Bottom-up approaches in synthetic biology and biomaterials for tissue engineering applications

  • Mitchell S. Weisenberger
  • Tara L. Deans
Biotechnology Methods - Original Paper


Synthetic biologists use engineering principles to design and construct genetic circuits for programming cells with novel functions. A bottom-up approach is commonly used to design and construct genetic circuits by piecing together functional modules that are capable of reprogramming cells with novel behavior. While genetic circuits control cell operations through the tight regulation of gene expression, a diverse array of environmental factors within the extracellular space also has a significant impact on cell behavior. This extracellular space offers an addition route for synthetic biologists to apply their engineering principles to program cell-responsive modules within the extracellular space using biomaterials. In this review, we discuss how taking a bottom-up approach to build genetic circuits using DNA modules can be applied to biomaterials for controlling cell behavior from the extracellular milieu. We suggest that, by collectively controlling intrinsic and extrinsic signals in synthetic biology and biomaterials, tissue engineering outcomes can be improved.



We gratefully acknowledge the funding from the University of Utah startup funds, a University of Utah SEED Grant [10045314], the National Science Foundation CAREER program [CBET-1554017], the Office of Naval Research Young Investigator Program [N00014-16-1-3012], and the National Institutes of Health Trailblazer Award [1R21EB025413-01].


  1. 1.
    Callura JM, Cantor CR, Collins JJ (2012) Genetic switchboard for synthetic biology applications. Proc Natl Acad Sci USA 109(15):5850–5855PubMedGoogle Scholar
  2. 2.
    Chang AL, Wolf JJ, Smolke CD (2012) Synthetic RNA switches as a tool for temporal and spatial control over gene expression. Curr Opin Biotechnol 23(5):679–688PubMedPubMedCentralGoogle Scholar
  3. 3.
    Deans TL, Cantor CR, Collins JJ (2007) A tunable genetic switch based on RNAi and repressor proteins for regulating gene expression in mammalian cells. Cell 130(2):363–372PubMedGoogle Scholar
  4. 4.
    Fitzgerald M, Gibbs C, Shimpi AA, Deans TL (2017) Adoption of the Q transcriptional system for regulating gene expression in stem cells. ACS Synth Biol 6(11):2014–2020PubMedGoogle Scholar
  5. 5.
    Gardner TS, Cantor CR, Collins JJ (2000) Construction of a genetic toggle switch in Escherichia coli. Nature 403(6767):339–342PubMedGoogle Scholar
  6. 6.
    Green AA et al (2014) Toehold switches: de-novo-designed regulators of gene expression. Cell 159(4):925–939PubMedPubMedCentralGoogle Scholar
  7. 7.
    Horner M, Weber W (2012) Molecular switches in animal cells. FEBS Lett 586(15):2084–2096PubMedGoogle Scholar
  8. 8.
    Kramer BP et al (2004) An engineered epigenetic transgene switch in mammalian cells. Nat Biotechnol 22(7):867–870PubMedGoogle Scholar
  9. 9.
    Mandal M et al (2003) Riboswitches control fundamental biochemical pathways in Bacillus subtilis and other bacteria. Cell 113(5):577–586PubMedGoogle Scholar
  10. 10.
    Polstein LR et al (2017) An engineered optogenetic switch for spatiotemporal control of gene expression, cell differentiation, and tissue morphogenesis. ACS Synth Biol 6(11):2003–2013PubMedGoogle Scholar
  11. 11.
    Schmidl SR et al (2014) Refactoring and optimization of light-switchable Escherichia coli two-component systems. ACS Synth Biol 3(11):820–831PubMedGoogle Scholar
  12. 12.
    Weber W, Fussenegger M (2011) Molecular diversity–the toolbox for synthetic gene switches and networks. Curr Opin Chem Biol 15(3):414–420PubMedGoogle Scholar
  13. 13.
    Aulehla A, Pourquie O (2008) Oscillating signaling pathways during embryonic development. Curr Opin Cell Biol 20(6):632–637PubMedGoogle Scholar
  14. 14.
    Danino T et al (2010) A synchronized quorum of genetic clocks. Nature 463(7279):326–330PubMedPubMedCentralGoogle Scholar
  15. 15.
    Elowitz MB, Leibler S (2000) A synthetic oscillatory network of transcriptional regulators. Nature 403(6767):335–338PubMedGoogle Scholar
  16. 16.
    Fung E et al (2005) A synthetic gene-metabolic oscillator. Nature 435(7038):118–122PubMedGoogle Scholar
  17. 17.
    Judd EM, Laub MT, McAdams HH (2000) Toggles and oscillators: new genetic circuit designs. BioEssays 22(6):507–509PubMedGoogle Scholar
  18. 18.
    Stricker J et al (2008) A fast, robust and tunable synthetic gene oscillator. Nature 456(7221):516–519PubMedGoogle Scholar
  19. 19.
    Tigges M et al (2009) A tunable synthetic mammalian oscillator. Nature 457(7227):309–312PubMedGoogle Scholar
  20. 20.
    Friedland AE et al (2009) Synthetic gene networks that count. Science 324(5931):1199–1202PubMedPubMedCentralGoogle Scholar
  21. 21.
    Weber W et al (2007) A synthetic time-delay circuit in mammalian cells and mice. Proc Natl Acad Sci USA 104(8):2643–2648PubMedGoogle Scholar
  22. 22.
    Bonnet J et al (2013) Amplifying genetic logic gates. Science 340(6132):599–603PubMedGoogle Scholar
  23. 23.
    Hasty J et al (2000) Noise-based switches and amplifiers for gene expression. Proc Natl Acad Sci USA 97(5):2075–2080PubMedGoogle Scholar
  24. 24.
    Guet CC et al (2002) Combinatorial synthesis of genetic networks. Science 296(5572):1466–1470PubMedGoogle Scholar
  25. 25.
    Mukherji S, van Oudenaarden A (2009) Synthetic biology: understanding biological design from synthetic circuits. Nat Rev Genet 10(12):859–871PubMedPubMedCentralGoogle Scholar
  26. 26.
    Schukur L, Fussenegger M (2016) Engineering of synthetic gene circuits for (re-)balancing physiological processes in chronic diseases. Wiley Interdiscip Rev Syst Biol Med 8(5):402–422PubMedGoogle Scholar
  27. 27.
    Siuti P, Yazbek J, Lu TK (2013) Synthetic circuits integrating logic and memory in living cells. Nat Biotechnol 31(5):448–452PubMedGoogle Scholar
  28. 28.
    Auslander D et al (2014) A synthetic multifunctional mammalian pH sensor and CO2 transgene-control device. Mol Cell 55(3):397–408PubMedGoogle Scholar
  29. 29.
    Bowsher CG, Swain PS (2014) Environmental sensing, information transfer, and cellular decision-making. Curr Opin Biotechnol 28C:149–155Google Scholar
  30. 30.
    Brenner M, Cho JH, Wong WW (2017) Synthetic biology: sensing with modular receptors. Nat Chem Biol 13(2):131–132PubMedGoogle Scholar
  31. 31.
    Daringer NM et al (2014) Modular extracellular sensor architecture for engineering mammalian cell-based devices. ACS Synth Biol 3(12):892–902PubMedPubMedCentralGoogle Scholar
  32. 32.
    Feng J et al (2015) A general strategy to construct small molecule biosensors in eukaryotes. Elife 4:1–23Google Scholar
  33. 33.
    Garcia JR et al (2009) Microbial nar-GFP cell sensors reveal oxygen limitations in highly agitated and aerated laboratory-scale fermentors. Microb Cell Fact 8:6PubMedPubMedCentralGoogle Scholar
  34. 34.
    Looger LL et al (2003) Computational design of receptor and sensor proteins with novel functions. Nature 423(6936):185–190PubMedGoogle Scholar
  35. 35.
    Saeidi N et al (2011) Engineering microbes to sense and eradicate Pseudomonas aeruginosa, a human pathogen. Mol Syst Biol 7:521PubMedPubMedCentralGoogle Scholar
  36. 36.
    Schwarz KA et al (2017) Rewiring human cellular input-output using modular extracellular sensors. Nat Chem Biol 13(2):202–209PubMedGoogle Scholar
  37. 37.
    Slomovic S, Collins JJ (2015) DNA sense-and-respond protein modules for mammalian cells. Nat Methods 12(11):1085–1090PubMedGoogle Scholar
  38. 38.
    Smole A et al (2017) A synthetic mammalian therapeutic gene circuit for sensing and suppressing inflammation. Mol Ther 25(1):102–119PubMedPubMedCentralGoogle Scholar
  39. 39.
    Wu F, Menn DJ, Wang X (2014) Quorum-sensing crosstalk-driven synthetic circuits: from unimodality to trimodality. Chem Biol 21(12):1629–1638PubMedPubMedCentralGoogle Scholar
  40. 40.
    Youk H, Lim WA (2014) Secreting and sensing the same molecule allows cells to achieve versatile social behaviors. Science 343(6171):1242782PubMedPubMedCentralGoogle Scholar
  41. 41.
    Auslander S et al (2012) Programmable single-cell mammalian biocomputers. Nature 487(7405):123–127PubMedGoogle Scholar
  42. 42.
    Callura JM et al (2010) Tracking, tuning, and terminating microbial physiology using synthetic riboregulators. Proc Natl Acad Sci USA 107(36):15898–15903PubMedGoogle Scholar
  43. 43.
    Ellis T, Wang X, Collins JJ (2009) Diversity-based, model-guided construction of synthetic gene networks with predicted functions. Nat Biotechnol 27(5):465–471PubMedPubMedCentralGoogle Scholar
  44. 44.
    Gitzinger M et al (2012) The food additive vanillic acid controls transgene expression in mammalian cells and mice. Nucleic Acids Res 40(5):e37PubMedGoogle Scholar
  45. 45.
    Guido NJ et al (2006) A bottom-up approach to gene regulation. Nature 439(7078):856–860PubMedGoogle Scholar
  46. 46.
    Isaacs FJ et al (2004) Engineered riboregulators enable post-transcriptional control of gene expression. Nat Biotechnol 22(7):841–847PubMedGoogle Scholar
  47. 47.
    Kaern M, Blake WJ, Collins JJ (2003) The engineering of gene regulatory networks. Annu Rev Biomed Eng 5:179–206PubMedGoogle Scholar
  48. 48.
    Khalil AS, Collins JJ (2010) Synthetic biology: applications come of age. Nat Rev Genet 11(5):367–379PubMedPubMedCentralGoogle Scholar
  49. 49.
    Khalil AS et al (2012) A synthetic biology framework for programming eukaryotic transcription functions. Cell 150(3):647–658PubMedPubMedCentralGoogle Scholar
  50. 50.
    Litcofsky KD et al (2012) Iterative plug-and-play methodology for constructing and modifying synthetic gene networks. Nat Methods 9(11):1077–1080PubMedPubMedCentralGoogle Scholar
  51. 51.
    Weber W et al (2009) A synthetic mammalian electro-genetic transcription circuit. Nucleic Acids Res 37(4):e33PubMedPubMedCentralGoogle Scholar
  52. 52.
    Paddon CJ et al (2013) High-level semi-synthetic production of the potent antimalarial artemisinin. Nature 496(7446):528–532PubMedGoogle Scholar
  53. 53.
    Ro DK et al (2006) Production of the antimalarial drug precursor artemisinic acid in engineered yeast. Nature 440(7086):940–943PubMedGoogle Scholar
  54. 54.
    Danino T et al (2015) Programmable probiotics for detection of cancer in urine. Sci Transl Med 7(289):289ra284Google Scholar
  55. 55.
    Folcher M, Fussenegger M (2012) Synthetic biology advancing clinical applications. Curr Opin Chem Biol 16(3–4):345–354PubMedGoogle Scholar
  56. 56.
    Forbes NS (2010) Engineering the perfect (bacterial) cancer therapy. Nat Rev Cancer 10(11):785–794PubMedPubMedCentralGoogle Scholar
  57. 57.
    Higashikuni Y, Chen WC, Lu TK (2017) Advancing therapeutic applications of synthetic gene circuits. Curr Opin Biotechnol 47:133–141PubMedGoogle Scholar
  58. 58.
    Kim T et al (2015) A synthetic erectile optogenetic stimulator enabling blue-light-inducible penile erection. Angew Chem Int Ed Engl 54(20):5933–5938PubMedGoogle Scholar
  59. 59.
    Kojima R, Aubel D, Fussenegger M (2016) Toward a world of theranostic medication: programming biological sentinel systems for therapeutic intervention. Adv Drug Deliv Rev. 105(Pt A):66–76PubMedGoogle Scholar
  60. 60.
    Nissim L, Bar-Ziv RH (2010) A tunable dual-promoter integrator for targeting of cancer cells. Mol Syst Biol 6:444PubMedPubMedCentralGoogle Scholar
  61. 61.
    Rossger K, Charpin-El-Hamri G, Fussenegger M (2013) A closed-loop synthetic gene circuit for the treatment of diet-induced obesity in mice. Nat Commun 4:2825PubMedPubMedCentralGoogle Scholar
  62. 62.
    Xie Z et al (2011) Multi-input RNAi-based logic circuit for identification of specific cancer cells. Science 333(6047):1307–1311PubMedGoogle Scholar
  63. 63.
    Ye H, Aubel D, Fussenegger M (2013) Synthetic mammalian gene circuits for biomedical applications. Curr Opin Chem Biol 17(6):910–917PubMedGoogle Scholar
  64. 64.
    Ye H et al (2013) Pharmaceutically controlled designer circuit for the treatment of the metabolic syndrome. Proc Natl Acad Sci USA 110(1):141–146PubMedGoogle Scholar
  65. 65.
    Ye H et al (2011) A synthetic optogenetic transcription device enhances blood-glucose homeostasis in mice. Science 332(6037):1565–1568PubMedGoogle Scholar
  66. 66.
    Ye H, Fussenegger M (2014) Synthetic therapeutic gene circuits in mammalian cells. FEBS Lett 588(15):2537–2544PubMedGoogle Scholar
  67. 67.
    Auslander S, Fussenegger M (2016) Engineering gene circuits for mammalian cell-based applications. Cold Spring Harb Perspect Biol 8(7):1–17Google Scholar
  68. 68.
    Deans TL (2014) Parallel networks: synthetic biology and artificial intelligence. ACM J Emerg Technol Comput Syst (JETC) 11(3):1–22Google Scholar
  69. 69.
    Baylin SB et al (2001) Aberrant patterns of DNA methylation, chromatin formation and gene expression in cancer. Hum Mol Genet 10(7):687–692PubMedGoogle Scholar
  70. 70.
    Golub TR et al (1999) Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. Science 286(5439):531–537PubMedGoogle Scholar
  71. 71.
    van ‘t Veer LJ et al (2002) Gene expression profiling predicts clinical outcome of breast cancer. Nature 415(6871):530–536Google Scholar
  72. 72.
    Caddeo S, Boffito M, Sartori S (2017) Tissue engineering approaches in the design of healthy and pathological in vitro tissue models. Front Bioeng Biotechnol 5:40PubMedPubMedCentralGoogle Scholar
  73. 73.
    Guvendiren M, Burdick JA (2012) Stiffening hydrogels to probe short- and long-term cellular responses to dynamic mechanics. Nat Commun 3:792PubMedGoogle Scholar
  74. 74.
    van den Broek LJ et al (2014) Human hypertrophic and keloid scar models: principles, limitations and future challenges from a tissue engineering perspective. Exp Dermatol 23(6):382–386PubMedPubMedCentralGoogle Scholar
  75. 75.
    Anesiadis N et al (2013) Analysis and design of a genetic circuit for dynamic metabolic engineering. ACS Synth Biol 2(8):442–452PubMedGoogle Scholar
  76. 76.
    Auslander S, Wieland M, Fussenegger M (2012) Smart medication through combination of synthetic biology and cell microencapsulation. Metab Eng 14(3):252–260PubMedGoogle Scholar
  77. 77.
    Ideker T et al (2001) Integrated genomic and proteomic analyses of a systematically perturbed metabolic network. Science 292(5518):929–934PubMedGoogle Scholar
  78. 78.
    Jeong H et al (2000) The large-scale organization of metabolic networks. Nature 407(6804):651–654PubMedGoogle Scholar
  79. 79.
    Park JH, Lee SY (2008) Towards systems metabolic engineering of microorganisms for amino acid production. Curr Opin Biotechnol 19(5):454–460PubMedGoogle Scholar
  80. 80.
    Teixeira AP, Fussenegger M (2017) Synthetic biology-inspired therapies for metabolic diseases. Curr Opin Biotechnol 47:59–66PubMedGoogle Scholar
  81. 81.
    Bloom RJ, Winkler SM, Smolke CD (2015) Synthetic feedback control using an RNAi-based gene-regulatory device. J Biol Eng 9:5PubMedPubMedCentralGoogle Scholar
  82. 82.
    Andrianantoandro E et al (2006) Synthetic biology: new engineering rules for an emerging discipline. Mol Syst Biol 2:1–14Google Scholar
  83. 83.
    Basu S et al (2004) Spatiotemporal control of gene expression with pulse-generating networks. Proc Natl Acad Sci USA 101(17):6355–6360PubMedGoogle Scholar
  84. 84.
    Chen AY et al (2014) Synthesis and patterning of tunable multiscale materials with engineered cells. Nat Mater 13(5):515–523PubMedPubMedCentralGoogle Scholar
  85. 85.
    Farzadfard F, Perli SD, Lu TK (2013) Tunable and multifunctional eukaryotic transcription factors based on CRISPR/Cas. ACS Synth Biol 2(10):604–613PubMedPubMedCentralGoogle Scholar
  86. 86.
    Miyamoto T et al (2013) Synthesizing biomolecule-based Boolean logic gates. ACS Synth Biol 2(2):72–82PubMedGoogle Scholar
  87. 87.
    Purcell O, Lu TK (2014) Synthetic analog and digital circuits for cellular computation and memory. Curr Opin Biotechnol 29C:146–155Google Scholar
  88. 88.
    Roquet N, Lu TK (2014) Digital and analog gene circuits for biotechnology. Biotechnol J 9(5):597–608PubMedPubMedCentralGoogle Scholar
  89. 89.
    Roquet N et al (2016) Synthetic recombinase-based state machines in living cells. Science 353(6297):aad8559PubMedGoogle Scholar
  90. 90.
    Yang L et al (2014) Permanent genetic memory with > 1-byte capacity. Nat Methods 11(12):1261–1266PubMedPubMedCentralGoogle Scholar
  91. 91.
    Chan G, Mooney DJ (2008) New materials for tissue engineering: towards greater control over the biological response. Trends Biotechnol 26(7):382–392PubMedGoogle Scholar
  92. 92.
    Deans TL, Elisseeff JH (2009) Mimicking extracellular matrix to direct stem cell differentiation. World Stem Cell Report, Genetics Policy InstituteGoogle Scholar
  93. 93.
    Deans TL, Elisseeff JH (2009) Stem cells in musculoskeletal engineered tissue. Curr Opin Biotechnol 20(5):537–544PubMedGoogle Scholar
  94. 94.
    Deans TL, Elisseeff JH (2010) The life of a cell: probing the complex relationships with the world. Cell Stem Cell 6(6):499–501PubMedGoogle Scholar
  95. 95.
    Cepko CL (1999) The roles of intrinsic and extrinsic cues and bHLH genes in the determination of retinal cell fates. Curr Opin Neurobiol 9(1):37–46PubMedGoogle Scholar
  96. 96.
    Jones DL, Wagers AJ (2008) No place like home: anatomy and function of the stem cell niche. Nat Rev Mol Cell Biol 9(1):11–21PubMedGoogle Scholar
  97. 97.
    Watt FM, Hogan BL (2000) Out of Eden: stem cells and their niches. Science 287(5457):1427–1430PubMedGoogle Scholar
  98. 98.
    Zon LI (2008) Intrinsic and extrinsic control of haematopoietic stem-cell self-renewal. Nature 453(7193):306–313PubMedGoogle Scholar
  99. 99.
    Aamodt JM, Grainger DW (2016) Extracellular matrix-based biomaterial scaffolds and the host response. Biomaterials 86:68–82PubMedPubMedCentralGoogle Scholar
  100. 100.
    Badylak SF, Freytes DO, Gilbert TW (2009) Extracellular matrix as a biological scaffold material: structure and function. Acta Biomater 5(1):1–13PubMedGoogle Scholar
  101. 101.
    Beachley VZ et al (2015) Tissue matrix arrays for high-throughput screening and systems analysis of cell function. Nat Methods 12(12):1197–1204PubMedPubMedCentralGoogle Scholar
  102. 102.
    Chen FM, Liu X (2016) Advancing biomaterials of human origin for tissue engineering. Prog Polym Sci 53:86–168PubMedGoogle Scholar
  103. 103.
    Chen XD et al (2007) Extracellular matrix made by bone marrow cells facilitates expansion of marrow-derived mesenchymal progenitor cells and prevents their differentiation into osteoblasts. J Bone Miner Res 22(12):1943–1956PubMedGoogle Scholar
  104. 104.
    Coburn JM et al (2012) Bioinspired nanofibers support chondrogenesis for articular cartilage repair. Proc Natl Acad Sci USA 109(25):10012–10017PubMedGoogle Scholar
  105. 105.
    Crapo PM, Gilbert TW, Badylak SF (2011) An overview of tissue and whole organ decellularization processes. Biomaterials 32(12):3233–3243PubMedPubMedCentralGoogle Scholar
  106. 106.
    Flaim CJ, Chien S, Bhatia SN (2005) An extracellular matrix microarray for probing cellular differentiation. Nat Methods 2(2):119–125PubMedGoogle Scholar
  107. 107.
    Gilbert TW, Sellaro TL, Badylak SF (2006) Decellularization of tissues and organs. Biomaterials 27(19):3675–3683PubMedGoogle Scholar
  108. 108.
    Griffith LG (2002) Emerging design principles in biomaterials and scaffolds for tissue engineering. Ann N Y Acad Sci 961:83–95PubMedGoogle Scholar
  109. 109.
    Griffith LG, Naughton G (2002) Tissue engineering–current challenges and expanding opportunities. Science 295(5557):1009–1014PubMedGoogle Scholar
  110. 110.
    Hillel AT et al (2011) Photoactivated composite biomaterial for soft tissue restoration in rodents and in humans. Sci Transl Med 3(93):93ra67PubMedPubMedCentralGoogle Scholar
  111. 111.
    Parmar PA et al (2015) Collagen-mimetic peptide-modifiable hydrogels for articular cartilage regeneration. Biomaterials 54:213–225PubMedPubMedCentralGoogle Scholar
  112. 112.
    Porzionato A et al (2015) Decellularized human skeletal muscle as biologic scaffold for reconstructive surgery. Int J Mol Sci 16(7):14808–14831PubMedPubMedCentralGoogle Scholar
  113. 113.
    Sachlos E, Czernuszka JT (2003) Making tissue engineering scaffolds work. Review: the application of solid freeform fabrication technology to the production of tissue engineering scaffolds. Eur Cell Mater 5:29–39 (discussion 39–40) PubMedGoogle Scholar
  114. 114.
    Bashor CJ et al (2010) Rewiring cells: synthetic biology as a tool to interrogate the organizational principles of living systems. Annu Rev Biophys 39:515–537PubMedPubMedCentralGoogle Scholar
  115. 115.
    Benenson Y (2012) Biomolecular computing systems: principles, progress and potential. Nat Rev Genet 13(7):455–468PubMedGoogle Scholar
  116. 116.
    Brophy JA, Voigt CA (2014) Principles of genetic circuit design. Nat Methods 11(5):508–520PubMedPubMedCentralGoogle Scholar
  117. 117.
    Ho P, Chen YY (2017) Mammalian synthetic biology in the age of genome editing and personalized medicine. Curr Opin Chem Biol 40:57–64PubMedGoogle Scholar
  118. 118.
    Karlsson M, Weber W (2012) Therapeutic synthetic gene networks. Curr Opin Biotechnol 23(5):703–711PubMedGoogle Scholar
  119. 119.
    Mathur M, Xiang JS, Smolke CD (2017) Mammalian synthetic biology for studying the cell. J Cell Biol 216(1):73–82PubMedPubMedCentralGoogle Scholar
  120. 120.
    Breithaupt H (2006) The engineer’s approach to biology. EMBO Rep 7(1):21–23PubMedPubMedCentralGoogle Scholar
  121. 121.
    Chin JW (2006) Programming and engineering biological networks. Curr Opin Struct Biol 16(4):551–556PubMedGoogle Scholar
  122. 122.
    Slusarczyk AL, Lin A, Weiss R (2012) Foundations for the design and implementation of synthetic genetic circuits. Nat Rev Genet 13(6):406–420PubMedGoogle Scholar
  123. 123.
    Evan GI, Vousden KH (2001) Proliferation, cell cycle and apoptosis in cancer. Nature 411(6835):342–348PubMedGoogle Scholar
  124. 124.
    Liu HS et al (1998) Lac/Tet dual-inducible system functions in mammalian cell lines. Biotechniques 24(4):624–628, 630–622Google Scholar
  125. 125.
    Lutz R, Bujard H (1997) Independent and tight regulation of transcriptional units in Escherichia coli via the LacR/O, the TetR/O and AraC/I1-I2 regulatory elements. Nucleic Acids Res 25(6):1203–1210PubMedPubMedCentralGoogle Scholar
  126. 126.
    Bertram R, Hillen W (2008) The application of Tet repressor in prokaryotic gene regulation and expression. Microb Biotechnol 1(1):2–16PubMedGoogle Scholar
  127. 127.
    Deuschle U, Meyer WK, Thiesen HJ (1995) Tetracycline-reversible silencing of eukaryotic promoters. Mol Cell Biol 15(4):1907–1914PubMedPubMedCentralGoogle Scholar
  128. 128.
    Aubel D, Fussenegger M (2010) Mammalian synthetic biology–from tools to therapies. BioEssays 32(4):332–345PubMedGoogle Scholar
  129. 129.
    Auslander S, Auslander D, Fussenegger M (2017) Synthetic biology-the synthesis of biology. Angew Chem Int Ed Engl 56(23):6396–6419PubMedGoogle Scholar
  130. 130.
    Auslander S, Fussenegger M (2013) From gene switches to mammalian designer cells: present and future prospects. Trends Biotechnol 31(3):155–168PubMedGoogle Scholar
  131. 131.
    Bacchus W, Aubel D, Fussenegger M (2013) Biomedically relevant circuit-design strategies in mammalian synthetic biology. Mol Syst Biol 9:691PubMedPubMedCentralGoogle Scholar
  132. 132.
    Black JB, Perez-Pinera P, Gersbach CA (2017) Mammalian synthetic biology: engineering biological systems. Annu Rev Biomed Eng 19:249–277PubMedGoogle Scholar
  133. 133.
    Cameron DE, Bashor CJ, Collins JJ (2014) A brief history of synthetic biology. Nat Rev Microbiol 12(5):381–390PubMedGoogle Scholar
  134. 134.
    Collins J (2012) Synthetic biology: bits and pieces come to life. Nature 483(7387):S8–10PubMedGoogle Scholar
  135. 135.
    Collins JJ et al (2014) Synthetic biology: how best to build a cell. Nature 509(7499):155–157PubMedGoogle Scholar
  136. 136.
    Deans TL, Grainger DW, Fussenegger M (2016) Synthetic biology: innovative approaches for pharmaceutics and drug delivery. Adv Drug Deliv Rev 105(Pt A):1–2PubMedGoogle Scholar
  137. 137.
    Dobrin A, Saxena P, Fussenegger M (2015) Synthetic biology: applying biological circuits beyond novel therapies. Integr Biol 8:409–430Google Scholar
  138. 138.
    Greber D, Fussenegger M (2007) Mammalian synthetic biology: engineering of sophisticated gene networks. J Biotechnol 130(4):329–345PubMedGoogle Scholar
  139. 139.
    Haellman V, Fussenegger M (2016) Synthetic Biology-toward therapeutic solutions. J Mol Biol 428(5):945–962PubMedGoogle Scholar
  140. 140.
    Kobayashi H et al (2004) Programmable cells: interfacing natural and engineered gene networks. Proc Natl Acad Sci USA 101(22):8414–8419PubMedGoogle Scholar
  141. 141.
    Lienert F et al (2014) Synthetic biology in mammalian cells: next generation research tools and therapeutics. Nat Rev Mol Cell Biol 15(2):95–107PubMedPubMedCentralGoogle Scholar
  142. 142.
    Lu TK, Khalil AS, Collins JJ (2009) Next-generation synthetic gene networks. Nat Biotechnol 27(12):1139–1150PubMedPubMedCentralGoogle Scholar
  143. 143.
    MacDonald IC, Deans TL (2016) Tools and applications in synthetic biology. Adv Drug Deliv Rev 105(Pt A):20–34PubMedGoogle Scholar
  144. 144.
    Ruder WC, Lu T, Collins JJ (2011) Synthetic biology moving into the clinic. Science 333(6047):1248–1252PubMedGoogle Scholar
  145. 145.
    Way JC et al (2014) Integrating biological redesign: where synthetic biology came from and where it needs to go. Cell 157(1):151–161PubMedGoogle Scholar
  146. 146.
    Weber W, Fussenegger M (2012) Emerging biomedical applications of synthetic biology. Nat Rev Genet 13(1):21–35Google Scholar
  147. 147.
    Guye P et al (2016) Genetically engineering self-organization of human pluripotent stem cells into a liver bud-like tissue using Gata6. Nat Commun 7:10243PubMedPubMedCentralGoogle Scholar
  148. 148.
    Saxena P et al (2016) A programmable synthetic lineage-control network that differentiates human IPSCs into glucose-sensitive insulin-secreting beta-like cells. Nat Commun 7:11247PubMedPubMedCentralGoogle Scholar
  149. 149.
    Gordley RM, Gersbach CA, Barbas CF 3rd (2009) Synthesis of programmable integrases. Proc Natl Acad Sci USA 106(13):5053–5058PubMedGoogle Scholar
  150. 150.
    Daniel R et al (2013) Synthetic analog computation in living cells. Nature 497(7451):619–623PubMedGoogle Scholar
  151. 151.
    Ajo-Franklin CM et al (2007) Rational design of memory in eukaryotic cells. Genes Dev 21(18):2271–2276PubMedPubMedCentralGoogle Scholar
  152. 152.
    Burrill DR et al (2012) Synthetic memory circuits for tracking human cell fate. Genes Dev 26(13):1486–1497PubMedPubMedCentralGoogle Scholar
  153. 153.
    Burrill DR, Silver PA (2010) Making cellular memories. Cell 140(1):13–18PubMedPubMedCentralGoogle Scholar
  154. 154.
    Inniss MC, Silver PA (2013) Building synthetic memory. Curr Biol 23(17):R812–R816PubMedGoogle Scholar
  155. 155.
    Kotula JW et al (2014) Programmable bacteria detect and record an environmental signal in the mammalian gut. Proc Natl Acad Sci USA 111(13):4838–4843PubMedGoogle Scholar
  156. 156.
    Weinberg BH et al (2017) Large-scale design of robust genetic circuits with multiple inputs and outputs for mammalian cells. Nat Biotechnol 35(5):453–462PubMedPubMedCentralGoogle Scholar
  157. 157.
    Gaj T, Gersbach CA, Barbas CF 3rd (2013) ZFN, TALEN, and CRISPR/Cas-based methods for genome engineering. Trends Biotechnol 31(7):397–405PubMedPubMedCentralGoogle Scholar
  158. 158.
    Xie M, Haellman V, Fussenegger M (2016) Synthetic biology-application-oriented cell engineering. Curr Opin Biotechnol 40:139–148PubMedGoogle Scholar
  159. 159.
    Dow LE et al (2015) Inducible in vivo genome editing with CRISPR-Cas9. Nat Biotechnol 33(4):390–394PubMedPubMedCentralGoogle Scholar
  160. 160.
    Fu Y et al (2014) Improving CRISPR-Cas nuclease specificity using truncated guide RNAs. Nat Biotechnol 32(3):279–284PubMedPubMedCentralGoogle Scholar
  161. 161.
    Gilbert LA et al (2013) CRISPR-mediated modular RNA-guided regulation of transcription in eukaryotes. Cell 154(2):442–451PubMedPubMedCentralGoogle Scholar
  162. 162.
    Kalhor R, Mali P, Church GM (2017) Rapidly evolving homing CRISPR barcodes. Nat Methods 14(2):195–200PubMedGoogle Scholar
  163. 163.
    Makarova KS et al (2011) Evolution and classification of the CRISPR-Cas systems. Nat Rev Microbiol 9(6):467–477PubMedGoogle Scholar
  164. 164.
    Sander JD, Joung JK (2014) CRISPR-Cas systems for editing, regulating and targeting genomes. Nat Biotechnol 32(4):347–355PubMedPubMedCentralGoogle Scholar
  165. 165.
    Zalatan JG et al (2015) Engineering complex synthetic transcriptional programs with CRISPR RNA scaffolds. Cell 160(1–2):339–350PubMedGoogle Scholar
  166. 166.
    Dai WJ et al (2016) CRISPR-Cas9 for in vivo gene therapy: promise and hurdles. Mol Ther Nucleic Acids 5:e349PubMedPubMedCentralGoogle Scholar
  167. 167.
    Maeder ML, Gersbach CA (2016) Genome-editing technologies for gene and cell therapy. Mol Ther 24(3):430–446PubMedPubMedCentralGoogle Scholar
  168. 168.
    Nelson CE et al (2016) In vivo genome editing improves muscle function in a mouse model of Duchenne muscular dystrophy. Science 351(6271):403–407PubMedGoogle Scholar
  169. 169.
    Ousterout DG et al (2015) Multiplex CRISPR/Cas9-based genome editing for correction of dystrophin mutations that cause Duchenne muscular dystrophy. Nat Commun 6:6244PubMedPubMedCentralGoogle Scholar
  170. 170.
    Perez-Pinera P, Ousterout DG, Gersbach CA (2012) Advances in targeted genome editing. Curr Opin Chem Biol 16(3–4):268–277PubMedPubMedCentralGoogle Scholar
  171. 171.
    Savic N, Schwank G (2016) Advances in therapeutic CRISPR/Cas9 genome editing. Transl Res 168:15–21PubMedGoogle Scholar
  172. 172.
    Long C et al (2014) Prevention of muscular dystrophy in mice by CRISPR/Cas9-mediated editing of germline DNA. Science 345(6201):1184–1188PubMedPubMedCentralGoogle Scholar
  173. 173.
    Li HL et al (2015) Precise correction of the dystrophin gene in duchenne muscular dystrophy patient induced pluripotent stem cells by TALEN and CRISPR-Cas9. Stem Cell Rep 4(1):143–154Google Scholar
  174. 174.
    Duportet X et al (2014) A platform for rapid prototyping of synthetic gene networks in mammalian cells. Nucleic Acids Res 42(21):13440–13451PubMedPubMedCentralGoogle Scholar
  175. 175.
    Inniss MC et al (2017) A novel Bxb1 integrase RMCE system for high fidelity site-specific integration of mAb expression cassette in CHO cells. Biotechnol Bioeng 114(8):1837–1846PubMedGoogle Scholar
  176. 176.
    Cech TR, Steitz JA (2014) The noncoding RNA revolution-trashing old rules to forge new ones. Cell 157(1):77–94PubMedGoogle Scholar
  177. 177.
    Fire A et al (1998) Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391(6669):806–811PubMedGoogle Scholar
  178. 178.
    Bloom RJ, Winkler SM, Smolke CD (2014) A quantitative framework for the forward design of synthetic miRNA circuits. Nat Methods 11(11):1147–1153PubMedGoogle Scholar
  179. 179.
    Pitner RA, Scarpelli AH, Leonard JN (2015) Regulation of bacterial gene expression by protease-alleviated spatial sequestration (PASS). ACS Synth Biol 4(9):966–974PubMedGoogle Scholar
  180. 180.
    Hartfield RM et al (2017) Multiplexing engineered receptors for multiparametric evaluation of environmental ligands. ACS Synth Biol 6(11):2042–2055PubMedGoogle Scholar
  181. 181.
    Irvine DJ (2016) A receptor for all occasions. Cell 164(4):599–600PubMedGoogle Scholar
  182. 182.
    Morsut L et al (2016) Engineering customized cell sensing and response behaviors using synthetic notch receptors. Cell 164(4):780–791PubMedPubMedCentralGoogle Scholar
  183. 183.
    Roybal KT et al (2016) Precision tumor recognition by T cells with combinatorial antigen-sensing circuits. Cell 164(4):770–779PubMedPubMedCentralGoogle Scholar
  184. 184.
    Vonderheide RH, June CH (2014) Engineering T cells for cancer: our synthetic future. Immunol Rev 257(1):7–13PubMedPubMedCentralGoogle Scholar
  185. 185.
    Engler AJ et al (2006) Matrix elasticity directs stem cell lineage specification. Cell 126(4):677–689PubMedGoogle Scholar
  186. 186.
    Fu J et al (2010) Mechanical regulation of cell function with geometrically modulated elastomeric substrates. Nat Methods 7(9):733–736PubMedPubMedCentralGoogle Scholar
  187. 187.
    Guilak F et al (2009) Control of stem cell fate by physical interactions with the extracellular matrix. Cell Stem Cell 5(1):17–26PubMedPubMedCentralGoogle Scholar
  188. 188.
    Legant WR et al (2010) Measurement of mechanical tractions exerted by cells in three-dimensional matrices. Nat Methods 7(12):969–971PubMedPubMedCentralGoogle Scholar
  189. 189.
    McBeath R et al (2004) Cell shape, cytoskeletal tension, and RhoA regulate stem cell lineage commitment. Dev Cell 6(4):483–495PubMedGoogle Scholar
  190. 190.
    Trappmann B et al (2012) Extracellular-matrix tethering regulates stem-cell fate. Nat Mater 11(7):642–649PubMedGoogle Scholar
  191. 191.
    Yang C et al (2014) Mechanical memory and dosing influence stem cell fate. Nat Mater 13(6):645–652PubMedPubMedCentralGoogle Scholar
  192. 192.
    Crowder SW et al (2016) Material cues as potent regulators of epigenetics and stem cell function. Cell Stem Cell 18(1):39–52PubMedPubMedCentralGoogle Scholar
  193. 193.
    Murphy WL, McDevitt TC, Engler AJ (2014) Materials as stem cell regulators. Nat Mater 13(6):547–557PubMedPubMedCentralGoogle Scholar
  194. 194.
    Vining KH, Mooney DJ (2017) Mechanical forces direct stem cell behaviour in development and regeneration. Nat Rev Mol Cell Biol 18(12):728–742PubMedPubMedCentralGoogle Scholar
  195. 195.
    Watt FM, Huck WT (2013) Role of the extracellular matrix in regulating stem cell fate. Nat Rev Mol Cell Biol 14(8):467–473PubMedGoogle Scholar
  196. 196.
    Madl CM et al (2017) Maintenance of neural progenitor cell stemness in 3D hydrogels requires matrix remodelling. Nat Mater 16(12):1233–1242PubMedPubMedCentralGoogle Scholar
  197. 197.
    Huber MC et al (2014) Introducing a combinatorial DNA-toolbox platform constituting defined protein-based biohybrid-materials. Biomaterials 35(31):8767–8779PubMedGoogle Scholar
  198. 198.
    Winnacker M (2017) Recent advances in the synthesis of functional materials by engineered and recombinant living cells. Soft Matter 13(38):6672–6677PubMedGoogle Scholar
  199. 199.
    Abdeen AA, Saha K (2017) Manufacturing cell therapies using engineered biomaterials. Trends Biotechnol 35(10):971–982PubMedGoogle Scholar
  200. 200.
    Hiew VV, Simat SFB, Teoh PL (2018) The advancement of biomaterials in regulating stem cell fate. Stem Cell Rev 14(1):43–57PubMedGoogle Scholar
  201. 201.
    Liu Z et al (2018) Looking into the future: toward advanced 3d biomaterials for stem-cell-based regenerative medicine. Adv Mater 2:1–20Google Scholar
  202. 202.
    Nuttelman CR, Tripodi MC, Anseth KS (2005) Synthetic hydrogel niches that promote hMSC viability. Matrix Biol 24(3):208–218PubMedGoogle Scholar
  203. 203.
    Parisi-Amon A et al (2017) Protein-nanoparticle hydrogels that self-assemble in response to peptide-based molecular recognition. ACS Biomater Sci Eng 3(5):750–756Google Scholar
  204. 204.
    Sawkins MJ et al (2013) Hydrogels derived from demineralized and decellularized bone extracellular matrix. Acta Biomater 9(8):7865–7873PubMedPubMedCentralGoogle Scholar
  205. 205.
    Sun F et al (2014) Synthesis of bioactive protein hydrogels by genetically encoded SpyTag-SpyCatcher chemistry. Proc Natl Acad Sci USA 111(31):11269–11274PubMedGoogle Scholar
  206. 206.
    Tibbitt MW, Anseth KS (2009) Hydrogels as extracellular matrix mimics for 3D cell culture. Biotechnol Bioeng 103(4):655–663PubMedPubMedCentralGoogle Scholar
  207. 207.
    Chilkoti A, Christensen T, MacKay JA (2006) Stimulus responsive elastin biopolymers: applications in medicine and biotechnology. Curr Opin Chem Biol 10(6):652–657PubMedPubMedCentralGoogle Scholar
  208. 208.
    MacEwan SR, Chilkoti A (2010) Elastin-like polypeptides: biomedical applications of tunable biopolymers. Biopolymers 94(1):60–77PubMedGoogle Scholar
  209. 209.
    MacEwan SR, Chilkoti A (2014) Applications of elastin-like polypeptides in drug delivery. J Control Release 190:314–330PubMedPubMedCentralGoogle Scholar
  210. 210.
    Nettles DL, Chilkoti A, Setton LA (2010) Applications of elastin-like polypeptides in tissue engineering. Adv Drug Deliv Rev 62(15):1479–1485PubMedPubMedCentralGoogle Scholar
  211. 211.
    Roberts S, Dzuricky M, Chilkoti A (2015) Elastin-like polypeptides as models of intrinsically disordered proteins. FEBS Lett 589(19 Pt A):2477–2486PubMedPubMedCentralGoogle Scholar
  212. 212.
    Stayton PS et al (1995) Control of protein-ligand recognition using a stimuli-responsive polymer. Nature 378(6556):472–474PubMedGoogle Scholar
  213. 213.
    Ruoslahti E (1996) RGD and other recognition sequences for integrins. Annu Rev Cell Dev Biol 12:697–715PubMedGoogle Scholar
  214. 214.
    Burdick JA, Anseth KS (2002) Photoencapsulation of osteoblasts in injectable RGD-modified PEG hydrogels for bone tissue engineering. Biomaterials 23(22):4315–4323PubMedGoogle Scholar
  215. 215.
    Liu JC, Heilshorn SC, Tirrell DA (2004) Comparative cell response to artificial extracellular matrix proteins containing the RGD and CS5 cell-binding domains. Biomacromol 5(2):497–504Google Scholar
  216. 216.
    Ruoslahti E, Pierschbacher MD (1987) New perspectives in cell adhesion: RGD and integrins. Science 238(4826):491–497PubMedGoogle Scholar
  217. 217.
    Salinas CN, Anseth KS (2008) The enhancement of chondrogenic differentiation of human mesenchymal stem cells by enzymatically regulated RGD functionalities. Biomaterials 29(15):2370–2377PubMedPubMedCentralGoogle Scholar
  218. 218.
    Hersel U, Dahmen C, Kessler H (2003) RGD modified polymers: biomaterials for stimulated cell adhesion and beyond. Biomaterials 24(24):4385–4415PubMedGoogle Scholar
  219. 219.
    Morrison CJ et al (2009) Matrix metalloproteinase proteomics: substrates, targets, and therapy. Curr Opin Cell Biol 21(5):645–653PubMedGoogle Scholar
  220. 220.
    Parmar PA et al (2017) Enhanced articular cartilage by human mesenchymal stem cells in enzymatically mediated transiently RGDS-functionalized collagen-mimetic hydrogels. Acta Biomater 51:75–88PubMedPubMedCentralGoogle Scholar
  221. 221.
    Macias MJ, Wiesner S, Sudol M (2002) WW and SH3 domains, two different scaffolds to recognize proline-rich ligands. FEBS Lett 513(1):30–37PubMedGoogle Scholar
  222. 222.
    Foo CTWP et al (2009) Two-component protein-engineered physical hydrogels for cell encapsulation. Proc Natl Acad Sci USA 106(52):22067–22072Google Scholar
  223. 223.
    Lupas A (1996) Coiled coils: new structures and new functions. Trends Biochem Sci 21(10):375–382PubMedGoogle Scholar
  224. 224.
    McAlinden A et al (2003) Alpha-helical coiled-coil oligomerization domains are almost ubiquitous in the collagen superfamily. J Biol Chem 278(43):42200–42207PubMedGoogle Scholar
  225. 225.
    Armony G et al (2016) Cross-linking reveals laminin coiled-coil architecture. Proc Natl Acad Sci USA 113(47):13384–13389PubMedGoogle Scholar
  226. 226.
    Dooling LJ, Tirrell DA (2016) Engineering the dynamic properties of protein networks through sequence variation. ACS Cent Sci 2(11):812–819PubMedPubMedCentralGoogle Scholar
  227. 227.
    Danmark S, Aronsson C, Aili D (2016) Tailoring supramolecular peptide-poly(ethylene glycol) hydrogels by coiled coil self-assembly and self-sorting. Biomacromol 17(6):2260–2267Google Scholar
  228. 228.
    Tropsha A et al (1991) Do interhelical side chain-backbone hydrogen bonds participate in formation of leucine zipper coiled coils? Proc Natl Acad Sci USA 88(21):9488–9492PubMedGoogle Scholar
  229. 229.
    Addi C et al (2017) A highly versatile adaptor protein for the tethering of growth factors to gelatin-based biomaterials. Acta Biomater 50:198–206PubMedGoogle Scholar
  230. 230.
    Reddington SC, Howarth M (2015) Secrets of a covalent interaction for biomaterials and biotechnology: SpyTag and SpyCatcher. Curr Opin Chem Biol 29:94–99PubMedGoogle Scholar
  231. 231.
    Zakeri B et al (2012) Peptide tag forming a rapid covalent bond to a protein, through engineering a bacterial adhesin. Proc Natl Acad Sci USA 109(12):E690–E697PubMedGoogle Scholar
  232. 232.
    Gao X et al (2016) Engineering protein hydrogels using SpyCatcher-SpyTag chemistry. Biomacromol 17(9):2812–2819Google Scholar
  233. 233.
    Schoene C et al (2014) SpyTag/SpyCatcher cyclization confers resilience to boiling on a mesophilic enzyme. Angew Chem Int Ed Engl 53(24):6101–6104PubMedPubMedCentralGoogle Scholar
  234. 234.
    Liu Z et al (2014) A novel method for synthetic vaccine construction based on protein assembly. Sci Rep 4:7266PubMedPubMedCentralGoogle Scholar
  235. 235.
    Tan LL, Hoon SS, Wong FT (2016) Kinetic controlled tag-catcher interactions for directed covalent protein assembly. PLoS One 11(10):e0165074PubMedPubMedCentralGoogle Scholar
  236. 236.
    Alam MK et al (2017) Synthetic modular antibody construction by using the SpyTag/SpyCatcher protein-ligase system. ChemBioChem 18(22):2217–2221PubMedGoogle Scholar
  237. 237.
    Yumura K et al (2017) Use of SpyTag/SpyCatcher to construct bispecific antibodies that target two epitopes of a single antigen. J Biochem 162(3):203–210PubMedGoogle Scholar
  238. 238.
    Brune KD et al (2016) Plug-and-display: decoration of virus-Like particles via isopeptide bonds for modular immunization. Sci Rep 6:19234PubMedPubMedCentralGoogle Scholar
  239. 239.
    Schloss AC et al (2016) Fabrication of modularly functionalizable microcapsules using protein-based technologies. ACS Biomater Sci Eng 2(11):1856–1861PubMedPubMedCentralGoogle Scholar
  240. 240.
    Bedbrook CN et al (2015) Genetically encoded spy peptide fusion system to detect plasma membrane-localized proteins in vivo. Chem Biol 22(8):1108–1121PubMedPubMedCentralGoogle Scholar
  241. 241.
    Deans TL et al (2012) Regulating synthetic gene networks in 3D materials. Proc Natl Acad Sci USA 109(38):15217–15222PubMedGoogle Scholar
  242. 242.
    Singh A, Deans TL, Elisseeff JH (2013) Photomodulation of cellular gene expression in hydrogels. Acs Macro Lett 2(3):269–272Google Scholar

Copyright information

© Society for Industrial Microbiology and Biotechnology 2018

Authors and Affiliations

  1. 1.Department of BioengineeringUniversity of UtahSalt Lake CityUSA

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