'Light Switch' Flips Genes On and Off

by Kai Kupferschmidt

Seeing blue. Cells equipped with a gene whose activity is driven by blue light were used to help diabetic mice control glucose levels.

Credit: Science/AAAS

Turning a gene on or off is usually a lot more difficult than just flipping a light switch. But a team of Swiss scientists has engineered cells that come pretty close: Only when they are bathed in blue light do the cells express a gene that has been inserted into them.

The feat is the latest trick in a rapidly growing discipline known as optogenetics, where light is used to control activities within cells. The new technique, described online today in Science, "has extraordinary potential," says synthetic biologist Christopher Voigt of the Massachusetts Institute of Technology (MIT) in Cambridge, who was not involved in the study. In one example, the research team put the production of an antidiabetes peptide in mice under the control of an optogenetic switch, allowing them to regulate glucose levels in the animals just by shining light on them.

At the heart of the new study is melanopsin, a light-sensitive molecule found on certain neurons in the retina that helps keep the biological clock of mammals in sync with the cycle of dusk and dawn. When these cells are illuminated by a strong light, a change in the structure of melanopsin triggers a molecular cascade that eventually leads to an influx of calcium ions into those neurons and an electrical pulse.

By transferring the gene for melanopsin into human embryonic kidney cells, synthetic biologist Martin Fussenegger of the Swiss Federal Institute of Technology in Zurich and colleagues made these cells light-sensitive as well. Illuminating them with blue light leads to an influx of calcium ions, just as it does in the neurons; in the kidney cells, this does not trigger an electrical pulse but allows a so-called transcription factor, NFAT, to move into the cells' nuclei, bind to certain DNA sequences called promoters, and thus activate certain genes. By introducing a gene with an NFAT promoter into the cells' genome as well, the scientists can put that gene under the control of light: Switch on the light, and the cells start producing the protein that the gene encodes.

Fussenegger says that this technique could be very useful in the cell-based manufacture of certain cancer therapeutics. Production of such compounds can be challenging, because some of them hurt the growth of the cells that are producing them or outright kill them. Yet cells altered by this new strategy could be grown to a certain density first and then induced to produce the medicine just by switching on a blue light in the bioreactor, Fussenegger says.

In another test of their technique, the researchers engineered cells to express, when illuminated, a variant of glucagon-like peptide 1, a compound that may have potential in treating type 2 diabetes. A few hundred transparent microcapsules filled with approximately 10 million of the cells each, were then implanted under the skin of diabetic mice. Pulsing blue light upon the mice for 48 hours led to an increase in the rodents' insulin levels and better tolerance of glucose compared with control mice.

Neuroscientists have used optogenetics methods to control the firing of neurons in animals, and others have also fused light-sensitive switches to enzymes, but this new approach goes beyond that to allow light to control a chosen gene, explains MIT neuroscientist Edward Boyden. "Now people are taking the light sensor and have it drive a whole cascade in the cell," says Boyden, who calls the study a "marriage of optogenetics and synthetic biology."