IN 1991 ROBERT GREENBERG was an M.D./Ph.D. student observing his first operation. On the table lay a blind man under local anesthesia. As Greenberg watched, an ophthalmic surgeon guided a tiny electrode into the man’s eye and brought it as close as possible to the surface of his retina.

“An assistant turned on the current, and the patient saw a spot of light,” Greenberg remembers. “Then he put in a second electrode, and the patient saw two spots of light.” The experiment was the first investigation into how a blind person’s retina would respond to electricity inside the eye and whether it might trigger something like sight.

What if you kept adding electrodes, Greenberg wondered. If he could find a way to deliver many precise bursts of electricity to targeted positions on the retina, it might produce a kind of synthetic vision. The idea combined two of his passions: medicine and electronics. That evening he told his girlfriend, “I think I know what I’m going to do with my career.”

Greenberg saw his task—bringing sight to the blind—as a relatively simple engineering problem. He would build a tiny implantable device with many electrodes, each producing a spot of light in the darkness, to restore the whole visual field. “I wanted to build it for my Ph.D. project,” says Greenberg.

Greenberg co-founded a company called Second Sight in 1998 to develop a retinal prosthetic, but it took until 2011 for the company’s Argus II device to be approved for market use in Europe; U.S. clinical approval came two years after that. And the device was not as effective in restoring vision as he had hoped. Activating its electrodes in careful patterns enables patients to see flickering arrangements of light and dark—just enough to make out a crosswalk or to tell whether someone’s face is turned their way.

Those limitations don’t obscure the extraordinary fact that this and other treatments for blindness are rapidly becoming a reality. And while the Argus II is the first artificial vision therapy to make it to the clinic, several other treatments are on their way, says Paul Sieving, director of the National Eye Institute.

“The retinal prosthesis is a tremendous advance that takes patients from nothing to something,” Sieving says. Other approaches to ending blindness use technology in similarly ingenious ways, he notes. In 2013, Sieving launched the NEI’s Audacious Goals Initiative to fund research on restoring vision by regenerating damaged cells in the retina. “We’ve made remarkable progress in understanding the biology of the eye,” Sieving says. “It seems time to harness this biology and do something big.”

Some therapies may eventually be adapted for treating people who are at the beginning stages of vision loss, making them more blindness prevention than cure. But Joan Miller, a retina specialist and chief of ophthalmology at Mass. Eye and Ear and Massachusetts General Hospital, says cures will probably always be needed. “People fall through cracks,” she says, “so the notion of having regenerative or hardware solutions is very appealing.”


Many of the most promising approaches fall into four categories: the retinal prosthetic, gene therapy, stem cell treatments, and a technique that uses optogenetics, a way to engineer nerves to fire in response to bursts of light. Each approach has shown potential in restoring at least partial vision, says Stephen Rose, chief research officer of the Foundation Fighting Blindness. His group funds research on all of them.

No single therapy is likely to restore natural vision in the near future, Rose cautions. Progress is rapid but the problem is complex, and the treatments being developed may not work for everyone. But he wants patients to know that a cure is on the way. “Too many people still get a diagnosis from their doctor and are told there’s nothing that can be done; they’d better learn to use a cane or a guide dog,” Rose says. “Instead, patients should be told that great advances are being made. There is true hope.”

MILLIONS ARE WAITING IN the darkness for that hope. The World Health Organization estimates that 39 million people worldwide are blind from a host of causes, including infectious disease and uncorrected cataracts. In well-off countries such as the United States, where 1.3 million people are legally blind, the most common causes involve the breakdown of cells in the retina.

The retina is a thin piece of tissue about the size of a postage stamp at the back of the eye; it’s so delicate that it’s often likened to wet, one-ply toilet paper. Light travels through the eyeball to reach the retina, then passes through several transparent layers of cells to strike the rod- and cone-shaped photoreceptor cells. The photoreceptors convert light into an electrical signal that travels along a complex network as a pattern of “firing” cells. It goes to a layer of bipolar cells for processing, and they convey the information to a layer of ganglion cells, which do more processing before sending the refined signal up the long sections (axons) of nerve cells that form the optic nerve, which brings the signal to the brain. There, the pattern of electrical pulses resolves into something recognizable—a landscape, printed words, a face.

Damage to any of these retinal cells can impair vision, and such damage is a major cause of blindness. It’s the root problem in macular degeneration, diabetic retinopathy, glaucoma and a handful of genetic diseases. Second Sight’s retinal prosthesis is currently approved only for patients with inherited retinal disorders (IRD), formerly known as retinitis pigmentosa, a group of genetic diseases characterized by a loss of photoreceptors.

A patient using the Argus II wears sunglasses with a tiny built-in video camera. A small processor that the person carries converts the camera’s stream of video data into simple patterns of light and dark on a grid of 60 pixels. The processor then sends that pattern wirelessly to a chip implanted above the retina, where 60 electrodes stimulate undamaged cells, creating signals that travel up the optic nerve. Two devices being developed by other companies, Retina Implant in Germany and Pixium Vision in France, operate on similar principles.

The Argus II’s 60 electrodes are trying to do the job of the eye’s roughly 125 million photoreceptor cells, so it’s not surprising that they produce extremely crude images. But Second Sight’s engineers are working on new software that will allow the video processors to increase resolution, an update that the more than 200 current users of Argus II will be able to download to their devices.

Second Sight’s other major initiative, dubbed Orion, has many similarities to the Argus II. It also uses sunglasses, a processor and an implant with electrodes to stimulate nerves. But the Orion implant is surgically installed on the brain’s surface, bypassing the retina and the optic nerve, sending data to electrodes pressed against the surface of the visual cortex. That connection may benefit those who have lost vision because of damage in the structures between the eye and the brain—the loss of an eye through trauma, for instance, or damage to the optic nerve. Greenberg expects clinical trials to begin this year.

LEBER CONGENTIAL AMAUROSIS (LCA) is another form of IRD that affects the retina and causes severely limited vision from infancy. Various forms of the disease stem from 24 currently recognized genetic mutations, each of which affects the function of retinal cells.

What sets LCA apart from other diseases of the retina, however, is that a treatment for one form of the disease is likely to be the first gene therapy for an inherited disease to be approved by the U.S. Food and Drug Administration. The treatment could help people who have a fault in a gene called RPE65, which causes problems in the retinal pigment epithelium (RPE), a thin layer of cells that support and nourish photoreceptors.

In 2007, a research group at Children’s Hospital of Philadelphia (CHOP) led by Jean Bennett began inserting a working version of the RPE65 gene into the eye by means of a harmless virus that carries the gene and “infects” the DNA of the RPE cells. Once the new gene was inserted, the previously defective RPE cells began to produce an enzyme crucial to photoreceptors. Because humans are born with a stable population of RPE cells that stay put throughout life, the researchers expected that fixing the cells once would make a lasting impact—and indeed, the vision of patients who got the therapy improved after a single treatment. Within a year, an eight-year-old boy went from walking with a cane to playing baseball.

The CHOP group founded Spark Therapeutics to refine and commercialize the treatment, and the company announced the successful results of the pivotal phase of human clinical trials in 2016. According to Katherine A. High, Spark’s president and chief scientific officer, the company will soon submit an application for FDA approval.

That clearance would be a high-water mark for gene therapy research, which suffered a major setback in 1999 with the death of a patient in a clinical trial for a liver disorder. A strong reaction by the patient’s immune system to a specific type of viral vector delivering the gene led to the failure of multiple organs.

In comparison, says High, gene therapies for the eye have two huge safety advantages. One is that the eye is physically separated from the body’s main blood supply and immune system, which means that a virus or other vector carrying a replacement gene won’t trigger a systemwide response. The other is that the adeno-associated virus (AAV) vectors used today are much safer than vectors previously used.

But the downside to this genetic approach to treating blindness is that it is one size fits one—each treatment has to be customized to address a specific genetic mutation. The 24 mutations currently known to cause different types of LCA are few compared with the 60 or more that are believed to contribute to IRDs. And creating a single therapy is a massive undertaking. The researchers behind Spark Therapeutics started with the RPE65 gene in part because there is a naturally occurring canine form of that genetic defect. Because they were able to test the treatment in blind dogs, they made faster progress toward the clinic. And even then, it took quite some time—their key canine study was published in 2001.

Some researchers seek gene therapies that might act more broadly on retinal cells, perhaps by using genes that produce proteins supporting the growth and health of nerve cells, which could be delivered before significant vision loss occurs. But High is skeptical: “In my experience as a biologist and a physician, if there’s one gene that’s defective, your best results will come from fixing that specific gene.” Now that Spark has grown and its therapy for the RPE65 gene is approaching an FDA decision, she says, the company is expanding its portfolio, with programs directed at new targets.

IN THE PUSH TO cure blindness, more than a half dozen efforts use therapies involving stem cells, undifferentiated cells that can turn into many different types of cell. While none of the research efforts is close to clinical use, early stage trials are under way in the United States, England, Israel and Japan. Most aim to treat macular degeneration, a common disorder among older people in which blurriness starts at the center of the visual field and produces a permanent blank spot. Stem cells are enlisted to attempt to repair retinal tissue.


First out of the gate was a company led by stem cell pioneer Robert Lanza that has since been acquired by the Japanese corporation Astellas Pharma. Lanza’s team figured out how to coax stem cells taken from human embryos into becoming the RPE cells that die off along with photoreceptors in macular degeneration, and in 2011 the team began injecting these manufactured cells into patients’ eyes. Most patients were able to read several additional lines on an eye chart after the treatment, and some regained the ability to thread a needle, use a computer or ride a bike. A larger clinical trial is planned for 2018.

Instead of starting with embryonic stem cells, as Astellas does, several other research groups are working with retinal progenitor cells found in the eye. These cells can develop into any type of retinal cell, including RPE cells or photoreceptors. And at Japan’s RIKEN Center for Developmental Biology, one pioneering group is taking induced pluripotent stem cells (iPS), mature cells reprogrammed to return to a state of pure potential, and turning them into RPE cells.

In 2014, RIKEN’s Masayo Takahashi made news by being first to use iPS cells in any human therapy. The patient had severe macular degeneration, and while vision did stabilize, it didn’t improve. Takahashi hopes to get approval for trials that intervene earlier in the progress of the disease. “For age-related macular degeneration, the best timing might be when the photoreceptors have lost function but haven’t yet died off,” she says.

THE NEWEST APPROACH TO curing blindness can claim yet another first—the first time that optogenetics, a novel type of genetic engineering, has been tried in humans. In Dallas, the company RetroSense Therapeutics began safety trials in February 2016; and GenSight Biologics, in Paris, is gearing up for its own trials this year. Rather than try to restore damaged photoreceptor cells, their treatments recruit other cells to do their job.

Optogenetics creates cells in the body that respond to light. This happens by inserting a gene (typically taken from a green algae) that produces a light-sensitive protein. In recent animal experiments, neuroscientists have genetically modified the neurons of mice and monkeys in this way, then snaked fiber optic cables into nearby brain tissue. Pulses of light then trigger the light-sensitive neurons to fire on command. The hope is that this approach could be used to treat neurological diseases.

Blindness researchers, however, propose several reasons why optogenetics could work better in the eye. Once the retinal cells began producing the light-sensitive protein, there would be no need for fiber optic cables to trigger them with pulses of light, because light passes naturally into the eye.

GenSight’s treatment is for people with damaged photoreceptor cells but intact ganglion cells; it inserts the gene into the ganglion cells, whose axons form the basis of the optic nerve. The treatment makes these ganglion cells act like photoreceptors, responding to patterns of light that pass through the retina and converting them into patterns of electricity that go directly to the brain. Like other forms of gene therapy, the optogenetic method could theoretically restore vision with a one-time treatment. “We are born with a pool of ganglion cells, and we’re going to die with those same cells,” says Bernard Gilly, CEO of GenSight. “If we transfer a gene into those cells, there’s no reason why it would stop being expressed.”

The current optogenetic methods for vision require some hardware. The altered ganglion cells respond to only one wavelength of light, which means that users will need to wear goggles that convert an image of the world into a simple pattern in the correct wavelength.

It’s not yet clear how well ganglion cells will work as stand-ins for photoreceptors, says Richard Masland, a senior scientist at Massachusetts Eye and Ear, who developed fundamental optogenetic techniques. “We don’t know how the brain will deal with the abnormal input,” Masland says. In a healthy eye, the visual signal goes through several stages of processing before it reaches the ganglion cells. “It’s simplest to use them—and there’s plenty of reason to think that the brain will learn to interpret the information,” he says.

Optogenetics researchers, like those taking other approaches to restoring sight, are up against not only the dizzying biological complexity of the eye, but how those inputs get processed by the brain. Step by step, these once-impenetrable organs are giving up their secrets. Patients are only just beginning to benefit from these therapies, and much work remains to take promising experiments into the clinic. But one thing is already clear: People who are blind are no longer waiting without hope. The miracle is in sight.