A cascade reaction network mimicking the basic functional steps of adaptive immune response

Biological systems use complex ‘information-processing cores’ composed of molecular networks to coordinate their external environment and internal states. An example of this is the acquired, or adaptive, immune system (AIS), which is composed of both humoral and cell-mediated components. Here we report the step-by-step construction of a prototype mimic of the AIS that we call an adaptive immune response simulator (AIRS). DNA and enzymes are used as simple artificial analogues of the components of the AIS to create a system that responds to specific molecular stimuli in vitro. We show that this network of reactions can function in a manner that is superficially similar to the most basic responses of the vertebrate AIS, including reaction sequences that mimic both humoral and cellular responses. As such, AIRS provides guidelines for the design and engineering of artificial reaction networks and molecular devices. Supplementary information The online version of this article (doi:10.1038/nchem.2325) contains supplementary material, which is available to authorized users.

[1]  P. Rothemund Folding DNA to create nanoscale shapes and patterns , 2006, Nature.

[2]  Teruo Fujii,et al.  Predator-prey molecular ecosystems. , 2013, ACS nano.

[3]  K. Bottomly 1984: All Idiotypes are Equal, But Some are More Equal Than Others , 1984, Immunological reviews.

[4]  D. Y. Zhang,et al.  Engineering Entropy-Driven Reactions and Networks Catalyzed by DNA , 2007, Science.

[5]  Bingling Li,et al.  Real-time detection of isothermal amplification reactions with thermostable catalytic hairpin assembly. , 2013, Journal of the American Chemical Society.

[6]  C. Gutiérrez,et al.  Helix-destabilizing activity of phi 29 single-stranded DNA binding protein: effect on the elongation rate during strand displacement DNA replication. , 1995, Journal of molecular biology.

[7]  Teruo Fujii,et al.  Bottom-up construction of in vitro switchable memories , 2012, Proceedings of the National Academy of Sciences.

[8]  G. Seelig,et al.  Dynamic DNA nanotechnology using strand-displacement reactions. , 2011, Nature chemistry.

[9]  Xi Chen,et al.  Shaping up nucleic acid computation. , 2010, Current opinion in biotechnology.

[10]  M. Ali,et al.  Rolling circle amplification: applications in nanotechnology and biodetection with functional nucleic acids. , 2008, Angewandte Chemie.

[11]  Friedrich C Simmel,et al.  Programming the dynamics of biochemical reaction networks. , 2013, ACS nano.

[12]  F. Simmel Towards biomedical applications for nucleic acid nanodevices. , 2007, Nanomedicine.

[13]  Cuichen Wu,et al.  A logical molecular circuit for programmable and autonomous regulation of protein activity using DNA aptamer-protein interactions. , 2012, Journal of the American Chemical Society.

[14]  R. Murray,et al.  Timing molecular motion and production with a synthetic transcriptional clock , 2011, Proceedings of the National Academy of Sciences.

[15]  J. Van De Sande,et al.  Parallel stranded DNA. , 1988, Science.

[16]  M. Montenarh,et al.  Antisense effect of oligodeoxynucleotides with inverted terminal internucleotidic linkages: a minimal modification protecting against nucleolytic degradation. , 1992, Antisense research and development.

[17]  Lulu Qian,et al.  Supporting Online Material Materials and Methods Figs. S1 to S6 Tables S1 to S4 References and Notes Scaling up Digital Circuit Computation with Dna Strand Displacement Cascades , 2022 .

[18]  E. Winfree,et al.  Construction of an in vitro bistable circuit from synthetic transcriptional switches , 2006, Molecular systems biology.

[19]  R. Weiss,et al.  Ultrasensitivity and noise propagation in a synthetic transcriptional cascade. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[20]  M. Van Ranst,et al.  Rolling-circle amplification of viral DNA genomes using phi29 polymerase. , 2009, Trends in microbiology.

[21]  D. Y. Zhang,et al.  Control of DNA strand displacement kinetics using toehold exchange. , 2009, Journal of the American Chemical Society.

[22]  Haisu Ma,et al.  Synthesizing a novel genetic sequential logic circuit: a push-on push-off switch , 2010, Molecular systems biology.

[23]  Xi Chen,et al.  Rational, modular adaptation of enzyme-free DNA circuits to multiple detection methods , 2011, Nucleic acids research.

[24]  Y. Sakai,et al.  Programming an in vitro DNA oscillator using a molecular networking strategy , 2011, Molecular systems biology.

[25]  Michael E Phelps,et al.  Systems Biology and New Technologies Enable Predictive and Preventative Medicine , 2004, Science.

[26]  Teruo Fujii,et al.  Spatial waves in synthetic biochemical networks. , 2013, Journal of the American Chemical Society.

[27]  Friedrich C Simmel,et al.  Nucleic acid based molecular devices. , 2011, Angewandte Chemie.

[28]  Jehoshua Bruck,et al.  Neural network computation with DNA strand displacement cascades , 2011, Nature.

[29]  Simon A McManus,et al.  Turning a kinase deoxyribozyme into a sensor. , 2013, Journal of the American Chemical Society.