On the Design Space of Discrete Diffusion Online Adaptation for Molecular Optimization

Molecular optimization often starts from a pretrained generative model that captures a broad prior over valid molecular structures. At test time, however, the goal is not to sample from this prior, but to use a limited oracle budget to shift generation toward task-specific high-reward molecules. We study this adaptation problem for discrete diffusion models. Each online round couples several choices. The loop must decide which candidates to evaluate, how rewards become model updates, which feedback to reuse, and how far to move beyond the pretrained prior. These choices have mostly been studied in isolation, leaving open whether they complement one another, become redundant, or interfere inside a full online adaptation loop. We conduct controlled studies across six small-molecule binding-affinity tasks and three protein-fitness tasks. We find that acquisition, reward shaping, and model debiasing provide complementary routes to higher reward, especially for small molecules. Replay further stabilizes learning, while validity penalties keep small-molecule exploration on the valid molecular manifold. Together, these findings point to a practical recipe for feedback-efficient molecular optimization: online fine-tuning with acquisition, reward shaping, debiasing, replay, and validity control. This recipe outperforms offline fine-tuning and inference-time search baselines under matched oracle-call budgets and GPU-hour accounting. The gains are largest when high-reward candidates require larger shifts from the pretrained prior.

Steering Generative Models with Experimental Data for Protein Fitness Optimization

Protein fitness optimization involves finding a protein sequence that maximizes desired quantitative properties in a combinatorially large design space of possible sequences. Recent developments in steering protein generative models (e.g diffusion models, language models) offer a promising approach. However, by and large, past studies have optimized surrogate rewards and/or utilized large amounts of labeled data for steering, making it unclear how well existing methods perform and compare to each other in real-world optimization campaigns where fitness is measured by low-throughput wet-lab assays. In this study, we explore fitness optimization using small amounts (hundreds) of labeled sequence-fitness pairs and comprehensively evaluate strategies such as classifier guidance and posterior sampling for guiding generation from different discrete diffusion models of protein sequences. We also demonstrate how guidance can be integrated into adaptive sequence selection akin to Thompson sampling in Bayesian optimization, showing that plug-and-play guidance strategies offer advantages compared to alternatives such as reinforcement learning with protein language models.

Learning Keypoints for Multi-Agent Behavior Analysis using Self-Supervision

The study of social interactions and collective behaviors through multi-agent video analysis is crucial in biology. While self-supervised keypoint discovery has emerged as a promising solution to reduce the need for manual keypoint annotations, existing methods often struggle with videos containing multiple interacting agents, especially those of the same species and color. To address this, we introduce B-KinD-multi, a novel approach that leverages pre-trained video segmentation models to guide keypoint discovery in multi-agent scenarios. This eliminates the need for time-consuming manual annotations on new experimental settings and organisms. Extensive evaluations demonstrate improved keypoint regression and downstream behavioral classification in videos of flies, mice, and rats. Furthermore, our method generalizes well to other species, including ants, bees, and humans, highlighting its potential for broad applications in automated keypoint annotation for multi-agent behavior analysis. Code available under: https://danielpkhalil.github.io/B-KinD-Multi