Synthetic biology

A brief history of synthetic biology

Journal name:
Nature Reviews Microbiology
Volume:
12,
Pages:
381–390
Year published:
DOI:
doi:10.1038/nrmicro3239
Published online

Abstract

The ability to rationally engineer microorganisms has been a long-envisioned goal dating back more than a half-century. With the genomics revolution and rise of systems biology in the 1990s came the development of a rigorous engineering discipline to create, control and programme cellular behaviour. The resulting field, known as synthetic biology, has undergone dramatic growth throughout the past decade and is poised to transform biotechnology and medicine. This Timeline article charts the technological and cultural lifetime of synthetic biology, with an emphasis on key breakthroughs and future challenges.

At a glance

Figures

  1. A brief history of synthetic biology.
    Figure 1: A brief history of synthetic biology.
  2. Examples of gene circuits reported during the foundational years of synthetic biology (2000-2003).
    Figure 2: Examples of gene circuits reported during the foundational years of synthetic biology (2000–2003).

    a | The toggle switch. A pair of repressor genes (lacI and cI) are arranged to antagonistically repress transcription of each other, resulting in a bistable genetic circuit in which only one of the two genes is active at a given time. The toggle can be 'flipped' to the desired transcriptional state using environmental inputs to disengage one of the repressors from its operator (for example, IPTG (isopropyl-β-D-thiogalactoside) is used to disengage LacI and heat is used to disengage cI). Once the input is removed, the desired transcriptional state persists for multiple generations. b | The repressilator. The circuit is constructed from three repressor–promoter interactions (between cI, LacI and TetR repressors and their associated promoters), which are linked together to form a ring-shaped network, in which TetR regulates a GFP-reporter node. When analysed at the single-cell level using time-lapse fluorescence microscopy, the circuit exhibits periodic oscillations in GFP expression, which persist for a number of generations; however, oscillations become dampened after a few periods and are generally noisy, with individual cells showing high variability in both the amplitude and period of their oscillations. c | Autoregulatory circuit. In this circuit, TetR-mediated negative-feedback regulation of its own transcription results in a narrow population-wide expression distribution, as measured by the co-transcribed GFP reporter. The circuit demonstrates a principle that was long-appreciated in control-systems engineering and nonlinear dynamics — that noise in a system can be reduced by introducing negative feedback.

  3. Examples of gene circuits reported during the intermediate years of synthetic biology (2004-2007).
    Figure 3: Examples of gene circuits reported during the intermediate years of synthetic biology (2004–2007).

    a | Modular riboregulator. A cis-repression sequence is appended to the 5′ UTR of a gene transcript to inhibit translation by blocking the ribosome binding site (RBS). Translation inhibition is reversed by the expression of an inducible transactivating sequence that tightly binds to the cis-repression sequence, thereby exposing the RBS to enable translation of GFP. b | Two-input AND gate. One of the first examples of the successful programming of logical operations in a cell was an AND-gate circuit in which simultaneous exposure of cells to two external inputs was converted into a transcriptional output. In response to arabinose, AraC-mediated induction of one promoter results in the transcription of a T7 polymerase that is engineered to contain two TAG (amber) stop codons in its coding sequence. The second promoter, which is activated by NahR in the presence of salicylate, controls the transcription of SupD, which is an amber suppressor tRNA that recognizes the TAG stop codon and adds a serine residue to the nascent polypeptide, enabling read-through translation of the T7 polymerase. Transcription and translation of T7 can occur only in the presence of both environmental inputs, which leads to GFP expression from the T7-dependent promoter. c | Multicellular pattern formation. The circuit, which was engineered to produce an ordered pattern on a two-dimensional field of bacterial cells, consists of genetic parts derived from Vibrio fischeri: LuxI, which is an enzyme that produces the quorum-sensing molecule acyl homoserine lactone (AHL), is expressed in 'sender' cells, whereas 'receiver' cells express LuxR, which is an AHL-sensitive transcriptional activator. By coupling LuxR function to a feedforward circuit architecture, receiver cells are programmed for bandpass detection of AHL, and fluorescent reporter gene expression is activated only at discreet concentrations of AHL. Adjusting the sensitivity of LuxR activation results in strains that have high-sensitivity (HS) or low-sensitivity (LS) AHL detection capabilities. HS and LS receiver strains are programmed with red fluorescent protein (RFP) and GFP output, respectively, and mixed together in a bacterial lawn in which sender cells are placed in the middle. This results in the emergence of a banded, bullseye pattern of fluorescent-reporter expression.

  4. Examples of gene circuits reported during the most recent era of synthetic biology (2008-2013).
    Figure 4: Examples of gene circuits reported during the most recent era of synthetic biology (2008–2013).

    a | Relaxation oscillator. The circuit uses well-characterized parts (specifically, AraC and LacI) that have been used in previous circuits, but its design is fundamentally different from the ring design of the repressilator (Fig. 2b) and is based instead on overlapping positive- and negative-feedback loops, in which AraC and LacI mediate positive and negative regulation, respectively. Circuit components were assembled on the basis of carefully parameterized modelling, and the circuit was analysed in a microfluidic device to ensure a precisely controlled microenvironment. These key advances resulted in a robust, stable, nearly population-wide oscillatory behaviour over multiple generations. b | Recombinase-based logic. These circuits take advantage of recombinase-based DNA inversion and the fundamental directionality of many biological parts to generate logic gate behaviour in genetic circuits. Using a small library of well-characterized parts, all 16 possible logic gates could be constructed. The input modules for the system remain constant, with small molecules used for the induction of the orthogonal recombinases (Rec1 and Rec2), which cause unidirectional inversion of their target sequences. Depending on the order and orientation of genetic parts in the uninduced circuit, the small molecule inputs produce a GFP output signal, as specified by the corresponding logic gate. For example, the AND-gate circuit only produces a GFP output signal when both inputs are present, causing the constitutive promoter and the GFP gene to be independently inverted such that they are in the appropriate orientation to enable constitutive GFP expression. c | Edge-detection circuit. A quorum-sensing system was combined with a hybrid two-component light sensor to compute the edge of an illuminated area. In the circuit, unilluminated bacteria function as sender cells that produce and secrete the quorum-sensing molecule AHL, whereas illuminated bacteria function as receiver cells that cannot produce AHL but can respond to it by expressing the LacZ enzyme to produce a visible black pigment. The illuminated receiver cells can only sense the AHL that is produced by the dark sender cells in regions in which the two cell types are in close proximity — at the edge of an illuminated area — thereby generating a visible outline of the image.

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Author information

  1. These authors contributed equally to this work.

    • D. Ewen Cameron &
    • Caleb J. Bashor

Affiliations

  1. Howard Hughes Medical Institute, the Center of Synthetic Biology and the Department of Biomedical Engineering, Boston University, Boston, Massachusetts, USA.

    • D. Ewen Cameron,
    • Caleb J. Bashor &
    • James J. Collins
  2. Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts, USA.

    • D. Ewen Cameron,
    • Caleb J. Bashor &
    • James J. Collins

Competing interests statement

The authors declare no competing interests.

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Author details

  • D. Ewen Cameron

    D. Ewen Cameron is a postdoctoral fellow in the laboratory of James J. Collins at Boston University, Massachusetts, USA. He received a B.S. in biology at Yale University, New Haven, Connecticut, USA, and a Ph.D. in microbiology and molecular genetics in the laboratory of John Mekalanos at Harvard Medical School, Boston, Massachusetts, USA. His research focuses on the development of synthetic biology tools to study and control bacterial systems.

  • Caleb J. Bashor

    Caleb J. Bashor is a postdoctoral fellow in the laboratory of James J. Collins at Boston University, Massachusetts, USA. He received a B.A. in biochemistry at Reed College and a Ph.D. in biophysics at the University of California San Francisco (UCSF), USA. His research interests are in structural biochemistry and synthetic biology, with a particular interest in the engineering of synthetic biological networks.

  • James J. Collins

    James J. Collins is an investigator at the Howard Hughes Medical Institute, Chevy Chase, Maryland, USA, and William F. Warren Distinguished Professor, University Professor, Professor of Biomedical Engineering and Director of the Center of Synthetic Biology at Boston University, Massachusetts, USA. He is also a core founding faculty member of the Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, Massachusetts, USA. His research group studies synthetic biology and systems biology, with a particular focus on using network biology approaches to study antibiotic action, bacterial defence mechanisms and the emergence of antibiotic resistance.

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