How Your Eyes ‘See’ — And How Technologies Might Help When They Can’t
As you read these words, the retinas in your eyes are absorbing the light that makes up the patterns of letters and words, and your brain is then using that information to interpret their meaning, which in turn allows you to understand this article.
Light is made up of photons, little discrete packets of energy that travel through space as waves. Those photons interact with highly specialized neurons in your retinas called photoreceptors, and somehow, that light energy is converted from packets of energy into an electrical neural ‘language’ your brain can understand in the form of a neural-chemical signal. But how? What actually happens in your retinas and what are the photoreceptors doing?
When this process breaks down due to the degeneration and death of photoreceptor neurons, the retinas can no longer convert light into the brain’s language, and blindness follows. The degree of blindness can vary however. It isn’t always complete blindness, but rather partial depending on how much and what parts of the retina are degenerating. This is the case in age-related macular degeneration (AMD), for example, which is the leading cause of blindness in industrialized in the later decades of life. A number of technologies are being developed in an attempt to slow down or reverse retinal degeneration, offering potential hope to affected patients and their families.
Phototransduction: From Photons of Light to Neural Signals
At their most fundamental, each of the five sensory systems is responsible taking in some form of energy from the environment and converting it — transducing it — into a set of neural signals the brain can interpret and understand. This is how the brain takes information from the outside world in order to assess risk and make decisions about how it needs to act with the environment in order for the organism to survive and thrive. In the case of touch the energy is mechanical, for example the pressure of a pencil pushing against the skin of your finger, or a feather brushing your cheek. This is referred to as mechanotransduction. Hearing it is also mechanical. Back and forth compression waves of vibrating molecules in the air set off a series of vibrations in your middle and inner ears that are eventually encoded by specialized hair cell neurons in your cochlea. Taste and smell involve chemical transduction. Molecules in foods interact with receptors on your tongue that your brain interprets as tastes, while molecules that enter your nose are interpreted as smells.
Vision, of course, begins in the eyes. Lining the back of both eyes is the neural sensory retina, a thin tissue paper-like piece of the brain that extends out to your eyes. It is made up of functionally and cellularly distinct layers of highly specialized neurons. The retinas are actually a part of the brain itself, and connect to the rest of the brain via the optic nerves, one from each eye.
The photons that enter the eye through the pupil are focused onto the retina by the optics of the eye, the cornea and lens. If your eyes can’t do that on their own, and the focal point is off the surface of the retina, your vision is blurry. Glasses and contact lens add extra optical layers to correct the bending of light so that the focus is on the retina.
When incoming photons are ‘absorbed’ by the retina, what that really means is that they interact in a very specific way with the photoreceptor neurons that make up one of the layers of the retina. It is in photoreceptors that the photons of light are converted from packets of light energy into electrical and chemical signals through a process called phototransduction.
At its simplest, photons are discrete packets of traveling waves of energy. Like any wave, the amount of energy of each photon can be characterized by its wavelength — how big or long the wave is. The shorter the wavelength, the greater the amount of energy — or punch — they posses. Photoreceptor neurons contain a specialized molecule called a photopigment, which is capable of interacting with photons. Each type of photopigment responds maximally to photons of a particular wavelength, and absorbs photons of other wavelengths progressively less as they move away from its peak response, producing a bell shaped like curve called the absorbance spectrum In fact, we perceive photons of different wavelengths as different colors.
When a photon of light is absorbed by a photopigment molecule in a photoreceptor, the energy in the photon is used to to break a specific chemical bond in the photopigment. When that chemical bond breaks, the photopigment ‘relaxes’ and changes shape. It’s what’s referred to as a confirmation change in the structure of the molecule. Imagine a molecule of photopigment like a set of tinker toys made up using different connector pieces. If you remove just the right connector piece, you can move and bend and change the shape of what you built in new ways. It’s a similar thing when the energy from photons breaks chemical bonds in photopigments.
After the photopigment changes shape, or confirmation, it sets off a series of biochemical reactions in the photoreceptor neuron that signals the arrival of the photon. That message then gets passed on to the other neurons in the retina, and eventually it travels to other parts of the brain that are responsible for putting all that visual information together in order to create a mental model of the physical world.
But amazingly, everything you see and experience visually, the entire richness of the visual world around you, always begins as the breaking of that one specific chemical bond in photoreceptors the exact same way every time. Billions and billions of times over and over again in spatially and temporally complex patterns, your retinas encode photons into neural signals your brain can understand.
But if photoreceptor neurons — and therefor phototransduction — are removed from the equation, as is the case in degenerative retinal disorders like AMD, it doesn’t matter how many photons hit the retinas, or the fact the rest of the visual system downstream of the photoreceptors may be working just fine. The result is an inability to see.
The reason photoreceptors degenerate is typically because a support cell called retinal pigment (RPE) epithelial cells stop functioning properly. RPE cells normally keep photoreceptors happy and healthy by removing toxic waste products associated with the biochemistry of phototransduction, and by delivering nutrients to them. In other cases retinal degeneration involves not the death of photoreceptors, but other types of neurons in the retina, such as retinal ganglion cells. These neurons make up the last retinal layer, and are the cells that project from the retina proper to the other parts of the brain that process visual information via the optic nerve. Again, the result is loss of vision.
To address these challenges, a number of different technologies from labs across the world are being developed in order to treat the blindness that results.
Technologies for Restoring Vision
Some technologies involve genetic or molecular manipulations, and build on methods and lessons being learned from similar strategies targeting other parts of the nervous system and the body. Gene therapy is targeting the genetic mutations responsible for the physiological changes in cells that result in a breakdown of their functions. If key mutations can be reversed early enough, it could slow down or stop the degeneration and loss of neurons in the first place.
Optogenetics induces specific genetic changes in cells not to reverse or restore physiological function, but to endow them with the ability to respond to light when they couldn’t previously. This is accomplished by delivering a specially constructed virus that delivers genes that then allow the target cells to produce light sensitive proteins called opsins. In fact, specific classes of opsins are one of the molecular components of the photopigments natively found in photoreceptor neurons. This approach might increase the light sensitivity of remaining photoreceptors, or even allow neurons in the retina that normally do not respond to light to all of a sudden do so. While there are many technically difficult challenges that remain to be solved before this approach can be used clinically, unlike gene therapy, it offers the possibility of restoring sight after degeneration has occurred and is agnostic to the cause of the degeneration in the first place.
Another approach is to use stem cells. In this case the objective isn’t to reverse or stop degeneration from happening, or to transform neurons into light sensitive cells, but rather to replace lost cells. Importantly, the stem cells do not necessarily need to start out as neuronal stem cells or even taken from another individual. Rather they might be mature skin cells taken from the patient themselves, for example, which are de-differentiated into stem cells which are then in turn differentiated into neurons that can be implanted in the retina. This technology is called induced pluripotent stem cells (iPSCs). It has the distinct advantage over other stem cell sources of being genetically unique to the patient, avoiding a host of challenges around rejection and other related considerations. However, like all these technologies, many challenges remain. One of the most important open problems being that the integration of transplanted stem cells into the retina do not always ‘connect up’ with the other neurons properly.
The last class of technology aimed at restoring sight is very different than the other ones. It does not involve molecular or cellular manipulations in the same way, but instead requires hardware and software capable of integrating with the retinas and the eyes. Retinal prosthesis involve the engineering and use of some form of photosensitive material that in one way or another produce electrical pulses when exposed to light. These pulses, in turn, stimulate the neurons in the retina. It is literally an engineered replacement to the degenerated neurons. Different devices and strategies are being developed to replace photoreceptors versus retinal ganglion cells, for example. The engineering involved is extensive, and depending on the details and strategies of the specific device may involve micro or nano fabrication, highly specialized computer algorithms and microprocessors, and advanced optics.
While much research and testing remains to be done for each of these approaches, the options — and hope — patients now have is very different than even just a few years ago. And even more so as these technologies continue to advance, the future for patients affected by potentially debilitating forms of blindness is quite bright.