Efficient Biological Data Acquisition through Inference Set Design

In drug discovery, highly automated high-throughput laboratories are used to screen a large number of compounds in search of effective drugs. These experiments are expensive, so we might hope to reduce their cost by experimenting on a subset of the compounds, and predicting the outcomes of the remaining experiments. In this work, we model this scenario as a sequential subset selection problem: we aim to select the smallest set of candidates in order to achieve some desired level of accuracy for the system as a whole. Our key observation is that, if there is heterogeneity in the difficulty of the prediction problem across the input space, selectively obtaining the labels for the hardest examples in the acquisition pool will leave only the relatively easy examples to remain in the inference set, leading to better overall system performance. We call this mechanism inference set design, and propose the use of an uncertainty-based active learning solution to prune out these challenging examples. Our algorithm includes an explicit stopping criterion that stops running the experiments when it is sufficiently confident that the system has reached the target performance. Our empirical studies on image and molecular datasets, as well as a real-world large-scale biological assay, show that deploying active learning for inference set design leads to significant reduction in experimental cost while obtaining high system performance.

Action abstractions for amortized sampling

As trajectories sampled by policies used by reinforcement learning (RL) and generative flow networks (GFlowNets) grow longer, credit assignment and exploration become more challenging, and the long planning horizon hinders mode discovery and generalization. The challenge is particularly pronounced in entropy-seeking RL methods, such as generative flow networks, where the agent must learn to sample from a structured distribution and discover multiple high-reward states, each of which take many steps to reach. To tackle this challenge, we propose an approach to incorporate the discovery of action abstractions, or high-level actions, into the policy optimization process. Our approach involves iteratively extracting action subsequences commonly used across many high-reward trajectories and `chunking' them into a single action that is added to the action space. In empirical evaluation on synthetic and real-world environments, our approach demonstrates improved sample efficiency performance in discovering diverse high-reward objects, especially on harder exploration problems. We also observe that the abstracted high-order actions are interpretable, capturing the latent structure of the reward landscape of the action space. This work provides a cognitively motivated approach to action abstraction in RL and is the first demonstration of hierarchical planning in amortized sequential sampling.

Improved Off-policy Reinforcement Learning in Biological Sequence Design

Designing biological sequences with desired properties is a significant challenge due to the combinatorially vast search space and the high cost of evaluating each candidate sequence. To address these challenges, reinforcement learning (RL) methods, such as GFlowNets, utilize proxy models for rapid reward evaluation and annotated data for policy training. Although these approaches have shown promise in generating diverse and novel sequences, the limited training data relative to the vast search space often leads to the misspecification of proxy for out-of-distribution inputs. We introduce $\delta$-Conservative Search, a novel off-policy search method for training GFlowNets designed to improve robustness against proxy misspecification. The key idea is to incorporate conservativeness, controlled by parameter $\delta$, to constrain the search to reliable regions. Specifically, we inject noise into high-score offline sequences by randomly masking tokens with a Bernoulli distribution of parameter $\delta$ and then denoise masked tokens using the GFlowNet policy. Additionally, $\delta$ is adaptively adjusted based on the uncertainty of the proxy model for each data point. This enables the reflection of proxy uncertainty to determine the level of conservativeness. Experimental results demonstrate that our method consistently outperforms existing machine learning methods in discovering high-score sequences across diverse tasks-including DNA, RNA, protein, and peptide design-especially in large-scale scenarios.

Adaptive teachers for amortized samplers

Amortized inference is the task of training a parametric model, such as a neural network, to approximate a distribution with a given unnormalized density where exact sampling is intractable. When sampling is implemented as a sequential decision-making process, reinforcement learning (RL) methods, such as generative flow networks, can be used to train the sampling policy. Off-policy RL training facilitates the discovery of diverse, high-reward candidates, but existing methods still face challenges in efficient exploration. We propose to use an adaptive training distribution (the Teacher) to guide the training of the primary amortized sampler (the Student) by prioritizing high-loss regions. The Teacher, an auxiliary behavior model, is trained to sample high-error regions of the Student and can generalize across unexplored modes, thereby enhancing mode coverage by providing an efficient training curriculum. We validate the effectiveness of this approach in a synthetic environment designed to present an exploration challenge, two diffusion-based sampling tasks, and four biochemical discovery tasks demonstrating its ability to improve sample efficiency and mode coverage.

GFlowNet Pretraining with Inexpensive Rewards

Generative Flow Networks (GFlowNets), a class of generative models have recently emerged as a suitable framework for generating diverse and high-quality molecular structures by learning from unnormalized reward distributions. Previous works in this direction often restrict exploration by using predefined molecular fragments as building blocks, limiting the chemical space that can be accessed. In this work, we introduce Atomic GFlowNets (A-GFNs), a foundational generative model leveraging individual atoms as building blocks to explore drug-like chemical space more comprehensively. We propose an unsupervised pre-training approach using offline drug-like molecule datasets, which conditions A-GFNs on inexpensive yet informative molecular descriptors such as drug-likeliness, topological polar surface area, and synthetic accessibility scores. These properties serve as proxy rewards, guiding A-GFNs towards regions of chemical space that exhibit desirable pharmacological properties. We further our method by implementing a goal-conditioned fine-tuning process, which adapts A-GFNs to optimize for specific target properties. In this work, we pretrain A-GFN on the ZINC15 offline dataset and employ robust evaluation metrics to show the effectiveness of our approach when compared to other relevant baseline methods in drug design.

Baking Symmetry into GFlowNets

GFlowNets have exhibited promising performance in generating diverse candidates with high rewards. These networks generate objects incrementally and aim to learn a policy that assigns probability of sampling objects in proportion to rewards. However, the current training pipelines of GFlowNets do not consider the presence of isomorphic actions, which are actions resulting in symmetric or isomorphic states. This lack of symmetry increases the amount of samples required for training GFlowNets and can result in inefficient and potentially incorrect flow functions. As a consequence, the reward and diversity of the generated objects decrease. In this study, our objective is to integrate symmetries into GFlowNets by identifying equivalent actions during the generation process. Experimental results using synthetic data demonstrate the promising performance of our proposed approaches.

Rectifying Reinforcement Learning for Reward Matching

The Generative Flow Network (GFlowNet) is a probabilistic framework in which an agent learns a stochastic policy and flow functions to sample objects with probability proportional to an unnormalized reward function. GFlowNets share a strong resemblance to reinforcement learning (RL), that typically aims to maximize reward, due to their sequential decision-making processes. Recent works have studied connections between GFlowNets and maximum entropy (MaxEnt) RL, which modifies the standard objective of RL agents by learning an entropy-regularized objective. However, a critical theoretical gap persists: despite the apparent similarities in their sequential decision-making nature, a direct link between GFlowNets and standard RL has yet to be discovered, while bridging this gap could further unlock the potential of both fields. In this paper, we establish a new connection between GFlowNets and policy evaluation for a uniform policy. Surprisingly, we find that the resulting value function for the uniform policy has a close relationship to the flows in GFlowNets. Leveraging these insights, we further propose a novel rectified policy evaluation (RPE) algorithm, which achieves the same reward-matching effect as GFlowNets, offering a new perspective. We compare RPE, MaxEnt RL, and GFlowNets in a number of benchmarks, and show that RPE achieves competitive results compared to previous approaches. This work sheds light on the previously unexplored connection between (non-MaxEnt) RL and GFlowNets, potentially opening new avenues for future research in both fields.

Amortizing intractable inference in diffusion models for vision, language, and control

Diffusion models have emerged as effective distribution estimators in vision, language, and reinforcement learning, but their use as priors in downstream tasks poses an intractable posterior inference problem. This paper studies amortized sampling of the posterior over data, $\mathbf{x}\sim p^{\rm post}(\mathbf{x})\propto p(\mathbf{x})r(\mathbf{x})$, in a model that consists of a diffusion generative model prior $p(\mathbf{x})$ and a black-box constraint or likelihood function $r(\mathbf{x})$. We state and prove the asymptotic correctness of a data-free learning objective, relative trajectory balance, for training a diffusion model that samples from this posterior, a problem that existing methods solve only approximately or in restricted cases. Relative trajectory balance arises from the generative flow network perspective on diffusion models, which allows the use of deep reinforcement learning techniques to improve mode coverage. Experiments illustrate the broad potential of unbiased inference of arbitrary posteriors under diffusion priors: in vision (classifier guidance), language (infilling under a discrete diffusion LLM), and multimodal data (text-to-image generation). Beyond generative modeling, we apply relative trajectory balance to the problem of continuous control with a score-based behavior prior, achieving state-of-the-art results on benchmarks in offline reinforcement learning.

SynFlowNet: Towards Molecule Design with Guaranteed Synthesis Pathways

Recent breakthroughs in generative modelling have led to a number of works proposing molecular generation models for drug discovery. While these models perform well at capturing drug-like motifs, they are known to often produce synthetically inaccessible molecules. This is because they are trained to compose atoms or fragments in a way that approximates the training distribution, but they are not explicitly aware of the synthesis constraints that come with making molecules in the lab. To address this issue, we introduce SynFlowNet, a GFlowNet model whose action space uses chemically validated reactions and reactants to sequentially build new molecules. We evaluate our approach using synthetic accessibility scores and an independent retrosynthesis tool. SynFlowNet consistently samples synthetically feasible molecules, while still being able to find diverse and high-utility candidates. Furthermore, we compare molecules designed with SynFlowNet to experimentally validated actives, and find that they show comparable properties of interest, such as molecular weight, SA score and predicted protein binding affinity.

Generative Active Learning for the Search of Small-molecule Protein Binders

Despite substantial progress in machine learning for scientific discovery in recent years, truly de novo design of small molecules which exhibit a property of interest remains a significant challenge. We introduce LambdaZero, a generative active learning approach to search for synthesizable molecules. Powered by deep reinforcement learning, LambdaZero learns to search over the vast space of molecules to discover candidates with a desired property. We apply LambdaZero with molecular docking to design novel small molecules that inhibit the enzyme soluble Epoxide Hydrolase 2 (sEH), while enforcing constraints on synthesizability and drug-likeliness. LambdaZero provides an exponential speedup in terms of the number of calls to the expensive molecular docking oracle, and LambdaZero de novo designed molecules reach docking scores that would otherwise require the virtual screening of a hundred billion molecules. Importantly, LambdaZero discovers novel scaffolds of synthesizable, drug-like inhibitors for sEH. In in vitro experimental validation, a series of ligands from a generated quinazoline-based scaffold were synthesized, and the lead inhibitor N-(4,6-di(pyrrolidin-1-yl)quinazolin-2-yl)-N-methylbenzamide (UM0152893) displayed sub-micromolar enzyme inhibition of sEH.