Hacking the cell
by a computer. 19 In this case, CRN++ translates logic sequences programmed by a human into a deterministic chemical reaction network governed by the concentrations of reactants and products. The program has its own framework for in silico simulation that has demonstrated high levels of accuracy, and which has been used in the paper to calculate highest-common-factors, and approximate pi and Euler’s number, amongst other algorithms.
The program relies upon sequences of orthogonal (modular and exclusive) logic expressions controlled temporally by a chemical oscillator that allows reactions to happen in order. It’s important to understand that CRN++ does not provide any solutions for the actual qualitative nature of the chemical reactions, but is simply a compiler
Figure 6 The CRN++ code for approximating pi using infinite series – a method notated mathematically as
program that converts logic to (theoretical) chemical concentrations. Regardless, these chemical reaction networks are designed to be produced in cells using genetic machinery, and as the chemical reactions themselves become more easily manipulatable and customisable through experimentation, user-accessible programs such as CRN++ could be used by healthcare providers to easily customise synthetic biological treatments, considering factors such as the patient’s weight, or comorbidities that could affect treatment, and aid greatly in constructing complex circuit networks for difficult cases and problematic illnesses that would be entirely inaccessible at the molecular level alone. Despite the field of synthetic biology focusing on biological circuits governed by gene expression, this is not the limit of its scope. In 2021, scientists at MIT created a synthetic protein-protein interaction circuit controlled by the phosphorylation/dephosphorylation of MAPK pathway proteins. 20 The circuit ‘ memorizes ’ exposure to sorbitol by localizing green-fluorescent-protein in the nucleus, and can be reset through exposure to isopentenyl adenine. Furthermore, the scientists then went on to reconfigure the circuit to prevent cell budding after exposure to sorbitol through the nuclear localization of a cytoskeletal protein, demonstrating the potential of the circuit to interface with basic cell functions. Whilst SBCs controlled by gene expression require the transcription and translation of genes, which takes around a minute per kbp even when disregarding splicing, 21 the phosphorylation reactions involved in protein-protein interactions can happen near-instantaneously, allowing for immediate activation of circuits. This technology is thus very pertinent to medical conditions such as heart arrythmias, when an immediate treatment may be required to avoid death. 22 Where gene-based circuits may be pointless, protein-protein interaction circuits could detect disruptions in the depolarization patterns of the heart’s electrical signals, and instantly adjust ion concentrations to restore normal and regular excitation – long before paramedics arrive – helping to combat the 17 million global fatalities from sudden cardiac arrest a year that make it the leading cause of death worldwide. 23
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