Modeling dynamical systems and unraveling their underlying causal relationships is central to many domains in the natural sciences. Various physical systems, such as those arising in cell biology, are inherently high-dimensional and stochastic in nature, and admit only partial, noisy state measurements. This poses a significant challenge for addressing the problems of modeling the underlying dynamics and inferring the network structure of these systems. Existing methods are typically tailored either for structure learning or modeling dynamics at the population level, but are limited in their ability to address both problems together. In this work, we address both problems simultaneously: we present StructureFlow, a novel and principled simulation-free approach for jointly learning the structure and stochastic population dynamics of physical systems. We showcase the utility of StructureFlow for the tasks of structure learning from interventions and dynamical (trajectory) inference of conditional population dynamics. We empirically evaluate our approach on high-dimensional synthetic systems, a set of biologically plausible simulated systems, and an experimental single-cell dataset. We show that StructureFlow can learn the structure of underlying systems while simultaneously modeling their conditional population dynamics -- a key step toward the mechanistic understanding of systems behavior.

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This paper investigates the flow of factual information in Mamba State-Space Model (SSM)-based language models. We rely on theoretical and empirical connections to Transformer-based architectures and their attention mechanisms. Exploiting this relationship, we adapt attentional interpretability techniques originally developed for Transformers--specifically, the Attention Knockout methodology--to both Mamba-1 and Mamba-2. Using them we trace how information is transmitted and localized across tokens and layers, revealing patterns of subject-token information emergence and layer-wise dynamics. Notably, some phenomena vary between mamba models and Transformer based models, while others appear universally across all models inspected--hinting that these may be inherent to LLMs in general. By further leveraging Mamba's structured factorization, we disentangle how distinct "features" either enable token-to-token information exchange or enrich individual tokens, thus offering a unified lens to understand Mamba internal operations.

Single-cell data provide high-dimensional measurements of the transcriptional states of cells, but extracting insights into the regulatory functions of genes, particularly identifying transcriptional mechanisms affected by biological perturbations, remains a challenge. Many perturbations induce compensatory cellular responses, making it difficult to distinguish direct from indirect effects on gene regulation. Modeling how gene regulatory functions shape the temporal dynamics of these responses is key to improving our understanding of biological perturbations. Dynamical models based on differential equations offer a principled way to capture transcriptional dynamics, but their application to single-cell data has been hindered by computational constraints, stochasticity, sparsity, and noise. Existing methods either rely on low-dimensional representations or make strong simplifying assumptions, limiting their ability to model transcriptional dynamics at scale. We introduce a Functional and Learnable model of Cell dynamicS, FLeCS, that incorporates gene network structure into coupled differential equations to model gene regulatory functions. Given (pseudo)time-series single-cell data, FLeCS accurately infers cell dynamics at scale, provides improved functional insights into transcriptional mechanisms perturbed by gene knockouts, both in myeloid differentiation and K562 Perturb-seq experiments, and simulates single-cell trajectories of A549 cells following small-molecule perturbations.

Vision-Language Models (VLMs) have recently demonstrated remarkable capabilities in comprehending complex visual content. However, the mechanisms underlying how VLMs process visual information remain largely unexplored. In this paper, we conduct a thorough empirical analysis, focusing on attention modules across layers. We reveal several key insights about how these models process visual data: (i) the internal representation of the query tokens (e.g., representations of "describe the image"), is utilized by VLMs to store global image information; we demonstrate that these models generate surprisingly descriptive responses solely from these tokens, without direct access to image tokens. (ii) Cross-modal information flow is predominantly influenced by the middle layers (approximately 25% of all layers), while early and late layers contribute only marginally.(iii) Fine-grained visual attributes and object details are directly extracted from image tokens in a spatially localized manner, i.e., the generated tokens associated with a specific object or attribute attend strongly to their corresponding regions in the image. We propose novel quantitative evaluation to validate our observations, leveraging real-world complex visual scenes. Finally, we demonstrate the potential of our findings in facilitating efficient visual processing in state-of-the-art VLMs.

We develop a novel data-driven framework as an alternative to dynamic flux balance analysis, bypassing the demand for deep domain knowledge and manual efforts to formulate the optimization problem. The proposed framework is end-toend, which trains a structured neural ODE process (SNODEP) model to estimate flux and balance samples using gene-expression time-series data. SNODEP is designed to circumvent the limitations of the standard neural ODE process model, including restricting the latent and decoder sampling distributions to be normal and lacking structure between context points for calculating the latent, thus more suitable for modeling the underlying dynamics of a metabolic system. Through comprehensive experiments (156 in total), we demonstrate that SNODEP not only predicts the unseen time points of real-world gene-expression data and the flux and balance estimates well but can even generalize to more challenging unseen knockout configurations and irregular data sampling scenarios, all essential for metabolic pathway analysis. We hope our work can serve as a catalyst for building more scalable and powerful models for genome-scale metabolic analysis. A distinctive characteristic of deep neural networks is their capability to implicitly learn complicated features and dynamics from data, significantly saving human effort in composing those handcrafted features and devising complex models. Therefore, there has been a growing interest in using them in a variety of scientific contexts, such as quantum chemistry (von Glehn et al., 2022), tokamak controller design (Degrave et al., 2022), climate sciences (Lam et al., 2022; Nguyen et al., 2023), molecule generation (Hoogeboom et al., 2022) and drug discovery (Askr et al., 2023), to name a few.

Network inference, the task of reconstructing interactions in a complex system from experimental observables, is a central yet extremely challenging problem in systems biology. While much progress has been made in the last two decades, network inference remains an open problem. For systems observed at steady state, limited insights are available since temporal information is unavailable and thus causal information is lost. Two common avenues for gaining causal insights into system behaviour are to leverage temporal dynamics in the form of trajectories, and to apply interventions such as knock-out perturbations. We propose an approach for leveraging both dynamical and perturbational single cell data to jointly learn cellular trajectories and power network inference. Our approach is motivated by min-entropy estimation for stochastic dynamics and can infer directed and signed networks from time-stamped single cell snapshots.

Deep learning models can extract predictive and actionable information from complex inputs. The richer the inputs, the better these models usually perform. However, models that leverage rich inputs (e.g., multi-modality) can be difficult to deploy widely, because some inputs may be missing at inference. Current popular solutions to this problem include marginalization, imputation, and training multiple models. Marginalization can obtain calibrated predictions but it is computationally costly and therefore only feasible for low dimensional inputs. Imputation may result in inaccurate predictions because it employs point estimates for missing variables and does not work well for high dimensional inputs (e.g., images). Training multiple models whereby each model takes different subsets of inputs can work well but requires knowing missing input patterns in advance. Furthermore, training and retaining multiple models can be costly. We propose an efficient way to learn both the conditional distribution using full inputs and the marginal distributions. Our method, Knockout, randomly replaces input features with appropriate placeholder values during training. We provide a theoretical justification of Knockout and show that it can be viewed as an implicit marginalization strategy. We evaluate Knockout in a wide range of simulations and real-world datasets and show that it can offer strong empirical performance.

The introduction of genome engineering technology has transformed biomedical research, making it possible to make precise changes to genetic information. However, creating an efficient gene-editing system requires a deep understanding of CRISPR technology, and the complex experimental systems under investigation. While Large Language Models (LLMs) have shown promise in various tasks, they often lack specific knowledge and struggle to accurately solve biological design problems. In this work, we introduce CRISPR-GPT, an LLM agent augmented with domain knowledge and external tools to automate and enhance the design process of CRISPR-based gene-editing experiments. CRISPR-GPT leverages the reasoning ability of LLMs to facilitate the process of selecting CRISPR systems, designing guide RNAs, recommending cellular delivery methods, drafting protocols, and designing validation experiments to confirm editing outcomes. We showcase the potential of CRISPR-GPT for assisting non-expert researchers with gene-editing experiments from scratch and validate the agent's effectiveness in a real-world use case. Furthermore, we explore the ethical and regulatory considerations associated with automated gene-editing design, highlighting the need for responsible and transparent use of these tools. Our work aims to bridge the gap between beginner biological researchers and CRISPR genome engineering techniques, and demonstrate the potential of LLM agents in facilitating complex biological discovery tasks.