Enlarge /. Two eyes and their optic nerves seen on a radial section.
Our visual system is complex, with photoreceptors that pick up incident light and at least three types of neurons between them and the brain. In the brain, the visual input is interpreted by several dedicated regions that create a scene from small shapes and movements. The result of this processing can be further interpreted by areas of the brain that handle things like reading or face recognition.
With all this complexity, a lot of different things can go wrong. Accordingly, we will likely need several solutions if we are to attempt to fix these issues. So it was nice to see the results this week of two very different approaches to solving vision problems that were tested on laboratory animals. One group manipulated biology to address problems with the transmission of information between the eye and the brain, while another group used electronics to completely circumvent the need for an eye.
Refreshing nerves
One of the most exciting developments in tissue repair was the discovery that we can turn many types of cells into stem cells by activating just four specific genes. Unfortunately, extensive activation of these genes in mice kills them as the genes also promote loss of normal cellular identity and uncontrolled division. A large collaboration in the US suggested that many of these problems were due to one of these four genes (MYC) and so focused on working with the remaining three. The first showed that activation of these three restored properties in cells of older mice that were typical of younger cells without losing normal cell function.
From there, the researchers focused on their real goal: the eye. In particular, they focused on a population of cells that connect the back of the retina to the brain, called retinal ganglion cells. The failure of these cells, which can occur in diseases such as glaucoma, leads to progressive loss of vision. When mice are born, these cells can regrow connections between the eye and the brain if these connections have been broken. But this ability is quickly lost.
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So the researchers damaged the optic nerve and then activated the three stem cell genes in the ganglion cells of the retina. With the active genes, the link was also restored in adult mice. The same was true when they artificially induced glaucoma in these mice. Tests of her eyesight showed that almost half of the lost visual acuity was restored by this gene treatment. The same was true for the loss of visual acuity with age, which was confirmed by comparing mice three months of age with mice about one year of age.
All of this happened without any new cell growth. Instead, the existing cells seemed to be able to repair or replace the damaged parts (called axons) that make up the optic nerve. The researchers also showed that this repair depends on changes in a type of chemical modification in DNA called methylation, which can alter the activity of many genes.
Avoid the eye
The second study, carried out by four European researchers, focuses on events far behind the eye. As soon as signals arrive in the brain, they are first interpreted by a region that has a one-to-one mapping to the retina. In other words, the geometry of the neurons in the part of the brain that receives signals from the retina mirrors the layout of the retina itself. The researchers use this correspondence and some electronic devices to try to activate the visual system without even involving the eye.
They rely on a series of electrodes called a Utah array to make connections to the neurons in that area of the brain. The Utah array doesn't have that many electrodes – Elon Musk regularly refers to how much more his Neuralink hardware will have – but since these are research animals, the researchers here are simply implanting a collection of Utah arrays into primates. Implanting 16 individual electrodes in a brain is not approved if the subject is human but it does what is needed in a research context.
The researchers use these implants to not just wire up the area where visual signals reach the brain and are first interpreted. They also join the area where these interpretations are processed. This will help them determine the correct amount of current to inject into the brain to stimulate a small portion of the visual field without overwhelming it. These small injections produce so-called "phosphenes", which are perceived as small flashes of light. And because of the geometry of this area of the brain, the researchers can control where the flashes of light appear in the field of view.
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Generally it worked. The primates normally focused their eyes on the point where they had perceived the flash of light as the origin, although in fact nothing had happened there that would have registered on their eye. The monkeys were also trained to determine if two points were vertical or horizontal, and they did so when the "points" were instead electrode-generated phosphenes. They weren't as good as when shown physical points, but they definitely did a lot better than one would expect from a random choice.
More dramatically, the monkeys were also trained to recognize letters, even if the letter was created through a job set of recent injections. In other words, the monkeys could see a pattern of phosphenes representing a letter – again not as well as they did when they were shown an actual letter, but far beyond chance.
Have visions
To start with, it's important to be clear that both are just early attempts to find out what can be done with experimental animals. We are far from treatments in humans. And it is difficult to interpret how much vision changes with either technique, as we laboratory animals cannot ask what they are seeing and have to rely on indirect tests of their visual ability. And there are many potential safety issues here, especially with something that alters the activity of human genes.
Of the two, however, the genetic engineering experiments are far more fascinating. We already knew that electrodes in the right part of the brain can create visual artifacts when activated. To some extent, organizing the visual artifacts used to convey information was a matter of engineering more than anything. However, the apparent restoration of nerve function lost due to age or injury is far more unexpected, as is the fact that it can be accomplished with a relatively small genetic intervention. If it can withstand replication, it definitely seems to point to applications that are far bigger than seeing.
Nature, 2020. DOI: 10.1038 / s41586-020-2975-4; Science, 2020. DOI: 10.1126 / science.abd7435 (About DOIs).
