Abstract
In mammalian cells, signalling pathways orchestrate cellular growth, differentiation and survival, as well as many other processes that are essential for the proper functioning of cells. Here we describe cutting-edge genetic-engineering technologies for the rewiring of signalling networks in mammalian cells. Specifically, we describe the recombination of native pathway components, cross-kingdom pathway transplantation, and the development of de novo signalling within cells and organelles. We also discuss how, by designing signalling pathways, mammalian cells can acquire new properties, such as the capacity for photosynthesis, the ability to detect cancer and senescent cell markers or to synthesize hormones or metabolites in response to chemical or physical stimuli. We also review the applications of mammalian cells in biocomputing. Technologies for engineering signalling pathways in mammalian cells are advancing basic cellular biology, biomedical research and drug discovery.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 /Â 30Â days
cancel any time
Subscribe to this journal
Receive 12 digital issues and online access to articles
$119.00 per year
only $9.92 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1038%2Fs41551-024-01237-z/MediaObjects/41551_2024_1237_Fig1_HTML.png)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1038%2Fs41551-024-01237-z/MediaObjects/41551_2024_1237_Fig2_HTML.png)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1038%2Fs41551-024-01237-z/MediaObjects/41551_2024_1237_Fig3_HTML.png)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1038%2Fs41551-024-01237-z/MediaObjects/41551_2024_1237_Fig4_HTML.png)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1038%2Fs41551-024-01237-z/MediaObjects/41551_2024_1237_Fig5_HTML.png)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1038%2Fs41551-024-01237-z/MediaObjects/41551_2024_1237_Fig6_HTML.png)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1038%2Fs41551-024-01237-z/MediaObjects/41551_2024_1237_Fig7_HTML.png)
Similar content being viewed by others
References
Shamir, M., Bar-On, Y., Phillips, R. & Milo, R. SnapShot: timescales in cell biology. Cell 164, 1302â1302 (2016).
Javdan, S. B. & Deans, T. L. Design and development of engineered receptors for cell and tissue engineering. Curr. Opin. Syst. Biol. 28, 100363 (2021).
Veggiani, G. et al. Engineered SH2 domains with tailored specificities and enhanced affinities for phosphoproteome analysis. Protein Sci. 28, 403â413 (2019).
Jones, R. D. et al. Robust and tunable signal processing in mammalian cells via engineered covalent modification cycles. Nat. Commun. 13, 1720 (2022).
Chen, P. et al. A plant-derived natural photosynthetic system for improving cell anabolism. Nature 612, 546â554 (2022).
Woodall, N. B. et al. De novo design of tyrosine and serine kinase-driven protein switches. Nat. Struct. Mol. Biol. 28, 762â770 (2021).
Way, J. C., Burrill, D. R. & Silver, P. A. Bioinspired design of artificial signaling systems. Biochemistry 62, 178â186 (2023).
Krawczyk, K., Scheller, L., Kim, H. & Fussenegger, M. Rewiring of endogenous signaling pathways to genomic targets for therapeutic cell reprogramming. Nat. Commun. 11, 608 (2020).
Ma, Y. et al. Synthetic mammalian signaling circuits for robust cell population control. Cell 185, 967â979 e912 (2022).
Atar, D. et al. Adapter CAR T cell therapy for the treatment of B-lineage lymphomas. Biomedicines 10, 2420 (2022).
Chung, H. K. et al. A compact synthetic pathway rewires cancer signaling to therapeutic effector release. Science 364, 6982 (2019).
Hicks, M., Bachmann, T. T. & Wang, B. Synthetic biology enables programmable cell-based biosensors. ChemPhysChem 21, 132â144 (2020).
Goni-Moreno, A. & Nikel, P. I. High-performance biocomputing in synthetic biology-integrated transcriptional and metabolic circuits. Front. Bioeng. Biotechnol. 7, 40 (2019).
Arndt, C. et al. Adaptor CAR platforms-next generation of T cell-based cancer immunotherapy. Cancers 12, 1302 (2020).
Li, H. S. et al. Multidimensional control of therapeutic human cell function with synthetic gene circuits. Science 378, 1227â1234 (2022).
Gaber, R. et al. Designable DNA-binding domains enable construction of logic circuits in mammalian cells. Nat. Chem. Biol. 10, 203â208 (2014).
Cai, K., Zhang, X. & Bai, X. C. Cryo-electron microscopic analysis of single-pass transmembrane receptors. Chem. Rev. 122, 13952â13988 (2022).
Armbruster, B. N., Li, X., Pausch, M. H., Herlitze, S. & Roth, B. L. Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand. Proc. Natl Acad. Sci. USA 104, 5163â5168 (2007).
Rao, R. et al. Ligand-gated ion channels as targets for treatment and management of cancers. Front. Physiol. 13, 839437 (2022).
Kawatkar, A. et al. CETSA beyond soluble targets: a broad application to multipass transmembrane proteins. ACS Chem. Biol. 14, 1913â1920 (2019).
Yang, Z. J., Yu, Z. Y., Cai, Y. M., Du, R. R. & Cai, L. Engineering of an enhanced synthetic Notch receptor by reducing ligand-independent activation. Commun. Biol. 3, 116 (2020).
Leopold, A. V., Thankachan, S., Yang, C., Gerashchenko, D. & Verkhusha, V. V. A general approach for engineering RTKs optically controlled with far-red light. Nat. Methods 19, 871â880 (2022).
Sloas, D. C., Tran, J. C., Marzilli, A. M. & Ngo, J. T. Tension-tuned receptors for synthetic mechanotransduction and intercellular force detection. Nat. Biotechnol. 41, 1287â1295 (2023).
Khamaisi, B., Luca, V. C., Blacklow, S. C. & Sprinzak, D. Functional comparison between endogenous and synthetic notch systems. ACS Synth. Biol. 11, 3343â3353 (2022).
Morsut, L. et al. Engineering customized cell sensing and response behaviors using synthetic notch receptors. Cell 164, 780â791 (2016).
Lindner, S. E., Johnson, S. M., Brown, C. E. & Wang, L. D. Chimeric antigen receptor signaling: functional consequences and design implications. Sci. Adv. 6, eaaz3223 (2020).
Cho, J. H., Collins, J. J. & Wong, W. W. Universal chimeric antigen receptors for multiplexed and logical control of T cell responses. Cell 173, 1426â1438 (2018).
Ruffo, E. et al. Post-translational covalent assembly of CAR and synNotch receptors for programmable antigen targeting. Nat. Commun. 14, 2463 (2023).
Leopold, A. V. & Verkhusha, V. V. Light control of RTK activity: from technology development to translational research. Chem. Sci. 11, 10019â10034 (2020).
Ma, Y. et al. Clustering of the zeta-chain can initiate T cell receptor signaling. Int. J. Mol. Sci. 21, 3498 (2020).
Zhu, H. & Roth, B. L. DREADD: a chemogenetic GPCR signaling platform. Int. J. Neuropsychopharmacol. 18, pyu007 (2014).
Tichy, A. M., So, W. L., Gerrard, E. J. & Janovjak, H. Structure-guided optimization of light-activated chimeric G-protein-coupled receptors. Structure 30, 1075â1087 (2022).
Koyanagi, M. et al. Optogenetic potentials of diverse animal opsins: parapinopsin, peropsin, LWS bistable opsin. Adv. Exp. Med. Biol. 1293, 141â151 (2021).
Geiser, A. H. et al. Bacteriorhodopsin chimeras containing the third cytoplasmic loop of bovine rhodopsin activate transducin for GTP/GDP exchange. Protein Sci. 15, 1679â1690 (2006).
Marcus, D. J. & Bruchas, M. R. Optical approaches for investigating neuromodulation and G protein-coupled receptor signaling. Pharm. Rev. 75, 1119â1139 (2023).
Leemann, S. & Kleinlogel, S. Functional optimization of light-activatable Opto-GPCRs: illuminating the importance of the proximal C-terminus in G-protein specificity. Front. Cell Dev. Biol. 11, 1053022 (2023).
Airan, R. D., Thompson, K. R., Fenno, L. E., Bernstein, H. & Deisseroth, K. Temporally precise in vivo control of intracellular signalling. Nature 458, 1025â1029 (2009).
Young, M. et al. Computational design of orthogonal membrane receptor-effector switches for rewiring signaling pathways. Proc. Natl Acad. Sci. USA 115, 7051â7056 (2018).
Wang, L. et al. Use of DREADD technology to identify novel targets for antidiabetic drugs. Annu. Rev. Pharmacol. Toxicol. 61, 421â440 (2021).
Magnus, C. J. et al. Ultrapotent chemogenetics for research and potential clinical applications. Science 364, 5282 (2019).
Marvin, J. S. et al. A genetically encoded fluorescent sensor for in vivo imaging of GABA. Nat. Methods 16, 763â770 (2019).
Sun, F. et al. A genetically encoded fluorescent sensor enables rapid and specific detection of dopamine in flies, fish and mice. Cell 174, 481â496 (2018).
Leopold, A. V., Shcherbakova, D. M. & Verkhusha, V. V. Fluorescent biosensors for neurotransmission and neuromodulation: engineering and applications. Front. Cell. Neurosci. 13, 474 (2019).
Kim, H., Baek, I. Y. & Seong, J. Genetically encoded fluorescent biosensors for GPCR research. Front Cell Dev. Biol. 10, 1007893 (2022).
Borowicz, P., Chan, H., Hauge, A. & Spurkland, A. Adaptor proteins: flexible and dynamic modulators of immune cell signalling. Scand. J. Immunol. 92, e12951 (2020).
Mugabo, Y. & Lim, G. E. Scaffold proteins: from coordinating signaling pathways to metabolic regulation. Endocrinology 159, 3615â3630 (2018).
Christensen, N. R. et al. PDZ domains as drug targets. Adv. Ther. 2, 1800143 (2019).
Martyn, G. D. et al. Engineered SH2 domains for targeted phosphoproteomics. ACS Chem. Biol. 17, 1472â1484 (2022).
Papaioannou, D., Geibel, S., Kunze, M. B., Kay, C. W. & Waksman, G. Structural and biophysical investigation of the interaction of a mutant Grb2 SH2 domain (W121G) with its cognate phosphopeptide. Protein Sci. 25, 627â637 (2016).
Diop, A. et al. SH2 domains: folding, binding and therapeutical approaches. Int. J. Mol. Sci. 23, 15944 (2022).
Jones, R. B., Gordus, A., Krall, J. A. & MacBeath, G. A quantitative protein interaction network for the ErbB receptors using protein microarrays. Nature 439, 168â174 (2006).
Findlay, G. M. et al. Interaction domains of Sos1/Grb2 are finely tuned for cooperative control of embryonic stem cell fate. Cell 152, 1008â1020 (2013).
Howard, P. L., Chia, M. C., Del Rizzo, S., Liu, F. F. & Pawson, T. Redirecting tyrosine kinase signaling to an apoptotic caspase pathway through chimeric adaptor proteins. Proc. Natl Acad. Sci. USA 100, 11267â11272 (2003).
Barnea, G. et al. The genetic design of signaling cascades to record receptor activation. Proc. Natl Acad. Sci. USA 105, 64â69 (2008).
Kongkrongtong, T., Sumigama, Y., Nagamune, T. & Kawahara, M. Reprogramming signal transduction through a designer receptor tyrosine kinase. Commun. Biol. 4, 752 (2021).
Kipniss, N. H. et al. Engineering cell sensing and responses using a GPCR-coupled CRISPRâCas system. Nat. Commun. 8, 2212 (2017).
Kroeze, W. K. et al. PRESTO-Tango as an open-source resource for interrogation of the druggable human GPCRome. Nat. Struct. Mol. Biol. 22, 362â369 (2015).
Zhan, Y., Li, A., Cao, C. & Liu, Y. CRISPR signal conductor 2.0 for redirecting cellular information flow. Cell Discov. 8, 26 (2022).
Boyden, E. S., Zhang, F., Bamberg, E., Nagel, G. & Deisseroth, K. Millisecond-timescale, genetically targeted optical control of neural activity. Nat. Neurosci. 8, 1263â1268 (2005).
Govorunova, E. G., Sineshchekov, O. A. & Spudich, J. L. Emerging diversity of channelrhodopsins and their structure-function relationships. Front. Cell. Neurosci. 15, 800313 (2021).
Chernov, K. G., Redchuk, T. A., Omelina, E. S. & Verkhusha, V. V. Near-infrared fluorescent proteins, biosensors and optogenetic tools engineered from phytochromes. Chem. Rev. 117, 6423â6446 (2017).
Hoang, X. L. T. et al. Histidine kinases: diverse functions in plant development and responses to environmental conditions. Annu Rev. Plant Biol. 72, 297â323 (2021).
Stabel, R. et al. Revisiting and redesigning light-activated cyclic-mononucleotide phosphodiesterases. J. Mol. Biol. 431, 3029â3045 (2019).
Hansen, J. et al. Transplantation of prokaryotic two-component signaling pathways into mammalian cells. Proc. Natl Acad. Sci. USA 111, 15705â15710 (2014).
Scheller, L. et al. Phosphoregulated orthogonal signal transduction in mammalian cells. Nat. Commun. 11, 3085 (2020).
Maze, A. & Benenson, Y. Artificial signaling in mammalian cells enabled by prokaryotic two-component system. Nat. Chem. Biol. 16, 179â187 (2020).
Yang, X., Her, J. & Bashor, C. J. Mammalian signaling circuits from bacterial parts. Nat. Chem. Biol. 16, 110â111 (2020).
Zhang, F. & Tzanakakis, E. S. Optogenetic regulation of insulin secretion in pancreatic β-cells. Sci. Rep. 7, 9357 (2017).
Henss, T. et al. Optogenetic tools for manipulation of cyclic nucleotides functionally coupled to cyclic nucleotide-gated channels. Br. J. Pharmacol. 179, 2519â2537 (2022).
Iseki, M. & Park, S. Y. Photoactivated adenylyl cyclases: fundamental properties and applications. Adv. Exp. Med. Biol. 1293, 129â139 (2021).
Scheib, U. et al. Rhodopsin-cyclases for photocontrol of cGMP/cAMP and 2.3-Ã structure of the adenylyl cyclase domain. Nat. Commun. 9, 2046 (2018).
Du, P. et al. De novo design of an intercellular signaling toolbox for multi-channel cellâcell communication and biological computation. Nat. Commun. 11, 4226 (2020).
Xu, C., Zhang, J., Mihai, D. M. & Washington, I. Light-harvesting chlorophyll pigments enable mammalian mitochondria to capture photonic energy and produce ATP. J. Cell Sci. 127, 388â399 (2014).
Agapakis, C. M. et al. Towards a synthetic chloroplast. PLoS ONE 6, e18877 (2011).
Cournoyer, J. E. et al. Engineering artificial photosynthetic life-forms through endosymbiosis. Nat. Commun. 13, 2254 (2022).
Van Steenkiste, N. W. L. et al. A new case of kleptoplasty in animals: marine flatworms steal functional plastids from diatoms. Sci. Adv. 5, eaaw4337 (2019).
Gabelein, C. G., Reiter, M. A., Ernst, C., Giger, G. H. & Vorholt, J. A. Engineering endosymbiotic growth of E. coli in mammalian cells. ACS Synth. Biol. 11, 3388â3396 (2022).
Wang, Z. et al. Oxygen-releasing biomaterials for regenerative medicine. J. Mater. Chem. B 11, 7300â7320 (2023).
Singh, D., Gupta, P., Singla-Pareek, S. L., Siddique, K. H. M. & Pareek, A. The journey from two-step to multi-step phosphorelay signaling systems. Curr. Genomics 22, 59â74 (2021).
Yang, L. et al. Reconstituting Arabidopsis CRY2 signaling pathway in mammalian cells reveals regulation of transcription by direct binding of CRY2 to DNA. Cell Rep. 24, 585â593 e584 (2018).
Stein, V. & Alexandrov, K. Protease-based synthetic sensing and signal amplification. Proc. Natl Acad. Sci. USA 111, 15934â15939 (2014).
Smith, A. J., Thomas, F., Shoemark, D., Woolfson, D. N. & Savery, N. J. Guiding biomolecular interactions in cells using de novo protein-protein interfaces. ACS Synth. Biol. 8, 1284â1293 (2019).
Holt, B. A. & Kwong, G. A. Protease circuits for processing biological information. Nat. Commun. 11, 5021 (2020).
Wu, Y., von Hauff, I. V., Jensen, N., Rossner, M. J. & Wehr, M. C. Improved split TEV GPCR β-arrestin-2 recruitment assays via systematic analysis of signal peptide and β-arrestin binding motif variants. Biosensors 13, https://doi.org/10.3390/bios13010048 (2022).
Gao, X. J., Chong, L. S., Kim, M. S. & Elowitz, M. B. Programmable protein circuits in living cells. Science 361, 1252â1258 (2018).
Fink, T. & Jerala, R. Designed protease-based signaling networks. Curr. Opin. Chem. Biol. 68, 102146 (2022).
Vlahos, A. E. et al. Protease-controlled secretion and display of intercellular signals. Nat. Commun. 13, 912 (2022).
Praznik, A. et al. Regulation of protein secretion through chemical regulation of endoplasmic reticulum retention signal cleavage. Nat. Commun. 13, 1323 (2022).
Chung, H. K. et al. Tunable and reversible drug control of protein production via a self-excising degron. Nat. Chem. Biol. 11, 713â720 (2015).
Mansouri, M., Ray, P. G., Franko, N., Xue, S. & Fussenegger, M. Design of programmable post-translational switch control platform for on-demand protein secretion in mammalian cells. Nucleic Acids Res. 51, e1 (2023).
Wu, Y. & Wang, Y. Protein circuits reprogram cells. Nat. Chem. Biol. 15, 96â97 (2019).
Lepeta, K. et al. Engineered kinases as a tool for phosphorylation of selected targets in vivo. J. Cell Biol. 221, e202106179 (2022).
Rosa, S., Bertaso, C., Pesaresi, P., Masiero, S. & Tagliani, A. Synthetic protein circuits and devices based on reversible protein-protein interactions: an overview. Life 11, 1171 (2021).
Ryu, J. & Park, S. H. Simple synthetic protein scaffolds can create adjustable artificial MAPK circuits in yeast and mammalian cells. Sci. Signal 8, ra66 (2015).
Good, M. C., Zalatan, J. G. & Lim, W. A. Scaffold proteins: hubs for controlling the flow of cellular information. Science 332, 680â686 (2011).
Merljak, E., Malovrh, B. & Jerala, R. Segmentation strategy of de novo designed four-helical bundles expands protein oligomerization modalities for cell regulation. Nat. Commun. 14, 1995 (2023).
Pan, K. et al. CAR race to cancer immunotherapy: from CAR T, CAR NK to CAR macrophage therapy. J. Exp. Clin. Cancer Res. 41, 119 (2022).
Martin, D. E., Torrance, B. L., Haynes, L. & Bartley, J. M. Targeting aging: lessons learned from immunometabolism and cellular senescence. Front. Immunol. 12, 714742 (2021).
Bashor, C. J., Hilton, I. B., Bandukwala, H., Smith, D. M. & Veiseh, O. Engineering the next generation of cell-based therapeutics. Nat. Rev. Drug Discov. 21, 655â675 (2022).
Grozinger, L. et al. Pathways to cellular supremacy in biocomputing. Nat. Commun. 10, 5250 (2019).
Vogl, T. et al. Engineered bidirectional promoters enable rapid multi-gene co-expression optimization. Nat. Commun. 9, 3589 (2018).
Patel, Y. D. et al. Control of multigene expression stoichiometry in mammalian cells using synthetic promoters. ACS Synth. Biol. 10, 1155â1165 (2021).
Di Blasi, R., Marbiah, M. M., Siciliano, V., Polizzi, K. & Ceroni, F. A call for caution in analysing mammalian co-transfection experiments and implications of resource competition in data misinterpretation. Nat. Commun. 12, 2545 (2021).
Renaud-Gabardos, E. et al. Internal ribosome entry site-based vectors for combined gene therapy. World J. Exp. Med. 5, 11â20, (2015).
Liu, Z. et al. Systematic comparison of 2A peptides for cloning multi-genes in a polycistronic vector. Sci. Rep. 7, 2193 (2017).
Qin, C. et al. Precise programming of multigene expression stoichiometry in mammalian cells by a modular and programmable transcriptional system. Nat. Commun. 14, 1500 (2023).
Dabi, Y. T., Andualem, H., Degechisa, S. T. & Gizaw, S. T. Targeting metabolic reprogramming of T-cells for enhanced anti-tumor response. Biologics 16, 35â45 (2022).
Mitra, A. et al. From bench to bedside: the history and progress of CAR T cell therapy. Front. Immunol. 14, 1188049 (2023).
Klichinsky, M. et al. Human chimeric antigen receptor macrophages for cancer immunotherapy. Nat. Biotechnol. 38, 947â953 (2020).
Khawar, M. B. & Sun, H. CAR-NK cells: from natural basis to design for kill. Front. Immunol. 12, 707542 (2021).
Mansouri, M., Strittmatter, T. & Fussenegger, M. Light-controlled mammalian cells and their therapeutic applications in synthetic biology. Adv. Sci. 6, 1800952 (2019).
Kawai, M. et al. Long-term selective stimulation of transplanted neural stem/progenitor cells for spinal cord injury improves locomotor function. Cell Rep. 37, 110019 (2021).
Pan, Y. et al. Mechanogenetics for the remote and noninvasive control of cancer immunotherapy. Proc. Natl Acad. Sci. USA 115, 992â997 (2018).
Ye, H. et al. Self-adjusting synthetic gene circuit for correcting insulin resistance. Nat. Biomed. Eng. 1, 0005 (2017).
Xie, M. et al. β-cell-mimetic designer cells provide closed-loop glycemic control. Science 354, 1296â1301 (2016).
Yu, G. et al. Far-red light-activated human islet-like designer cells enable sustained fine-tuned secretion of insulin for glucose control. Mol. Ther. 30, 341â354 (2022).
Von Molitor, E., Riedel, K., Hafner, M., Rudolf, R. & Cesetti, T. Sensing senses: optical biosensors to study gustation. Sensors 20, 1811 (2020).
Choi, Y. et al. Correlation between in vitro binding activity of sweeteners to cloned human sweet taste receptor and sensory evaluation. Food Sci. Biotechnol. 30, 675â682 (2021).
Li, F. et al. A piggyBac-based TANGO GFP assay for high throughput screening of GPCR ligands in live cells. Cell Commun. Signal. 17, 49 (2019).
Nguyen, Q. T. et al. An in vivo biosensor for neurotransmitter release and in situ receptor activity. Nat. Neurosci. 13, 127â132 (2010).
Lacin, E., Muller, A., Fernando, M., Kleinfeld, D. & Slesinger, P. A. Construction of cell-based neurotransmitter fluorescent engineered reporters (CNiFERs) for optical detection of neurotransmitters in vivo. J. Vis. Exp. https://doi.org/10.3791/53290 (2016).
Ingles-Prieto, A. et al. Light-assisted small-molecule screening against protein kinases. Nat. Chem. Biol. 11, 952â954 (2015).
Smirnova, L., Morales Pantoja, I. E. & Hartung, T. Organoid intelligence (OI)âthe ultimate functionality of a brain microphysiological system. ALTEX 40, 191â203 (2023).
Baumgardner, J. et al. Solving a hamiltonian path problem with a bacterial computer. J. Biol. Eng. 3, 11 (2009).
Esau, M. et al. Solving a four-destination traveling salesman problem using Escherichia coli cells as biocomputers. ACS Synth. Biol. 3, 972â975 (2014).
van Delft, F. et al. Something has to give: scaling combinatorial computing by biological agents exploring physical networks encoding NP-complete problems. Interface Focus 8, 20180034 (2018).
Savanur, M. A., Weinstein-Marom, H. & Gross, G. Implementing logic gates for safer immunotherapy of cancer. Front. Immunol. 12, 780399 (2021).
Zhao, Z. & Sadelain, M. CAR T cell design: approaching the elusive AND-gate. Cell Res. 33, 739â740 (2023).
Abbott, R. C., Hughes-Parry, H. E. & Jenkins, M. R. To go or not to go? Biological logic gating engineered T cells. J. Immunother. Cancer 10, e004185 (2022).
Schukur, L., Geering, B., Charpin-El Hamri, G. & Fussenegger, M. Implantable synthetic cytokine converter cells with AND-gate logic treat experimental psoriasis. Sci. Transl. Med. 7, 318ra201 (2015).
Barros, M. T., Doan, P., Kandhavelu, M., Jennings, B. & Balasubramaniam, S. Engineering calcium signaling of astrocytes for neural-molecular computing logic gates. Sci. Rep. 11, 595 (2021).
Cai, H. et al. Brain organoid reservoir computing for artificial intelligence. Nat. Electron. 6, 1032â1039 (2023).
Morales Pantoja, I. E. et al. First Organoid Intelligence (OI) workshop to form an OI community. Front. Artif. Intell. 6, 1116870 (2023).
Ji, J. et al. Large-scale cardiac muscle cell-based coupled oscillator network for vertex coloring problem. Adv. Intell. Syst 5, 2200356 (2023).
Doerr, A. Transfer of a plant-derived photosynthetic system to mammalian cells. Nat. Biotechnol. 41, 21 (2023).
Lacerda, Q. et al. Improved tumor control following radiosensitization with ultrasound-sensitive oxygen microbubbles and tumor mitochondrial respiration inhibitors in a preclinical model of head and neck cancer. Pharmaceutics 15, 1302 (2023).
Blazek, M., Santisteban, T. S., Zengerle, R. & Meier, M. Analysis of fast protein phosphorylation kinetics in single cells on a microfluidic chip. Lab Chip 15, 726â734 (2015).
Zhang, Y. et al. Fast and sensitive GCaMP calcium indicators for imaging neural populations. Nature 615, 884â891 (2023).
Baek, H. J., Kim, H. S., Ahn, M., Cho, H. & Ahn, S. Ergonomic issues in brainâcomputer interface technologies: current status, challenges and future direction. Comput. Intell. Neurosci. 2020, 4876397 (2020).
Chamola, V., Vineet, A., Nayyar, A. & Hossain, E. Brain-computer interface-based humanoid control: a review. Sensors 20, 3620 (2020).
Rashid, M. et al. Current status, challenges and possible solutions of EEG-based brain-computer interface: a comprehensive review. Front. Neurorobot. 14, 25 (2020).
Weyand, S. & Chau, T. Challenges of implementing a personalized mental task near-infrared spectroscopy brain-computer interface for a non-verbal young adult with motor impairments. Dev. Neurorehabil. 20, 99â107 (2017).
Jumper, J. et al. Highly accurate protein structure prediction with AlphaFold. Nature 596, 583â589 (2021).
Sato, K., Sugawara, K. & Ogawa, W. A novel view of the insulin signaling pathway based on prediction of protein structure by the AI platform AlphaFold. J. Diabetes Investig. 14, 635â639 (2023).
Dauparas, J. et al. Robust deep learning-based protein sequence design using ProteinMPNN. Science 378, 49â56 (2022).
Watson, J. L. et al. De novo design of protein structure and function with RFdiffusion. Nature 620, 1089â1100 (2023).
Sanchez-Gutierrez, M. E. & Gonzalez-Perez, P. P. Modeling and simulation of cell signaling networks for subsequent analytics processes using big data and machine learning. Bioinform. Biol. Insights 16, 11779322221091739 (2022).
Pun, F. W., Ozerov, I. V. & Zhavoronkov, A. AI-powered therapeutic target discovery. Trends Pharmacol. Sci. 44, 561â572 (2023).
You, Y. et al. Artificial intelligence in cancer target identification and drug discovery. Signal Transduct. Target. Ther. 7, 156 (2022).
Yan, X., Liu, X., Zhao, C. & Chen, G. Q. Applications of synthetic biology in medical and pharmaceutical fields. Signal Transduct. Target. Ther. 8, 199 (2023).
Wang, G., Kong, Q., Wang, D. & Asmi, F. Ethical and social insights into synthetic biology: predicting research fronts in the post-COVID-19 era. Front. Bioeng. Biotechnol. 11, 1085797 (2023).
Kim, S. et al. CRISPR RNAs trigger innate immune responses in human cells. Genome Res. 28, 367â373 (2018).
Maimon, B. E. et al. Optogenetic peripheral nerve immunogenicity. Sci. Rep. 8, 14076 (2018).
Ferreira, L. M. R., Muller, Y. D., Bluestone, J. A. & Tang, Q. Next-generation regulatory T cell therapy. Nat. Rev. Drug Discov. 18, 749â769 (2019).
Cappell, K. M. & Kochenderfer, J. N. Long-term outcomes following CAR T cell therapy: what we know so far. Nat. Rev. Clin. Oncol. 20, 359â371 (2023).
Erdmann, A., Rehmann-Sutter, C. & Bozzaro, C. Patientsâ and professionalsâ views related to ethical issues in precision medicine: a mixed research synthesis. BMC Med. Ethics 22, 116 (2021).
Potnis, K. C. et al. Cost-effectiveness of chimeric antigen receptor T-cell therapy in adults with relapsed or refractory follicular lymphoma. Blood Adv. 7, 801â810 (2023).
Riva, L. & Petrini, C. A few ethical issues in translational research for gene and cell therapy. J. Transl. Med. 17, 395 (2019).
Fink, T. et al. Design of fast proteolysis-based signaling and logic circuits in mammalian cells. Nat. Chem. Biol. 15, 115â122 (2019).
Acknowledgements
This work was supported by research grants from the US National Institutes of Health (GM122567), the Finland Cancer Foundation and the Jane and Aatos Erkko Foundation (220011).
Author information
Authors and Affiliations
Contributions
A.V.L. analysed the papers, wrote the paper and drew the figures. V.V.V. conceived the idea and revised the paper and figures.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Peer review
Peer review information
Nature Biomedical Engineering thanks Yuchen Liu and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Additional information
Publisherâs note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Leopold, A.V., Verkhusha, V.V. Engineering signalling pathways in mammalian cells. Nat. Biomed. Eng 8, 1523â1539 (2024). https://doi.org/10.1038/s41551-024-01237-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41551-024-01237-z