Why There’s New Hope About Ending Blindness

From the day Christian Guardino was born, his mother, Elizabeth, knew that something was wrong with his eyes. They would jiggle and jerk and roll up into his head. One eye turned inward. When she fed him, instead of gazing up at her, Christian would stare at the brightest light around—a lamp if they were indoors, the sun if they were out. It was unsettling.

The first eye doctor who saw Christian grimly referred the family to a specialist at New York’s Mount Sinai Hospital. The specialist performed an electroretinogram (ERG), a procedure in which a tiny electronic sensor placed on the eye measures the retina’s response to bursts of light. A healthy retina will respond by firing an electrical signal down the optic nerve that produces, on the ERG machine’s printout, a deep valley followed by a tall peak. Christian’s ERG produced no such thing: only squiggles, ill-formed and weak.

Christian, the doctor told Elizabeth, had a retinal disease called Leber congenital amaurosis (LCA). His vision, already bad, would never significantly improve. Nothing could be done. The boy would see little of the world and would always walk, once he learned how, with a cane.

Christian did need a cane, and his mother’s guiding hand, when in 2012, at age 12, he first visited a clinic run by the University of Pennsylvania’s Scheie Eye Institute. Yet this January he walked through the institute’s main building cane free and seemingly fearless. Joking and chatting, the teen led a klatch of Ph.D.’s, M.D.’s, lab techs, and me through the airy lobby. He marveled at the towering atrium, the shiny balconies where people sat having coffee.

“Whoa!” he said as we neared the building’s exit—for before us an enormous revolving door turned its huge blades. His mother was some distance behind; he was on his own. Christian neither stopped nor paused. He walked calmly through the opening of the spinning wedge of steel and glass and held his pace as one glass wall closed behind him and another smoothly swung out of his way. He stepped into the sunlight.

Christian Guardino could see. Everything that had posed an obstacle before—light and dark, steel and glass, the mobile and the immovable—now brought him pleasure. The world had opened before him.

“Can you believe this?” Elizabeth asked a few minutes later. Ahead of her, Christian walked with Jean Bennett, whose lab at Penn produced the gene-laced fluid that gave Christian sight. “It happened so fast,” Elizabeth said. Just three days after his first eye was treated, Christian could see her. “I went from wondering if my son would ever know what I looked like to … well, this,” she said, gesturing at him walking unaided. “It’s like a miracle.”

Christian’s miracle was hard-won. It rose from 20 years of unrelenting work by Bennett and her collaborators, who identified the genetic mutation that crippled Christian’s retina, then figured out how to sneak a good copy of that gene into his eye. Bennett started trials for the therapy merely hoping “that we could detect some hint of improvement.” Nine years later she is astonished that it seems to have worked so well.

Bennett takes care not to aggrandize her work or underplay the obstacles to further progress. Yet the gains so far for Christian and other patients give Bennett guarded hope that this basic gene-replacement approach might work for other forms of blindness. She and others believe that variations on her technique might soon help doctors find and fix similar genetic defects early enough—perhaps even in utero—to reverse or prevent eye damage.

Within roughly the past decade, efforts in two other areas, stem cells and biomedical, or “bionic,” implants, have also given at least some sight to people previously sightless. Stem cells—cells in early stages of development, before they differentiate into the building blocks of eyes, brains, arms, and legs—show increasing promise to replace or revive the failing retinal cells that underlie many causes of blindness. And the first generation of bionic retinas—microchips that replace failed retinal cells by collecting or amplifying light—is bringing a low-resolution version of sight to people who for years saw nothing.

These advances encourage talk of something unthinkable just 10 or 20 years ago: ending human blindness, and soon.

Is this even remotely realistic? Some advocates and fund-raisers are suggesting so. Businessman Sanford Greenberg, who lost his sight to glaucoma while in college, has founded End Blindness by 20/20, which offers three million dollars in gold to the person or persons who contribute most to ending blindness by that date. The National Eye Institute, one of the U.S. National Institutes of Health, is aggressively funding eye research with large awards from an Audacious Goals Initiative. The World Health Organization and the International Agency for the Prevention of Blindness’s Vision 2020 initiative states a goal of “eliminating avoidable blindness by 2020.” Meanwhile many a breathless media story about work like Bennett’s seems to assume we’ll pull this off.

Anyone following Christian Guardino around town might be tempted to agree. Yet as University of California, Irvine stem cell researcher Henry Klassen put it, “You want to quickly find ways to cure the hardest cases? Good luck. This is not an easy job.”

Most researchers agree. Jean Bennett, for instance, knows that the genetic therapy that gave Christian sight (and still needs replication elsewhere) is remarkable because it defies a long history of disappointment, delay, even disaster.

Bennett has seen countless gene-therapy efforts fail. In a recent paper she bluntly lists the daunting obstacles to expanding her therapeutic approach even to other genetic causes of LCA. For example, the gene she inserted into Christian’s eye, known as RPE65, fits nicely in the modified, benign virus she used to carry it into his cells—but many other genes that lead to LCA are too big to fit. In addition, most other harmful LCA mutations do their damage far earlier in life, or operate in areas of the eye less friendly to gene replacement, and so can’t be treated well with the currently available viruses.

Such barriers—and similar ones affecting stem cells and bionic implants—won’t fall overnight. Most gains will be hard-won and incremental. Many a miracle cure will prove fleeting.

When assessing the sight-restoring potential of gene therapy, stem cells, and retinal implants, it’s fair to view them as a sort of three-legged stool. Right now it’s unsteady—but strong enough to support our weight if we move carefully in our quest to end untreatable blindness.

The challenge of ending treatable blindness, though, is another matter altogether.

Roughly one in every 200 people on Earth—39 million of us—can’t see. Another 246 million have low vision to degrees that impose moderate or severe limits. Vision loss also affects hundreds of millions more people, often relatives, devoted to aiding those who can’t see.

These burdens alone justify the search for new treatments. Yet the eye is also getting increased attention because it provides a safe, accessible spot to test treatments that might also be used elsewhere in the body.

To start with, researchers can look directly into the eye to see what’s wrong and whether a treatment is working. Likewise, the eye’s owner can see out of it (or not), providing a quick, vital measure of function. The eye also offers feedback such as pupil dilation or electrical activity in the optic nerve. In addition, a researcher running an experimental treatment on one eye can usually use the other as a control—and as a backup in case something goes awry.

The eye is also tough. Within the eye’s spherical refuge, the immune system restrains itself in a way that makes the eye “immune privileged,” tolerant of invaders that might cause troublesome inflammation in other organs. This means you can more safely try a remedy in the eye, such as gene therapy, that might wreak havoc elsewhere.

Neuroscientists love the eye because “it’s the only place you see the brain without drilling a hole,” as one put it to me. The retina, visible through the pupil, is basically a bowl of neurons tied to the brain by the optic nerve; the eye as a whole is an “outpouching of the brain,” formed during fetal development by stretching away from it. Like the eye, the brain enjoys immune privilege, so treatments that work in the eye may readily transfer to the brain or spinal cord.

These advantages take on extra importance because experimental strategies now focused on the eye may drive future treatments for the whole human organism. Gene therapy offers the promise of fixing faulty genes that cause illnesses of all kinds. Stem cells offer the promise of replacing entire tissue structures; bionic implants may replace failing organs. The eye is becoming a window not just to the soul, but also to the possibilities—and limits—of therapeutic approaches on which medicine is betting its future.

Imagine a high-contrast, low-resolution, flickering black-and-white picture—a downgrade from the first television images of the 1920s—and you’ve imagined something close to what Rhian Lewis sees with her bionic eye. Lewis, 50, of Cardiff, Wales, has retinitis pigmentosa, a disease in which photoreceptors die because of a gene deficiency and vision dims from the periphery. Over time the tunnel of sight shrinks to nothing—“like a dimmer switch slowly going dark,” Lewis says.

The condition struck Lewis early. While still crawling, she wouldn’t leave a room if it meant going into an unlit hall; she once ran headlong into a barbwire fence. She nonetheless got through school and college; tended bar by knowing the precise location of every bottle, glass, and tap pull; and later, even as her right eye completely failed, worked 20 years in a book and stationery shop by memorizing every section and learning to tell pens apart by the feel of their barrels or packages. Since the bookstore closed, she has mostly stayed home raising her twins, who are now in their late teens.

In June 2015 she went to Oxford Eye Hospital, lay on a table, surrendered to anesthesia, and, 10 hours later, awoke with a bionic eye. In what was “without doubt the most complex operation I’ve ever done,” says surgeon Robert MacLaren, the Oxford team slipped between her retina’s delicate layers a freckle-size microchip laden with 1,600 tiny photodiodes. MacLaren’s clinical trial is exploring whether this chip, known as the Alpha, can replace the dead photoreceptors (the famous rods and cones) in the center of Lewis’s retina by translating light into bursts of current that the existing neural network will relay to the brain.

When they turned on the device, Lewis told me last November, “I couldn’t believe it. Suddenly—oh, my God—there’s something there.”

But what? Her brain interpreted the chip’s electrical signals not as objects or scenes, but as strongly contrasting flashes and shimmers. “Not an image as such,” she says, “just sort of an awareness that there’s a difference.”

Since then she’s been learning to interpret these bursts of light as sight. This includes formal training at MacLaren’s lab that “is like triple maths,” she says, laughing. “I hate it.” But it’s paying off. She has learned to recognize one kind of patterned flashing as a person, another as a tree. She’s getting better at distinguishing contrast in the dreaded task she calls the “50 shades of gray test” (it’s really seven). She can read a big high-contrast clockface at arm’s length. The week before I visited, she took a walk around Oxford with MacLaren’s team and found that she could tell, for the first time in years, a building’s windows from its walls.

Yet the gains are modest, and Lewis still does almost everything—dresses, bathes, moves around the house, gets the kids out the door, feeds Chopsy the dog, gets the mail—by feel and the fading sight of her good eye. Her bionic eye is taxing to use; she usually leaves it turned off.

Such limits are to be expected with these early prototypes, says Eberhart Zrenner, the German eye surgeon who began developing the Alpha more than 20 years ago. “The idea was never to get full vision,” he says, “but to improve a patient’s ability to recognize objects and move around.” It’s doing that. Lewis again sees the lights of her Christmas tree. Zrenner describes a patient who can again read his own name; another who can again see the kitchen sink; another who beheld for the first time his fiancée’s face “and saw that it was laughing.” Nearly half the 29 patients who received a similar, previous version of the implant, he says, find it truly useful.

Lewis also has found hers useful, and for this she is grateful. Even if it gets no better, she says, the chip’s often indecipherable image constitutes a miracle of sorts—light replacing dark. She expects that as her left eye inevitably fails altogether, this bionic eye, or perhaps a successor, will allow her to still do all the things she does now.

She’s also glad to be part of this wild experiment. “My motivation is for my kids,” she says, both of whom see fine now but stand at increased risk of developing retinitis pigmentosa, which is inheritable. “Anything I can do now can help people down the line.”

MacLaren says the implant project is teaching valuable lessons. For starters, its demonstration that photodiodes can substitute for natural photoreceptors is a huge stride: In the exacting machine that is the eye, we’ve fashioned a cog that fits, even if imperfectly. The devices also show that patients can learn to interpret new presentations of visual stimuli. In addition, MacLaren says, the implants show that “there’s still visual potential once the photoreceptors are gone, because the other nerves are still intact. This is something I never thought could be shown.”

MacLaren says that these lessons learned are already spurring advances in the other two cutting-edge areas: gene therapy and stem cells.

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In California an eyeball dream team is running a stem cell trial that evolved almost directly from an implant. One of the leaders is Mark Humayun, a courteous, efficient, impeccably besuited man. Like MacLaren, Humayun seems to be running projects in every possible therapy for every part of the eye.

His first big project was co-inventing the Argus II, which in the early 2010s became the first retinal implant to go to market. Like Zrenner’s Alpha, the Argus uses an electrode array embedded in the back of the retina. But rather than collect light, this grid of just 60 electrodes pulls signals from a tiny eyeglass-mounted camera that relays them through a processing unit carried on a belt or in a bag. All this gear imposes a stiffer set of limitations and demands than the Alpha does. In addition, the Argus’s external camera means that, unlike the Alpha, it cannot exploit the eyeball’s constant small movements, known as microsaccades, that play a mysterious but vital role in vision.

Fitting that implant into people’s retinas, however, helped inspire the stem cell device Humayun is now developing. He and his fellow principal investigator, University of California, Santa Barbara stem cell biologist Dennis Clegg, call it simply a patch. That patch’s chassis, made of the same stuff used to coat wiring for pacemakers and neural implants, is wafer thin, bottle shaped, and the size of a fat grain of rice. Onto this speck Clegg distributes 120,000 cells derived from embryonic stem cells.

Humayun and Clegg propose to use this patch to treat a condition called age-related macular degeneration (AMD). Going blind from AMD is the reverse of what happens in retinitis pigmentosa: A blurry spot fogs the middle of one’s vision, then slowly darkens and spreads until you’re functionally blind. It’s the most common untreatable cause of vision loss, accounting for five percent of all blindness.

AMD rises from cell decay in the eye’s rearmost layer, the retinal pigment epithelium. The RPE gives key support for the photoreceptor layer lying just in front of it. Humayun and Clegg hope the patch’s stem cell–derived RPE cells will replace these failed RPE cells.

The cells can’t just be injected. In animal studies that Humayun and Clegg conducted, the cells integrated most effectively with the photoreceptor layer’s complicated architecture if they were on a well-placed patch. Positioning the patch in just the right spot will be tricky business—precisely the kind of challenge that surgeons like Humayun crave.

The trial just started and should end by 2018. If it works—a big if, as with all these projects—it could be useful in treating AMD and other forms of blindness. Humayun and Clegg also might learn things about how to fuse such cells into biological structures in other organs, paving the way for other cell-patch implants.

The untapped potential of stem cells has drawn others pursuing blindness cures, including Henry Klassen of the University of California, Irvine. Klassen has spent 30 years studying how to coax progenitor cells—former stem cells that have begun to move toward being specific cell types—into replacing or rehabilitating failed retinal cells. Having successfully used retinal progenitor cells to improve vision in mice, rats, cats, dogs, and pigs, he’s testing a similar treatment in people with advanced retinitis pigmentosa.

In a procedure that Klassen calls “Zen-like” in its simplicity, a surgeon uses a needle to quickly inject into the eye a half million to three million progenitor cells meant to play multiple roles in rescuing the failed retina. Some retinitis pigmentosa patients who’ve had the procedure are seeing significantly more light and shape. Kristin Macdonald, a 50-something California resident who was nearly totally blind from retinitis pigmentosa, received the treatment in one eye in June 2015. Now she can see more of her furniture, a van across a street, and, at a swimming pool, “a pale hue”—the reflected turquoise of the water that once was just black and white. Klassen hopes such gains will prove his premise that if you send the right cells to the right spots, they’ll know what to do.

Namibian eye surgeon Helena Ndume likes to recount what patients do when they’re given sight after years of blindness. She tells of a man who, having once almost walked into an elephant, thanked Ndume after treatment because he could now see wandering animals; of a woman whom, after treatment, Ndume found utterly absorbed in removing every last bone from the fish she was eating; of a woman who, at 46, could finally see her young son.

Ndume has collected many such stories during the past 20 years as she has pursued her own experiment in ending blindness. The experiment’s findings are in one sense unambiguous: In two decades some 30,000 patients have received treatment, and some 30,000 regained their sight. Clearly the cure works. Yet the treatment—a simple, thoroughly proven cataract operation—is not what Ndume’s experiment is testing. She and others doing similar work are testing whether humanity, once possessing a cure, will bother to deliver it to all who need it.

Cataracts, a disease of poverty, cause half of all blindness on Earth. In the developed world, people with cataracts routinely get treated as soon as they have trouble seeing the TV. In the developing world, people with cataracts routinely go blind. The treatment everywhere is simple: Get clinician and patient in the same room, prep the latter, spend 15 to 20 minutes replacing the cloudy natural lens with a clear artificial lens, do a post-op checkup. In developing countries, treatment usually costs $15 to $100. Yet it reaches few who need it.

Working with Namibia and other African governments and the nonprofit SEE International, Ndume is trying to fix this by running “cataract camps.” At these gatherings in underserved areas, Ndume and other surgeons operate on up to 500 people a week. The United Nations last year recognized Ndume’s “service to humanity” with its inaugural Nelson Rolihlahla Mandela Prize.

It’s a fitting honor for someone who 41 years ago, as a girl of 15, left a different kind of darkness when she fled the apartheid that the South African government had imposed on Namibia. With three friends she made her way to a camp in Angola run by the Namibian resistance movement SWAPO; survived a machine gun attack soon after she arrived; braved hippo-infested rivers and hostile helicopter patrols to find safety in Zambia; told SWAPO she’d like to go to fashion school but was sent instead to medical school in Leipzig, Germany; and there married a countryman who soon after was killed in Angola. She bore their baby alone, finished her ophthalmology training, rejoiced when Namibia won its independence in 1990, and returned for good in 1996 with her child, her education, and a determination to help those who could not see.

My favorite Ndume story is about a woman she treated in the first year of the camps, at a clinic in Rundu, on Namibia’s northern border. More than 200 patients had signed up. Only 82 came, because so many were scared of having their eyes cut open. This woman was one of the brave ones.

When Ndume held the camp at Rundu the next year, the same woman came in, exultant. She wanted to show the doctor her farm, which she’d been able to vastly expand: “I make so many crops now!” she told Ndume. But first she pulled Ndume by the hand to the clinic door.

“I brought some of my friends,” the woman said. Outside were scores of people eager for the surgery after seeing what it did for others. “They talk of it like a miracle,” the woman said.

Ndume treated hundreds that week. As her colleague Sven Obholzer put it, patients “walked in with their hands on the shoulders of the people in front of them and walked out on their own.”

The UN honor was a great boost. Yet despite Ndume’s work and others’, some 20 million people worldwide remain blind from cataracts. Treat them all, and you’ve cured half of all blindness. Doing that, however, will require not just camps but also permanent infrastructure to make treatment routine. This is one reason former NBA star Dikembe Mutombo built a hospital in his hometown of Kinshasa, Democratic Republic of the Congo. When Ndume visited, the hospital’s value, and inadequacy, were made clear. Scheduled for five days, she stayed for seven, did more than a hundred operations, and left a waiting list of hundreds. “It is like this everywhere,” she told me. For every patient she treats, dozens go unseen and unseeing: “Always more.”

When I mentioned to Ndume the causes of blindness this story would address, this was her gentle response: “These other things, macular degeneration, retinitis pigmentosa, they are nothing next to cataracts.” The most generous of souls, Ndume did not mean those conditions are inconsequential or that no one should seek cures for them. She meant that in the quest to end blindness, medicine’s biggest challenge is not just finding cures but also delivering them.

That day Ndume performed nine cataract operations before lunch. Observing one, I saw for the first time a knife slice into an eyeball. The sight disturbed me—in part, I realized, because nothing symbolizes awareness as much as an eye wide open. Here was an eye absurdly wide open, thanks to the ophthalmic speculum holding back its lids—yet utterly oblivious to the steel carving a curve in its cornea.

Recognizing that made it easier to watch. I knew that the anesthetic would soon fade and that once it did, the eye would see clearly.