Making blind mice see

Evolution connects all living things on earth, from the arsenic tolerant bacteria in the news this week to the human scientists and bloggers chatting about it. Eyes are intricately complex structures made up of many many cells, but even single-celled microbes can sense and respond to light through the function of proteins that share evolutionary similarity with the light receptors of the human retina. Incredibly, genetic engineering is showing us just how similar these proteins can be--transferring the genes that code for these processes leads to functional proteins, even when huge evolutionary distances separate the donor and the recipient. Not only can such studies tell us about evolution and physiology, transplanting genes can short-circuit diseased systems and even partially restore vision in blind mice.

I just saw an amazing talk by Volker Busskamp, the lead author on a recent paper showing how gene therapy can be used to treat mice suffering from retinal degeneration. Retinitis pigmentosa is a devastating degenerative disease of the retina affecting two million people worldwide. As the disease progresses the part of the cone cells in the retina that senses light breaks down, leaving stumps of cells that can no longer respond to light and complete blindness. However, since the base of the cells and all the connections that lead to the brain remain intact, replacing the receptors can theoretically restore some vision.

Volker replaced the faulty photoreceptors through gene therapy, engineering a virus to inject a different photoreceptor gene into the cone cells of the mouse's retina. Using a gene sequence that is only activated inside of the cone cells and injecting the virus directly into the eye, he was able to show highly specific targeting of the new gene only in the cone cells. In the figure on the left you can see the fluorescent signal bound to the new protein showing up only in the thin layer of degenerated cone cells.

In mammals, the pathways that connect the photoreceptors on the surface of the cone cells to the electrical signal that is sent to the brain are made up of a complex chain of protein interactions. In many single-celled organisms however, the electrical signal is directly activated when light hits the receptor--light changes the shape of the receptor allowing charged molecules to flow through the cell membrane, activating an electrical signal. Volker and his colleagues replaced the complex mammalian protein cascade with just such a light-activated channel from Natronomonas pharaonis, an extremophile archaea found in salty, alkaline African lakes. Amazingly, it worked.

The archaeal receptor is optimally activated with wavelengths of light in the orange range of the visible spectrum, between 550 and 600 nanometers. Shining different wavelengths of light and recording the electrical signal from the engineered retina shows bursts of activity reaching a maximum output in the same orange range. The system seems to work in live mice too, not just in isolated cells. Mice that were blind before the treatment display evidence of visually aided behavior after the gene therapy.

There is obviously huge potential here for treating people with retinitis pigmentosa. The type of viral gene therapy used in this study has already been approved for and used to target other eye diseases and clinical trials are already being planned. Of course, the narrow activation spectrum of the archaeal receptor limits what it will be possible for people to see--there are a lot more colors out there than orange. Other microbial photoreceptors respond to different wavelengths of light, but until research can be done on engineering in multiple colors Connie Cepko, a collaborator of Volker's team speculates about other technological aids-- goggles that will be able to convert the image a person is looking at into a single-color version that can activate their engineered photoreceptors.

This technology is still in early stages and it's important to be cautious when people's health is involved, but the work is totally fascinating. Looking through crazy lake environments can affect our understanding of how cells work and at the same time expand our genetic engineering toolkit.