Multimodal Microorganism Development: Integrating Top-Down Biological Engineering with Bottom-Up Rational Design

Biological engineering has unprecedented potential to solve society's most pressing challenges. Engineering approaches must consider complex technical, economic, and social factors. This requires methods that confer gene/pathway-level functionality and organism-level robustness in rapid and cost-effective ways. This article compares foundational engineering approaches – bottom-up, gene-targeted engineering, and top-down, whole-genome engineering – and identifies significant complementarity between them. Cases drawn from engineering Saccharomyces cerevisiae exemplify the synergy of a combined approach. Indeed, multimodal engineering streamlines strain development by leveraging the complementarity of whole-genome and gene-targeted engineering to overcome the gap in design knowledge that restricts rational design. As biological engineers target more complex systems, this dual-track approach is poised to become an increasingly important tool to realize the promise of synthetic biology.