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  • Review Article
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Synthetic biology: understanding biological design from synthetic circuits

Nature Reviews Genetics volume 10, pages 859–871 (2009)Cite this article

Key Points

  • An important aim of synthetic biology is to uncover the design principles of natural biological systems through the rational design of gene and protein circuits.

  • Inducible gene circuits have been used to directly observe the burst-like nature of mRNA and protein synthesis.

  • Combinatorial promoter libraries highlight the constraints on the positioning of transcription factor binding sites in a promoter.

  • A layered transcriptional–post-transcriptional synthetic regulatory circuit was used to suggest that the decision to undergo apoptosis depends on reaching a threshold level of Bax.

  • Chimeric pathway sensors allow the activation of a pathway by novel stimuli, so precise, specific inputs can be used to measure pathway transfer functions.

  • Rationally rewired bacterial two-component systems confirm the existence of specificity residues in the constituent proteins that prevent pathway crosstalk.

  • Robust, tunable oscillations can be achieved by interlocking negative and positive feedback loops.

  • Randomly generated gene networks show that the Escherichia coli transcriptional network is robust to rewiring and that networks of differing topology can yield the same Boolean truth table.

  • Synthetic circuits built to specifically respond to rapidly increasing activators can be used to form patterns.

  • Synthetic circuits controlling cell–cell interactions were used to characterize predator–prey dynamics and Simpson's paradox, paving the way for future research in the field of synthetic ecology.

Abstract

An important aim of synthetic biology is to uncover the design principles of natural biological systems through the rational design of gene and protein circuits. Here, we highlight how the process of engineering biological systems — from synthetic promoters to the control of cell–cell interactions — has contributed to our understanding of how endogenous systems are put together and function. Synthetic biological devices allow us to grasp intuitively the ranges of behaviour generated by simple biological circuits, such as linear cascades and interlocking feedback loops, as well as to exert control over natural processes, such as gene expression and population dynamics.

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Figure 1: Controlling the flow of information from DNA to proteins using synthetic elements.
Figure 2: An integrated transcription and translation circuit for controlling gene expression in mammalian systems.
Figure 3: Using synthetic circuits to engineer cell–cell interactions.

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Acknowledgements

We apologize to our colleagues whose work was not discussed. This work was supported by grants from the US National Institutes of Health and the National Science Foundation.

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Authors and Affiliations

  1. Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA

    Shankar Mukherji

  2. Department of Physics and Department of Biology, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA

    Alexander van Oudenaarden

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  1. Shankar Mukherji
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Correspondence to Alexander van Oudenaarden.

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Glossary

Modularity

A property of a system such that it can be broken down into discrete subparts that perform specific tasks independently of the other subparts.

Bioremediation

The treatment of pollution with microorganisms.

Motif

A subcircuit that is embedded in a larger network and that is found to be statistically overrepresented in that larger network when compared with a random network with similar graphical properties.

Transfer function

A mathematical or graphical representation of the relationship between the input and output of a system.

Higher-order moment

For a probability distribution, a number that characterizes the shape of the distribution, as opposed to the mean.

Variance

The second-order moment of a probability distribution; it characterizes the width of the distribution.

Boolean function

A special class of transfer function that takes binary values as inputs, performs a logical operation and yields binary values as outputs.

Combinatorial promoter library

A collection of promoters that is constructed by randomly ligating together promoter subregions, such as the sequence between −35 and −10 from the start codon, taken from different promoters. Such random ligation of subregions allows for the combinatorial generation of novel promoters from a small number of parts.

Aptamer

A short nucleic acid or peptide sequence that specifically binds to a target molecule.

Riboswitch

A segment of an mRNA molecule that specifically binds a target molecule; riboswitches are closely related to aptamers.

Basal expression

The level of transcription that occurs in the absence of an inducer.

Directed evolution

A cyclic sequence of steps, including modification, selection and amplification. It is used, typically in vitro, to enrich for proteins or nucleic acids that show properties that are desired by the researcher but that are not necessarily found in nature.

Metabolic flux

The rate of turnover of metabolites in a metabolic pathway.

Allosteric site

A region of an enzyme that is physically distinct from the active site and that can induce conformational changes, usually by binding small molecules, to affect the accessibility or efficiency of the active site.

Osmotic shock

A sudden change of the osmotic pressure gradient generated by the balance of the concentration of dissolved molecules inside and outside the cell.

Two-component system

The dominant architecture of environmental signal transduction systems in bacteria. It consists of a sensor kinase that transforms the environmental signal to a phosphate signal, and a cognate response regulator that further transmits the signal to the ultimate effector molecules.

Microfluidic device

A device in which fluids are conveyed to samples in channels with diameters in the order of 1 μm; these chambers can be used to precisely and dynamically control the microenvironment to which cells are exposed.

Bode plot

A special class of transfer function that relates the frequency of the input, such as a stimulus that triggers a signalling cascade, to the output of the system, such as the amplitude of the response.

Scaffold protein

An element of a signal transduction pathway that simultaneously binds multiple members of the pathway. Scaffold proteins increase the local concentrations of pathway proteins and therefore increase the probability of them interacting.

Mutual inhibition

A network architecture that consists of two interacting pathways in which the output of each pathway inhibits the activity of the other pathway.

Kinetic insulation

A mechanism in which a signal is transduced through a particular pathway based on the temporal profile of the signal; for example, a transient signal can be interpreted by the cell as using one particular pathway, whereas a slowly varying signal can be interpreted as using a different pathway.

Boolean truth table

The table of inputs and outputs that specifies a certain Boolean function.

Bistable

A property of a dynamical system in which two discrete states of the system are stable; in a biological setting, bistability implies that a system will persist in a given state even if the stimulus that drove it to that state is removed.

Bayesian inference

A method in which observations are used to calculate the probability that a particular hypothesis about the data is true, such as whether two genes in a network interact.

Relaxation oscillator

An oscillator made up of two states and characterized by cycles of relatively long persistence in a state followed by rapid transitions to the other state.

Limit cycle oscillation

A periodic solution to a set of differential equations that is characterized by either attracting or repelling nearby solutions.

Lotka–Volterra model

A first-order nonlinear set of ordinary differential equations that are used to model the interactions between predators and prey. The model is most well known for admitting periodic solutions in which predator numbers rise and fall with prey numbers after a specified lag time.

Turing test

In computer science, a hypothetical test that is meant to decide whether a machine is displaying intelligent behaviour.

Syncytium

A collection of cytoplasm that contains several nuclei.

Reaction–diffusion

A class of mathematical models in which the concentrations of the molecules being modelled are tracked in space as well as time, taking into account the chemical transformations that the molecules can undergo and their diffusive motion.

Turing instability

A mathematical condition in reaction–diffusion systems in which differences in the diffusion of activating and inhibiting morphogenic molecules result in pattern formation; particular patterns form when inhibitors diffuse faster than autoactivators.

Quorum-sensing pathway

A signalling pathway used by microbes to determine the abundance of related and unrelated microbes in the local environment through the exchange of specific small molecules.

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Mukherji, S., van Oudenaarden, A. Synthetic biology: understanding biological design from synthetic circuits. Nat Rev Genet 10, 859–871 (2009). https://doi.org/10.1038/nrg2697

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