From Robustness to Vulnerability in Complex Biological Systems

Systems cell biology asks how cellular networks are both robust and vulnerable. Here, we use this framework to identify hidden weaknesses that appear when these networks are perturbed. Using common pathogen driven rewiring as a probe, we uncover latent dependencies in essential systems, particularly intracellular trafficking. By combining genetic screens with quantitative proteomics, we identify induced states that expose synthetic lethal interactions not seen in unperturbed cells. These conditional vulnerabilities reveal points of fragility within otherwise stable networks. In parallel, we develop nanobody-based effectors that target highly constrained molecular features, enabling durable engagement of these critical components. Together, this work shows how understanding robustness can be turned into a strategy to find and exploit its weakest points.