Researchers at ETH Zurich have tapped natural signaling pathways to build a genetic network in living cells that has enabled light to trigger and control genes. Inserting these cells under the skin of mice, the researchers shine blue light onto the implant externally, and are thus able to precisely regulate the target gene.1 The approach is promising for treatment of type 2 diabetes, among other diseases.
The cell implants are exposed to the light either via an ultra-thin glass fiber-optic cable or, if the implant is placed directly under the skin, simply by placing the animals under a blue lamp. For the light source, the researchers used commercially available LEDs or a blue-light lamp marketed to combat depression. Because there is no ultraviolet component, the light is not harmful to the skin.
The photosensitive “switch” activated by the light is made of melanopsin, a protein found in the retina of the human eye that forms a complex with Vitamin A. When blue light hits this complex, it triggers the first signaling cascade, which ensures that calcium accumulates inside the cell—a process that also takes place naturally in the eye and is responsible for setting the body’s biological clock. The scientists have re-connected this, however, to a signaling pathway that plays a key role in immunoregulation: Thus, the calcium inside the cell activates an enzyme that separates the phosphate group (P) from the protein NFAT-P. When NFAT enters the cell nucleus, it binds to a synthetic control sequence and switches the introduced gene. The gene becomes active and the cell produces numerous copies of the protein, for which the gene is the template. By controlling the amount of light and its intensity, the researchers can also regulate how much of the protein is produced.
In their experiments, the researchers tested the light-controlled production of GLP-1, a hormone that controls the production of insulin and thus regulates blood glucose levels. The result was encouraging: the GLP-1 that was upregulated using light helped diabetic mice improve insulin production, quickly remove the glucose from the blood and restore the blood-sugar balance. Prof. Martin Fussenegger, who led the research, envisions how the GLP-1 gene therapy could replace insulin injection one day: People with type 2 diabetes could have an implant placed under the skin and black bandage containing LED lamps could shield that area of skin from the daylight. As needed, the patient could press a button to shine light onto the implant for a few minutes at a time.
1. H. Ye et al., Science online, doi:10.1126/science.1203535 (June 24, 2011).