title: A synthetic multifunctional mammalian pH sensor and CO2 transgene-control device.
abstract: All metabolic activities operate within a narrow pH range that is controlled by the CO2-bicarbonate buffering system. We hypothesized that pH could serve as surrogate signal to monitor and respond to the physiological state. By functionally rewiring the human proton-activated cell-surface receptor TDAG8 to chimeric promoters, we created a synthetic signaling cascade that precisely monitors extracellular pH within the physiological range. The synthetic pH sensor could be adjusted by organic acids as well as gaseous CO2 that shifts the CO2-bicarbonate balance toward hydrogen ions. This enabled the design of gas-programmable logic gates, provided remote control of cellular behavior inside microfluidic devices, and allowed for CO2-triggered production of biopharmaceuticals in standard bioreactors. When implanting cells containing the synthetic pH sensor linked to production of insulin into type 1 diabetic mice developing diabetic ketoacidosis, the prosthetic network automatically scored acidic pH and coordinated an insulin expression response that corrected ketoacidosis.
authors.affiliation: Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, 4058 Basel, Switzerland.
authors.forename: David
authors.initials: D
authors.lastname: Ausländer
authors.affiliation: Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, 4058 Basel, Switzerland.
authors.forename: Simon
authors.initials: S
authors.lastname: Ausländer
authors.affiliation: IUT Lyon 1, Département Génie Biologique, 74 Boulevard Niels Bohr, 69622 Villeurbanne Cedex, France.
authors.forename: Ghislaine
authors.initials: G
authors.lastname: Charpin-El Hamri
authors.affiliation: Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, 4058 Basel, Switzerland.
authors.forename: Ferdinand
authors.initials: F
authors.lastname: Sedlmayer
authors.affiliation: Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, 4058 Basel, Switzerland.
authors.forename: Marius
authors.initials: M
authors.lastname: Müller
authors.affiliation: Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, 4058 Basel, Switzerland.
authors.forename: Olivier
authors.initials: O
authors.lastname: Frey
authors.affiliation: Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, 4058 Basel, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Hierlemann
authors.affiliation: Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, 4058 Basel, Switzerland.
authors.forename: Jörg
authors.initials: J
authors.lastname: Stelling
authors.affiliation: Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, 4058 Basel, Switzerland. Electronic address: fussenegger@bsse.ethz.ch.
authors.forename: Martin
authors.initials: M
authors.lastname: Fussenegger
mesh_terms: D000818:Animals; D016466:CHO Cells; D002245:Carbon Dioxide / Q000378:metabolism*; D002460:Cell Line; D017690:Cell Transplantation; D003412:Cricetulus; D016883:Diabetic Ketoacidosis / Q000503:physiopathology* / Q000628:therapy; D004195:Disease Models, Animal; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D051379:Mice; D046210:Microfluidic Analytical Techniques / Q000379:methods*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D058615:Synthetic Biology / Q000379:methods*
chemical_list: C513334:GPR65 protein, human; D043562:Receptors, G-Protein-Coupled; D002245:Carbon Dioxide