Timeline | Published:

A brief history of synthetic biology

Nature Reviews Microbiology volume 12, pages 381390 (2014) | Download Citation

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from $8.99

All prices are NET prices.

References

  1. 1.

    A grand challenge in biology. Science 333, 1200 (2011).

  2. 2.

    & From gene switches to mammalian designer cells: present and future prospects. Trends Biotechnol. 31, 155–168 (2013).

  3. 3.

    & Therapeutic synthetic gene networks. Curr. Opin. Biotechnol. 23, 703–711 (2012).

  4. 4.

    & Teleonomic mechanisms in cellular metabolism, growth, and differentiation. Cold Spring Harb. Symp. Quant. Biol. 26, 389–401 (1961).

  5. 5.

    & On the regulation of gene activity. Cold Spring Harb. Symp. Quant. Biol. 26, 193–211 (1961).

  6. 6.

    , & A genetic switch in a bacterial virus. Sci. Am. 247, 128–130 (1982).

  7. 7.

    et al. Integrated genomic and proteomic analyses of a systematically perturbed metabolic network. Science 292, 929–934 (2001).

  8. 8.

    & The evolution of molecular biology into systems biology. Nature Biotech. 22, 1249–1252 (2004).

  9. 9.

    , , , & The large-scale organization of metabolic networks. Nature 407, 651–654 (2000).

  10. 10.

    , , & From molecular to modular cell biology. Nature 402, C47–C52 (1999).

  11. 11.

    Protein molecules as computational elements in living cells. Nature 376, 307–312 (1995).

  12. 12.

    Synthetic biology: act natural. Nature 421, 118 (2003).

  13. 13.

    & Circuit simulation of genetic networks. Science 269, 650–656 (1995).

  14. 14.

    & Towards a circuit engineering discipline. Curr. Biol. 10, R318–R320 (2000).

  15. 15.

    , & Construction of a genetic toggle switch in Escherichia coli. Nature 403, 339–342 (2000).

  16. 16.

    & A synthetic oscillatory network of transcriptional regulators. Nature 403, 335–338 (2000).

  17. 17.

    , , & Computational studies of gene regulatory networks: in numero molecular biology. Nature Rev. Genet. 2, 268–279 (2001).

  18. 18.

    , & The engineering of gene regulatory networks. Annu. Rev. Biomed. Engineer. 5, 179–206 (2003).

  19. 19.

    , & Foundations for the design and implementation of synthetic genetic circuits. Nature Rev. Genet. 13, 406–420 (2012).

  20. 20.

    , & Engineered gene circuits. Nature 420, 224–230 (2002).

  21. 21.

    & Engineering stability in gene networks by autoregulation. Nature 405, 590–593 (2000).

  22. 22.

    , & Positive feedback in eukaryotic gene networks: cell differentiation by graded to binary response conversion. EMBO J. 20, 2528–2535 (2001).

  23. 23.

    , , & Prediction and measurement of an autoregulatory genetic module. Proc. Natl Acad. Sci. USA 100, 7714–7719 (2003).

  24. 24.

    , , & Development of genetic circuitry exhibiting toggle switch or oscillatory behavior in Escherichia coli. Cell 113, 597–607 (2003).

  25. 25.

    , , & Combinatorial synthesis of genetic networks. Science 296, 1466–1470 (2002).

  26. 26.

    & The device physics of cellular logic gates. First Workshop on Non-Silicon Computation , (2002).

  27. 27.

    , , , & Regulation of noise in the expression of a single gene. Nature Genet. 31, 69–73 (2002).

  28. 28.

    , , & Stochastic gene expression in a single cell. Science 297, 1183–1186 (2002).

  29. 29.

    , , & Noise in eukaryotic gene expression. Nature 422, 633–637 (2003).

  30. 30.

    & in DNA Computing (eds Condon, A. & Rozenberg, G.) 1–16 (Springer, 2001).

  31. 31.

    , & Rewiring MAP kinase pathways using alternative scaffold assembly mechanisms. Science 299, 1061–1064 (2003).

  32. 32.

    Synthetic biology: starting from scratch. Nature 431, 624–626 (2004).

  33. 33.

    Synthetic biology. Microbes made to order. Science 303, 158–161 (2004).

  34. 34.

    Foundations for engineering biology. Nature 438, 449–453 (2005).

  35. 35.

    et al. Engineered riboregulators enable post-transcriptional control of gene expression. Nature Biotech. 22, 841–847 (2004).

  36. 36.

    & Programmable ligand-controlled riboregulators of eukaryotic gene expression. Nature Biotech. 23, 337–343 (2005).

  37. 37.

    , & Environmental signal integration by a modular AND gate. Mol. Systems Biol. 3, 133 (2007).

  38. 38.

    , , , & A synthetic multicellular system for programmed pattern formation. Nature 434, 1130–1134 (2005).

  39. 39.

    , , & Programmed population control by cell–cell communication and regulated killing. Nature 428, 868–871 (2004).

  40. 40.

    et al. Synthetic biology: engineering Escherichia coli to see light. Nature 438, 441–442 (2005).

  41. 41.

    , , , & Engineering a mevalonate pathway in Escherichia coli for production of terpenoids. Nature Biotech. 21, 796–802 (2003).

  42. 42.

    et al. Production of the antimalarial drug precursor artemisinic acid in engineered yeast. Nature 440, 940–943 (2006).

  43. 43.

    et al. Combinatorial polyketide biosynthesis by de novo design and rearrangement of modular polyketide synthase genes. Nature Biotech. 23, 1171–1176 (2005).

  44. 44.

    & Combinatorial biosynthesis for drug development. Curr. Opin. Microbiol. 10, 238–245 (2007).

  45. 45.

    , , & Environmentally controlled invasion of cancer cells by engineered bacteria. J. Mol. Biol. 355, 619–627 (2006).

  46. 46.

    Five hard truths for synthetic biology. Nature 463, 288–290 (2010).

  47. 47.

    Idempotent vector design for standard assembly of BioBricks. MIT Synthethic Biology Working Group Technical Reports , (2003).

  48. 48.

    , & A one pot, one step, precision cloning method with high throughput capability. PLoS ONE 3, e3647 (2008).

  49. 49.

    et al. Enzymatic assembly of DNA molecules up to several hundred kilobases. Nature Methods 6, 343–345 (2009).

  50. 50.

    , , , & Standard biological parts knowledgebase. PLoS ONE 6, e17005 (2011).

  51. 51.

    & Contextualizing context for synthetic biology — identifying causes of failure of synthetic biological systems. Biotechnol. J. 7, 856–866 (2012).

  52. 52.

    & The second wave of synthetic biology: from modules to systems. Nature Rev. Mol. Cell Biol. 10, 410–422 (2009).

  53. 53.

    & in Synthetic Biology Project , (Woodrow Wilson International Center for Scholars, 2008).

  54. 54.

    Building outside of the box: iGEM and the BioBricks Foundation. Nature Biotech. 27, 1099–1102 (2009).

  55. 55.

    Life from information. Nature Methods 5, 27–28 (2008).

  56. 56.

    et al. A fast, robust and tunable synthetic gene oscillator. Nature 456, 516–519 (2008).

  57. 57.

    , , & A synchronized quorum of genetic clocks. Nature 463, 326–330 (2010).

  58. 58.

    et al. A sensing array of radically coupled genetic 'biopixels'. Nature 481, 39–44 (2012).

  59. 59.

    et al. Synthetic gene networks that count. Science 324, 1199–1202 (2009).

  60. 60.

    , & Synthetic circuits integrating logic and memory in living cells. Nature Biotech. 31, 448–452 (2013).

  61. 61.

    , , , & Amplifying genetic logic gates. Science 340, 599–603 (2013).

  62. 62.

    , & Robust multicellular computing using genetically encoded NOR gates and chemical 'wires'. Nature 469, 212–215 (2011).

  63. 63.

    , , , & Genetic programs constructed from layered logic gates in single cells. Nature 491, 249–253 (2012).

  64. 64.

    et al. A synthetic genetic edge detection program. Cell 137, 1272–1281 (2009).

  65. 65.

    et al. Sequential establishment of stripe patterns in an expanding cell population. Science 334, 238–241 (2011).

  66. 66.

    & Higher-order cellular information processing with synthetic RNA devices. Science 322, 456–460 (2008).

  67. 67.

    , , & Model-driven engineering of RNA devices to quantitatively program gene expression. Science 334, 1716–1719 (2011).

  68. 68.

    et al. Metabolic engineering of Escherichia coli using synthetic small regulatory RNAs. Nature Biotech. 31, 170–174 (2013).

  69. 69.

    , & RNA-guided genetic silencing systems in bacteria and archaea. Nature 482, 331–338 (2012).

  70. 70.

    et al. Repurposing CRISPR as an RNA-guided platform for sequence-specific control of gene expression. Cell 152, 1173–1183 (2013).

  71. 71.

    et al. CRISPR interference (CRISPRi) for sequence-specific control of gene expression. Nature Protoc. 8, 2180–2196 (2013).

  72. 72.

    et al. Programmable repression and activation of bacterial gene expression using an engineered CRISPR–Cas system. Nucleic Acids Res. 41, 7429–7437 (2013).

  73. 73.

    , , & Using engineered scaffold interactions to reshape MAP kinase pathway signaling dynamics. Science 319, 1539–1543 (2008).

  74. 74.

    , , & Engineering robust control of two-component system phosphotransfer using modular scaffolds. Proc. Natl Acad. Sci. USA 109, 18090–18095 (2012).

  75. 75.

    et al. Synthetic protein scaffolds provide modular control over metabolic flux. Nature Biotech. 27, 753–759 (2009).

  76. 76.

    , , , & Designing synthetic regulatory networks capable of self-organizing cell polarization. Cell 151, 320–332 (2012).

  77. 77.

    , , , & Architecture-dependent noise discriminates functionally analogous differentiation circuits. Cell 139, 512–522 (2009).

  78. 78.

    et al. Evolvability and hierarchy in rewired bacterial gene networks. Nature 452, 840–845 (2008).

  79. 79.

    et al. Systems metabolic engineering of microorganisms for natural and non-natural chemicals. Nature Chem. Biol. 8, 536–546 (2012).

  80. 80.

    , & Non-fermentative pathways for synthesis of branched-chain higher alcohols as biofuels. Nature 451, 86–89 (2008).

  81. 81.

    et al. Conversion of proteins into biofuels by engineering nitrogen flux. Nature Biotech. 29, 346–351 (2011).

  82. 82.

    et al. Microbial production of fatty-acid-derived fuels and chemicals from plant biomass. Nature 463, 559–562 (2010).

  83. 83.

    & Microbial production of short-chain alkanes. Nature 502, 571–574 (2013).

  84. 84.

    et al. Metabolic engineering of Escherichia coli for direct production of 1,4-butanediol. Nature Chem. Biol. 7, 445–452 (2011).

  85. 85.

    & Engineering static and dynamic control of synthetic pathways. Cell 140, 19–23 (2010).

  86. 86.

    , & Dynamic metabolic engineering for increasing bioprocess productivity. Metab. Eng. 10, 255–266 (2008).

  87. 87.

    , & Design of a dynamic sensor–regulator system for production of chemicals and fuels derived from fatty acids. Nature Biotech. 30, 354–359 (2012).

  88. 88.

    et al. High-level semi-synthetic production of the potent antimalarial artemisinin. Nature 496, 528–532 (2013).

  89. 89.

    , & Synthetic biology moving into the clinic. Science 333, 1248–1252 (2011).

  90. 90.

    & Dispersing biofilms with engineered enzymatic bacteriophage. Proc. Natl Acad. Sci. USA 104, 11197–11202 (2007).

  91. 91.

    , & Next-generation synthetic gene networks. Nature Biotech. 27, 1139–1150 (2009).

  92. 92.

    , & Advancing bacteriophage-based microbial diagnostics with synthetic biology. Trends Biotechnol. 31, 325–327 (2013).

  93. 93.

    , & Genetically programmable pathogen sense and destroy. ACS Synthet. Biol. 2, 715–723 (2013).

  94. 94.

    & Engineered bacterial communication prevents Vibrio cholerae virulence in an infant mouse model. Proc. Natl Acad. Sci. USA 107, 11260–11264 (2010).

  95. 95.

    , , , & Tracking, tuning, and terminating microbial physiology using synthetic riboregulators. Proc. Natl Acad. Sci. USA 107, 15898–15903 (2010).

  96. 96.

    et al. Creation of a bacterial cell controlled by a chemically synthesized genome. Science 329, 52–56 (2010).

  97. 97.

    et al. Synthetic chromosome arms function in yeast and generate phenotypic diversity by design. Nature 477, 471–476 (2011).

  98. 98.

    et al. Programming cells by multiplex genome engineering and accelerated evolution. Nature 460, 894–898 (2009).

  99. 99.

    et al. Precise manipulation of chromosomes in vivo enables genome-wide codon replacement. Science 333, 348–353 (2011).

  100. 100.

    , , , & RNA-guided editing of bacterial genomes using CRISPR–Cas systems. Nature Biotech. 31, 233–239 (2013).

  101. 101.

    et al. Genome engineering in Saccharomyces cerevisiae using CRISPR–Cas systems. Nucleic Acids Res. 41, 4336–4343 (2013).

  102. 102.

    , & Automated design of synthetic ribosome binding sites to control protein expression. Nature Biotech. 27, 946–950 (2009).

  103. 103.

    , & Diversity-based, model-guided construction of synthetic gene networks with predicted functions. Nature Biotech. 27, 465–471 (2009).

  104. 104.

    et al. Precise and reliable gene expression via standard transcription and translation initiation elements. Nature Methods 10, 354–360 (2013).

  105. 105.

    et al. Measurement and modeling of intrinsic transcription terminators. Nucleic Acids Res. 41, 5139–5148 (2013).

  106. 106.

    et al. Quantitative estimation of activity and quality for collections of functional genetic elements. Nature Methods 10, 347–353 (2013).

  107. 107.

    , & Refactoring bacteriophage T7. Mol. Systems Biol. 1, 2005.0018 (2005).

  108. 108.

    , & Refactoring the nitrogen fixation gene cluster from Klebsiella oxytoca. Proc. Natl Acad. Sci. USA 109, 7085–7090 (2012).

  109. 109.

    , , , & RNA processing enables predictable programming of gene expression. Nature Biotech. 30, 1002–1006 (2012).

  110. 110.

    , , , & Ribozyme-based insulator parts buffer synthetic circuits from genetic context. Nature Biotech. 30, 1137–1142 (2012).

  111. 111.

    et al. Queueing up for enzymatic processing: correlated signaling through coupled degradation. Mol. Systems Biol. 7, 561 (2011).

  112. 112.

    & The biomass objective function. Curr. Opin. Microbiol. 13, 344–349 (2010).

  113. 113.

    , & Genetic switchboard for synthetic biology applications. Proc. Natl Acad. Sci. USA 109, 5850–5855 (2012).

  114. 114.

    et al. Therapeutic modulation of microbiota–host metabolic interactions. Sci. Transl. Med. 4, 137rv6 (2012).

  115. 115.

    & Community health care: therapeutic opportunities in the human microbiome. Sci. Transl. Med. 3, 78ps12 (2011).

  116. 116.

    & Genome-scale engineering for systems and synthetic biology. Mol. Systems Biol. 9, 641 (2013).

  117. 117.

    et al. Life with 6000 genes. Science 274, 563–567 (1996).

  118. 118.

    et al. The complete genome sequence of Escherichia coli K-12. Science 277, 1453–1462 (1997).

Download references

Acknowledgements

The authors thank T. Lu and J. Dueber for helpful discussions during the preparation of this Perspective article. This work is supported by the Howard Hughes Medical Institute.

Author information

Author notes

    • D. Ewen Cameron
    •  & Caleb J. Bashor

    These authors contributed equally to this work.

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

Authors

  1. Search for D. Ewen Cameron in:

  2. Search for Caleb J. Bashor in:

  3. Search for James J. Collins in:

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to James J. Collins.

Glossary

Abstraction hierarchies

Organizational schemes that simplify the engineering process by describing building blocks according to modular properties, thus enabling the construction of increasingly complex systems. In synthetic biology, molecular elements that are categorized as 'parts' (which is the lowest level of the hierarchy) can be used to construct devices (which are parts assembled together to yield a desired function), which can, in turn, be further combined into systems.

Flux-balance analysis

A mathematical approach to simulate steady-state metabolism in a living system.

Forward-engineer

To move from an abstract description of a desired function to the physical implementation that produces that function. In the context of synthetic biology, it is the construction of genetic systems that produce a desired behaviour.

Logic gate

A device or system that carries out a Boolean logic operation by computing a set of digital inputs to generate a digital output; for example, a genetic circuit that activates gene expression only in the presence of a specified set of environmental signals would constitute an 'AND' gate.

Parts standardization

For an engineering discipline, the adoption of a widely used set of building blocks that have well-defined properties and modes of connectivity.

Reverse-engineer

To examine the constituent components of a system in order to understand their integrated function. In systems biology, this may involve making perturbations to a cellular network and then constructing a model that describes the relationship between the behaviour of the molecular components and that of the entire system.

Systems biology

An interdisciplinary approach that attempts to develop and test holistic models of living systems. A 'top-down' systems approach uses quantitative modelling to identify and describe the underlying biosynthetic and regulatory networks of a system, whereas a complementary 'bottom-up' approach attempts to model the systems-wide phenotypes that emerge from component interactions.

About this article

Publication history

Published

DOI

https://doi.org/10.1038/nrmicro3239