合成生物学在疾病诊疗中的应用

doi:10.12211/2096-8280.2022-059

合成生物学 ›› 2023, Vol. 4 ›› Issue (2): 244-262.doi: 10.12211/2096-8280.2022-059

合成生物学在疾病诊疗中的应用

吴晓昊¹, 廖荣东², 李飞云¹, 欧阳中天¹, 冉怡¹, 公维远¹, 曲明灏¹, 陈明珏¹, 林荔军², 肖国芝¹

^1.南方科技大学医学院，广东深圳 518055
^2.南方医科大学珠江医院关节骨病外科，广东广州 510280

收稿日期:2022-10-31 修回日期:2023-02-01 出版日期:2023-04-30 发布日期:2023-04-27
通讯作者: 林荔军,肖国芝
作者简介:吴晓昊（1991—），男，博士研究生。研究方向为骨关节稳态和疾病发生的分子机制。E-mail：wxho0606@163.com
廖荣东（1996—），男，博士研究生。研究方向为骨科疾病的发病机制。E-mail：lrdyxs12138@163.com
林荔军（1976—），男，博士，主任医师，博士生导师。主要从事合成生物学与骨科疾病诊治领域方面的研究，利用合成生物学方法构建新型材料用于骨关节炎、骨折不愈合等骨科多发疾病的治疗，研究方向为骨关节炎发病分子机制研究、骨肉瘤侵袭和转移的分子机制研究、骨组织3D打印和生物力学研究学。E-mail：gost1@smu.edu.cn
肖国芝（1963—），男，教授，乌克兰国家工程院外籍院士。主要研究方向是骨骼发育和疾病的相关分子基础。E-mail：xiaogz@sustech.edu.cn
基金资助:
国家重点研发计划(2019YFA0906004);国家自然科学基金(82230081)

Applications of synthetic biology in disease diagnosis and treatment

Xiaohao WU¹, Rongdong LIAO², Feiyun LI¹, Zhongtian OUYANG¹, Yi RAN¹, Weiyuan GONG¹, Minghao QU¹, Mingjue CHEN¹, Lijun LIN², Guozhi XIAO¹

^1.School of Medicine，Southern University of Science and Technology，Shenzhen 518055，Guangdong，China
^2.Department of Orthopedics，Zhujiang Hospital，Southern Medical University，Guangzhou 510280，Guangdong，China

Received:2022-10-31 Revised:2023-02-01 Online:2023-04-30 Published:2023-04-27
Contact: Lijun LIN, Guozhi XIAO

摘要/Abstract

摘要：

合成生物学是一门新兴学科。从广义上讲，合成生物学是通过将基因工程、系统生物学、计算机工程等多学科作为工具，根据特定需求进行设计，乃至重新合成生物体系。近20年来，合成生物学领域的相关研究不断取得突破，并已在针对人类疾病的诊断、临床治疗、药物研发等诸多方面获得重要应用。合成生物学不仅为疾病的早期、精确诊断提供新的思路和技术手段，还发展出多种新型的疾病治疗手段，包括基于合成生物学原理设计的细胞疗法、细菌疗法、疫苗、生物医学材料等。利用合成生物学方法，我们可以精确诊断早期疾病、精准改造细胞或细菌、进行疾病机制研究和药物筛选、快速生产新型疫苗和生物医学材料。基于合成生物学的疾病诊疗方法将是科研领域重要的发展方向之一，并将在未来彻底改变临床疾病的诊疗方式。本文综述合成生物学原理和技术在疾病诊断和治疗中的应用，并进一步探讨合成生物学在疫苗生产、生物医学材料、新药研发等方面的应用。

关键词: 合成生物学, 疾病, 诊断, 治疗, 新药研发

Abstract:

Synthetic biology (SB) is an emerging discipline, which utilizes genetic engineering, systems biology, computer science, and other disciplines as tools to design, and even re-synthesize biological systems for specific needs. In the past 20 years, milestone breakthroughs in SB have been achieved and applied in the diagnosis and treatment of human diseases, particularly in the discovery of new drugs. SB not only provides new ideas and technical tools for the early and accurate diagnosis of diseases, but also develops a variety of new approaches for treating diseases, including cell therapy, bacteriotherapy, vaccines, and biomedical materials. Using SB-based methods, we can precisely diagnose diseases at an early stage, specifically engineer cells or bacteria, conduct mechanistic studies and drug screening, and rapidly produce vaccines and biomedical materials. SB with the "design-build-test" cycle greatly facilitates the development of new diagnostic and therapeutic approaches. Moreover, SB applies engineering principles (modularity, composability, abstraction, and standardization) to redefine biological systems in a more modular and composable way. Through this framework, the basic units of the biological system are fully characterized as standardized motifs (DNA sequences or gene-encoded products), and these motifs are mixed and matched to construct a fully functional genetic apparatus. By utilizing recently developed gene editing tools, such as the clustered regularly interspaced palindromic repeats (CRISPR/Cas9) technology, SB can integrate programmed devices into a chassis (e.g., bacteria and yeast), create new systems capable of producing target biomolecules or behaviors, and precisely manipulate the genome of cells and individuals to repair genetic defects. SB-based disease diagnosis and treatment will be one of the important development directions in the field of scientific research to completely change the way of diagnosis and clinical treatment of diseases in the future. This article reviews the applications of SB-based technologies in disease diagnosis and treatment, as well as in the production of vaccines and biomedical materials, as well as in new drug development.

Key words: synthetic biology, disease, diagnosis, treatment, drug development

中图分类号:

吴晓昊, 廖荣东, 李飞云, 欧阳中天, 冉怡, 公维远, 曲明灏, 陈明珏, 林荔军, 肖国芝. 合成生物学在疾病诊疗中的应用[J]. 合成生物学, 2023, 4(2): 244-262, doi: 10.12211/2096-8280.2022-059.

Xiaohao WU, Rongdong LIAO, Feiyun LI, Zhongtian OUYANG, Yi RAN, Weiyuan GONG, Minghao QU, Mingjue CHEN, Lijun LIN, Guozhi XIAO. Applications of synthetic biology in disease diagnosis and treatment[J]. Synthetic Biology Journal, 2023, 4(2): 244-262, doi: 10.12211/2096-8280.2022-059.

图/表 5

表1

图1

图2

表2

图3

参考文献 139

1	YE H F, FUSSENEGGER M. Synthetic therapeutic gene circuits in mammalian cells[J]. FEBS Letters, 2014, 588(15): 2537-2544.
2	ELOWITZ M B, LEIBLER S. A synthetic oscillatory network of transcriptional regulators[J]. Nature, 2000, 403(6767): 335-338.
3	GARDNER T S, CANTOR C R, COLLINS J J. Construction of a genetic toggle switch in Escherichia coli [J]. Nature, 2000, 403(6767): 339-342.
4	KRAMER B P, FISCHER C, FUSSENEGGER M. BioLogic gates enable logical transcription control in mammalian cells[J]. Biotechnology and Bioengineering, 2004, 87(4): 478-484.
5	BECSKEI A, SERRANO L. Engineering stability in gene networks by autoregulation[J]. Nature, 2000, 405(6786): 590-593.
6	KITADA T, DIANDRETH B, TEAGUE B, et al. Programming gene and engineered-cell therapies with synthetic biology[J]. Science, 2018, 359(6376): eaad1067.
7	BATEY R T, GILBERT S D, MONTANGE R K. Structure of a natural guanine-responsive riboswitch complexed with the metabolite hypoxanthine[J]. Nature, 2004, 432(7015): 411-415.
8	BADORREK C S, GHERGHE C M, WEEKS K M. Structure of an RNA switch that enforces stringent retroviral genomic RNA dimerization[J]. Proceedings of the National Academy of Sciences of the United States of America, 2006, 103(37): 13640-13645.
9	SIUTI P, YAZBEK J, LU T K. Synthetic circuits integrating logic and memory in living cells[J]. Nature Biotechnology, 2013, 31(5): 448-452.
10	KEMMER C, GITZINGER M, DAOUD-EL BABA M, et al. Self-sufficient control of urate homeostasis in mice by a synthetic circuit[J]. Nature Biotechnology, 2010, 28(4): 355-360.
11	RICHARDS R M, ZHAO F F, FREITAS K A, et al. NOT-gated CD93 CAR T cells effectively target AML with minimized endothelial cross-reactivity[J]. Blood Cancer Discovery, 2021, 2(6): 648-665.
12	GIBSON D G, YOUNG L, CHUANG R Y, et al. Enzymatic assembly of DNA molecules up to several hundred kilobases[J]. Nature Methods, 2009, 6(5): 343-345.
13	MCNERNEY M P, DOIRON K E, NG T L, et al. Theranostic cells: emerging clinical applications of synthetic biology[J]. Nature Reviews Genetics, 2021, 22(11): 730-746.
14	ENDY D. Foundations for engineering biology[J]. Nature, 2005, 438(7067): 449-453.
15	SLUSARCZYK A L, LIN A, WEISS R. Foundations for the design and implementation of synthetic genetic circuits[J]. Nature Reviews Genetics, 2012, 13(6): 406-420.
16	WANG Y H, WEI K Y, SMOLKE C D. Synthetic biology: advancing the design of diverse genetic systems[J]. Annual Review of Chemical and Biomolecular Engineering, 2013, 4: 69-102.
17	ISHINO Y, SHINAGAWA H, MAKINO K, et al. Nucleotide sequence of the iap gene, responsible for alkaline phosphatase isozyme conversion in Escherichia coli, and identification of the gene product[J]. Journal of Bacteriology, 1987, 169(12): 5429-5433.
18	YIN H, XUE W, CHEN S D, et al. Genome editing with Cas9 in adult mice corrects a disease mutation and phenotype[J]. Nature Biotechnology, 2014, 32(6): 551-553.
19	BAKONDI B, LV W J, LU B, et al. In vivo CRISPR/Cas9 gene editing corrects retinal dystrophy in the S334ter-3 rat model of autosomal dominant retinitis pigmentosa[J]. Molecular Therapy, 2016, 24(3): 556-563.
20	LIANG C, LI F F, WANG L Y, et al. Tumor cell-targeted delivery of CRISPR/Cas9 by aptamer-functionalized lipopolymer for therapeutic genome editing of VEGFA in osteosarcoma[J]. Biomaterials, 2017, 147: 68-85.
21	KAN M J, DOUDNA J A. Treatment of genetic diseases with CRISPR genome editing[J]. JAMA, 2022, 328(10): 980-981.
22	SOLEIMANY A P, BHATIA S N. Activity-based diagnostics: an emerging paradigm for disease detection and monitoring[J]. Trends in Molecular Medicine, 2020, 26(5): 450-468.
23	SLOMOVIC S, PARDEE K, COLLINS J J. Synthetic biology devices for in vitro and in vivo diagnostics[J]. Proceedings of the National Academy of Sciences of the United States of America, 2015, 112(47): 14429-14435.
24	TIAN Q, PRICE N D, HOOD L. Systems cancer medicine: towards realization of predictive, preventive, personalized and participatory (P4) medicine[J]. Journal of Internal Medicine, 2012, 271(2): 111-121.
25	SIU A L. Screening for breast cancer: U.S. preventive services task force recommendation statement[J]. Annals of Internal Medicine, 2016, 164(4): 279-296.
26	US Preventive Services Task Force. Screening for colorectal cancer: US preventive services task force recommendation statement[J]. JAMA, 2016, 315(23): 2564-2575.
27	SIEGEL R L, MILLER K D, JEMAL A. Cancer statistics, 2020[J]. CA: A Cancer Journal for Clinicians, 2020, 70(1): 7-30.
28	LUTZ A M, WILLMANN J K, COCHRAN F V, et al. Cancer screening: a mathematical model relating secreted blood biomarker levels to tumor sizes[J]. PLoS Medicine, 2008, 5(8): e170.
29	KWONG G A, GHOSH S, GAMBOA L, et al. Synthetic biomarkers: a twenty-first century path to early cancer detection[J]. Nature Reviews Cancer, 2021, 21(10): 655-668.
30	HANAHAN D, WEINBERG R A. Hallmarks of cancer: the next generation[J]. Cell, 2011, 144(5): 646-674.
31	KWON E J, DUDANI J S, BHATIA S N. Ultrasensitive tumour-penetrating nanosensors of protease activity[J]. Nature Biomedical Engineering, 2017, 1: 54.
32	KESSENBROCK K, PLAKS V, WERB Z. Matrix metalloproteinases: regulators of the tumor microenvironment[J]. Cell, 2010, 141(1): 52-67.
33	DUDANI J S, IBRAHIM M, KIRKPATRICK J, et al. Classification of prostate cancer using a protease activity nanosensor library[J]. Proceedings of the National Academy of Sciences of the United States of America, 2018, 115(36): 8954-8959.
34	KWONG G A, VON MALTZAHN G, MURUGAPPAN G, et al. Mass-encoded synthetic biomarkers for multiplexed urinary monitoring of disease[J]. Nature Biotechnology, 2013, 31(1): 63-70.
35	DUDANI J S, WARREN A D, BHATIA S N. Harnessing protease activity to improve cancer care[J]. Annual Review of Cancer Biology, 2018, 2: 353-376.
36	BHANG H E C, GABRIELSON K L, LATERRA J, et al. Tumor-specific imaging through progression elevated gene-3 promoter-driven gene expression[J]. Nature Medicine, 2011, 17(1): 123-129.
37	AALIPOUR A, CHUANG H Y, MURTY S, et al. Engineered immune cells as highly sensitive cancer diagnostics[J]. Nature Biotechnology, 2019, 37(5): 531-539.
38	NIU G, CHEN X Y. Molecular imaging with activatable reporter systems[J]. Theranostics, 2012, 2(4): 413-423.
39	REAGAN M R, KAPLAN D L. Concise review: mesenchymal stem cell tumor-homing: detection methods in disease model systems[J]. Stem Cells, 2011, 29(6): 920-927.
40	ZHOU S B, GRAVEKAMP C, BERMUDES D, et al. Tumour-targeting bacteria engineered to fight cancer[J]. Nature Reviews Cancer, 2018, 18(12): 727-743.
41	WEI T Y, CHENG C M. Synthetic biology-based point-of-care diagnostics for infectious disease[J]. Cell Chemical Biology, 2016, 23(9): 1056-1066.
42	SHORR A F, MICEK S T, JACKSON W L, et al. Economic implications of an evidence-based sepsis protocol: can we improve outcomes and lower costs?[J]. Critical Care Medicine, 2007, 35(5): 1257-1262.
43	MANI V, WANG S Q, INCI F, et al. Emerging technologies for monitoring drug-resistant tuberculosis at the point-of-care[J]. Advanced Drug Delivery Reviews, 2014, 78: 105-117.
44	COURBET A, ENDY D, RENARD E, et al. Detection of pathological biomarkers in human clinical samples via amplifying genetic switches and logic gates[J]. Science Translational Medicine, 2015, 7(289): 289ra83.
45	DONALDSON T, DATTELBAUM J D. Designing a thermostable switch-based biosensor[J]. Biophysical Journal, 2014, 106(2): 810a.
46	SILVERMAN A D, KARIM A S, JEWETT M C. Cell-free gene expression: an expanded repertoire of applications[J]. Nature Reviews Genetics, 2020, 21(3): 151-170.
47	TAN X, LETENDRE J H, COLLINS J J, et al. Synthetic biology in the clinic: engineering vaccines, diagnostics, and therapeutics[J]. Cell, 2021, 184(4): 881-898.
48	GREEN A A, SILVER P A, COLLINS J J, et al. Toehold switches: de-novo-designed regulators of gene expression[J]. Cell, 2014, 159(4): 925-939.
49	MAKAROVA K S, WOLF Y I, IRANZO J, et al. Evolutionary classification of CRISPR-Cas systems: a burst of class 2 and derived variants[J]. Nature Reviews Microbiology, 2020, 18(2): 67-83.
50	LESLIE H H, SPIEGELMAN D, ZHOU X, et al. Service readiness of health facilities in Bangladesh, Haiti, Kenya, Malawi, Namibia, Nepal, Rwanda, Senegal, Uganda and the United Republic of Tanzania[J]. Bulletin of the World Health Organization, 2017, 95(11): 738-748.
51	JUNE C H, SADELAIN M. Chimeric antigen receptor therapy[J]. New England Journal of Medicine, 2018, 379(1): 64-73.
52	LANITIS E, DANGAJ D, IRVING M, et al. Mechanisms regulating T-cell infiltration and activity in solid tumors[J]. Annals of Oncology, 2017, 28(): xii18-xii32.
53	LANITIS E, IRVING M, COUKOS G. Targeting the tumor vasculature to enhance T cell activity[J]. Current Opinion in Immunology, 2015, 33: 55-63.
54	KLOSS C C, CONDOMINES M, CARTELLIERI M, et al. Combinatorial antigen recognition with balanced signaling promotes selective tumor eradication by engineered T cells[J]. Nature Biotechnology, 2013, 31(1): 71-75.
55	WU M R, JUSIAK B, LU T K. Engineering advanced cancer therapies with synthetic biology[J]. Nature Reviews Cancer, 2019, 19(4): 187-195.
56	FEDOROV V D, THEMELI M, SADELAIN M. PD-1- and CTLA-4-based inhibitory chimeric antigen receptors (iCARs) divert off-target immunotherapy responses[J]. Science Translational Medicine, 2013, 5(215): 215ra172.
57	SADELAIN M. Chimeric antigen receptors: a paradigm shift in immunotherapy[J]. Annual Review of Cancer Biology, 2017, 1: 447-466.
58	XU N, PALMER D C, ROBESON A C, et al. STING agonist promotes CAR T cell trafficking and persistence in breast cancer[J]. The Journal of Experimental Medicine, 2021, 218(2): e20200844.
59	LÓPEZ-LÁZARO M. The migration ability of stem cells can explain the existence of cancer of unknown primary site. Rethinking metastasis[J]. Oncoscience, 2015, 2(5): 467-475.
60	LANDSKRON G, DE LA FUENTE M, THUWAJIT P, et al. Chronic inflammation and cytokines in the tumor microenvironment[J]. Journal of Immunology Research, 2014, 2014: 149185.
61	ABOODY K S, NAJBAUER J, DANKS M K. Stem and progenitor cell-mediated tumor selective gene therapy[J]. Gene Therapy, 2008, 15(10): 739-752.
62	SPAETH E, KLOPP A, DEMBINSKI J, et al. Inflammation and tumor microenvironments: defining the migratory itinerary of mesenchymal stem cells[J]. Gene Therapy, 2008, 15(10): 730-738.
63	TAKAYAMA Y, KUSAMORI K, NISHIKAWA M. Click chemistry as a tool for cell engineering and drug delivery[J]. Molecules, 2019, 24(1): 172.
64	LAYEK B, SADHUKHA T, PRABHA S. Glycoengineered mesenchymal stem cells as an enabling platform for two-step targeting of solid tumors[J]. Biomaterials, 2016, 88: 97-109.
65	HARGADON K M, JOHNSON C E, WILLIAMS C J. Immune checkpoint blockade therapy for cancer: an overview of FDA-approved immune checkpoint inhibitors[J]. International Immunopharmacology, 2018, 62: 29-39.
66	DARVIN P, TOOR S M, SASIDHARAN NAIR V, et al. Immune checkpoint inhibitors: recent progress and potential biomarkers[J]. Experimental & Molecular Medicine, 2018, 50(12): 1-11.
67	HU Q Y, SUN W J, WANG J Q, et al. Conjugation of haematopoietic stem cells and platelets decorated with anti-PD-1 antibodies augments anti-leukaemia efficacy[J]. Nature Biomedical Engineering, 2018, 2(11): 831-840.
68	STÜDEMANN T, RÖSSINGER J, MANTHEY C, et al. Contractile force of transplanted cardiomyocytes actively supports heart function after injury[J]. Circulation, 2022, 146(15): 1159-1169.
69	LLOYD-PRICE J, ABU-ALI G, HUTTENHOWER C. The healthy human microbiome[J]. Genome Medicine, 2016, 8(1): 51.
70	YU H. Bacteria-mediated disease therapy[J]. Applied Microbiology and Biotechnology, 2011, 92(6): 1107-1113.
71	FLORES BUESO Y, LEHOURITIS P, TANGNEY M. In situ biomolecule production by bacteria; a synthetic biology approach to medicine[J]. Journal of Controlled Release: Official Journal of the Controlled Release Society, 2018, 275: 217-228.
72	LIM B, YIN Y T, YE H, et al. Reprogramming synthetic cells for targeted cancer therapy[J]. ACS Synthetic Biology, 2022, 11(3): 1349-1360.
73	CHOWDHURY S, CASTRO S, COKER C, et al. Programmable bacteria induce durable tumor regression and systemic antitumor immunity[J]. Nature Medicine, 2019, 25(7): 1057-1063.
74	GURBATRI C R, LIA I, VINCENT R, et al. Engineered probiotics for local tumor delivery of checkpoint blockade nanobodies[J]. Science Translational Medicine, 2020, 12(530): eaax0876.
75	LEVENTHAL D S, SOKOLOVSKA A, LI N, et al. Immunotherapy with engineered bacteria by targeting the STING pathway for anti-tumor immunity[J]. Nature Communications, 2020, 11: 2739.
76	高梦学, 王丽娜, 黄鹤. 合成生物学在肠道微生态疗法研发中的应用[J]. 合成生物学, 2022, 3(1): 35-52.
	GAO M X, WANG L N, HUANG H. Advances in synthetic biology assisted intestinal microecological therapy[J]. Synthetic Biology Journal, 2022, 3(1): 35-52.
77	STEIDLER L, HANS W, SCHOTTE L, et al. Treatment of murine colitis by lactococcus lactis secreting interleukin-10[J]. Science, 2000, 289(5483): 1352-1355.
78	VANDENBROUCKE K, DE HAARD H, BEIRNAERT E, et al. Orally administered L. lactis secreting an anti-TNF nanobody demonstrate efficacy in chronic colitis[J]. Mucosal Immunology, 2010, 3(1): 49-56.
79	FANG X, ZHOU X T, MIAO Y Q, et al. Therapeutic effect of GLP-1 engineered strain on mice model of Alzheimer's disease and Parkinson's disease[J]. AMB Express, 2020, 10(1): 80.
80	CHEN T T, TIAN P Y, HUANG Z X, et al. Engineered commensal bacteria prevent systemic inflammation-induced memory impairment and amyloidogenesis via producing GLP-1[J].Applied Microbiology and Biotechnology, 2018, 102(17): 7565-7575.
81	CECARINI V, BONFILI L, GOGOI O, et al. Neuroprotective effects of p62(SQSTM1)-engineered lactic acid bacteria in Alzheimer's disease: a pre-clinical study[J]. Aging, 2020, 12(16): 15995-16020.
82	LINDNER F, DIEPOLD A. Optogenetics in bacteria-applications and opportunities[J]. FEMS Microbiology Reviews, 2022, 46(2): fuab055.
83	BAUMSCHLAGER A, KHAMMASH M. Synthetic biological approaches for optogenetics and tools for transcriptional light-control in bacteria[J]. Advanced Biology, 2021, 5(5): e2000256.
84	WEI J J, Jin F. Illuminating bacterial behaviors with optogenetics[J]. Current Opinion in Solid State and Materials Science, 2022, 26(6): 101023.
85	TANDAR S T, SENOO S, TOYA Y, et al. Optogenetic switch for controlling the central metabolic flux of Escherichia coli [J]. Metabolic Engineering, 2019, 55: 68-75.
86	MIYAKE K, ABE K, FERRI S, et al. A green-light inducible lytic system for cyanobacterial cells[J].Biotechnology for Biofuels, 2014, 7: 56.
87	LI X, ZHANG C C, XU X P, et al. A single-component light sensor system allows highly tunable and direct activation of gene expression in bacterial cells[J]. Nucleic Acids Research, 2020, 48(6): e33.
88	ZHANG J Y, LUO Y H, POH C L. Blue light-directed cell migration, aggregation, and patterning[J]. Journal of Molecular Biology, 2020, 432(10): 3137-3148.
89	CHEN X J, LIU R M, MA Z C, et al. An extraordinary stringent and sensitive light-switchable gene expression system for bacterial cells[J]. Cell Research, 2016, 26(7): 854-857.
90	SUN R, LIU M Z, LU J P, et al. Bacteria loaded with glucose polymer and photosensitive ICG silicon-nanoparticles for glioblastoma photothermal immunotherapy[J]. Nature Communications, 2022, 13: 5127.
91	KANEKIYO M, ELLIS D, KING N P. New vaccine design and delivery technologies[J]. The Journal of Infectious Diseases, 2019, 219(S1): S88-S96.
92	SKWARCZYNSKI M, TOTH I. Peptide-based synthetic vaccines[J]. Chemical Science, 2016, 7(2): 842-854.
93	ALLEMAN M M, JORBA J, GREENE S A, et al. Update on vaccine-derived poliovirus outbreaks-worldwide, July 2019-February 2020[J]. MMWR Morbidity and Mortality Weekly Report, 2020, 69(16): 489-495.
94	POLACK F P, HOFFMAN S J, CRUJEIRAS G, et al. A role for nonprotective complement-fixing antibodies with low avidity for measles virus in atypical measles[J]. Nature Medicine, 2003, 9(9): 1209-1213.
95	LE NOUËN C, COLLINS P L, BUCHHOLZ U J. Attenuation of human respiratory viruses by synonymous genome recoding[J]. Frontiers in Immunology, 2019, 10: 1250.
96	COLEMAN J R, PAPAMICHAIL D, SKIENA S, et al. Virus attenuation by genome-scale changes in codon pair bias[J]. Science, 2008, 320(5884): 1784-1787.
97	BURNS C C, SHAW J, CAMPAGNOLI R, et al. Modulation of poliovirus replicative fitness in HeLa cells by deoptimization of synonymous codon usage in the capsid region[J]. Journal of Virology, 2006, 80(7): 3259-3272.
98	SCHLUB T E, BUCHMANN J P, HOLMES E C. A simple method to detect candidate overlapping genes in viruses using single genome sequences[J]. Molecular Biology and Evolution, 2018, 35(10): 2572-2581.
99	ATHEY J, ALEXAKI A, OSIPOVA E, et al. A new and updated resource for codon usage tables[J]. BMC Bioinformatics, 2017, 18(1): 391.
100	TULLOCH F, ATKINSON N J, EVANS D J, et al. RNA virus attenuation by codon pair deoptimisation is an artefact of increases in CpG/UpA dinucleotide frequencies[J]. eLife, 2014, 3: e04531.
101	JONES K L, DRANE D, GOWANS E J. Long-term storage of DNA-free RNA for use in vaccine studies[J]. BioTechniques, 2007, 43(5): 675-681.
102	MCMAHON H T, GALLOP J L. Membrane curvature and mechanisms of dynamic cell membrane remodelling[J]. Nature, 2005, 438(7068): 590-596.
103	GUPTA A, ANDRESEN J L, MANAN R S, et al. Nucleic acid delivery for therapeutic applications[J]. Advanced Drug Delivery Reviews, 2021, 178: 113834.
104	WHITEHEAD K A, LANGER R, ANDERSON D G. Knocking down barriers: advances in siRNA delivery[J]. Nature Reviews Drug Discovery, 2009, 8(2): 129-138.
105	ALLEN T M, CULLIS P R. Liposomal drug delivery systems: from concept to clinical applications[J]. Advanced Drug Delivery Reviews, 2013, 65(1): 36-48.
106	ALLISON S J, MILNER J. RNA interference by single- and double-stranded siRNA with a DNA extension containing a 3′ nuclease-resistant mini-hairpin structure[J]. Molecular Therapy-Nucleic Acids, 2014, 2: e141.
107	KUDCHODKAR S B, CHOI H, REUSCHEL E L, et al. Rapid response to an emerging infectious disease - lessons learned from development of a synthetic DNA vaccine targeting Zika virus[J]. Microbes and Infection, 2018, 20(11/12): 676-684.
108	TEBAS P, KRAYNYAK K A, PATEL A, et al. Intradermal SynCon® Ebola GP DNA vaccine is temperature stable and safely demonstrates cellular and humoral immunogenicity advantages in healthy volunteers[J]. The Journal of Infectious Diseases, 2019, 220(3): 400-410.
109	WOLFF J A, LUDTKE J J, ACSADI G, et al. Long-term persistence of plasmid DNA and foreign gene expression in mouse muscle[J]. Human Molecular Genetics, 1992, 1(6): 363-369.
110	LI L, PETROVSKY N. Molecular mechanisms for enhanced DNA vaccine immunogenicity[J]. Expert Review of Vaccines, 2016, 15(3): 313-329.
111	GAUDINSKI M R, HOUSER K V, MORABITO K M, et al. Safety, tolerability, and immunogenicity of two Zika virus DNA vaccine candidates in healthy adults: randomised, open-label, phase 1 clinical trials[J]. The Lancet, 2018, 391(10120): 552-562.
112	REICHMUTH A M, OBERLI M A, JAKLENEC A, et al. mRNA vaccine delivery using lipid nanoparticles[J]. Therapeutic Delivery, 2016, 7(5): 319-334.
113	PARDI N, HOGAN M J, WEISSMAN D. Recent advances in mRNA vaccine technology[J]. Current Opinion in Immunology, 2020, 65: 14-20.
114	CHEN R, WANG S K, BELK J A, et al. Engineering circular RNA for enhanced protein production[J]. Nature Biotechnology, 2023, 41, 262-272.
115	WANG J, TAVAKOLI J, TANG Y H. Bacterial cellulose production, properties and applications with different culture methods - a review[J]. Carbohydrate Polymers, 2019, 219: 63-76.
116	SINGH A, WALKER K T, LEDESMA-AMARO R, et al. Engineering bacterial cellulose by synthetic biology[J]. International Journal of Molecular Sciences, 2020, 21(23): 9185.
117	MATHUR D, MEDINTZ I L. The growing development of DNA nanostructures for potential healthcare-related applications[J]. Advanced Healthcare Materials, 2019, 8(9): e1801546.
118	LI M, ZHENG M X, WU S Y, et al. In vivo production of RNA nanostructures via programmed folding of single-stranded RNAs[J]. Nature Communications, 2018, 9: 2196.
119	MCDANIEL J R, RADFORD D C, CHILKOTI A. A unified model for de novo design of elastin-like polypeptides with tunable inverse transition temperatures[J]. Biomacromolecules, 2013, 14(8): 2866-2872.
120	IBÁÑEZ-FONSECA A, FLORA T, ACOSTA S, et al. Trends in the design and use of elastin-like recombinamers as biomaterials[J]. Matrix Biology, 2019, 84: 111-126.
121	DURAJ-THATTE A M, DORVAL COURCHESNE N M, PRAVESCHOTINUNT P, et al. Hydrogels: genetically programmable self-regenerating bacterial hydrogels[J]. Advanced Materials, 2019, 31(40): 1901826.
122	SANKARAN S, BECKER J, WITTMANN C, et al. Optoregulated drug release from an engineered living material: self-replenishing drug depots for long-term, light-regulated delivery[J]. Small, 2019, 15(5): e1804717.
123	OU B M, YANG Y, THAM W L, et al. Genetic engineering of probiotic Escherichia coli Nissle 1917 for clinical application[J]. Applied Microbiology and Biotechnology, 2016, 100(20): 8693-8699.
124	XU L J, WANG X Y, SUN F, et al. Harnessing proteins for engineered living materials[J]. Current Opinion in Solid State and Materials Science, 2021, 25(1): 100896.
125	RYNGAJŁŁO M, JĘDRZEJCZAK-KRZEPKOWSKA M, KUBIAK K, et al. Towards control of cellulose biosynthesis by Komagataeibacter using systems-level and strain engineering strategies: current progress and perspectives[J]. Applied Microbiology and Biotechnology, 2020, 104(15): 6565-6585.
126	ELBAZ J, YIN P, VOIGT C A. Genetic encoding of DNA nanostructures and their self-assembly in living bacteria[J]. Nature Communications, 2016, 7: 11179.
127	VARANKO A K, SU J C, CHILKOTI A. Elastin-like polypeptides for biomedical applications[J]. Annual Review of Biomedical Engineering, 2020, 22: 343-369.
128	WANG Y Y, AN B L, XUE B, et al. Living materials fabricated via gradient mineralization of light-inducible biofilms[J]. Nature Chemical Biology, 2021, 17(3): 351-359.
129	ZHOU P, YANG X L, WANG X G, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin[J]. Nature, 2020, 579(7798): 270-273.
130	SEFIK E, ISRAELOW B, MIRZA H, et al. A humanized mouse model of chronic COVID-19[J]. Nature Biotechnology, 2022, 40(6): 906-920.
131	YE C Y, QI L N, WANG J, et al. COVID-19 pandemic: advances in diagnosis, treatment, organoid applications and impacts on cancer patient management[J]. Frontiers in Medicine, 2021, 8: 606755.
132	CHEN D, SU X, CHEN H B, et al. Human organoids as a promising platform for fighting COVID-19[J]. International Journal of Biological Sciences, 2022, 18(3): 901-910.
133	HAN Y L, DUAN X H, YANG L L, et al. Identification of SARS-CoV-2 inhibitors using lung and colonic organoids[J]. Nature, 2021, 589(7841): 270-275.
134	EBISUDANI T, SUGIMOTO S, HAGA K, et al. Direct derivation of human alveolospheres for SARS-CoV-2 infection modeling and drug screening[J]. Cell Reports, 2021, 35(10): 109218.
135	PARK J W, LAGNITON P N P, LIU Y, et al. mRNA vaccines for COVID-19: what, why and how[J]. International Journal of Biological Sciences, 2021, 17(6): 1446-1460.
136	JAHANSHAHLU L, REZAEI N. Monoclonal antibody as a potential anti-COVID-19[J]. Biomedicine & Pharmacotherapy, 2020, 129: 110337.
137	MOOSAVI B, MOUSAVI B, YANG W C, et al. Yeast-based assays for detecting protein-protein/drug interactions and their inhibitors[J]. European Journal of Cell Biology, 2017, 96(6): 529-541.
138	郑美云, 李妙君, 沈国婴, 等. 用酵母双杂交系统筛选抗人p53单链抗体[J] 细胞与分子免疫学杂志, 2016, 32(1): 112-117.
	ZHENG M Y, LI M J, SHEN G Y, et al. Screening of special scFv antibody against human p53 protein by yeast two-hybrid system[J]. Chinese Journal of Cellular and Molecular Immunology, 2016, 32(1):112-117.
139	ROZENBLATT-ROSEN O, REGEV A, OBERDOERFFER P, et al. The human tumor atlas network: charting tumor transitions across space and time at single-cell resolution[J]. Cell, 2020, 181(2): 236-249.

项目	酶传感器	质粒传感器	哺乳动物细胞传感器	细菌传感器
原始信号	酶活性失调	转录活性改变	转录或代谢活性改变	生化特性改变（如营养物质，pH等）
放大方式	催化放大尿液浓缩	分泌物增加	细胞增殖分泌物增加	细菌增殖催化放大尿液浓缩
信号特征	底物信号扩大	特异性转录	肿瘤微环境驱动信号激活	特异性肿瘤靶向浸润
检测方式	尿液，血液，呼吸	尿液，血液	尿液，血液	尿液，血液

材料种类	材料名称	材料特性	参考文献
多糖材料	细菌纤维素	高物理强度和高保水能力，可生产人造血管支架	[115]
多糖材料	纤维素-几丁质共聚物	可作为静脉假体，在动物体内能被降解	[116]
核酸材料	ssDNA纳米材料	制作病原体传感器，对动物体内的病原体进行探测	[117]
核酸材料	RNA纳米材料	控制体内细胞代谢过程	[118]
蛋白质材料	弹性蛋白样多肽	用于组织工程和药物递送	[119]
蛋白质材料	弹性蛋白样重组体	制作基于ELR的水凝胶，用于传递药物和疫苗	[120]
活细胞材料	curli纳米纤维	与生物膜融合后可结合在特定表面，用于治疗小鼠胃肠道炎症	[121]
	大肠杆菌ECM材料	生产抗肿瘤药物——脱氧紫罗兰素	[122]
	E.coli Nissle材料	一种无毒性的大肠杆菌材料，对患者进行持续给药	[123]
	枯草芽孢杆菌水凝膜	具有多功能再生和可调性，可作为潜在的医疗生物材料	[124]

[1]	吕海龙, 王建, 吕浩, 王金, 徐勇, 顾大勇. 合成生物学在下一代基因诊断技术中的应用进展[J]. 合成生物学, 2023, 4(2): 318-332.
[2]	申赵铃, 吴艳玲, 应天雷. 合成生物学与病毒疫苗研发[J]. 合成生物学, 2023, 4(2): 333-346.
[3]	马孟丹, 刘宇辰. 合成生物学在疾病信息记录与实时监测中的应用潜力[J]. 合成生物学, 2023, 4(2): 301-317.
[4]	陈青黎, 童贻刚. 工程噬菌体的合成生物学“智造”[J]. 合成生物学, 2023, 4(2): 283-300.
[5]	高纤云, 牛灵雪, 见妮, 管宁子. 微生物合成生物学在疾病诊疗上的应用进展[J]. 合成生物学, 2023, 4(2): 263-282.
[6]	谢君鸿, 何晶晶, 周鹏辉. 合成生物学与工程化T细胞治疗[J]. 合成生物学, 2023, 4(2): 373-393.
[7]	朱骊宇, 赵玉龙, 李伟, 王立宾. 哺乳动物染色体工程研究进展[J]. 合成生物学, 2023, 4(2): 394-406.
[8]	于袁欢, 周阳, 王欣怡, 孔德强, 叶海峰. 光遗传学照进生物医学研究进展[J]. 合成生物学, 2023, 4(1): 102-140.
[9]	王喜先, 孙晴, 刁志钿, 徐健, 马波. 拉曼光谱技术在单细胞表型检测与分选中的应用进展[J]. 合成生物学, 2023, 4(1): 204-224.
[10]	朱振, 田晶, 江静, 王旺银, 曹旭鹏. 微藻叶绿体细胞器工厂研究进展[J]. 合成生物学, 2022, 3(6): 1218-1234.
[11]	董佳钰, 李敏, 肖宗华, 胡明, 松田侑大, 汪伟光. 米曲霉异源表达天然产物研究进展[J]. 合成生物学, 2022, 3(6): 1126-1149.
[12]	崔金玉, 张爱娣, 栾国栋, 吕雪峰. 微藻光驱固碳合成技术的发展现状与未来展望[J]. 合成生物学, 2022, 3(5): 884-900.
[13]	史梦琳, 周琳, 王庆, 赵磊. 植物二氧化碳代谢途径改造研究进展[J]. 合成生物学, 2022, 3(5): 985-1005.
[14]	陶飞, 孙韬, 王钰, 魏婷, 倪俊, 许平. “双碳”背景下聚球藻底盘研究的挑战与机遇[J]. 合成生物学, 2022, 3(5): 932-952.
[15]	赵权宇. 面向碳中和的微藻适应性实验室进化研究进展[J]. 合成生物学, 2022, 3(5): 901-914.

合成生物学在疾病诊疗中的应用

Applications of synthetic biology in disease diagnosis and treatment

RichHTML

PDF (PC)

可视化

摘要/Abstract

引用本文

使用本文

图/表 5

参考文献 139

相关文章 15

编辑推荐

Metrics

本文评价