Oscillator

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.

i-eeb64e933f48cf3897ddf4eb45f506cd-targeting2-thumb-250x183-58898.pngVolker 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.

i-c2d0a374d97d4961424903dfe01e8117-responsetolight.png

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.

i-d39176a6c45798668b038a178fd988e0-geordilaforge2367-thumb-200x285-58903.jpgThere 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.

i-89396506ae9b623af42a9d12582a540b-roboglasses-thumb-510x328-58905.jpg

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.

Comments

  1. #1 MutantBuzzard
    December 8, 2010

    Is there any thing technology can’t do?

  2. #2 BMEGradStudent
    December 8, 2010

    It’s worth also looking at a earlier paper on this, on which Busskamp is also an author. Lagali et al. 2008, Nat. Neuroscience. This paper used ChR2, a complementary stimulatory light-sensitive opsin.

  3. #3 Christina Agapakis
    December 8, 2010

    Definitely! Here’s a link to the paper: http://www.nature.com/neuro/journal/v11/n6/abs/nn.2117.html

    and here’s a Neurophilosophy post about that research: http://scienceblogs.com/neurophilosophy/2008/05/channelrhodopsin_restores_vision.php

  4. #4 PanicWallet
    December 9, 2010

    When I last spoke with Volker he said that Novartis are pushing the development of this technology as a priority.

  5. #5 Inferno
    December 9, 2010

    It would be interesting to see if this could also be applied towards influencing sight in the ultraviolet spectra as well as the three primary colors. That would be a revolutionary breakthrough and I think would cause innumerable benefits.

  6. #6 Dior
    December 13, 2010

    Check out a paper by Dan Von Segern of the Nemerow lab the scripps research institute. we did a similar experiment with gfp adenovirus to deliver genes to treat maculardegeneration in mice and dogs. our delivery looks much like the pic you posted and one reviewer rejected our first publication attempt because he thought it was too perfect.

  7. #7 Damien Joseph
    December 16, 2010

    This is interesting. When was the lecture by Volker? I am intrigued at what can come from this and the possibilities for the future seems bright.
    -Damien Joseph-
    http:/themystified.com

  8. #8 Markus Schmidt
    January 24, 2011

    Once they can see, why not add another color dimension to their vision? This publication
    on engineering enhanced color vision in mice could interest the Mus+ folks among us ;-)

    The authors transfered a human photopigmet to mice in order to change the mouse natural bichromatic vision into a trichromatic one. The engineered trichromatic vision seems to work due to the existing visual and sufficiently plastic neural system that is able to deal somehow with the new sensory information.
    What is challenging is that the effect depends on a plastic information processing device (system) that is not properly understood, thus many uncertaintes arise.
    Plus it is from 2007 ….

    ——
    Emergence of Novel Color Vision in Mice Engineered to Express a Human
    Cone Photopigment

    Science 23 March 2007: Vol. 315. no. 5819, pp. 1723 – 1725

    Gerald H. Jacobs,* Gary A. Williams, Hugh Cahill, Jeremy Nathans

    http://www.sciencemag.org/cgi/content/abstract/315/5819/1723