Programmable chemical controllers made from DNA

Abstract

Biological organisms use complex molecular networks to navigate their environment and regulate their internal state. The development of synthetic systems with similar capabilities could lead to applications such as smart therapeutics or fabrication methods based on self-organization. To achieve this, molecular control circuits need to be engineered to perform integrated sensing, computation and actuation. Here we report a DNA-based technology for implementing the computational core of such controllers. We use the formalism of chemical reaction networks as a 'programming language', and our DNA architecture can, in principle, implement any behaviour that can be mathematically expressed as such. Unlike logic circuits, our formulation naturally allows complex signal processing of intrinsically analogue biological and chemical inputs. Controller components can be derived from biologically synthesized (plasmid) DNA, which reduces errors associated with chemically synthesized DNA. We implement several building-block reaction types and then combine them into a network that realizes, at the molecular level, an algorithm used in distributed control systems for achieving consensus between multiple agents.

Strong Turing Completeness of Continuous Chemical Reaction Networks and Compilation of Mixed Analog-Digital Programs

“…Then we derive from the proof of these results a compiler of behavioural specifications 6 into elementary reaction systems, without prejudging of their biochemical implementation, by enzymatic reactions [37], DNA [13] or RNA for instance.…”

Molecular circuits for dynamic noise filtering

“…As a proof of principle, we forward-engineered and tested a DNA-based filtering circuit in vitro as DNA strand displacement (DSD) cascades (6,7,(27)(28)(29). Strand displacement is a competitive hybridization reaction where an incoming single-stranded DNA molecule binds to a complementary strand, in the process displacing an incumbent strand.…”

“…2 was mapped to a DSD circuit (SI Appendix, section S.5 and Fig. S.10) under the join-fork paradigm (6,32) and quantified experimentally using calibrated fluorescence measurements (SI Appendix, section S.6.1). An initial perturbation experiment was performed to check the circuit's sensitivity with respect to small changes in M and to compute initial estimates of kinetic parameters (SI Appendix, section S.6.1.4).…”

“…synthetic circuits | optimal filtering | noise cancellation | adaptive design R ecent developments in synthetic biology have enabled a revolution of biomolecular engineering (1,2), prompting numerous applications in therapeutics (3)(4)(5), biocomputing (6)(7)(8), and plant engineering (9), for instance. However, a variety of practical limitations have to be addressed before the field can achieve its full promise.…”

From Cells as Computation to Cells as Apps

“…Further research directions have spawned from the approach, examples being the development of DNA-based technology for implementing the computational core of sensing and control processes of synthetic biological components [15], and experiments on building RNA-based logical gates as the basis for the development of "in vivo logic processing" [53].…”