Genetically Encoded Protein Thermometer Enables Precise Electrothermal Control of Transgene Expression. Issue 21 (8th September 2021)

• Record Type: Journal Article
• Authors: Stefanov, Bozhidar‐Adrian; Teixeira, Ana P.; Mansouri, Maysam; Bertschi, Adrian; Krawczyk, Krzysztof; Hamri, Ghislaine Charpin‐El; Xue, Shuai; Fussenegger, Martin
• Is Part Of: Advanced science. Volume 8:Issue 21(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-09-08
• Subjects: diabetes -- gene regulation -- gene switches -- synthetic biology -- temperature; Science -- Periodicals; 505
• DOI: 10.1002/advs.202101813
• Languages: English
• ISSNs: 2198-3844

Abstract

Abstract: Body temperature is maintained at around 37 °C in humans, but may rise to 40 °C or more during high‐grade fever, which occurs in most adults who are seriously ill. However, endogenous temperature sensors, such as ion channels and heat‐shock promoters, are fully activated only at noxious temperatures above this range, making them unsuitable for medical applications. Here, a genetically encoded protein thermometer (human enhanced gene activation thermometer; HEAT) is designed that can trigger transgene expression in the range of 37–40 °C by linking a mutant coiled‐coil temperature‐responsive protein sensor to a synthetic transcription factor. To validate the construct, a HEAT‐transgenic monoclonal human cell line, FeverSense, is generated and it is confirmed that it works as a fever sensor that can temperature‐ and exposure‐time‐dependently trigger reporter gene expression in vitro and in vivo. For translational proof of concept, microencapsulated designer cells stably expressing a HEAT‐controlled insulin production cassette in a mouse model of type‐1 diabetes are subcutaneously implanted and topical heating patches are used to apply heat corresponding to a warm sensation in humans. Insulin release is induced, restoring normoglycemia. Thus, HEAT appears to be suitable for practical electrothermal control of cell‐based therapy, and may also have potential for next‐generation treatment of fever‐associated medical conditions. Abstract : Existing cellular temperature sensors, such as ion channels and heat‐shock promoters, are fully activated only by heat at a painful level, making them unsuitable for bioengineering‐inspired medical applications. Here, a temperature‐sensing protein is developed functional in the physiological range of 37–40 °C. This enables precise electrothermal control of cellular therapies in living animals using a simple, programmable heatpad.