We present a new algorithm that synthesizes functional reactive programs from observation data. The key novelty is to iterate between a functional synthesis step, which attempts to generate a transition function over observed states, and an automata synthesis step, which adds any additional latent state necessary to fully account for the observations. We develop a functional reactive DSL called Autumn that can express a rich variety of causal dynamics in time-varying, Atari-style grid worlds, and apply our method to synthesize Autumn programs from data. We evaluate our algorithm on a benchmark suite of 30 Autumn programs as well as a third-party corpus of grid-world-style video games. We find that our algorithm synthesizes 27 out of 30 programs in our benchmark suite and 21 out of 27 programs from the third-party corpus, including several programs describing complex latent state transformations, and from input traces containing hundreds of observations. We expect that our approach will provide a template for how to integrate functional and automata synthesis in other induction domains.

Biocatalysis is a promising approach to sustainably synthesize pharmaceuticals, complex natural products, and commodity chemicals at scale. However, the adoption of biocatalysis is limited by our ability to select enzymes that will catalyze their natural chemical transformation on non-natural substrates. While machine learning and in silico directed evolution are well-posed for this predictive modeling challenge, efforts to date have primarily aimed to increase activity against a single known substrate, rather than to identify enzymes capable of acting on new substrates of interest. To address this need, we curate 6 different high-quality enzyme family screens from the literature that each measure multiple enzymes against multiple substrates. We compare machine learning-based compound-protein interaction (CPI) modeling approaches from the literature used for predicting drug-target interactions. Surprisingly, comparing these interaction-based models against collections of independent (single task) enzyme-only or substrate-only models reveals that current CPI approaches are incapable of learning interactions between compounds and proteins in the current family level data regime. We further validate this observation by demonstrating that our no-interaction baseline can outperform CPI-based models from the literature used to guide the discovery of kinase inhibitors. Given the high performance of non-interaction based models, we introduce a new structure-based strategy for pooling residue representations across a protein sequence. Altogether, this work motivates a principled path forward in order to build and evaluate meaningful predictive models for biocatalysis and other drug discovery applications.

We present Omega, a probabilistic programming language with support for counterfactual inference. Counterfactual inference means to observe some fact in the present, and infer what would have happened had some past intervention been taken, e.g. “given that medication was not effective at dose x, what is the probability that it would have been effective at dose 2x?.” We accomplish this by introducing a new operator to probabilistic programming akin to Pearl’s do, define its formal semantics, provide an implementation, and demonstrate its utility through examples in a variety of simulation models.