基因回路在癌症检测与治疗中的应用

Gene Circuits in Cancer Detection and Treatment

自然进化过程中,细胞为了适应环境变化,必须感知内外繁多的信号,进行逻辑处理并执行相应功能,完成这一过程的信号转导通路是由细胞内自然存在的分子构成的。应用合成生物学手段构建的基因回路是一个根据检测或治疗目的定制的人工信号转导通路,由工程化改造或从头设计的生物分子构成,包含传感器模块、逻辑处理模块和应答模块3部分。经过理性设计的基因回路可感知肿瘤生物学标志物或失衡的病理状态,根据设定的条件释放示踪分子或治疗产物来识别或杀伤癌细胞。这些在细菌或人类细胞中量身定制的基因回路具有前所未有的特异性,已在动物实验中用于检测或治疗癌症。应用基因回路治疗癌症有3类手段:基于工程菌、基于CAR-T细胞和直接导入核酸的治疗。在对基因回路的模块性、正交性、可调性、可组装性进行优化的探索中,蛋白质回路展现出了明显的优势:反应速度快、不引起永久的基因改变和整合性佳。多传感器基因回路设计和控制论指导的基因回路设计是当下基因回路发展的两大主流方向,而开发拥有多传感器及调节元件的复杂单转录本蛋白质回路为该方向上的重点。本文主要对基因回路在癌症检测与治疗中的研究进行综述,重点阐述蛋白酶及其特异性切割位点在基因回路中的应用,其调节的灵活性使得蛋白质回路的开发成为可能,为新一代基因回路的研究拓展思路。

In natural evolution,cells need to sense various internal and external signals,then process them and execute different functions to adapt environmental changes,the process of which is completed by signal pathways composed of molecules naturally existing in cells.Gene circuits are artificial signal pathways tailored by synthetic biology using engineered or de novo designed biomolecules to realize specific aims like detection or treatment.Gene ciruits consist of 3 components:sensors,prcessors,and actuators.After rational design,gene circuits can sense tumor biomarkers or unbalanced pathological conditions,then release tracer molecules or toxic products to identify or kill tumor cells.These tailored gene circuits exhibited unprecedented specificity in both bacteria and human cells,which has been used to treat cancer in animal experiments.There are 3 approaches when applying gene circuits in cancer treatment:cancer-targeting bacteria based therapies,CAR-T based therapies,and nucleic acid based therapies.Optimization of gene circuits mainly focus on the modularity,orthogonality,adjustability,and composability,in the process of which protein circuits exhibited obvious advantages.They have high reaction rates,excellent composability,and never cause permanent gene changes.The design of gene circuits with multiple sensors and cybernetics-guided design are 2 major research directions of synthetic circuits.Developing sophisticated single transcript protein circuits with multiple sensors and regulators enables new generations of programmable synthetic devices.Here we reviewed the progression of gene circuits in the detection and treatment of cancer,particularly focusing on the application of protease and corresponding cut sites in the design of gene circuits.The flexibility of gene circuit regulation made the design of protein circuits possible,providing ideas for the research of new generation of gene circuits.