Review Article | Published:

Foundations for the design and implementation of synthetic genetic circuits

Nature Reviews Genetics volume 13, pages 406420 (2012) | Download Citation

Abstract

Synthetic gene circuits are designed to program new biological behaviour, dynamics and logic control. For all but the simplest synthetic phenotypes, this requires a structured approach to map the desired functionality to available molecular and cellular parts and processes. In other engineering disciplines, a formalized design process has greatly enhanced the scope and rate of success of projects. When engineering biological systems, a desired function must be achieved in a context that is incompletely known, is influenced by stochastic fluctuations and is capable of rich nonlinear interactions with the engineered circuitry. Here, we review progress in the provision and engineering of libraries of parts and devices, their composition into large systems and the emergence of a formal design process for synthetic biology.

Key points

  • Synthetic gene circuits are designed to implement novel biologic function, including cellular logic, dynamics and complex cellular and multicellular behaviours. A decade after emerging as a discipline, synthetic biology is entering the mainstream of biological research in molecular and systems biology, biotechnology and biomedicine.

  • One important current frontier in synthetic biology is the design and implementation of circuits and networks which are larger and more sophisticated than those of the early years of the field. A formalized design process, which has been essential in other engineering disciplines for scaling to larger systems, is being developed.

  • Design in synthetic biology combines top-down decomposition to break down complex problems into smaller subproblems with known solutions and bottom-up assembly, which combines components such as promoters, genes or higher-order modules into systems that solve the high-level problem.

  • At the level of molecular parts such as transcription factors, sensors and actuators, formalized design requires availability of large and compatible classes of components. Zinc finger and transcription-activator-like effector proteins, synthetic microRNAs and engineered cell surface receptors will each advance the field.

  • At the level of modules, much early work in synthetic biology has created and evaluated basic dynamic network motifs such as switches, oscillators and cascades, and an empirically informed choice of optimal circuit topologies for a given purposes is now possible. Cell–cell communication modules based on quorum sensing have been widely used; establishing similarly versatile modules in eukaryotic cells is now a priority. Eukaryotic signal processing based on protein–protein interactions has also been engineered.

  • A small number of large, sophisticated, integrated synthetic biological systems has been published. They have built on previously well-characterized dynamic modules as well as parts. Top-down decomposition and bottom-up assembly have allowed such reuse.

  • As the field moves forward, part standardization and computational design tools are likely to make the design and implementation of regulatory networks more predictable. New classes of sensors for chemical or optic stimuli, and new classes of actuators such as master regulators of mammalian cellular processes will broaden the scope of synthetic biology.

  • Interactions with the cellular and extracellular context, nongenetic phenomena such as the sensing and actuation of mechanical forces, and complex nonlinear interactions will require strategies for orthogonalization and insulation and may benefit from combining rational design with library selections.

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Acknowledgements

A.L.S. is pleased to thank the Boehringer Ingelheim Fonds for support through a Ph.D. fellowship. Work in the Weiss laboratory is supported by the US Defense Advanced Research Projects Agency, the US National Institutes of Health and the US National Science Foundation.

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Affiliations

  1. Department of Biological Engineering, Massachusetts Institute of Technology. 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.

    • Adrian L. Slusarczyk
    • , Allen Lin
    •  & Ron Weiss
  2. Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.

    • Ron Weiss

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The authors declare no competing financial interests.

Corresponding author

Correspondence to Ron Weiss.

Glossary

Abstraction

The process of hiding the extraneous details of a specific implementation to highlight the salient and general features of a system or design.

Actuation

The action on the internal or external environment that constitutes the output of a synthetic gene circuit.

TIM barrel

A conserved protein fold named after triose phosphate isomerase (TIM) and shared among many enzymes with widely differing substrate specificities and catalytic activities.

Immunoglobulin fold

A very common protein fold that is based on a β-sandwich. Contains hypervariable loops, which can accommodate almost any sequence and bind a wide variety of partners.

Photocaged unnatural amino acids

Unnatural amino acids containing a photosensitive masking group, which following activation by light reveals a biologically active functional group.

Quorum sensing

Sensing of population density by cell–cell communication.

Oscillators

A circuit with a periodically varying output signal.

Bandpass filters

A circuit that lets through signals within a certain frequency range but not outside it.

Topology

In a network, the set of all connections among nodes. Depending on what the network signifies (for example, molecular binding, genetic regulation or metabolic fluxes), the network topology takes different meanings. For synthetic gene circuits, topology usually refers to regulatory relationships.

Two-component signalling systems

A type of response system commonly found in bacteria and typically consisting of a membrane-bound, sensory histidine kinase and a soluble response regulator.

Signal transduction

The triggering of an intracellular event following detection of an extracellular cue by a transmembrane receptor molecule.

NAND gate

A digital logic gate that implements the logical NAND, or 'NOT AND'. Its output is low when all inputs are high and is otherwise high.

NOR gates

A digital logic gate that implements the logical NOR, or 'NOT OR'. Its output is low when at least one input is high and is otherwise high.

AND gates

Digital logic gates that implement the logical AND. Their output is high when all inputs are high and is otherwise low.

Binary addition with carry

Addition of numbers represented in a base-2 numeral system, where care is taken to carry digits to the left as necessary. For example, 01b + 01b = 10b (in decimal numbers, 1 + 1 = 2).

Emergent

A term used to describe a phenomenon whereby a system is more than the sum of its parts. An emergent property or behaviour is irreducible.

Kinetic parameters

In a mass action kinetic model of biological dynamics, the kinetic parameters are the constants in the differential equations governing the dynamics of a system, such as rate constants and Hill coefficients.

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