of archaeal lipid biochemistry while retaining archaeal genes and provides a route for the development of membranous organelles such as the Golgi apparatus and endoplasmic reticulum. Advantages, limitations and variations of the "third-space" models are discussed. REVIEWERS: This article was reviewed by Damien Devos, Buzz Baum and Michael Gray.