“Our expansion of optogenetics as a field involved an approach to convert electromagnetic waves from the visible range of blue light into a sustained transcription response, which allows genes to be controlled by shining blue light onto them,” says Martin Fussenegger, Ph.D., professor of biotechnology and bioengineering at ETH Zürich.
The strategy used by Dr. Fussenegger and colleagues takes advantage of the signal cascade of melanopsin, the photopigment found in the photosensitive ganglion cells from the retina, which is most sensitive to blue light (~480 nm). Upon light exposure, melanopsin activates a G protein, triggering a subsequent signal transduction cascade that leads to an intracellular calcium surge.
This calcium surge was rewired to the nuclear factor of activated T-cells, which can initiate gene transcription from specific promoters. After demonstrating the functionality of this synthetic device in mammalian cells, Dr. Fussenegger and colleagues subsequently illustrated its use in a mouse model, where it enabled the light-induced expression of a transgene.
In a type 2 diabetes mouse model harboring these transgenic synthetic devices in intraperitoneal hollow-fiber or subcutaneous implants, the investigators reported that, upon exposure to light, the animals showed increased glucagon-like peptide 1 expression, reduced glycemic excursions, and decreased glycemic levels.
“This system is ready for clinical applications,” emphasizes Dr. Fussenegger. A key feature, fundamental for the clinical use of this synthetic device, is that it is fully humanized, and it does not contain any components that would elicit an immune response.
As individual parts, such as promoters, open reading frames, terminators, and transcription factors are combined to generate pathways and circuits, one of the goals of synthetic biology is to generate synthetic chromosomes and genomes, some of which have never existed before.
An important milestone was reached less than a year ago, with the publication of the first partially synthetic eukaryotic chromosome—that of the budding yeast. This advancement, along with other developments in the field, are signaling the beginning of a new era, one that provides a new level of scientific inquiry and promises to reshape medicine, biomedical research, and biotechnology.