Sequential Design of Genetic Circuits Under Uncertainty With Reinforcement Learning
Authors: Michal Kobiela, Diego A. Oyarzún, Michael U. Gutmann
Organizations: School of Informatics, The University of Edinburgh, UK · School of Informatics, School of Biological Sciences, The University of Edinburgh, UK · School of Informatics, The University of Edinburgh,, UK
Abstract
The design of biological systems is hindered by uncertainty arising from both intrinsic stochasticity of biomolecular reactions and variability across laboratory or experimental conditions. In this work, we present a sequential framework to optimize genetic circuits under both forms of uncertainty. By employing simulator models based on differential equations or Markov jump processes alongside a reinforcement learning (RL) policy-based approach, our method suggests experiments that adapt to unknown laboratory conditions while accounting for inherent stochasticity. While previous Bayesian methods address uncertainty through iterative experiment-inference-optimization cycles, they typically require computationally expensive inference and optimization steps after each experimental round, leading to delays. To overcome this bottleneck, we propose an amortized approach trained up-front across a distribution of possible uncertain parameters. This strategy sidesteps the need for explicit parameter inference during the design cycle, enabling immediate, observation-based adaptation. We demonstrate our framework on models for heterologous gene expression and a repressilator circuit, showing that it efficiently handles both molecular noise and cross-laboratory variability.
Genetic circuit design remains a laborious, expert-driven process despite decades of progress in synthetic biology. We study this problem through code generation: models produce Python code in pysbol3 to construct genetic circuits in the Synthetic Biology Open Language (SBOL), a formal representation that supports automated verification. We introduce GenCircuit-RL, a reinforcement learning framework built around hierarchical verification rewards that decompose correctness into five levels, from code execution to task-specific topological checks, and a four-stage curriculum that shifts optimization pressure from code generation to functional reasoning. We also introduce SynBio-Reason, a benchmark of 4,753 circuits spanning six canonical circuit types and nine tasks from code repair to de novo design, with held-out biological parts for out-of-distribution evaluation. Hierarchical verification improves task success on functional reasoning tasks by 14 to 16 percentage points over binary rewards, and curriculum learning is required for strong design performance. The resulting models generate topologically correct circuits, generalize to novel biological parts, and rediscover canonical designs from the synthetic biology literature.
General chemical reaction conditions that achieve consistently high performance across multiple substrates are important for practical applications such as library synthesis and high-throughput experimentation. However, identifying such conditions efficiently has been a longstanding challenge, as it requires decision making under uncertainty with respect to both conditions and substrates, while minimizing the number of required experiments. Here, we introduce CurryBO, a high-level framework for generality-oriented optimization. By formalizing the problem as Bayesian optimization over curried functions, CurryBO provides a unified framework that accommodates different generality definitions (e.g., mean yield across substrates), and supports a range of substrate and condition selection strategies. We evaluate this framework on four benchmark tasks in experimental reaction optimization, and systematically analyze key algorithmic components. Our results show that efficient experiment planning can be achieved by emphasizing exploration when selecting reaction conditions, followed by the uncertainty-guided prioritization of substrates in a sequential decison-making scheme. Based on these insights, we design and validate an optimization policy that substantially improves sample efficiency relative to previously reported approaches across all benchmarks. Overall, the flexibility and modularity of CurryBO facilitate the integration of generality-oriented optimization into experimental settings, enabling more efficient identification of solutions that perform robustly across diverse tasks.
Stefan P. Schmid, Ella Miray Rajaonson, Cher Tian Ser +6
Reinforcement learning (RL) is primarily known as a computational method for optimizing control tasks, but it is increasingly used to explain biological behavior. While RL successfully captures key aspects of biology, a major gap remains: between-agent behavioral variability. Consistent individual differences naturally permeate biological populations, yet RL models typically present only the single best individual or the population average. Addressing this gap requires moving beyond current practices to generate behavioral diversity using biologically plausible mechanisms. Here, we examine approaches from various subfields of RL and outline potential paths forward to close the gap between biology and simulation.
Patrick Govoni, Palina Bartashevich, Clémence Bergerot +3