Novel Diagnostic and Therapeutic Opportunities by Engineering Molecular Systems into Cells - NCCR MSE

Novel Diagnostic and Therapeutic Opportunities by Engineering Molecular Systems into Cells

Anti-obesity designer implant. The implanted designer cells monitor the blood-fat levels of obese animals and coordinate expression of an appetite-suppressing peptide hormone which tells the animal that it is full. Consequently, food intake drops and body weight decreases until the animal reaches its normal body weight.
Anti-obesity designer implant. The implanted designer cells monitor the blood-fat levels of obese animals and coordinate expression of an appetite-suppressing peptide hormone which tells the animal that it is full. Consequently, food intake drops and body weight decreases until the animal reaches its normal body weight.

Benefitting from synergies and the unique expertise of various projects within the NCCR Molecular Systems Engineering, the focus will be on the design of cellular diagnosis and therapeutic production factories that detect and correct physiological disorders.

In modern medicine, diagnosis of disorders kick-off therapeutic interventions and early-stage discovery of pathologies significantly improves therapeutic success. However, most disorders will only be diagnosed when discomfort urges a patient to seek medical advice. In these cases treatment may be too late.

Tumour markers, immune response proteins and pathology-associated metabolites are monitored for diagnosis and therapy management by quantitative analysis of blood samples or biopsies. This requires medical intervention that is typically initiated when the patient has symptoms and is seeking medical advice. However, preventive medical check-ups for the prognosis of physiological disorders are not receiving enough attention.

Synthetic gene circuits that constantly monitor physiological processes, detect a pathological situation and produce diagnostic output or coordinate therapeutic interventions could change our health-care system from the standard symptom-treatment scheme to a symptom-free preventive care strategy.

Scientific Highlight

Mind-Controlled Gene Expression (read the publication in full here): The Fussenegger-Group has designed a synthetic mind-controlled gene switch that enables human brain activities and mental states to wirelessly program transgene expression in cells. This device harnesses the electric energy of a person’s brainwaves thanks to an electro-encephalogram to trigger a light-emitting diode, which remotely activates light-inducible genes (optogenetic switch) in a small implant placed in mice. This technolgy, which was selected by the Scientist as one of 2014’s “Big-Advance” in Science, may provide cell-based treatments that respond to specific mental states.


A. Bertschi, B. Stefanov, S. Xue, G. Charpin-El Hamri, A. P. Teixeira, M. Fussenegger “Controlling therapeutic protein expression via inhalation of a butter flavor molecule“ Nucleic Acids Res. 2023. [DOI]
M. Mahameed, P. Wang, S. Xue, M. Fussenegger “Engineering receptors in the secretory pathway for orthogonal signalling control“ Nat. Commun. 2022. [DOI]
S. Galvan, O. Madderson, S. Xue, A. P. Teixeira, M. Fussenegger “Regulation of Transgene Expression by the Natural Sweetener Xylose“ Adv. Sci. 2022. [DOI]
M. Mansouri, P. G. Ray, N. Franko, S. Xue, M. Fussenegger “Design of programmable post-translational switch control platform for on-demand protein secretion in mammalian cells“ Nucleic Acids Res. 2022. [DOI]
B. A. Stefanov, M. Fussenegger “Biomarker-driven feedback control of synthetic biology systems for next-generation personalized medicine“ Front. Bioeng. Biotechnol. 2022. [DOI]
B. Stefanov, M. Mansouri, G. Charpin-El Hamri, M. Fussenegger “Sunlight-Controllable Biopharmaceutical Production for Remote Emergency Supply of Directly Injectable Therapeutic Proteins“ Small 2022. [DOI]
T. Strittmatter, Y. Wang, A. Bertschi, L. Scheller, P. C. Freitag, P. G. Ray, P. Stuecheli, J. V. Schaefer, T. Reinberg, D. Tsakiris, A. Plückthun, H. Ye, M. Fussenegger “Programmable DARPin-based receptors for the detection of thrombotic markers“ Nat. Chem. Biol. 2022. [DOI]
V. Haellman, M. Pirkl, A. Akmammedov, P. Saxena, N. Beerenwinkel, R. Paro, A. P. Teixeira, M. Fussenegger “dCas9-mediated dysregulation of gene expression in human induced pluripotent stem cells during primitive streak differentiation“ Metab. Eng. 2022 [More Information]
M. Fussenegger “Autonomous push button-controlled rapid insulin release from a piezoelectrically activated subcutaneous cell implant“ Sci. Adv. 2022. [DOI]
D. Monserrat Lopez, V. Grimaudo, G. Prone, A. Flisch, A. Riedo, R. Zboray, T. Lüthi, M. MayorM. Fussenegger, P. Broekmann, P. Wurz, E. Lörtscher “Automated, 3-D and Sub-Micron Accurate Ablation-Volume Determination by Inverse Molding and X-Ray Computed Tomography“ Adv. Sci. 2022. [DOI]
M. Mansouri, M. Fussenegger “Electrogenetics: Bridging synthetic biology and electronics to remotely control the behavior of mammalian designer cells“ Current Opinion in Chemical Biology 2022. [DOI]
M. Mahameed, M. Fussenegger “Engineering Autonomous Closed-loop Designer Cells for Disease Therapy“ iScience 2022. [DOI]
M. Mahameed, S. Xue, B. Stefanov, G. C. Hamri, M. Fussenegger “Engineering a Rapid Insulin Release System Controlled By Oral Drug Administration“ Adv. Sci. 2022. [DOI]
H. Wang, M. Xie, G. Rizzi, X. Li, K. Tan, M. Fussenegger “Identification of Sclareol As a Natural Neuroprotective Cav1.3-Antagonist Using Synthetic Parkinson-Mimetic Gene Circuits and Computer-Aided Drug Discovery“ Adv. Sci. 2022. [DOI]
A. P. Teixeira, P. Stücheli, D. Ausländer, P. Schönenberger, S. Hürlemann, M. Fussenegger “CelloSelect – A synthetic cellobiose metabolic pathway for selection of stable transgenic CHO cell lines“ Metab. Eng. 2022. [DOI]
M. Mansouri, M. Fussenegger “Remote Control of Mammalian Therapeutic Designer Cells“ Cell Engineering 2021. [DOI]
N. Franko, A. P. Teixeira, S. Xue, G. Charpin-El Hamri, M. Fussenegger “Design of modular autoproteolytic gene switches responsive to anti-coronavirus drug candidates“ Nat. Commun. 2021. [DOI]
M. Mansouri, M. Fussenegger “Synthetic Biology-based Optogenetic Approaches to Control Therapeutic Designer Cells“ Curr. Opin. Syst. Biol. 2021. [DOI]
M. Mansouri, M. Fussenegger “Therapeutic cell engineering: designing programmable synthetic genetic circuits in mammalian cells“ Protein Cell 2021. [DOI]
T. Strittmatter, P. Argast, P. Buchman, K. Krawczyk, M. Fussenegger “Control of gene expression in engineered mammalian cells with a programmable shear-stress inducer“ Biotechnol. Bioeng. 2021. [DOI]
B. Stefanov, A. P. Teixeira, M. Mansouri, A. Bertschi, K. Krawczyk, G. C. Hamri, S. Xue, M. Fussenegger “Genetically Encoded Protein Thermometer Enables Precise Electrothermal Control of Transgene Expression“ Adv. Sci. 2021. [DOI]
M. Mansouri, S. Xue, M. Hussherr, T. Strittmatter, G. Camenisch, M. Fussenegger “Smartphone-Flashlight-Mediated Remote Control of Rapid Insulin Secretion Restores Glucose Homeostasis in Experimental Type-1 Diabetes“ Small 2021. [DOI]
O. Madderson, A. P. Teixeira, M. Fussenegger “Emerging mammalian gene switches for controlling implantable cell therapies“ Curr. Opin. Chem. Biol. 2021. [DOI]
M. Mansouri, M. Hussherr, T. Strittmatter, P. Buchmann, S. Xue, G. Camenisch, M. Fussenegger “Smart-watch-programmed green-light-operated percutaneous control of therapeutic transgenes“ Nat. Commun. 2021. [DOI]
V. Haellman, T. Strittmatter, A. Bertschi, P. Stücheli, M. Fussenegger “A Versatile Plasmid Architecture for Mammalian Synthetic Biology (Vamsyb)“ Metab. Eng. 2021. [DOI]
F. Sedlmayer, A. Woischnig, V. Unterreiner, F. Fuchs, D. Baeschlin, N. Khanna, M. Fussenegger “5-Fluorouracil Blocks Quorum-Sensing of Biofilm-Embedded Methicillin-Resistant Staphylococcus Aureus in Mice“ Nucleic Acids Res. 2021. [DOI]
V. Haellman, P. Saxena, Y. Jiang, M. Fussenegger “Rational Design and Optimization of Synthetic Gene Switches for Controlling Cell-Fate Decisions in Pluripotent Stem Cells“ Metab. Eng. 2021. [DOI]
T. Strittmatter, S. Egli, A. Bertschi, R. Plieninger, D. Bojar, M. Xie, M. Fussenegger “Gene switch for l-glucose-induced biopharmaceutical production in mammalian cells“ Biotechnol. Bioeng. 2021. [DOI]
F. Teng, M. Fussenegger “Shedding Light on Extracellular Vesicle Biogenesis and Bioengineering“ Adv. Sci. 2020. [DOI]
M. Xie, M. Viviani, M. Fussenegger “Engineering Precision Therapies: Lessons and Motivations from the Clinic“ Synth. Biol. 2020. [DOI]
D. Ausländer, P. F. Lang, M. Kemi, M. Fussenegger “Design of Multipartite Transcription Factors for Multiplexed Logic Genome Integration Control in Mammalian Cells“ ACS Synth. Biol. 2020. [DOI]
M. Mansouri, S. Lichtenstein, T. Strittmatter, P. Buchmann, M. Fussenegger “Construction of a Multiwell Light-Induction Platform for Traceless Control of Gene ExpressionGeneexpression in Mammalian Cells“ Photoswitching Proteins : Methods and Protocols 2020. [DOI]
L. Scheller, M. Schmollack, A. Bertschi, M. Mansouri, P. Saxena, M. Fussenegger “Phosphoregulated orthogonal signal transduction in mammalian cells“ Nat. Commun. 2020. [DOI]
K. Krawczyk, S. Xue, P. Buchmann, G. Charpin-El-Hamri, P. Saxena, M. Hussherr, J. Shao, H. Ye, M. Xie, M. Fussenegger “Electrogenetic cellular insulin release for real-time glycemic control in type 1 diabetic mice“ Science 2020. [DOI]
P. Stücheli, S. Sieber, D. W. Fuchs, L. Scheller, T. Strittmatter, P. Saxena, K. Gademann, M. Fussenegger “Genetically encoded betaxanthin-based small-molecular fluorescent reporter for mammalian cells“ Nucleic Acids Res. 2020. [DOI]
C. E. Meyer, J. Liu, I. Craciun, D. Wu, H. Wang, M. Xie, M. FusseneggerC. G. Palivan “Segregated Nanocompartments Containing Therapeutic Enzymes and Imaging Compounds within DNA-Zipped Polymersome Clusters for Advanced Nanotheranostic Platform“ Small 2020. [DOI]
K. Krawczyk, L. Scheller, H. Kim, M. Fussenegger “Rewiring of endogenous signaling pathways to genomic targets for therapeutic cell reprogramming“ Nat. Commun. 2020. [DOI]
B. M. Gaub, K. C. Kasuba, E. Mace, T. Strittmatter, P. R. Laskowski, S. A. Geissler, A. Hierlemann, M. FusseneggerB. RoskaD. J. Müller “Neurons differentiate magnitude and location of mechanical stimuli“ Proc. Natl. Acad. Sci. U.S.A. 2019. [DOI]
D. Bojar, M. Fussenegger “The Role of Protein Engineering in Biomedical Applications of Mammalian Synthetic Biology“ Small 2019. [DOI]
P. Bai, Y. Liu, S. Xue, G. C. Hamri, P. Saxena, H. Ye, M. Xie, M. Fussenegger “A fully human transgene switch to regulate therapeutic protein production by cooling sensation“ Nat. Med. 2019. [DOI]
H. Chassin, M. Müller, M. Tigges, L. Scheller, M. Lang, M. Fussenegger “A modular degron library for synthetic circuits in mammalian cells“ Nat. Commun. 2019. [DOI]
L. Scheller, M. Fussenegger “From synthetic biology to human therapy: engineered mammalian cells“ Curr. Opin. Biotechnol. 2019, 58:108-16. [DOI]
H. Kim, D. Bojar, M. Fussenegger “A CRISPR/Cas9-based central processing unit to program complex logic computation in human cells“ Proc. Natl. Acad. Sci. U.S.A. 2019. [DOI]
F. Tolle, P. Stücheli, M. Fussenegger “Genetic circuitry for personalized human cell therapy“ Curr. Opin. Biotechnol. 2019, 59:31-38. [DOI]
D. Bojar, T. Fuhrer, M. Fussenegger “Purity by design: Reducing impurities in bioproduction by stimulus-controlled global translational downregulation of non-product proteins“ Metab. Eng. 2018. [DOI]
M. Mansouri, T. Strittmatter, M. Fussenegger “Light-Controlled Mammalian Cells and Their Therapeutic Applications in Synthetic Biology“ Adv. Sci. 2018. [DOI]
Y. Liu, G. Charpin-El Hamri, H. Ye, M. Fussenegger “A synthetic free fatty acid-regulated transgene switch in mammalian cells and mice“ Nucleic Acids Res. 2018. [DOI]
A. P. Teixeira, M. Fussenegger “Engineering mammalian cells for disease diagnosis and treatment“ Curr. Opin. Biotechnol. 2018. [DOI]
D. Bojar, M. Fussenegger “Programming mammalian gene expression with the antibiotic simocyclinone D8 and the flavonoid luteolin“ AIChE J. 2018. [DOI]
Y. Liu, P. Bai, A. Woischnig, G. Charpin-El Hamri, H. Ye, M. Folcher, M. Xie, N. Khanna, M. Fussenegger “Immunomimetic Designer Cells Protect Mice from MRSA Infection“ Cell 2018. [DOI]
D. Bojar, L. Scheller, G. C. Hamri, M. Xie, M. Fussenegger “Caffeine-inducible gene switches controlling experimental diabetes“ Nat. Commun. 2018. [DOI]
M. Xie, M. Fussenegger “Designing cell function: assembly of synthetic gene circuits for cell biology applications“ Nat. Rev. Mol. Cell Biol. 2018. [DOI]
Y. Okamoto, R. Kojima, F. Schwizer, E. Bartolami, T. Heinisch, S. MatileM. FusseneggerT. R. Ward “A cell-penetrating artificial metalloenzyme regulates a gene switch in a designer mammalian cell“ Nat. Commun. 2018. [DOI]
R. Kojima, M. Fussenegger “Engineering Whole Mammalian Cells for Target‐Cell‐Specific Invasion/Fusion“ Adv. Sci. 2018. [DOI]
L. Scheller, T. Strittmatter, D. Fuchs, D. Bojar, M. Fussenegger “Generalized extracellular molecule sensor platform for programming cellular behavior“ Nat. Chem. Biol. 2018. [DOI]
A. Tastanova, M. Folcher, M. Müller, G. Camenisch, A. Ponti, T. Horn, M. S. Tikhomirova, M. Fussenegger “Synthetic biology-based cellular biomedical tattoo for detection of hypercalcemia associated with cancer“ Sci. Transl. Med. 2018. [DOI]
R. Kojima, D. Bojar, G. Rizzi, G. C. Hamri, M. D. El-Baba, P. Saxena, S. Ausländer, K. R. Tan, M. Fussenegger “Designer exosomes produced by implanted cells intracerebrally deliver therapeutic cargo for Parkinson’s disease treatment“ Nat. Commun. 2018. [DOI]
H. Wang, M. Xie, G. Charpin-El Hamri, H. Ye, M. Fussenegger “Treatment of chronic pain by designer cells controlled by spearmint aromatherapy“ Nat. Biomed. Eng. 2018. [DOI]
S. Ausländer, X. Pierrat, L. Hellmann, L. Rachid, M. Fussenegger “Programmable full-adder computations in communicating three-dimensional cell cultures“ Nat. Methods 2017. [DOI]
R. Kojima, L. Scheller, M. Fussenegger “Nonimmune cells equipped with T-cell-receptor-like signaling for cancer cell ablation“ Nat. Chem. Biol. 2017. [DOI]
H. Chassin, B. Geering, L. Schukur, D. Ausländer, B. Lang, M. Fussenegger “Sensing and responding to allergic response cytokines through a genetically encoded circuit“ Nat. Commun. 2017. [DOI]
V. Haellman, M. Fussenegger “Synthetic biology – Engineering cell-based biomedical devices“ Curr. Opin. Biomed. Eng. 2017. [DOI]
F. Sedlmayer, T. Jaeger, U. Jenal, M. Fussenegger “Quorum-Quenching Human Designer Cells for Closed-Loop Control of Pseudomonas aeruginosa Biofilms“ Nano Lett. 2017. [DOI]
P. Saxena, D. Bojar, H. Zulewski, M. Fussenegger “Generation of glucose-sensitive insulin-secreting beta-like cells from human embryonic stem cells by incorporating a synthetic lineage-control network“ J. Biotechnol. 2017. [DOI]
M. Xie, D. Aubel, M. Fussenegger “Closed-loop control systems – The quest for precision therapies for diabetes“ Curr. Opin. Syst. Biol. 2017. [DOI]
A. P. Teixeira, M. Fussenegger “Synthetic biology-inspired therapies for metabolic diseases“ Curr. Opin. Biotechnol. 2017. [DOI]
D. Ausländer, M. Fussenegger “Synthetic Biology‐The Synthesis of Biology“ Angew. Chem. Int. Ed. 2017, 56:6396-419. [DOI]
S. Ausländer, M. Fussenegger “Synthetic RNA-based switches for mammalian gene expression control“ Curr. Opin. Biotechnol. 2017, 48:54-60. [DOI]
M. Muller, D. Auslander, A. Spinnler, J. Sikorski, M. Folcher, M. Fussenegger “Designed cell consortia as fragrance-programmable analog-to-digital converters“ 2017, 13:309-16. [DOI]
M. Xie, H. Ye, H. Wang, G. Charpin-El Hamri, C. Lormeau, P. Saxena, J. StellingM. Fussenegger “β-cell–mimetic designer cells provide closed-loop glycemic control“ Science 2016, 354:1296-1301. [DOI]
R. Kojima, D. Aubel, M. Fussenegger “Toward a world of theranostic medication: Programming biological sentinel systems for therapeutic intervention“ Adv. Drug Delivery Rev. 2016, 105:66-76. [DOI]
M. Xie, V. Haellman, M. FusseneggerV. Hällman “Synthetic biology-application-oriented cell engineering.“ Curr. Opin. Biotechnol. 2016, 40:139. [DOI]
P. Saxena, B. C. Heng, P. Bai, M. Folcher, H. Zulewski, M. Fussenegger “A programmable synthetic lineage-control network that differentiates human IPSCs into glucose-sensitive insulin-secreting beta-like cells“ Nat. Commun. 2016, 7:DOI:10.1038/ncomms11247. [DOI] [More Information]
P. Bai, H. Ye, M. Xie, P. Saxena, H. Zulewski, G. Charpin-El Hamri, V. Djonov, M. Fussenegger “A synthetic biology-based device prevents liver injury in mice“ J. Hepatol. 2016, 65:84. [DOI]
D. Auslaender, D. W. Fuchs, S. Huerlemann, M. Fussenegger “Engineering a ribozyme cleavage-induced split fluorescent aptamer complementation assay“ Nucleic Acids Res. 2016, 44:e94. [DOI]
A. Tastanova, A. Schulz, A. Tolstrup, A. Puklowski, H. Kaufmann, M. Fussenegger “Overexpression of YY1 increases the protein production in mammalian cells“ J. Biotechnol. 2016, 219:72. [DOI]
P. Saxena, G. Charpin-El Hamri, M. Folcher, H. Zulewski, M. Fussenegger “Synthetic gene network restoring endogenous pituitary-thyroid feedback control in experimental Graves' disease“ Proc. Natl. Acad. Sci. U.S.A. 2016, 113:1244. [DOI]
B. Geering, Z. Zokouri, S. Hurlemann, B. Gerrits, D. Auslander, A. Britschgi, M. P. Tschan, H. U. Simon, M. Fussenegger “Identification of Novel Death-Associated Protein Kinase 2 Interaction Partners by Proteomic Screening Coupled with Bimolecular Fluorescence Complementation“ Mol. Cell. Biol. 2016, 36:132-43. [DOI]
L. Lina Schukur, B. Geering, G. Charpin-El Hamri, M. Fussenegger “Implantable synthetic cytokine converter cells with AND-gate logic treat experimental psoriasis“ Sci. Transl. Med. 2015, 7:DOI: 10.1126/scitranslmed.aac4964. [DOI]
B. C. Heng, D. Aubel, M. Fussenegger “Prosthetic gene networks as an alternative to standard pharmacotherapies for metabolic disorders“ Curr. Opin. Biotechnol. 2015, 35:37-45. [DOI]
L. Schukur, B. Geering, M. Fussenegger “Human whole-blood culture system for ex vivo characterization of designer-cell function“ Biotechnol. Bioeng. 2015, 113:588. [DOI]
V. Haellman, M. FusseneggerV. Hällman “Synthetic Biology-Toward Therapeutic Solutions“ J. Mol. Biol. 2015, 428:945. [DOI]
H. Wang, H. Ye, M. Xie, M. Daoud El-Baba, M. Fussenegger “Cosmetics-triggered percutaneous remote control of transgene expression in mice“ Nucleic Acids Res. 2015, 43:e91. [DOI]
R. Kojima, D. Aubel, M. Fussenegger “Novel theranostic agents for next-generation personalized medicine: small molecules, nanoparticles, and engineered mammalian cells“ Curr. Opin. Chem. Biol. 2015, 28:29. [DOI]
M. Xie, M. Fussenegger “Mammalian designer cells: Engineering principles and biomedical applications.“ Biotechnol. J. 2015, 10:1005. [DOI]
T. Kim, M. Folcher, M. Doaud-El Baba, M. Fussenegger “A Synthetic Erectile Optogenetic Stimulator Enabling Blue-Light-Inducible Penile Erection“ Angew. Chem. Int. Ed. 2015, 54:5933. [DOI] [More Information]
T. Kim, M. Folcher, G. Charpin-El Hamri, M. Fussenegger “A synthetic cGMP-sensitive gene switch providing Viagra((R))-controlled gene expression in mammalian cells and mice“ Metab. Eng. 2015, 29:169-79. [DOI]
B. Geering, M. Fussenegger “Synthetic immunology: modulating the human immune system“ Trends Biotechnol. 2015, 33:65-79. [DOI]