Collaborative Research: ProteoCell: The Fat-Free Cell

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This project seeks to build functional, lipid-free, 'living' cells by using proteins to create multi-compartment 'ProteoCells' that can self-generate, house reactions to produce products, interact with other ProteoCells, and in total, define a new type of cell-like structure with fundamentally novel properties. Cells are the most basic unit defining living systems, yet despite years of study, it remains unclear why nature chose to use lipids as its hallmark compartment-formers, and how compartmentalization enables a complex 'soup' of biological molecules to function as an autonomous and self-sustainable unit. This project addresses these questions by using engineering principles to design new protein synthesis reactions, new compartment-forming proteins, and new protein catalysts, and by studying how these 'designer' protein molecules interact with one another to create collective cell-like units. This work will address fundamental Rules of Life questions surrounding the roles of lipids and proteins as essential cellular 'building blocks,' and the importance of compartmentalization in cellular function. Synthetic ProteoCells may ultimately provide an innovative tool to solve societal problems related to human health, sustainability, and the environment. Development of the ProteoCell platform also provides unique educational opportunities and opportunities to engage in a two-way dialog with the public regarding the meaning of a synthetic cell, and the possibilities, benefits, and concerns related to creating new forms of cellular life.Scientifically, this project will define how to 'bottom-up' construct lipid-free ProteoCells, including a self-assembling physical boundary, a genetically programmable cytoplasm, and encapsulated multicomponent reactions. ProteoCells will provide insights into the relationship between the dynamic synthesis of polypeptide/protein building blocks, their self-assembly, and the design rules to create functional ProteoCells that can ultimately self-generate and self-support. The project approach consists of modular and iterative engineering, production, and integration of membrane-forming polypeptides/proteins; protein machinery for CO2 transformation; and machinery to support gene expression. The four aims of the project will create composable ProteoCells and define the range of possible properties; construct rudimentary organelles and define the properties necessary for producing organic molecules from CO2; build multi-cellular ProteoCell 'communities' with defined organization; and probe the US public's perceptions of risks/benefits of constructing a synthetic cell.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.