Table 1.

ON–OFF switches in mammalian synthetic biology.

switch levela	no.	name	ON switchb	OFF switchc	origin	effectord	applications	references
transcriptional switches
	1	ABA	yes	no	Arabidopsis thaliana, yeast	abscisic acid	gene therapy, experimental tool to control diverse cellular activities in vivo	[19]
	2	AIR	yes	no	Aspergillus nidulans	acetaldehyde	gas-adjustable transgene expression, biopharmaceutical manufacturing	[20]
	3	ART	yes	no	Chlamydia pneumoniae	l-arginine	biopharmaceutical manufacturing, gene therapy	[21]
	4	BEARON, BEAROFF	yes	yes	Campylobacter jejuni	bile acid	gene- and cell-based therapies	[22]
	5	BirA-tTA	no	yes	Escherichia coli	biotin (vitamin H)	biopharmaceutical manufacturing, cell therapy	[23]
	6	BIT	yes	no	Escherichia coli	biotin (vitamin H)	gene therapy, tissue engineering, biopharmaceutical manufacturing	[24]
	7	Cry2-CIB1	yes	no	Arabidopsis thaliana, yeast	blue light	protein translocation, transcription control, Cre-mediated DNA recombination using light	[25]
	8	CTA, CTS	yes	yes	Comamonas testosteroni, Homo sapiens	food additives (benzoate, vanillate)	gene- and cell-based therapy	[26]
	9	cTA, rcTA	yes	yes	Pseudomonas putida	cumate	regulation of gene expression level and duration	[27]
	10	Ecdysone	yes	no	Homo sapiens, Drosophila melanogaster	Ecdysone	transient inducible expression, gene therapy	[28]
	11	EcR:RXR	yes	no	Homo sapiens, Locusta migratoria	ecdysone	ligand-dependent induction of reporter gene, gene therapy	[29]
	12	electro-genetic	yes	no	Aspergillus nidulans	electricity, acetaldehyde	electric power-adjustable transcription control; mammalian cell-based control of microelectronic circuits	[30]
	13	ER-p65-ZF	yes	no	Homo sapiens, yeast	4,4′-dyhydroxybenzil	generating a wide array of orthogonal gene switches	[31]
	14	E.REX	yes	yes	Escherichia coli	erythromycin	gene therapy, tissue engineering, in vivo gene-function analyses, drug discovery, biopharmaceutical manufacturing	[32]
	15	EthR	no	yes	Mycobacterium tuberculosis	2-phenylethyl-butyrate	drug discovery	[33]
	16	GAL4-ER	yes	yes	yeast, Homo sapiens	oestrogen, 4-hydroxytamoxifen	regulating heterologous genes, identifying Fos (oncogene) targets	[34]
	17	GAL4-hPR	yes	yes	yeast, Homo sapiens	mifepristone	positive and negative regulation of gene expression, also in vivo	[35,36]
	18	GAL4-Raps	yes	yes	yeast, Homo sapiens	rapamycin and rapamycin derivatives	targeted gene expression control	[37]
	19	GAL4-TR	yes	no	yeast, Homo sapiens	thyroid hormone	study nuclear receptor signalling	[38]
	20	GyrB	yes	yes	Escherichia coli	coumermycin, novobiocin	rapid regulation of gene expression	[39]
	21	HEA-3	yes	no	Homo sapiens	4-hydroxytamoxifen	gene therapy	[40]
	22	Intramer	no	yes	synthetic SELEX-derived aptamers	theophylline	controlling transgene expression, construction of complex gene networks	[41]
	23	LacI	yes	no	Escherichia coli	IPTG	reversible regulation of gene expression, predictable levels of de-repressed gene expression	[42–46]
	24	LAD	yes	no	Arabidopsis thaliana, yeast	blue light	light-controlled gene expression regulation; protein hetero- and homo-dimerization induced by light	[47]
	25	LightOn	yes	no	Neurospora crassa, yeast	blue light	light-switchable transcription control	[48]
	26	NICE	yes	yes	Arthrobacter nicotinovorans	6-hydroxynicotine	therapeutic cell engineering, biopharmaceutical manufacturing	[49]
	27	PPAR*	yes	no	Homo sapiens	rosiglitazone	gene therapy	[50]
	28	PEACE	no	yes	Pseudomonas putida	flavonoids (e.g. phloretin)	biopharmaceutical manufacturing, gene- and cell-based therapies	[51]
	29	PIT	yes	yes	Streptomyces coelicolor	pristinamycin I, virginiamycin	compatible with the Tet-OFF system, thus two different gene activities can be controlled in the same cell	[12]
	30	REDOX	no	yes	Streptomyces coelicolor	NADH	process development, biopharmaceutical manufacturing	[52]
	31	QuoRex	yes	yes	Streptomyces coelicolor, Streptomyces pristinaespiralis	butyrolactones (e.g. SCB1)	small molecule-adjustable gene control systems for clinical application	[53]
	32	ST-TA	yes	yes	Streptomyces coelicolor, Escherichia coli, Herpes simplex	γ-butyrolactone, tetracycline	Design of therapeutic gene circuits for gene and cell-based therapies	[54]
	33	TIGR	no	yes	Streptomyces albus	temperature	temperature-inducible gene regulation	[55]
	34	TraR	yes	no	Agrobacterium tumefaciens	N-(3-oxo-octanoyl)homoserine lactone	versatile gene expression control	[56]
	35	TET-OFF, TET-ON	yes	yes	Escherichia coli, Herpes simplex	tetracycline, doxycycline	reversible and tight gene expression control	[11,57]
	36	TRT	yes	no	Chlamydia trachomatis	l-tryptophan	synthetic bidirectional communication between mammalian cells	[58]
	37	UREX	yes	no	Deinococcus radiodurans	uric acid	self-sufficient control of pathologic metabolites, gene- and cell-based therapies	[59]
	38	VAC	yes	yes	Caulobacter crescentus	vanillic acid	biopharmaceutical manufacturing, gene- and cell-based therapies	[60]
	39	ZF-ER, ZF-RXR/EcR	yes	yes	Mus musculus, Homo sapiens, Drosophila melanogaster	4-hydroxytamoxifen, ponasterone-A	spatio-temporal control of gene expression, genomic and proteomic research, gene therapy	[61]
	40	ZF-Raps	yes	no	Homo sapiens	rapamycin	gene expression control, gene therapy	[62]
	41	ZF switches	yes	no	Mus musculus, Homo sapiens, Drosophila melanogaster	4-hydroxytamoxifen, mifepristone	study of gene function, alteration of phenotypes of cells or organisms	[63]
	42	ZF(TF)s	yes	no	Xenopus laevis, Homo sapiens	ethyl-4-hydroxybenzoate, propyl-4-hydroxybenzoate	genomic and proteomic research, gene therapy	[64]
post-transcriptional switches
	1	aptamer RNAi	yes	no	synthetic SELEX-derived aptamer	theophylline	regulation of gene expression by small molecules without engineered proteins	[65]
	2	aptamer RNAi	no	yes	synthetic SELEX-derived aptamer	theophylline	construction of conditional RNAi systems	[66]
	3	aptamer RNAi miRNA	yes	no	synthetic SELEX-derived aptamer	theophylline, tetracycline, hypoxanthine	probing and programming of cellular function	[67]
	4	aptamer Splicing	yes	yes	Homo sapiens, MS2 bacteriophage	MS2, p65, p50, b-catenin	programmable sensing-actuation devices for autonomous cell behaviour control	[68]
	5	aptazyme	no	yes	synthetic SELEX-derived aptamer, Schistosoma mansoni	theophylline	regulation of therapeutic gene expression	[69]
	6	replicon CytTS	yes	no	Sindbis virus	temperature	expression of toxic proteins, bioprocess engineering	[70]
	7	TET-OFF-shRNA, TET-ON-shRNA	yes	yes	Escherichia coli, Herpes simplex, Homo sapiens	doxycycline	basic or translational research, development of gene-based therapeutics	[71]
	8	theo aptamer	no	yes	synthetic SELEX-derived aptamer	theophylline	basic, biotechnological, and biomedical research	[72]
	9	3′ UTR aptazyme	yes	no	synthetic SELEX-derived aptamers, tobacco ringspot virus	theophylline, tetracycline	functional response regulation, gene and cellular therapy	[73]
	10	5′ UTR aptazyme	no	yes	synthetic SELEX-derived aptamer, Schistosoma mansoni	theophylline	control of gene expression, gene therapy	[74]
translational switches
	1	Hoechst aptamer	no	yes	synthetic RNA sequence	Hoechst dyes	translational gene regulation, biology and medical research	[75]
	2	H23 aptamer	no	yes	Archaeoglobus fulgidus	L7Ae, L7KK	gene expression regulation, construction of a NOR gate	[76]
	3	L7Ae aptamer	yes	yes	Archaeoglobus fulgidus	L7Ae	detection, repair or rewiring of intrinsic cellular defects, characterization of complex circuits	[77]
	4	MS2 aptamer	no	yes	MS2 bacteriophage	MS2	study RNA–protein interactions, clone RNA-binding proteins	[78]
post-translational switches
	1	AID	no	yes	Arabidopsis thaliana, Oryza sativa, Gossypium hirsutum	auxins (e.g. IAA)	control protein expression and study protein function	[79]
	2	ER DD	no	yes	Homo sapiens	CMP8, 4-hydroxytamoxifen	regulate the intracellular concentration of any protein	[80]
	3	FM	yes	no	Homo sapiens	AP21998	delivery of polypeptides that require rapid and regulated delivery	[81]
	4	HaloTag	no	yes	Rhodococcus sp. RHA1	HyT13	validating potential drug targets in disease models	[82,83]
	5	HDV-aptazyme	no	yes	hepatitis delta virus	theophylline, guanine	dynamic range of gene regulation	[84]
	6	PROTAC	no	yes	Homo sapiens	proteolysis targeting chimeric molecules (PROTACS)	chemical knockouts, control of protein function	[85]
	7	shield DD	yes	no	Homo sapiens	shields (e.g. Shld1)	conditional control of proteins levels	[86]
	8	shield LID	no	yes	Homo sapiens	shields (e.g. Shld1)	conditional control of proteins levels	[87]
	9	TMP DD	yes	no	Escherichia coli	trimethoprim (TMP)	tuneable regulation of protein expression in the mammalian central nervous system	[88]

^aLevel of gene expression where the switching occurs.

^bON switchability by an effector; other than removing the effector which confers the OFF state.

^cOFF switchability by an effector; other than removing the effector which confers the ON state.

^dA ligand or other physical stimuli (e.g. temperature, electromagnetic radiation, electricity) which stabilizes the switch either in its ON or OFF state.