Harnessing heterogeneity for the rational design of cell manufacturing

Owing to the complexity of living cells, multicellular systems exhibit heterogeneity at both the macro (different cell types) and the micro (molecular states within a cell type) levels. Traditionally, such heterogeneity has challenged the yield and quality of stem cell-derived cell therapy manufacturing. Here, we argue that heterogeneity can instead be harnessed as a design feature in the quality-by-design toolkit to optimize cell therapy yield and quality, thereby improving bioprocess robustness. We propose a framework for mapping input cell state to output cell fate using systems and synthetic biology tools. This framework can be used to define material and critical quality attributes at the molecular level that better predict drug safety and efficacy. By understanding the sources and consequences of heterogeneity, we can harness it to conquer complex cell therapy manufacturing and bring it to the level of robustness currently only achieved for biologics and small molecules.