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

摘要/Abstract

摘要：

合成生物学通过在细胞中整合入功能性的基因网络,从而赋予细胞新的功能。合成生物学领域的科学家们通过过表达,阻断和重排等手段,重新编辑细胞的天然基因通路,使其完成多样的生物学功能,并应用在诸多领域,如药物筛选,生物制药,基因治疗和组织工程等等。本文重点综述目前合成生物传感器技术在疾病筛查领域的应用。我们首先介绍了合成生物传感器设计思路和方法,之后分别对简单合成生物传感器,即对单一输入信号做出相应反应的合成生物传感器,和复杂生物传感器,即对多个输入信号做出相应反应的合成生物传感器,包括布尔门生物传感器,级联放大生物传感器,延时生物传感器,振荡器生物传感器,滞后生物传感器的设计特点和应用做了介绍。尽管合成生物感受器在疾病检测方面已展现了巨大的潜在优势,但这一技术依旧处在其发展的最初阶段。在识别和构建更多的疾病相关调控系统方面有待深入研究,同时需要在设计过程中利用计算机工具进一步提高合成生物传感器的精准性。合成生物感受器的最终发展目标是成为一种将疾病诊断作为输入和疾病治疗效果作为输出的感应-效应装置,从而为将来细胞及基因水平的治疗提供一体化的诊断和治疗解决方案。

关键词: 合成生物传感器, 基因线路, 疾病检测

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

补充说明: 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。

基金资助: 国家自然科学基金(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.

图/表 4

Table 1

Characteristics of various simple synthetic biosensors"

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

Table 1

Continue to Table 1

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