Seeing the bright future of vision improvement

As a child I was fascinated by the origins of Spiderman, who obtained his superpowers after a bite from a radioactive spider. As the result of my blissful childish ignorance and imagination, I did not realise how dangerous the consequences of a radioactive spider’s bite could be (say mutations, cancer and almost certain death). I was instead accepting the fantastic possibility that a casual (I mean, it’s not like we are surrounded by radioactive spiders) and dangerous circumstance could bring such an amazing outcome. I was even wondering how cool it would be to inherit non-human abilities from animals, such as night vision, the ability to fly or even the ability to see what humans can’t see. I would love to see the world through the eyes of a bee, which sees in the ultraviolet spectrum, or through the numerous ocelli of a spider.

Could that be possible? Well, sort of. A collaborative effort led by scientists at the Friedrich Miescher Institute in Basel, Switzerland, recently developed a novel method for gene therapy exploiting snakes’ visual system. The aim being partial restoration of vision in blind mice (Nelidova et al., Science 2020).

Snakes see infrared radiation instead of visible light. In mammals, the radiation of the visible spectrum is detected by photoreceptors in the retina, where it starts a series of photochemical reactions that culminate in the translation of the light detected into the objects, shapes and colours we see. In snakes there are Transient Receptor Potential (TRP) ion channels instead of photoreceptors. TRPs are temperature-sensitive and infrared signals induce warming, which activates the receptors. This allows the predator to detect its prey thanks to its warm blood, even in the absence of visible light.

How does the method work? There are two primary components to this system:

• Genetic component: temperature-sensitive TRP channels. Channels from the TRP family are located at the plasma membrane of various cell types and are present in many species. Once activated, they open and let transit cations inside the cell. Nelidova and colleagues tested two types of TRPs in adult mice: rat TRP family V member 1 (TRPV1) channels and TRP family A member 1 channel from the Texas rat snake (sTRPA1). To activate them, they used near-infrared light, emitted at wavelengths just outside of the visible spectrum.
• Nanomaterial component: gold nanorods (essentially gold nanoparticles) conjugated to antibodies that recognise a tag on the TRP channels. Depending on their specific characteristics, i.e. their length-to-width ratio, their peak absorption wavelength changes. The nanorods were built in order to have a light absorption maximum at either 915 nm or 980 nm. Once the gold nanorods are hit by near-infrared (NIR) light, they generate heat via surface plasmon resonance. This is a phenomenon in which light leads to resonant oscillation of free electrons in gold particles. These oscillations elicit thermal, electrical and optical phenomena, depending on the properties of the gold particles and light emitted.

The scientists used a mouse model with severe retinal degeneration, rd1 miceThey have no rods anymore and cones are no longer light-sensitive. The scientists delivered nanorods and adeno-associated viruses for the expression of the TRP channels’ genes via eye injection. Both the rat and the snake receptors were successfully expressed in the cones of treated animals, and the activity of cones expressing these receptors was restored.

Is higher visual function restored? The visual system of mammals takes the light signal detected by photoreceptors and propagates it to the cerebral cortex, where it is processed and sent back to the eye as an image. In order to detect the activation of the neurons in the visual cortex and see if this kind of heat-induced sensory stimulus could be translated in a visual stimulus for the mice, Nelidova and colleagues used two-photon calcium imaging. Basically, they expressed a calcium indicator (GCaMP6s) in neurons of the primary visual cortex (V1) of treated mice. GCaMP6s activates when the neuron is excited, thus allowing the flow of calcium inside the cell and emitting green fluorescence. While animals expressing either the rat or the snake channels showed neuronal activity in the primary visual cortex, the snake TRPA1 gave the best results.

Are mice expressing TRPs in their retinas really able to see near-infrared light? Given that these mice have restored activity in the retina and in the visual cortex, another question is whether they can see something. To determine this, the researchers performed behavioural experiments in which the near-infrared light stimulus was associated with the release of water. This leads to a pre-anticipatory licking of the mice if they can sense the light stimulus. Animals expressing either the rat or the snake TRP channel would perform an anticipatory lick between the light stimulus and the release of water, but the snake channel almost doubled the licking rate. This means that the use of snake TRPs is more efficient in partially restoring sight through infrared sensing.

What are the implications of this work for humans? Many patients affected by degenerative blindness have only partial degeneration of the photoreceptors in their retina. Systems based on visible light have been developed, but they require light intensities that are too high for the human eye and interfere with the functioning of those photoreceptors that are still working. Eventually, they can even lead to further degeneration of the retina. Therefore, these systems are more suitable for patients with complete retinal degeneration. The method set-up by Nelidova and colleagues could instead allow patients with only partial degeneration to restore part of their vision, without interfering with the residual vision they still have.

What are the strong points and limitations of this system? The possibility of using near-infrared-activated channels in the human retina will open new avenues in the field of gene therapy to restore vision in blind patients. Preliminary experiments performed by Nelidova and colleagues show that snake TRPs also work well in human retinal explants. Further experiments and clinical studies to assess whether they also work on patients will need to be performed. It is also not clear how visual stimuli induced by visible light and those induced by near-infrared light will integrate in the human visual cortex, and what the result will be in terms of ability to see for the patients.

Meanwhile, a biotech company has developed special vision goggles for patients with vision impairments. These goggles have an external camera that collects light, which is then processed by a signal processing unit. Thanks to micromirror arrays, the light patterns are projected to the retina. The display of these goggles is near-infrared light-compatible. This could be very useful to amplify the light signals perceived by patients, as the natural light (both visual or near-infrared) emitted by most objects would not be intense enough to activate the restored photoreceptors. It could also help shed light on how patients can integrate the two types of light stimuli during clinical trials, which will probably require some training before they learn to do it.

Far from the comic book superhero stories, the method described in this Science paper shows us that we can benefit from other biological organisms, not to gain a superpower but to learn how to restore functions lost due to disease or degeneration. However, that requires a lot of research into the techniques used, the stability of the system and its components (gold nanorods showed great stability at very challenging conditions, and both them and near-infrared light did not induce an immune response in mice). Rather than obtaining superpowers, it feels like we are stepping into the future. That fictional future in which Geordi La Forge, blind since birth, can perceive electromagnetic radiations all the way from extremely low radio waves to extremely high ultraviolet radiations thanks to his visor.

 

Written by Chiara Galante; Edited by Radhika Menon. Featured Image: NGC/Design.

Resources:

Nelidova et al., Science 368 (2020), 1108-1113. DOI: 10.1126/science.aaz5887 (Link)
Franke & Vlasits, Science 368 (2020), 1057-1058. DOI: 10.1126/science.abc2294 (Link)
Quin & Bischof, Chem. Soc. Rev., (2012) 41, 1191–1217. DOI: 10.1039/c1cs15184c (Link)
For an explanatory video on the vision goggles, visit: https://www.gensight-biologics.com/optogenetics/