Predicting how perturbations reshape cellular trajectories with PerturbGen

Abstract A major challenge in biology is predicting how cells transition between states over time and how perturbations disrupt these transitions. Understanding such dynamics is critical for identifying interventions that reverse pathological programs or reprogram cells toward desired states. Although recent computational approaches can predict single-cell perturbation responses in silico, they cannot predict responses across dynamic cell trajectories, for example how early perturbations reconfigure later cell states. To address this gap, we introduce PerturbGen, a generative foundation model trained on over 100 million single-cell transcriptomes that predicts perturbation responses along cellular trajectories. PerturbGen predicts how genetic perturbation at source state shapes downstream states, alters gene programs and trajectories across time, for example in differentiation or disease progression. We apply PerturbGen to three newly generated multi-condition human single-cell datasets spanning immune responses, hematopoiesis and skin development. In an in vivo immune challenge, PerturbGen predicts that knocking out an IL1B signal in myeloid cells attenuates later cytokine-interferon programs, with downstream changes consistent with a reversal of IL-1β stimulation signature. In hematopoiesis, anchoring perturbation-induced programs to human genetics enables simulation of monogenic blood disorders, recapitulates established disease-associated biology whilst systematically revealing lineage-specific programs, including in lineages where this was not previously possible. In skin organoids, PerturbGen predicted that Wnt activation enhances stromal differentiation recapitulating the trajectory observed in human prenatal skin, findings that were functionally validated by experimentally activating Wnt signaling. Together, PerturbGen extends modeling of gene perturbations from static to dynamic cellular systems. We envision PerturbGen enabling the creation of in silico, trajectory-aware perturbation atlases and virtual cells across diverse biological scenarios, supporting optimization of disease models and prioritization of candidate molecular interventions for therapeutic discovery. Competing Interest Statement M.L. has equity interests in Relation Therapeutics, is a scientific co-founder and part-time employee of AI VIVO, and serves on the scientific advisory board of Novo Nordisk.