Synthetic biology circuits: temperature and myocardial infarction sensors for precision therapeutics

Abstract

Personalized medicine is the science for developing remedies tailored to the individual necessities of each and every patient. The regulatory approval of the first engineered mammalian cell therapies enhanced the anticipation that these are to become the next pillar of medical care for complex and chronic disease. Although such cells are biological entities, they are modified using engineering principles in what is now established as the field of synthetic biology, and could thus be better described as biocomputing units. The foundations of these systems lie in the integrated therapeutic circuitry, which may provide an open or closed-loop control over the beneficial cellular functions. Open-loops would allow for more flexibility as the input strength and processes can be varied, while closed-loops are rigid and closely emulate the natural physiology. A common feature of every cellular circuit are the input converters, which may also be transcription factors activated by specialized cues. In this work we engineered the first mammalian transcription factor directly sensing temperatures in the physiological range from 38 to 40 °C. This enabled its use as a fever sensor in pyrexia animal models as well as for precise thermoelectrical control over therapeutic implants of engineered cells for controlling glycemia in a type-1-diabetes model. Capitalizing on this work, we envisioned natural energy sources such as sunlight as facilitators for temperature-based cellular control. In particular, we engineered endocrine cells to accumulate diverse therapeutic proteins in their storage granules and release them within minutes upon thermal stimulation in physiological saline. This generated injection ready solutions in an emergency biopharmaceutical process for production of therapeutics in remote areas. Finally, we engineered a closed-loop circuit capable of sensing cardiac troponin I, a protein considered as a gold standard biomarker for myocardial infarction, and responding to it with the secretion of a half-life optimized cardioprotective peptide.