合成生物传感器在疾病检测领域的应用技术进展： 设计、分类和展望

doi:10.24920/003483

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This article systematically reviews the current technologies of simple and complex synthetic biosensors for disease detection, and highlights some synthetic biology strategies that have been developed to target allergy, liver injuries, insulin resistance, Graves' disease, urate homeostasis and inflammation.

Abstract

Synthetic biology aims to endow living cells with new functions by incorporating functional gene networks into them. By overexpressing, blocking and rewiring native gene pathways, synthetic biologists have harnessed this promising technology to reprogram cells to perform diverse tasks such as drug discovery, biopharmaceutical manufacturing, gene therapy and tissue engineering, etc. In this review, we focus on current technologies of synthetic biosensors for disease detection. We start with the design principle of synthetic biosensors. Then we move towards the characteristics of simple synthetic biosensors, which can respond to a single input signal, and complex synthetic biosensors including Boolean gate biosensors, cascade biosensors, time-delay biosensors, oscillator biosensors and hysteretic biosensors, which can respond to more than two input signals and perform complex tasks. Synthetic biosensor has showed great potential in disease detection, but it is still in its infancy stage. More efforts should be made in identifying and constructing clinically relevant regulation systems. Computational tools are also needed in the design process in order to guarantee the precision of the synthetic biosensor. The ultimate goal of a synthetic biosensor is to act as a therapeutic sensor-effector device that connects diagnostic input with therapeutic output and therefore provides all-in-one diagnostic and therapeutic solutions for future gene- and cell-based therapies.

Key words: synthetic biosensor, gene circuit, disease detection

Article information: 本文系统综述了不同类型合成生物传感器的设计原理以及在疾病诊疗方面的最新应用，包括免疫调控、肝损伤、胰岛素抵抗、Grave's病、以及尿酸内稳态等方面。

Funding: Supported by the National Natural Science Foundation of China (81770491) and the Ministry of Education Innovation Team Development Program of China(81770491)

Chen Xue,Lv Yi,Wu Rongqian. Current Technologies of Synthetic Biosensors for Disease Detection: Design, Classification and Future Perspectives[J].Chinese Medical Sciences Journal, 2018, 33(4): 240-251.

Figures/Tables 4

Figure 1.

Classification of signal	On/Off	Signals	Regulation factor	Regulation factor fused domain	Chimeric regulation factor	Applications	Reference
Antibiotic
	On and Off	Macrolide (erythromycin, clarithromycin, and roxithromycin)	MphR(A)	VP16 and KRAB	ET	Gene therapy, tissue engineering, in vivo gene function analyses, drug discovery, biopharmaceutical manufacturing	5
	On and Off	Pristinamycin I	Pip	VP16 and KRAB	PIT	Compatible with the Tet-OFF system, thus two different gene activities can be controlled in the same cell	6
Amino acid
	On	L-arginine	ArgR	ART	VP16	Gene therapy and manufacturing of protein pharmaceuticals	7
	On	Tryptophan	TrpR	VP16	TRT	Targeted gene expression control	57
Small molecular
	On and Off	Cumate	CymR	VP16	cTA, rcTA	Regulation of gene expression level and duration	58
Gas
	On	Acetaldehyde	AlcR	-	AlcR	Therapeutic transgene dosing and biopharmaceutical manufacturing	59
	On	6-hydroxy-nicotine	HdnoR	VP16	-	Drug-responsive homologs in basic research, therapeutic cell engineering and biopharmaceutical manufacturing.	60
	On	pH/CO2	TDAG8	-	-	Remote control of cellular behavior inside microfluidic devices; CO2-triggered production of biopharmaceuticals in standard bioreactors	61
Drug compound
	On	2-phenylethyl-butyrate	EthR	VP16	-	Generic screening platform to discover drug candidates	62
Qutam sensing signal
	On	Butyrolactones	ScbR SpbR	VP16	SCA, SPA	Clinical application	9
	On	3-oxo-C₈-HSL	TraR	NF-κB p65	p65NTraR	Versatile gene expression control	10
Metabolites
	On	Uric acid	HucR	KRAB	mUTS	Self-sufficient control of pathologic metabolites, gene- and cell-based therapies	54
	On	Bile acids	TGR5	-	p65NTraR	Liver injuries protection	44
	On	Fatty acid	TtgR	-	LSR	Metabolic disorders treatment	63
Food additive
	Off	Phloretin	TtgR	VP16	TtgA	Biopharmaceutical manufacturing, gene- and cell- based therapies	8
	On	Vanillic acid	MOR9-1	-	-	Cell differentiation	64
	On and Off	Vanillic acid	VanR	VP16 and KRAB	VanA₁ and VanA₄	Biopharmaceutical manufacturing, gene- and cell- based therapies	65
Allergic biomarkers
	On	Histamine	HRH2	-	-	Allergy diagnostics	40
	On	Acrylate	AcuR	-	-	Investigate characteristics of inducible transcriptional regulators	66
	On	Glucarate	CdaR	-	-
	On	Erythromycin	MphR	-	-
	On	Naringenin	TtgR	-	-
Vitamin
	Off	Biotin	BirA	-	-	Cell therapy and biopharmaceutical manufacturing	67
	On	Biotin	BirA	VP16	BIT	Gene therapy, tissue engineering, biopharmaceutical manufacturing	68
Hormone	On and Off	Thyroid hormone	TSHR	-	TSR	Thyroid hormone regulation	52
Inflammation factor	On	NF-kB	NF-kB-responsive elements	-	-	Inflammation monitor	56

Figure 2.

References 68

[1]	Slomovic S, Pardee K, Collins JJ . Synthetic biology devices for in vitro and in vivo diagnostics. Proc Natl Acad Sci U S A 2015; 112(47):14429-35. doi: 10.1073/pnas.1508521112. doi: 10.1073/pnas.1508521112 pmid: 26598662
[2]	Jacob F, Monod J . Genetic regulatory mechanisms in the synthesis of proteins. J Mol Biol 1961; 3(3):318-56. doi: 10.1016/s0022-2836(61)80072-7. doi: 10.1016/s0022-2836(61)80072-7 pmid: 13718526
[3]	Ramos JL, Martinez-Bueno M, Molina-Henares AJ , et al. The TetR family of transcriptional repressors. Microbiol Mol Biol Rev 2005; 69(2):326-56. doi: 10.1128/MMBR.69.2.326-356.2005. doi: 10.1128/MMBR.69.2.326-356.2005 pmid: 15944459
[4]	Gossen M, Bujard H . Tight control of gene expression in mammalian cells by tetracycline-responsive promoters. Proc Natl Acad Sci USA 1992; 89(12):5547-51. doi: 10.1073/pnas.89.12.5547. doi: 10.1073/pnas.89.12.5547 pmid: 1319065
[5]	Weber W, Fux C , Daoud-EI Baba M, et al. Macrolide- based transgene control in mammalian cells and mice. Nat Biotechnol 2002; 20(9):901-7. doi: 10.1038/nbt731. doi: 10.1038/nbt731 pmid: 12205509
[6]	Fussenegger M, Morris RP, Fux C , et al. Streptogramin-based gene regulation systems for mammalian cells. Nat Biotechnol 2000; 18(11):1203-8. doi: 10.1038/81208. doi: 10.1038/81208 pmid: 11062442
[7]	Hartenbach S , Daoud-El Baba M, Weber W, et al. An engineered L-arginine sensor of Chlamydia pneumoniae enables arginine-adjustable transcription control in mammalian cells and mice. Nucleic Acids Res 2007; 35(20):e136. doi: 10.1093/nar/gkm652. doi: 10.1093/nar/gkm652 pmid: 2175317
[8]	Gitzinger M, Kemmer C, El-Baba MD , et al. Controlling transgene expression in subcutaneous implants using a skin lotion containing the apple metabolite phloretin. Proc Natl Acad Sci USA 2009; 106(26):10638-43. doi: 10.1073/pnas.0901501106. doi: 10.1073/pnas.0901501106 pmid: 19549857
[9]	Weber W, Schoenmakers R, Spielmann M , et al. Streptomyces-derived quorum-sensing systems engineered for adjustable transgene expression in mammalian cells and mice. Nucleic Acids Res 2003; 31(14):e71. doi: 10.1093/nar/gng071. doi: 10.1093/nar/gng071 pmid: 12853648
[10]	Neddermann P, Gargioli C, Muraglia E , et al. A novel, inducible, eukaryotic gene expression system based on the quorum-sensing transcription factor TraR. EMBO Rep 2003; 4(2):159-65. doi: 10.1038/sj.embor.embor734. doi: 10.1038/sj.embor.embor734
[11]	Miller M, Hafner M, Sontag E , et al. Modular design of artificial tissue homeostasis: robust control through synthetic cellular heterogeneity. PLoS Comput Biol 2012; 8(7):e1002579. doi: ARTN e100257910.1371/journal.pcbi.1002579. doi: ARTN e100257910.1371/journal.pcbi.1002579 pmid: 22829755
[12]	Cuthbertson L, Nodwell JR . The TetR family of regulators. Microbiol Mol Biol Rev 2013; 77(3):440-75. doi: 10.1128/MMBR.00018-13. doi: 10.1128/MMBR.00018-13
[13]	Agha-Mohammadi S, Lotze MT . Regulatable systems: applications in gene therapy and replicating viruses. J Clin Invest 2000; 105(9):1177-83. doi: 10.1172/JCI10027. doi: 10.1172/JCI10027 pmid: 315455
[14]	Urlinger S, Baron U, Thellmann M , et al. Exploring the sequence space for tetracycline-dependent transcriptional activators: novel mutations yield expanded range and sensitivity. Proc Natl Acad Sci U S A 2000; 97(14):7963-8. doi: 10.1073/pnas.130192197. doi: 10.1073/pnas.130192197 pmid: 10859354
[15]	Vieyra DS, Goodell MA . Pluripotentiality and conditional transgene regulation in human embryonic stem cells expressing insulated tetracycline-ON transactivator. Stem Cells 2007; 25(10):2559-66. doi: 10.1634/stemcells.2007-0248. doi: 10.1634/stemcells.2007-0248 pmid: 17628023
[16]	Wu Z, Chen J, Ren J , et al. Generation of pig induced pluripotent stem cells with a drug-inducible system. J Mol Cell Biol 2009; 1(1):46-54. doi: 10.1093/jmcb/mjp003. doi: 10.1093/jmcb/mjp003 pmid: 19502222
[17]	Zhao X, Yu Y, Zhao Z , et al. Establishment of tetracycline-inducible, survivin-expressing CHO cell lines by an optimized screening method. Biosci Biotechnol Biochem 2012; 76(10):1909-12. doi: 10.1271/bbb.120395. doi: 10.1271/bbb.120395 pmid: 23047106
[18]	Jones J, Nivitchanyong T, Giblin C , et al. Optimization of tetracycline-responsive recombinant protein production and effect on cell growth and ER stress in mammalian cells. Biotechnol Bioeng 2005; 91(6):722-32. doi: 10.1002/bit.20566. doi: 10.1002/bit.20566 pmid: 15981277
[19]	Forster K, Helbl V, Lederer T , et al. Tetracycline-induci-ble expression systems with reduced basal activity in mammalian cells. Nucleic Acids Res 1999; 27(2):708-10. doi: 10.1093/nar/27.2.708. doi: 10.1093/nar/27.2.708 pmid: 148237
[20]	Zhang J, Wang C, Ke N , et al. A more efficient RNAi inducible system for tight regulation of gene expression in mammalian cells and xenograft animals. RNA 2007; 13(8):1375-83. doi: 10.1261/rna.520707. doi: 10.1261/rna.520707 pmid: 17616554
[21]	Tigges M, Fussenegger M . Recent advances in mammalian synthetic biology-design of synthetic transgene control networks. Curr Opin Biotechnol 2009; 20(4):449-60. doi: 10.1016/j.copbio.2009.07.009. doi: 10.1016/j.copbio.2009.07.009 pmid: 19762224
[22]	Zhao W, Bonem M , McWhite C, et al. Sensitive detection of proteasomal activation using the Deg-On mammalian synthetic gene circuit. Nat Commun 2014; 5(5):3612. doi: ARTN 361210.1038/ncomms4612. doi: ARTN 361210.1038/ncomms4612 pmid: 24710080
[23]	Weber W, Stelling J, Rimann M , et al. A synthetic time-delay circuit in mammalian cells and mice. Proc Natl Acad Sci USA 2007; 104(8):2643-8. doi: 10.1073/pnas.0606398104. doi: 10.1073/pnas.0606398104 pmid: 17296937
[24]	Tigges M, Marquez-Lago TT, Stelling J , et al. A tunable synthetic mammalian oscillator. Nature 2009; 457(7227):309-12. doi: 10.1038/nature07616. doi: 10.1038/nature07616
[25]	Tigges M, Denervaud N, Greber D , et al. A synthetic low-frequency mammalian oscillator. Nucleic Acids Res 2010; 38(8):2702-11. doi: 10.1093/nar/gkq121. doi: 10.1093/nar/gkq121 pmid: 2860125
[26]	Burrill DR, Inniss MC, Boyle PM , et al. Synthetic memory circuits for tracking human cell fate. Genes Dev 2012; 26(13):1486-97. doi: 10.1101/gad.189035.112. doi: 10.1101/gad.189035.112 pmid: 22751502
[27]	Kramer BP, Weber W, Fussenegger M . Artificial regulatory networks and cascades for discrete multilevel transgene control in mammalian cells. Biotechnol Bioeng 2003; 83(7):810-20. doi: 10.1002/bit.10731. doi: 10.1002/bit.10731 pmid: 12889021
[28]	Kramer BP, Fischer C, Fussenegger M . BioLogic gates enable logical transcription control in mammalian cells. Biotechnol Bioeng 2004; 87(4):478-84. doi: 10.1002/bit.20142. doi: 10.1002/bit.20142 pmid: 15286985
[29]	Riglar DT, Giessen TW, Baym M , et al. Engineered bacteria can function in the mammalian gut long-term as live diagnostics of inflammation. Nat Biotechnol 2017; 35(7):653-8. doi: 10.1038/nbt.3879. doi: 10.1038/nbt.3879 pmid: 28553941
[30]	Angelici B, Mailand E, Haefliger B , et al. Synthetic biology platform for sensing and integrating endogenous transcriptional inputs in mammalian cells. Cell Rep 2016; 16(9):2525-37. doi: 10.1016/j.celrep.2016.07.061. doi: 10.1016/j.celrep.2016.07.061 pmid: 27545896
[31]	Wieland M, Fussenegger M . Engineering molecular circuits using synthetic biology in mammalian cells. Annu Rev Chem Biomol Eng. 2012; 3(1):209-34. doi: 10.1146/annurev-chembioeng-061010-114145. doi: 10.1146/annurev-chembioeng-061010-114145 pmid: 22468602
[32]	Monk NA . Oscillatory expression of Hes1, p53, and NF-kappaB driven by transcriptional time delays. Curr Biol 2003; 13(16):1409-13. doi: 10.1016/s0960-9822(03)00494-9. doi: 10.1016/s0960-9822(03)00494-9 pmid: 12932324
[33]	Matsuo T, Yamaguchi S, Mitsui S , et al. Control mechanism of the circadian clock for timing of cell division in vivo. Science 2003; 302(5643):255-9. doi: 10.1126/science.1086271. doi: 10.1126/science.1086271 pmid: 12934012
[34]	Inagaki N, Honma S, Ono D , et al. Separate oscillating cell groups in mouse suprachiasmatic nucleus couple photoperiodically to the onset and end of daily activity. Proc Natl Acad Sci U S A 2007; 104(18):7664-9. doi: 10.1073/pnas.0607713104. doi: 10.1073/pnas.0607713104 pmid: 17463091
[35]	Schibler U. The daily rhythms of genes, cells and organs. Biological clocks and circadian timing in cells. EMBO Rep 2005; 6 Spec No( 6 Spec No):S9-S13. doi: 10.1038/sj.embor.7400424. doi: 10.1038/sj.embor.7400424
[36]	Sha W, Moore J, Chen K , et al. Hysteresis drives cell-cycle transitions in Xenopus laevis egg extracts. Proc Natl Acad Sci U S A 2003; 100(3):975-80. doi: 10.1073/pnas.0235349100. doi: 10.1073/pnas.0235349100 pmid: 12509509
[37]	Xiong W, Ferrell JE Jr . A positive-feedback-based bistable ‘memory module’ that governs a cell fate decision. Nature 2003; 426(6965):460-5. doi: 10.1038/nature02089. doi: 10.1038/nature02089
[38]	Ausl?nder S, Fussenegger M . Engineering gene circuits for mammalian cell-based applications. Cold Spring Harb Perspect Biol 2016; 8(7). doi: 10.1101/cshperspect.a023895 doi: 10.1101/cshperspect.a023895 pmid: 27194045
[39]	Wu F, Wang X . Applications of synthetic gene networks. Sci Prog 2015; 98(Pt 3):244-52. doi: 10.3184/003685015x14368807556441. doi: 10.3184/003685015x14368807556441 pmid: 26601339
[40]	Auslander D, Eggerschwiler B, Kemmer C , et al. A designer cell-based histamine-specific human allergy profiler. Nat Commun 2014; 5:4408. doi: 10.1038/ncomms5408. doi: 10.1038/ncomms5408 pmid: 4143915
[41]	Thomas C, Pellicciari R, Pruzanski M , et al. Targeting bile-acid signalling for metabolic diseases. Nat Rev Drug Discov 2008; 7(8):678-93. doi: 10.1038/nrd2619. doi: 10.1038/nrd2619
[42]	Hofmann AF . Bile acids: trying to understand their chemistry and biology with the hope of helping patients. Hepatology 2009; 49(5):1403-18. doi: 10. 1002/hep.22789. doi: 10. 1002/hep.22789 pmid: 19296471
[43]	Péan N, Doignon I, Garcin I , et al. The receptor TGR5 protects the liver from bile acid overload during liver regeneration in mice. Hepatology 2013; 58(4):1451-60. doi: 10.1002/hep.26463. doi: 10.1002/hep.26463 pmid: 23686672
[44]	Bai P, Ye H, Xie M , et al. A synthetic biology-based device prevents liver injury in mice. J Hepatol 2016; 65(1):84-94. doi: 10.1016/j.jhep.2016.03.020. doi: 10.1016/j.jhep.2016.03.020 pmid: 4914822
[45]	Johnson AM, Olefsky JM . The origins and drivers of insulin resistance. Cell 2013; 152(4):673-84. doi: 10.1016/j.cell.2013.01.041. doi: 10.1016/j.cell.2013.01.041 pmid: 23415219
[46]	Samuel VT, Shulman GI . Mechanisms for insulin resis-tance: common threads and missing links. Cell 2012; 148(5):852-71. doi: 10.1016/j.cell.2012.02.017. doi: 10.1016/j.cell.2012.02.017
[47]	Ye H, Xie M, Xue S , et al. Self-adjusting synthetic gene circuit for correcting insulin resistance. Nat Bio-med Eng 2017; 1(1):0005. doi: 10.1038/s41551-016-0005. doi: 10.1038/s41551-016-0005 pmid: 28480128
[48]	Jacob KK, Whittaker J, Stanley FM . Insulin receptor tyrosine kinase activity and phosphorylation of tyrosines 1162 and 1163 are required for insulin-increased prolactin gene expression. Mol Cell Endocrinol 2002; 186(1):7-16. doi: 10.1016/s0303-7207(01)00674-8. doi: 10.1016/s0303-7207(01)00674-8 pmid: 11850117
[49]	Siddle K . Signalling by insulin and IGF receptors: supporting acts and new players. J Mol Endocrinol 2011; 47(1):R1-10. doi: 10.1530/JME-11-0022. doi: 10.1530/JME-11-0022 pmid: 21498522
[50]	Keeley MB, Busch J, Singh R , et al. TetR hybrid transcription factors report cell signaling and are inhibited by doxycycline. BioTechniques 2005; 39(4):529-36. doi: 10.2144/000112002. doi: 10.2144/000112002 pmid: 16235565
[51]	Mullur R, Liu YY, Brent GA . Thyroid hormone regulation of metabolism. Physiol Rev 2014; 94(2):355-82. doi: 10.1152/physrev.00030.2013. doi: 10.1152/physrev.00030.2013 pmid: 24692351
[52]	Saxena P , Charpin-El Hamri G, et al. Synthetic gene network restoring endogenous pituitary-thyroid feedback control in experimental Graves’ disease. Proc Natl Acad Sci U S A 2016; 113(5):1244-9. doi: 10.1073/pnas. 1514383113. doi: 10.1073/pnas. 1514383113
[53]	Neogi T . Clinical practice. Gout. N Engl J Med 2011; 364(5):443-52. doi: 10.1056/NEJMcp1001124. doi: 10.1056/NEJMcp1001124
[54]	Kemmer C, Gitzinger M , Daoud-El Baba M, et al. Self-sufficient control of urate homeostasis in mice by a synthetic circuit. Nat Biotechnol 2010; 28(4):355-60. doi: 10.1038/nbt.1617. doi: 10.1038/nbt.1617 pmid: 20351688
[55]	Schukur L, Geering B, Charpin-El Hamri G , et al. Implantable synthetic cytokine converter cells with AND-gate logic treat experimental psoriasis. Sci Transl Med 2015; 7(318):318ra201. doi: 10.1126/scitranslmed.aac4964. doi: 10.1126/scitranslmed.aac4964
[56]	Smole A, Lain?cek D, Bezeljak U , et al. A Synthetic Mammalian Therapeutic Gene Circuit for Sensing and Suppressing Inflammation. Mol Ther 2017; 25(1):102-19. doi: 10.1016/ j.ymthe.2016.10.005. doi: 10.1016/ j.ymthe.2016.10.005 pmid: 28129106
[57]	Bacchus W, Weber W, Fussenegger M . Increasing the dynamic control space of mammalian transcription devices by combinatorial assembly of homologous regulatory elements from different bacterial species. Metab Eng 2013; 15(1):144-50. doi: 10.1016/j.ymben.2012.11.003. doi: 10.1016/j.ymben.2012.11.003 pmid: 23178502
[58]	Mullick A, Xu Y, Warren R , et al. The cumate gene-switch: a system for regulated expression in mammalian cells. BMC Biotechnol 2006; 6(1):43. doi: 10.1186/1472-6750-6-43. doi: 10.1186/1472-6750-6-43 pmid: 17083727
[59]	Weber W, Rimann M, Spielmann M , et al. Gas-inducible transgene expression in mammalian cells and mice. Nat Biotechnol 2004; 22(11):1440-4. doi: 10.1038/nbt1021. doi: 10.1038/nbt1021 pmid: 15502819
[60]	Malphettes L, Weber CC, El-Baba MD , et al. A novel mammalian expression system derived from components coordinating nicotine degradation in arthrobacter nicotinovorans pAO1. Nucleic Acids Res 2005; 33(12):e107. doi: 10.1093/nar/gni107. doi: 10.1093/nar/gni107
[61]	Ausl?nder D, Ausl?nder S , Charpin-El Hamri G, et al. A synthetic multifunctional mammalian pH sensor and CO2 transgene-control device. Mol Cell 2014; 55(3):397-408. doi: 10.1016/j.molcel.2014.06.007. doi: 10.1016/j.molcel.2014.06.007 pmid: 25018017
[62]	Weber W, Schoenmakers R, Keller B , et al. A synthe-tic mammalian gene circuit reveals antituberculosis compounds. Proc Natl Acad Sci USA 2008; 105(29):9994-8. doi: 10.1073/pnas.0800663105. doi: 10.1073/pnas.0800663105
[63]	R?ssger K , Charpin-El-Hamri G, Fussenegger M. A closed-loop synthetic gene circuit for the treatment of diet-induced obesity in mice. Nat Commun 2013; 4(7):2825. doi: ARTN 282510.1038/ncomms3825. doi: ARTN 282510.1038/ncomms3825 pmid: 24281397
[64]	Saxena P, Heng BC, Bai P , et al. A programmable synthetic lineage-control network that differentiates human IPSCs into glucose-sensitive insulin-secreting beta-like cells. Nat Commun 2016; 7:11247. doi: 1124710.1038/ncomms11247. doi: 1124710.1038/ncomms11247 pmid: 27063289
[65]	Gitzinger M, Kemmer C, Fluri DA , et al. The food additive vanillic acid controls transgene expression in mammalian cells and mice. Nucleic Acids Res 2012; 40(5):e37. doi: 10.1093/nar/gkr1251. doi: 10.1093/nar/gkr1251 pmid: 3300003
[66]	Rogers JK, Guzman CD, Taylor ND , et al. Synthetic biosensors for precise gene control and real-time monitoring of metabolites. Nucleic Acids Res 2015; 43(15):7648-60. doi: 10.1093/nar/gkv616. doi: 10.1093/nar/gkv616 pmid: 26152303
[67]	Weber W, Bacchus W , Daoud-El Baba M, et al. Vitamin H-regulated transgene expression in mammalian cells. Nucleic Acids Res 2007; 35(17):e116. doi: 10.1093/nar/gkm466. doi: 10.1093/nar/gkm466 pmid: 17827215
[68]	Weber W, Lienhart C , Daoud-EI Baba M, et al. A biotin-triggered genetic switch in mammalian cells and mice. Metab Eng 2009; 11(2):117-24. doi: 10.1016/j.ymben.2008.12.001. doi: 10.1016/j.ymben.2008.12.001 pmid: 19271268

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