Adaptability and resiliency of Lepidoptera and their cells in culture - linking evolutionary biology to biotechnological advantage.

Lepidopteran cells are an important tool for producing recombinant proteins, vaccines, and other biomolecules, and there is growing interest in using lepidopteran cells for other industries such as cultivated meat or as bioactuators. Lepidopteran cells are favored over mammalian cells for these applications because they grow in relatively simple systems in low-cost culture media and are adaptable to a wide range of culture conditions. Although these advantages of lepidopteran cells are well known, the mechanistic basis for these advantages are not well understood. Here, we consider the evolutionary and physiological pressures guiding cell-level adaptations in Lepidoptera and how these adaptations lead to favorable cell culture behavior. Specifically, we link lepidopteran cell resiliency (i.e., ability to withstand environmental stressors) with a robust antioxidant system, altered chromosome structure, polyploidy, and pre-conditioning of cell stress pathways. We also link lepidopteran cell adaptability (i.e., ability to grow in a range of media formulations) to metabolic flexibility, variable resource allocation options and efficient energy budgeting. We then consider the evolutionary pressures that led to selection for these favorable cell culture traits, including exposure to high oxidative stress, environmental clastogens, small size, metamorphosis, and limited food access and diversity. Finally, we highlight key future experiments to facilitate an improved understanding of lepidopteran resiliency and adaptability for biomanufacturing goals with insect cells, as well as ideas for utilizing this knowledge to improve vertebrate cell culture.