Daily Papers

In single-cell research, tracing and analyzing high-throughput single-cell differentiation trajectories is crucial for understanding biological processes. Key to this is the robust modeling of hierarchical structures that govern cellular development. Traditional methods face limitations in computational cost, performance, and stability. VAE-based approaches have made strides but still require branch-specific network modules, limiting their scalability and stability, while often suffering from posterior collapse. To overcome these challenges, we introduce HDTree, a generative modeling framework designed for robust lineage inference. HDTree captures tree relationships within a hierarchical latent space using a unified hierarchical codebook and employs a quantized diffusion process to model continuous cell state transitions. By aligning the generative process with the Waddington landscape, this method not only improves stability and scalability but also enhances the biological plausibility of inferred lineages. HDTree's effectiveness is demonstrated through comparisons on both general-purpose and single-cell datasets, where it outperforms existing methods in lineage inference accuracy, reconstruction quality, and hierarchical consistency. These contributions enable accurate and efficient modeling of cellular differentiation paths, offering reliable insights for biological discovery.\footnote{Code is available at https://github.com/zangzelin/code\_HDTree\_icml.

The capacity to precisely edit genomes has outpaced our ability to predict the consequences. A cell can be genetically perfect and therapeutically useless: edited exactly as intended, yet unstable, drifting toward unintended fates, or selected for properties that compromise safety. This paradox reflects a deeper gap in how we evaluate biological intervention. Current frameworks excel at measuring what was done to a cell but remain blind to what the cell has become. We argue that this blindness stems from treating cells as collections of independent variables rather than as dynamical systems occupying positions on high-dimensional state manifolds. Drawing on Waddington's epigenetic landscape, we propose geometric stability as a missing axis of evaluation: the directional coherence of cellular responses to perturbation. This metric distinguishes interventions that guide cells coherently toward stable states from those that scatter them across the state manifold. Validation across diverse perturbation datasets reveals that geometric stability captures regulatory architecture invisible to conventional metrics, discriminating pleiotropic master regulators from lineage-specific factors without prior biological annotation. As precision medicine increasingly relies on cellular reprogramming, the question shifts from ``did the intervention occur?'' to ``is the resulting state stable?'' Geometric stability provides a framework for answering.