Genetically Encoded Protein Thermometer Enables Precise Electrothermal Control of Transgene Expression

Area of Science:

• Biotechnology
• Molecular Biology
• Synthetic Biology

Background:

• Human body temperature is tightly regulated around 37°C.
• High-grade fevers (≥40°C) in serious illness activate endogenous sensors only at noxious temperatures, limiting medical use.
• Existing temperature sensors are not suitable for precise medical applications within the fever range.

Purpose of the Study:

• To design a genetically encoded protein thermometer (human enhanced gene activation thermometer; HEAT) for precise transgene expression control between 37-40°C.
• To validate the HEAT system's functionality as a fever sensor in vitro and in vivo.
• To demonstrate the translational potential of HEAT for electrothermal control of cell-based therapies.

Main Methods:

• A mutant coiled-coil temperature-responsive protein sensor was linked to a synthetic transcription factor to create the HEAT system.
• A HEAT-transgenic human cell line (FeverSense) was generated for validation.
• Microencapsulated designer cells with a HEAT-controlled insulin cassette were implanted in a type-1 diabetes mouse model and heated externally.

Main Results:

• The HEAT system successfully triggered reporter gene expression in a temperature- and exposure-time-dependent manner.
• The FeverSense cell line functioned as a reliable fever sensor.
• External heating of implanted cells induced insulin release, restoring normoglycemia in diabetic mice.

Conclusions:

• The HEAT system provides a novel tool for precise, temperature-triggered transgene expression within the physiological fever range.
• HEAT demonstrates suitability for electrothermal control of cell-based therapies.
• This technology holds potential for next-generation treatments targeting fever-associated conditions.