Deep Neural Networks for Predicting Single-Cell Responses and Probability Landscapes

Abstract

Engineering biology relies on the accurate prediction of cell responses. However, making these predictions is challenging for a variety of reasons, including the stochasticity of biochemical reactions, variability between cells, and incomplete information about underlying biological processes. Machine learning methods, which can model diverse input–output relationships without requiring a priori mechanistic knowledge, are an ideal tool for this task. For example, such approaches can be used to predict gene expression dynamics given time-series data of past expression history. To explore this application, we computationally simulated single-cell responses, incorporating different sources of noise and alternative genetic circuit designs. We showed that deep neural networks trained on these simulated data were able to correctly infer the underlying dynamics of a cell response even in the presence of measurement noise and stochasticity in the biochemical reactions. The training set size and the amount of past data provided as inputs both affected prediction quality, with cascaded genetic circuits that introduce delays requiring more past data. We also tested prediction performance on a bistable auto-activation circuit, finding that our initial method for predicting a single trajectory was fundamentally ill-suited for multimodal dynamics. To address this, we updated the network architecture to predict the entire distribution of future states, showing it could accurately predict bimodal expression distributions. Overall, these methods can be readily applied to the diverse prediction tasks necessary to predict and control a variety of biological circuits, a key aspect of many synthetic biology applications.

Deep model predictive control of gene expression in thousands of single cells

“…Another direction to explore regarding aging would be to re-train prediction models on-the-fly, as data is acquired during control experiments, to see if the controller can adapt to changes in system behavior. Yet another limitation is that our predictive model also does not provide any information about prediction uncertainty or noise, which could help improve control accuracy, and may be critical for the control of multistable genetic systems 49,50 . Finally, our use of a model predictive control framework requires that hundreds or thousands of model inferences are made per cell and timepoint.…”