The drawing above is the retina at the cellular level by Santiago Ramon y Cajal
By Eric James McDermott
Do you see it? Look around. If you can see —if you can see anything at all— from the words you are reading to the trees outside to your steaming cup of coffee, it is because you have, among other things, a fully functioning retina. The retina is a light-sensitive tissue which is involved in receiving and processing sensory information. As you may very well know, light is composed of a myriad of different wavelengths; the ones we can see generally range from about 400 nanometers, which is perceived as violet, to around 700 nanometers, which is perceived as red. Isaac Newton famously brought attention to these components of sunlight during his prism experiment in the 17th century. He saw these colors the same way you or I would.
Light first passes through the lens and is bent toward the back of the eye where it encounters the multiple layers of retinal cells. These cells transduce light into electrical signals which propagate along the optic nerve until they meet the lateral geniculate nucleus. The signals then travel onward to the visual cortex, then continue to higher visual areas and then work their way to the frontal cortex. This pathway is not only complex, but also extremely layered with each layer playing a role in visual perception. Some fascinating case studies help elucidate some of the functions of these layers, for instance, there is a report of a woman who had damage to an area known as “V5/MT” and the world for her became still (1). Imagine, everything you see appears without motion. Blink. Everything is in a slightly altered position. Blink. Again, life became for her but a series of snapshots with gaps in continuity. She reported severe difficulties with everyday activities like crossing the road or pouring a cup of tea. This story is one of many, and the blueprints to our visual architecture are slowly, but surely, becoming uncovered. However, even with the building plans in hand, everything we see hinges on one crucial layer of cells in the retina: the photoreceptors.
Photoreceptors have a very important job: to encode light and transduce it into electricity. Photoreceptors are broken into two main cell groups, rods and cones. The rods afford us our light sensitivity, whereas the cones afford us our color vision and our visual acuity. These cells have intrinsic light-sensitive mechanisms which upon activation begin a molecular cascade of activity along the visual pathway. Without them, we are effectively blind, and unfortunately, about 1 in 300 people are affected by retinal degenerative diseases leading to progressive photoreceptor loss (2). This results in many people with intact cortical visual architecture, but without the ability to utilize it. Think of something akin to having a perfectly functioning car without the key to turn it on. This very situation is what researchers around the world are working to solve: how do we start the car?
Left: An optical coherence tomography image of a healthy retina
Right: An optical coherence tomography image of a retina with retinitis pigmentosa
Image source: Eric McDermott
Researchers are exploring several methods: pharmacological methods (3) and gene replacement therapies (4, 5) focus on slowing down photoreceptor degeneration, while retinal implants (6, 7), stem cells (8, 9), photochemical ligands (10), and optogenetics (2, 11, 12) are ways to give the car a new key. The laboratories of Eberhart Zrenner in Tübingen and Günther Zeck in Reutlingen research retinal implants for vision restoration, and my own Master’s thesis revolving around restoring vision through optogenetics was conducted in the laboratory of Thomas Münch. While all of these methodologies hold merit, including them all is beyond the scope of this article, and therefore the following will focus solely on the optogenetic approach.
The main idea of the optogenetics approach to vision restoration is to restore the light-transducing element of the visual system by introducing light-sensitive proteins into the retina. One of the first and most widely used proteins is channelrhodopsin-2 (ChR2), which was discovered in the unicellular algae Chlamydomonas reinhardtii (13). These algae primarily use this light-sensitive protein as a means to increase photosynthesis: by sensing where light is coming from they can orient and move toward it. ChR2 is not the only optogenetic protein, for example, Wyk and Kleinlogel (2) developed a novel optogenetic tool called Opto-mGluR6 which reportedly (and supported by my own data) is more light-sensitive than ChR2. Reports show that ChR2 is responsive to 1 order of magnitude, or only the uppermost 8.33% intensity levels of the normal dynamic range of humans (11), while Opto-mGluR6 is reportedly responsive to 4.3 orders of magnitude, or the uppermost 35.8% intensity levels of the normal dynamic range (2). This is important because this expanded range of Opto-mGluR6 allows the retina to respond to lower light levels and not only to the extremely high, rare, and photo-toxic light levels needed to activate ChR2. These light-sensitive proteins can be extracted, replicated, and now can be relatively precisely expressed into cells in different environments, such as in the retina. This is exactly what the optogenetic method for visual restoration strives to do. The concept is to take a biologically derived light-sensitive protein and circumvent the failing natural system to activate the remains of the intact visual architecture. At the moment, the optogenetic proteins we have in hand do not afford all the detailed responses photoreceptors do, but they do at least grant the ability to catch light once again.
Eric James McDermott graduated from the Neural and Behavioral Neuroscience Masters Program ’16. He is currently a PhD candidate in Neuroscience in Tübingen.
- Zihl, J., Von Cramon, D., & Mai, N. (1983). Selective disturbance of movement vision after bilateral brain damage. Brain, 106(2), 313-340.
- van Wyk, M., Pielecka-Fortuna, J., Löwel, S., & Kleinlogel, S. (2015). Restoring the ON switch in blind retinas: opto-mGluR6, a next-generation, cell-tailored optogenetic tool. PLoS Biol, 13(5), e1002143.
- Beltran, W. A. (2008). On the Role of CNTF as a Pontential Therapy for Retinal Degeneration: Dr. Jekyll or Mr. Hyde?. In Recent Advances in Retinal Degeneration (pp. 45-51). Springer New York.
- Bainbridge, J. W., Smith, A. J., Barker, S. S., Robbie, S., Henderson, R., Balaggan, K., … & Petersen-Jones, S. (2008). Effect of gene therapy on visual function in Leber’s congenital amaurosis. New England Journal of Medicine, 358(21), 2231-2239.
- Krol, J., Busskamp, V., Markiewicz, I., Stadler, M. B., Ribi, S., Richter, J., … & Oertner, T. G. (2010). Characterizing light-regulated retinal microRNAs reveals rapid turnover as a common property of neuronal microRNAs. Cell, 141(4), 618-631.
- Zrenner, E., Bartz-Schmidt, K. U., Benav, H., Besch, D., Bruckmann, A., Gabel, V. P., … & Koch, J. (2011). Subretinal electronic chips allow blind patients to read letters and combine them to words. Proceedings of the Royal Society of London B: Biological Sciences, 278(1711), 1489-1497.
- Rizzo, J. F., & Wyatt, J. (1997). REVIEW: Prospects for a Visual Prosthesis. The Neuroscientist, 3(4), 251-262.
- Li, T., Lewallen, M., Chen, S., Yu, W., Zhang, N., & Xie, T. (2013). Multipotent stem cells isolated from the adult mouse retina are capable of producing functional photoreceptor cells. Cell research, 23(6), 788-802.
- Santos‐Ferreira, T., Postel, K., Stutzki, H., Kurth, T., Zeck, G., & Ader, M. (2015). Daylight vision repair by cell transplantation. Stem Cells, 33(1), 79-90.
- Polosukhina, A., Litt, J., Tochitsky, I., Nemargut, J., Sychev, Y., De Kouchkovsky, I., … & Kramer, R. H. (2012). Photochemical restoration of visual responses in blind mice. Neuron, 75(2), 271-282.
- Lagali, P. S., Balya, D., Awatramani, G. B., Münch, T. A., Kim, D. S., Busskamp, V., … & Roska, B. (2008). Light-activated channels targeted to ON bipolar cells restore visual function in retinal degeneration. Nature neuroscience, 11(6), 667-675.
- Busskamp, V., Duebel, J., Balya, D., Fradot, M., Viney, T. J., Siegert, S., … & Biel, M. (2010). Genetic reactivation of cone photoreceptors restores visual responses in retinitis pigmentosa. science, 329(5990), 413-417.
- Nagel, G., Szellas, T., Huhn, W., Kateriya, S., Adeishvili, N., Berthold, P., … & Bamberg, E. (2003). Channelrhodopsin-2, a directly light-gated cation-selective membrane channel. Proceedings of the National Academy of Sciences, 100(24), 13940-13945.