Bridging the Gap Between Primitive and Modern Phase Separation

Liquid-liquid phase separation (LLPS) is a process that often occurs due to binding between oppositely charged biopolymers, and has gained increasing attention recently due to their ubiquity in biological systems and ability to direct essential cellular processes. For example, aberrant biological LLPS can lead to the emergence and progression of various diseases and disorders, and many significant advances have been made in the biological phase separation field. However, while these discoveries in biology are recent, the field of origins of life has been investigating LLPS for nearly 100 years, ever since the first suggestions by Oparin and Haldane that primitive LLPS could have been precursors to the first cells on Earth. Since then, a significant amount of work has been done to elucidate different primitive LLPS systems that could have been relevant as protocellular models. Given the structural similarities between primitive LLPS and modern membraneless organelles, there may even be an evolutionary link between the two, although this remains a question to be answered. Nevertheless, in order to answer this, a source that compares aspects of modern and primitive LLPS is necessary. Here, we first focus on the assembly of membraneless organelles from intrinsically disordered proteins (IDPs) and nucleic acids, and discuss an example by which aberrant LLPS can result in progression of a disease (tumorigenesis). Then, as a parallel, we explore assembly of primitive membraneless compartments from simple biopolymers such as short peptides and nucleic acids. This is followed by a discussion of how the first biomolecules on Earth may have originated, analyzing the environmental and chemical conditions that could have favored primitive LLPS processes. Finally, we directly compare various aspects of LLPS assembly from both a primitive and a modern perspective, further discussing the potential of primitive IDPs on early Earth, but also the evolution from membraneless to membrane-bound cells. This review aims to provide a comparison of modern and primitive phase separation, including assembly and function, in order to help researchers in both fields understand the current state of knowledge, how this knowledge evolved, and the current gaps that need to be further addressed.