Learning developmental dynamics from lineage context
Gokul Gowri, Nic Fishman, William N. Colgan, Minming Wang, Yusuke Kijima, Sachin A. Kumar, Aleksandr Zimin, Luke W. Koblan 等 13 位作者
AI 速览：作者提出“谱系修补”（lineage inpainting）生成建模方法，利用树结构Transformer与随机插值从谱系上下文预测细胞状态动态。
A central goal of biology is to predict the dynamics of multicellular systems. Lineage context (the states of a cell's sisters, cousins, etc.) could inform these predictions, but how best to leverage it remains unclear. Here we introduce lineage inpainting, a generative modeling approach that uses lineage context with tree-structured transformers and stochastic interpolants to model cell state dynamics across lineage trees. Applied to a lineage-traced transcriptional atlas of mouse embryogenesis, it recovers dynamics not resolved by gene expression alone, including multiple transcriptional convergence events where distinct lineages are drawn to a common state. Despite being fit on unperturbed development, lineage inpainting can generate hypotheses about perturbation responses by simulating counterfactuals. These simulations agree in many cases with observed developmental phenotypes, including a single-cell measurement of the Tbx5 knockout response. Our results show that lineage information provides a rich source of context for learning multicellular dynamics.
Clinical practice guidelines encode evidence-based recommendations as conditional decision flows, which makes them a natural source of process supervision for training reasoning models. Two properties of clinical reasoning make this supervision difficult to use. A decision flow consistent with a guideline does not by itself determine the correct answer for a given patient, which we call the path--answer gap, and several valid decision flows can support the same clinical decision, which we call path multiplicity. Current training approaches address parts of this problem. Answer rewards supervise the final decision, and process rewards computed against a reference flow supervise one valid decision flow per case. Supervised fine-tuning on annotated flows teaches guideline-consistent reasoning but constrains the model to one trajectory per case and can reduce answer accuracy. We introduce GUIDER, a method that jointly optimizes a decision flow controller and a reasoning policy. The controller learns to generate plausible decision flows from guideline-derived supervision, and the policy learns to generate a decision flow and a final answer for each patient case. GUIDER computes the process reward for the policy over several controller-generated flows, which accounts for path multiplicity, and gates this reward on answer correctness, which addresses the path--answer gap. Joint training allows the process supervision to evolve with the policy. On MedGUIDE, GUIDER with Qwen3-14B achieves 82.5 weighted accuracy and 73.5 guideline adherence, 3.3 and 3.1 points above the strongest clinical reinforcement learning baseline. With Qwen3-14B and Gemma4-12B backbones, GUIDER also improves over CRPO, MRPO, and FaithMed on the out-of-domain benchmarks AMEGA-LLM, RealMedQA, and CancerGUIDE.
Boyang Fu, Sameer Gabbita, George Dasoulas, Xiang Lin, Shanghua Gao, Xiaorui Su, Soumya Ghosh, Marinka Zitnik
Prediction of the transcriptional response of a cell to a genetic perturbation is a central problem in the computational modeling of gene regulation. Perturbations of the same gene can produce different transcriptional responses depending on the targeted locus, such as an alternative transcription start site or a distal regulatory element, and gene-level perturbation models represent these distinct interventions with a single gene identifier. We introduce STRAND, a generative model that encodes the regulatory DNA sequence at the perturbation locus and uses this encoding to parameterize a conditional transport process from control to perturbed single-cell states. Sequence conditioning enables zero-shot prediction for perturbation targets absent from training and supports locus-resolved inputs at 128 bp model resolution within a 524 kb sequence window. On CRISPRi screens in K562, Jurkat, and RPE1 cells, STRAND achieves the best average rank on few-shot and unseen-gene benchmarks, with gains of up to 33% in perturbation discrimination, and improves transfer to held-out cell lines by up to 0.12 in $Δ$Pearson. Ablation studies attribute these gains to sequence conditioning and to conditional transport. At the locus level, STRAND distinguishes alternative transcription start sites and validated regulatory elements that gene-identifier models represent as a single perturbation. STRAND is available at https://github.com/mims-harvard/STRAND.