A compiler for biological networks on silicon chips

The explosive growth in semiconductor integrated circuits was made possible in large part by design automation software. The design and/or analysis of synthetic and natural circuits in living cells could be made more scalable using the same approach. We present a compiler which converts standard representations of chemical reaction networks and circuits into hardware configurations that can be used to simulate the network on specialized cytomorphic hardware. The compiler also creates circuit–level models of the target configuration, which enhances the versatility of the compiler and enables the validation of its functionality without physical experimentation with the hardware. We show that this compiler can translate networks comprised of mass–action kinetics, classic enzyme kinetics (Michaelis–Menten, Briggs–Haldane, and Botts–Morales formalisms), and genetic repressor kinetics, thereby allowing a large class of models to be transformed into a hardware representation. Rule–based models are particularly well–suited to this approach, as we demonstrate by compiling a MAP kinase model. Development of specialized hardware and software for simulating biological networks has the potential to enable the simulation of larger kinetic models than are currently feasible or allow the parallel simulation of many smaller networks with better performance than current simulation software.Author summary: We present a “silicon compiler” that is capable of translating biochemical models encoded in the SBML standard into specialized analog cytomorphic hardware and transfer function–level simulations of such hardware. We show how the compiler and hardware address challenges in analog computing: 1) We ensure that the integration of errors due to the mismatch between analog circuit parameters does not become infinite over time but always remains finite via the use of total variables (the solution of the “divergence problem”); 2) We describe the compilation process through a series of examples using building blocks of biological networks, and show the results of compiling two SBML models from the literature: the Elowitz repressilator model and a rule–based model of a MAP kinase cascade. Source code for the compiler is available at https://doi.org/10.5281/zenodo.3948393.