By: Donovan Smith, MSc
Neuroscience Graduate Student
Picture this: for the last 40 years, you’ve been suffering from a rare genetic disease known as Retinitis Pigmentosa (RP), causing a gradual breakdown of your retina, which your eyes use to process visual information. Since your diagnosis, your vision has slowly deteriorated, worsening with each passing year, leaving you legally blind and only able to perceive light. To make matters worse, in the 40 years following your diagnosis there have been no effective treatments for RP, leaving you without hope of ever restoring your vision. That is, until you heard about an experimental therapy known as Optogenetics…
For one participant in a recent clinical trial, this was their reality. After having lived with RP for over 40 years, a 58-year old male was able to regain partial vision through optogenetics after having previously only been able to perceive light. While wearing specially designed goggles that shone an orange light onto the retinas, he was able to locate and reach out to objects placed in front of him on a desk, a simple task that was almost impossible to complete prior to the trial. But how exactly does this therapy work?
Controlling Cells with Light
At its basis, optogenetics uses light to control the activity of neurons. Normally, neurons are controlled by input from the brain, which can tell them to either increase or decrease their activity. Think about moving your hand to touch your face; your brain instructs the neurons that control the muscles in your arm and hand to increase their activity, causing a muscle contraction and resulting movement of your limb. Optogenetics can replicate this control over neurons, but without the need for input from the brain.
Optogenetics works by inserting light-sensitive receptors (called opsins) into the neuron. These opsins can be used to control the activity of neurons, but only in the presence of light; the brain is not able to exert any control over how the opsins function. Opsins can either increase activity of neurons (i.e., causing movement of a limb in our previous example) or decrease activity of neurons (i.e., causing a healthy moving limb to stop moving). While movement is one example, opsins can produce many different responses, all depending on what type of neurons they are inserted into. For example, researchers used opsins in the brains of mice to control the fear response to a loud noise. By using opsins that decrease the activity of neurons, researchers were able to “turn off” the neurons responsible for recognizing and reacting to a loud noise, allowing for mice to hear this noise without being startled. Interestingly, this only occurred while an implanted LED light was shining on their brain; however, once the light was turned off, the fear response to the noise returned.
Therapeutic Potential
Although it sounds like science fiction, we are now able to control neurons with the flip of a (light) switch. And the best part is, optogenetics can be used to control neurons that have either deteriorated or no longer receive input from the brain. For example, researchers have recently used optogenetics to allow mice with spinal cord injuries to walk again, even though the neurons that control walking movements no longer receive input from the brain. The implications of this landmark study are nearly limitless, demonstrating that optogenetics can be used to control parts of the body that were once thought to be permanently lost either due to disease or injury.
While this has been limited to animal models of disease and injury in the past, recent advances in the field have pushed optogenetics into the clinic and into the nervous systems of real patients. As alluded to above, optogenetics were recently used to partially restore vision in a blind patient. Even though a rare genetic disease deteriorated this patient’s retina, optogenetic therapy allowed for improved activation of the neurons controlling the retina, to an extent that is impossible through connections from the brain alone. One can only imagine that if vision can be restored with this therapy in humans, other conditions might also soon be fixed through optogenetics. So why aren’t we using this technique more often?
Unfortunately, implementing optogenetic therapies can be a logistical nightmare. To start, the opsins must be injected directly into the target nerve, requiring invasive surgeries. Next, in order to activate the neuron of interest, the activating light source must be in extremely close proximity, and must be strong enough to shine through surrounding neural tissue and reach the injected opsins. In the case of the blind patient mentioned above, this was achieved by shining light through the eye with a pair of goggles that contained a projector in the eyepiece. This allowed for light to hit the retina, activating the injected opsins and partially restoring vision. While this technique works well for neurons in the retina, nerves deep in the body provide a further challenge. For example, if researchers wanted to use optogenetics to restore movement in a patient living with a spinal cord injury, the target nerves would be located within the spinal cord itself. Activating these nerves with light would require direct implantation of a light source over the spinal cord, which is no easy feat. Not to mention, what happens if the light stops working? Or if the device moves after implantation? These are all considerations in the current research focusing on optogenetics and implantable light sources. Just this year, a research group out of Switzerland custom-made an implantable light source that was used to activate spinal neurons in mice through optogenetics. The result? A freely moving mouse that had previously suffered a spinal cord injury.
While it will likely be years until we use optogenetics to fully restore walking in humans, the work conducted so far bodes well for the future. Researchers have harnessed the power of light to awaken neurons that were once thought to be lost due to injury or disease, a concept that sounds straight from a comic book. But with every new discovery made in the field, these concepts that were once viewed as fiction get closer and closer to becoming reality. The light on the horizon may be closer than we think.
References
Sahel, JA., Boulanger-Scemama, E., Pagot, C. et al. Partial recovery of visual function in a blind patient after optogenetic therapy. Nat Med 27, 1223–1229 (2021). https://doi.org/10.1038/s41591-021-01351-4
Shen Y, Campbell RE, Côté DC and Paquet M-E (2020) Challenges for Therapeutic Applications of Opsin-Based Optogenetic Tools in Humans. Front. Neural Circuits 14:41. doi: 10.3389/fncir.2020.00041
Luchkina NV, Bolshakov VY. Diminishing fear: Optogenetic approach toward understanding neural circuits of fear control. Pharmacol Biochem Behav. 2018 Nov;174:64-79. doi: 10.1016/j.pbb.2017.05.005. Epub 2017 May 11. PMID: 28502746; PMCID: PMC5681900.
Petersen ED, Sharkey ED, Pal A, Shafau LO, Zenchak-Petersen J, Peña AJ, Aggarwal A, Prakash M and Hochgeschwender U (2022) Restoring Function After Severe Spinal Cord Injury Through BioLuminescent-OptoGenetics. Front. Neurol. 12:792643. doi: 10.3389/fneur.2021.792643
Kathe, C., Skinnider, M.A., Hutson, T.H. et al. The neurons that restore walking after paralysis. Nature 611, 540–547 (2022). https://doi.org/10.1038/s41586-022-05385-7