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1. Reactamole: Functional Reactive Molecular Programming

   Klinge, Titus H.; Lathrop, James I.; Osera, Peter-Michael; Rogers, Allison (January 2021, 27th International Conference on DNA Computing and Molecular Programming (DNA 27))

   Lakin, Matthew R.; Šulc, Petr (Ed.)

   Chemical reaction networks (CRNs) are an important tool for molecular programming, a field that is rapidly expanding our ability to deploy computer programs into biological systems for a variety of applications. However, CRNs are also difficult to work with due to their massively parallel nature, leading to the need for higher-level languages that allow for easier computation with CRNs. Recently, research has been conducted into a variety of higher-level languages for deterministic CRNs but modeling CRN parallelism, managing error accumulation, and finding natural CRN representations are ongoing challenges. We introduce Reactamole, a higher-level language for deterministic CRNs that utilizes the functional reactive programming (FRP) paradigm to represent CRNs as a reactive dataflow network. Reactamole equates a CRN with a functional reactive program, implementing the key primitives of the FRP paradigm directly as CRNs. The functional nature of Reactamole makes reasoning about molecular programs easier, and its strong static typing allows us to ensure that a CRN is well-formed by virtue of being well-typed. In this paper, we describe the design of Reactamole and how we use CRNs to represent the common datatypes and operations found in FRP. We also demonstrate the potential of this functional reactive approach to molecular programming by giving an extended example where a CRN is constructed using FRP to modulate and demodulate an amplitude modulated signal. 

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2. A Framework for Testing Chemical Reaction Networks

   https://doi.org/10.1145/3551349.3559562  

   Gerten, Michael C. (October 2022, 37th IEEE/ACM International Conference on Automated Software Engineering (ASE '22) Doctoral Symposium)

   The use of non-traditional computing devices is growing rapidly. One paradigm of interest is chemical reaction networks (CRNs) which can model and use chemical interactions for computation. These CRNs are used to develop programs at the nanoscale for applications such as intelligent drug delivery. In practice, these programs are developed in simulation environments, and then compiled into physical systems. A challenge when designing CRNs for computation is the lack of techniques to verify and validate correctness. In this work, we adapt software testing and repair techniques for use in this domain. In initial work, we designed a testing framework to handle the challenges presented by CRN programs; this includes distributed computation and stochastic behavior. We extended this framework to implement automated program repair of CRN models and automated test generation via program invariants. For future work, we will develop a notion of fault localization for these programs, develop a theory of mutation generation, and address issues regarding flakiness present in this computing paradigm. 

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3. Programming and simulating chemical reaction networks on a surface

   https://doi.org/10.1098/rsif.2019.0790  

   Clamons, Samuel; Qian, Lulu; Winfree, Erik (May 2020, Journal of The Royal Society Interface)

   Models of well-mixed chemical reaction networks (CRNs) have provided a solid foundation for the study of programmable molecular systems, but the importance of spatial organization in such systems has increasingly been recognized. In this paper, we explore an alternative chemical computing model introduced by Qian & Winfree in 2014, the surface CRN, which uses molecules attached to a surface such that each molecule only interacts with its immediate neighbours. Expanding on the constructions in that work, we first demonstrate that surface CRNs can emulate asynchronous and synchronous deterministic cellular automata and implement continuously active Boolean logic circuits. We introduce three new techniques for enforcing synchronization within local regions, each with a different trade-off in spatial and chemical complexity. We also demonstrate that surface CRNs can manufacture complex spatial patterns from simple initial conditions and implement interesting swarm robotic behaviours using simple local rules. Throughout all example constructions of surface CRNs, we highlight the trade-off between the ability to precisely place molecules and the ability to precisely control molecular interactions. Finally, we provide a Python simulator for surface CRNs with an easy-to-use web interface, so that readers may follow along with our examples or create their own surface CRN designs. 

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4. CRN++: Molecular Programming Language

   https://doi.org/10.1007/978-3-030-00030-1_1  

   Vasic, M; Soloveichik, D; Khurshid, S (January 2018, DNA Computing and Molecular Programming. DNA 2018.)

   Synthetic biology is a rapidly emerging research area, with expected wide-ranging impact in biology, nanofabrication, and medicine. A key technical challenge lies in embedding computation in molecular contexts where electronic micro-controllers cannot be inserted. This necessitates effective representation of computation using molecular components. While previous work established the Turing-completeness of chemical reactions, defining representations that are faithful, efficient, and practical remains challenging. This paper introduces CRN++, a new language for programming deterministic (mass-action) chemical kinetics to perform computation. We present its syntax and semantics, and build a compiler translating CRN++ programs into chemical reactions, thereby laying the foundation of a comprehensive framework for molecular programming. Our language addresses the key challenge of embedding familiar imperative constructs into a set of chemical reactions happening simultaneously and manipulating real-valued concentrations. Although some deviation from ideal output value cannot be avoided, we develop methods to minimize the error, and implement error analysis tools. We demonstrate the feasibility of using CRN++ on a suite of well-known algorithms for discrete and real-valued computation. CRN++ can be easily extended to support new commands or chemical reaction implementations, and thus provides a foundation for developing more robust and practical molecular programs. 

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5. Computing Threshold Circuits with Bimolecular Void Reactions in Step Chemical Reaction Networks

   Anderson, Rachel; Fu, Bin; Massie, Aiden; Mukhopadhyay, Gourab; Salinas, Adrian; Schweller, Robert; Tomai, Evan; Wylie, Tim (June 2024, Springer Nature)

   Step Chemical Reaction Networks (step CRNs) are an augmentation of the Chemical Reaction Network (CRN) model where additional species may be introduced to the system in a sequence of “steps.” We study step CRN systems using a weak subset of reaction rules, void rules, in which molecular species can only be deleted. We demonstrate that step CRNs with only void rules of size (2,0) can simulate threshold formulas (TFs) under linear resources. These limited systems can also simulate threshold circuits (TCs) by modifying the volume of the system to be exponential. We then prove a matching exponential lower bound on the required volume for simulating threshold circuits in a step CRN with (2,0)-size rules under a restricted gate-wise simulation, thus showing our construction is optimal for simulating circuits in this way. 

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