Photographs by Mike DeFilippo
It had to be the world’s least sexy topic. As far as I knew, macular degeneration was an icky rotting of some odd little structure in the back of the eyeball that doomed a few unfortunate elderly folk to blindness. Already nearsighted, I was a bit phobic about the vision thing, print being both my life’s work and (sex, wine and dark chocolate notwithstanding) its main pleasure. Fate would never dare pluck out my eyes, I told myself. Repeatedly.
But the young ophthalmologist spoke so passionately about research puzzles and breakthroughs, he swept right past my defenses. Dr. Rajendra Apte (medical degree from the University of Bombay, ophthalmology residency and doctorate in immunology at the University of Texas, retina and vitreoretinal fellowship at Johns Hopkins) is on a vision quest.
Some form of age-related macular degeneration affects almost7 million people in the United States alone, he tells me when, still wary, I agree to meet with him. Not only is it the leading cause of blindness in people over 50, but with the Baby Boomers sailing past midlife, it’s about to reach epidemic proportions. I squint down at my notepad and scribble faster. Just 10 years ago, physicians had few clues and fewer options for treating AMD and similar disorders. Finally, in 2000, a cold laser procedure came along; then two breakthrough drugs were approved, one in 2004, one just last year. Now ophthalmologists are shooting laser beams, dyes and drugs like star warriors, freezing blood vessels, squeezing the eye with silicone bands, sucking the vitreous gel right out of the eyeball and using blind mice to find gene therapies that could restore sight.
OK, a little sexier than I thought.
But still terrifying.
A Shot in the Dark
We’re standing in an empty treatment room at the Barnes Retina Institute. “These used to be very large,” Apte says, using a key to turn on a sleek gray molded-plastic piece of equipment that turns out to be a laser with a rainbow of wavelengths: argon yellow, argon green, krypton red ... He shows me the eye filter—“because you don’t want to get lasered while you are lasering your patient!”—and the aiming beam. A colleague recently went skeet shooting and was asked how he’d gotten so good at the sport. He shrugged and said, “I do it in the office every day.”
Apte reverently lifts the white plastic drape over a cold laser, with a much higher wavelength, for the Visudyne procedure that was approved in 2000. “Before that, there was really nothing for maculardegeneration,” he says, “because it affects the very center of the retina. Use the hot laser and you are essentially left with a blind spot”—which is a lousy way to cure blindness.
With the cold laser procedure, dye injected into blood vessels in the arm travels to the eye and gloms onto abnormal blood vessels under the retina. “There’s a nice little picture over here,” Apte says, gesturing toward a lurid orange eyeball poster that, in another context, might tout a cult film. “The drug is inactive until we shine the laser beam, which photosynthesizes the dye and causes the blood vessels to shrink.”
The next breakthrough came in 2004 with Macugen, a drug injected straight into the eyeball. I feel my shoulders hunch protectively. “Why,” I ask, trying to sound casual, “do some of us recoil from the idea of injecting an eyeball?”
“It’s a visceral reaction,” Apte says. “It tells you how important sight is to people.”
True. But I’d rather be disemboweled than have one of those bloodless, painless vision-correcting surgeries people save up for. I once clawed my eye with a torn fingernail in my sleep; I raced to the doctor the next morning and spent the rest of the day telling co-workers, in tones of hushed hysteria, that I had a scratch on my eyeball.
Apte has moved on to the drug that excites him most: Lucentis. “Its real name is Ranibizumab,” he confides. “They all sound like dinosaurs.”
Like Macugen, but with even better results, Lucentis blocks a compound called VEGF (vascular endothelial growth factor) that’s important elsewhere in the body for blood circulation and wound healing, but that can cause abnormal, weak blood vessels to develop and leak into the eye. “Now we’re not just looking at halting vision loss,” Apte exults. “We actually have a reasonable expectation of vision improvement—for AMD and other disorders as well.”
He’s also seen vision improve with steroid injections—and Thelma Hartnett still can’t get over it. She taught consumer economics at Ursuline Academy for 27 years and is now its alumni director. She golfs, plays the stock market, ushers at the Fox Theatre, reads Forbes and every other money magazine on the newsstands and travels—to Alaska, to English cathedrals, by boat from Vienna to Amsterdam. But one morning last fall, she rose at her usual 5 a.m., sat down with the newspaper and realized she couldn’t see out of her left eye.
She was referred to Apte, who diagnosed a swelling in the back of the eyeball—“They don’t even know what causes it,” she exclaims, outraged—and injected Kenalog, a steroid. Her vision returned—then left again, just as suddenly. He gave her a second injection (these are not permanent one-shot cures—not yet). She can now read without the glasses she’s worn since college.
Seeing the Light
Against a velvety black background, a giant orange sun glows, its surface covered with red rivers. “Those are arteries supplying the blood, and veins taking it away,” Apte says, explaining that orange is the eyeball’s natural color, because of the retina’s pigments.
Light enters through the pupil (one who learns), but it’s the retina, at the back of the eye, that focuses the light, giving the optic nerve an image to send to the brain. In the center of the retina is the macula, a tiny, exquisitely sensitive area 100 times more aware of detail than the surrounding 95 percent of the retina. The duller mass gives us peripheral vision; that sweet spot in the center lets us read fine print and recognize every freckle on a loved one’s face.
In our visual culture especially, seeing is power—it’s how we learn to claim the world. “Seeing” means you understand. “Seeing someone” means you’re coupled. “Seeing eye to eye” means you agree.
A sudden blindness means your world has vanished.
“See these tortuous vessels? That’s a squiggle of dilated vessels because the tissue on top is damaged and you can see through it,” says Apte, pointing to a dark cloud of blood around the macula. “That is wet AMD. And see those yellow dots? Those are deposits, called drusen, that you also see in dry AMD.”
Dry AMD is an earlier, milder form of the disease; it slowly lessens vision but doesn’t always lead to wet AMD, which causes more sudden and dramatic losses. The “wetness” is the blood or fluid that leaks out of weakened blood vessels, scarring or damaging the retina so that the images sent on to the brain are blurred. Words fall out of books; pictures take on funhouse shapes; utility bills blur and shimmer until you feel like you’re seeing them in heat waves, through a cracked windshield, crossing the Mojave.
Apte turns to another visual aid, this one a slide produced by a revolutionary test called optical coherence tomography, which uses light waves to map damaged areas of the retina by cross-sections.
Queasy at the thought of eyeball cross-sections, I distract myself with art: The image’s starry Van Gogh sky is the cavity of the eyeball; pointillist dots of bluish green show the layers of the retina. “What’s the squiggly white line?” I ask, feeling observant and scientific.
“Um ... that’s just a line someone drew to help calculate the retina’s thickness,” Apte says. “We dilate the pupil to get a good view of the back, where the optic nerve is. People say, ‘Do you take the eyeball out for surgery?’ Well, we don’t, because it’s got hardware plugged into the brain.”
What he will take out, he tells me, is the vitreous, a clear jelly-like substance that fills the middle of the eyeball. Over time, the gel can separate from the eye wall, causing the patient to see floaters (clumps of liquefied gel that cast shadows on the retina) or flashes (streaks of electricity, like strobe lights, set off when the gel shrinks and tugs on the retina).
With diabetes, excess sugar can break down blood-vessel walls, and the resulting hemorrhages can cloud the gel or cause the retina to develop tears or holes. The gel can then ooze underneath the retina and basically lift it off, detaching it from the back of the eye.
“When you are a baby, the gel is like Jell-O,” Apte says. “As you get older, parts of it liquefy. You don’t need it anymore; early on, its collagen fibers are a scaffold on which the lens and retina can develop, but once you are an adult, the vitreous does nothing but cause problems.”
I grow even paler as he describes his sutureless surgery: “There’s a little pen with a metal point you poke into the white part of the eye, the sclera. You make ports and put the instruments through them to go into the back of the eye. The needle’s only 25 gauge. You also put in another opening to pump in saline, because something has to keep the eye inflated as you remove the gel.”
He uses both hands and feet to operate the vitreous cutter: “You press on a pedal with your foot, and it cuts and sucks,” he explains. “You can’t just suck the vitreous out with a needle, or it will pull the retina out. So it’s like Pac-Man; you are cutting it and eating it up. Isn’t that nice?”
Pricier Than Gold
We enter the McMillan Building at Washington University School of Medicine and take the elevator to Apte’s seventh-floor lab. “The vial was empty when we opened the shipment,” he tells an assistant, then murmurs to me, “It costs $1,900 for one 2 cc vial of Lucentis. It’s pricier than gold.” He chats about new studies—one to measure the protective powers of antioxidants, zinc and other supplements; another to test the wisdom of injecting steroids into the inflamed eyes of people with diabetes. “People started doing these injections a few years ago, without any randomized clinical trials,” he says. “Physicians get frustrated, looking for something better.”
Apte came to the Washington University School of Medicine four years ago determined to establish a center for retinal vascular disease research. He wants to know how the eye changes over time; how the immune system interacts with blood vessels; what treatments could cure, and not just stall, eye disease; how gene therapy could save vision.
I flash back to age 8, when I was charged with putting drops in Grandpa’s eyes. He’d dutifully tilt his head back, the Naugahyde chair squeaking, and I’d slide his eyelid up and squeeze out the drops as fast as I could. I was terrified by his helplessness, and I always felt an overwhelming relief when he replaced his steel spectacles and normalcy was restored.
I can’t even begin to imagine what it would feel like to restore someone’s sight.
“People function with poor vision from birth and are just fine,” Apte says. “But people who are not born visually impaired are so dependent on vision. We need it for most of our daily life and work. The biggest fear of most of my patients is ‘I cannot not be able to drive.’”
In quality-of-life studies, people rate complete blindness as worse than heart failure, kidney failure with home dialysis or symptomatic AIDS. They even rate wet AMD, without complete blindness, as worse than symptomatic AIDS. People who have lost vision are more likely to be depressed and, in nursing-home studies, more likely to die.
As a little girl, my Aunt Mary lost sight in one eye. By the time I knew her, the eye looked like clotted milk, with streaks of buttery yellow and marble-swirls of pale green and blue. Otherwise healthy and vibrant, she socialized only with family and rarely left the house. Devoutly Catholic, she “went to Mass” by watching the televised version every Sunday morning.
She didn’t want anyone to see her bad eye.
300 Blind Mice
“In case you are wondering what happened to all the mice, they are in two other buildings,” Apte volunteers. “One has four floors just for housing mice.”
I’m not wondering. I don’t want to think about it. But he takes me to a room filled with mice that have had surgery and can’t return to the sterile facility. There’s a warm, musky smell, and I see cage after cage of black and brown mice scuffling in their bedding or standing against the glass, little pink paws splayed.
“We’re using animal models to study AMD and diabetic retinopathy,” Apte explains. “We use approved animal-research guidelines. Still, when I tell people I take mice’s eyes out, they recoil and say, ‘Oh no!’ Other researchers take organs and bone marrow, and nobody says a word.”
He uses a krypton laser to injure a membrane in the mice’s eyes, prompting the growth of abnormal blood vessels. “Then we anesthetize the mouse and inject dye into his heart. The dye travels to the eye. We kill the mouse and take the eyeballs out, mounting sections that are lit up with green dye so we can measure the volume of the blood vessels.”
The main targets of Apte’s attention are the macrophages: bone marrow cells that play complicated immune-system roles throughout the body. Last year, his research showed that macrophages in the eye can inhibit the growth of blood vessels. “We are now finding out that they can actually promote growth, too,” he says. “So what makesthe difference?”
To figure it out, he focused on a macrophage that produces a protein molecule, interleukin-10, that promotes blood-vessel growth in the eye. Then he cloned a transgenic “knockout” mouse whose IL-10 gene had been removed in embryo.
Turns out that injecting macrophages taken from old mice stimulates blood-vessel growth, injecting macrophages from young mice reduces blood-vessel growth and injecting macrophages from the knockout mice really inhibits blood-vessel growth. “So if you can alter those macrophage cells, you will have an immune-based therapy that alters, or at least delays, the disease process.
“A very interesting mouse has come out of all this,” Apte adds. “We created a mouse that expressed IL-10 at high levels in the eye. The gene we used to drive that is also expressed in the brain and spinal cord, so it up-regulated IL-10 levels there too. The mice developed hind-limb paralysis, tremors and tremendous amounts of inflammation, and the nerve cells in the spinal cord were either dead or dying. Can you imagine? This could be a spontaneous mouse model for mysterious autoimmune diseases like MS and ALS.”
He sighs. “There’s this big gap: All this here—” he waves toward the centrifuge and the slanted black machine that amplifies DNA genes—“and then the patients waiting in my clinic. Applying this research in clinical trials will take millions of dollars and probably require some pharmaceutical companies. They’re not all evil, though.”
He walks to a freezer. “These are blood-vessel cells from humans. We can make them or buy them commercially.” He adds different agents to these cells to see if he can alter their growth, experimenting with tissue cultures so he’s not using animal or human subjects yet. From another shelf, he selects a glass vial and carefully carries it to a microscope, showing off spindle-shaped melanoma cells pigmented the amber-red of sherry. His hope? That if his team can identify factors that slow blood-vessel growth, they can reduce the blood supply that feeds these cancer cells.
He moves on to a dark room in which an assistant is measuring blood-vessel volumes from mice eyes on a microscope. “They’re stained magenta for the macrophages in the retina,” he says. “We can even do time-lapse microscopy—it’s like taking a video with live cells, so we can see how the cells are moving around.”
“Do they move much?”
“Oh yes. You’ll be surprised. It’s kind of scary to think what is going on in our body.”
Sight for Sore Eyes
“The only way you could ever understand it is if you had been unable to see and then you got your sight back,” Mary Lou Baldwin says fervently. A blue-eyed redhead who won fame as the Apple Butter Lady (a picture of “Moo Baldwin” was on every jar), she worked at Silver Dollar City for 30 years. “I was in my late fifties when I noticed that my arm wasn’t long enough,” she says, remembering how she had to hold budgets and seminar notes farther and farther away. “Kid, I never wore glasses. My eyes were always 20/20.”
She gave in, got some specs. But pieces of the world started eluding her. At 72, a little overwhelmed, she retired and moved to Salem, Ill., to be closer to her daughter. “I’d go to reach for something, and it wasn’t there,” she recalls, the shock still in her voice. “My daughter would take my hand and move it over.” The rooms of her own home lost definition, with shadowy forms everywhere she looked, and she started feeling scared to live alone.
An optometrist in Salem peered and tested and told her, “I’m sorry, ma’am, but you are way out of my league. I think you’ve got something really bad wrong with your eyes.” He called it “a bleeding,” went straight to the phone and called Apte.
“When I first met Dr. Apte, I couldn’t see very well, so I had no idea he was such a little hunk,” Baldwin confides now. “His nurse, Eva, said, ‘Oh, Moo, I’ll be so glad when you can see. He picks out his own clothes—wait till you see the shirts he wears.’ See, I couldn’t even see the colors.
“It’s kind of heart-rending, when you think you have two good eyes and—” she takes a ragged breath. “He gave me this black heavy thing that covered one eye, and I said, ‘Well, when are you going to put something up for me to see?’ And they said they had.” She couldn’t even see the wall. “Oh my,” she said, tears streaming down her face.
Apte hurriedly moved to the other eye, with which Baldwin could read the jumbo E at the top of the chart. “We have to go to work on the good eye and save it,” he told her. Then he tactfully asked how well she could see to drive. “Well, not very good, but I’m all there is, I have to drive myself here,” she said.
“No, no, no, not to St. Louis,” he said. “I’ll start meeting you in Mt. Vernon; I have an office there.”
First, at the institute, he tried a laser procedure, but he didn’t get the results he wanted. He moved on to injections.
“When you see a needle coming at your eye!” Baldwin exclaims, shuddering. “And I’m a toughie; I’ve been through lung surgery. But they put this little cage thing in your eye, feels like wire, and it holds your eye open, and—” she slips into Apte’s calm tone—“‘You’ve got to hold still now, Mrs. Baldwin.’ And it does hurt that first day; all you want is to be home in the dark. Sunlight, whoa. But when you wake up that next morning—
“I have a five-bladed ceiling fan over my bed, and oh dear God. I could count every one of those blades.”
After the second shot, Baldwin pronounced Apte a magician, but he wanted even better results. He scheduled a third shot early in 2007. When he met with her beforehand, he said quietly, “Well, Moo, there’s a new drug called Lucentis. I’ve been studying it, and I think it’s our miracle drug.”
It was indeed. Now her good eye was 20/30—“not bad for a 77-year-old, kid”—and she could read and drive. It was time to work on the other eye, the one she could no longer see out of at all. Apte injected Lucentis again.
“The next morning I jumped out of bed and held my hand over my good eye,” she says, “and I could kind of see me, in the mirror.” Two weeks later, she went back for a checkup and saw Apte in the hall from a distance. “Oh, he had on a gorgeous striped shirt and the colors were just wonderful, pale green and blue,” she says. “I yelled, ‘Oh, Dr. Apte, I can see your shirt!’ and he grinned at me. ‘You can?’
“Someone once asked me, ‘If you had to choose between your eyes and your hearing, think a minute, which would you pick?’” she recalls. “I said, ‘I don’t even have to think.’ You reach for a doorknob in the bathroom, and you are fumbling so you feel with the flat of your hand. It makes you kind of sick at your stomach. It makes you feel like, ‘Oh, life’s over for me.’
“Now I’m standing here, I see all my pretty glasses in my china cabinet, and I can see the yellow line to drive. The girls at water aerobics will test me, they’ll say, ‘Moo, what am I doing?’ and I’ll say, ‘Well, you are trying to do the Twist, but you are not doing a very good job.’”
Her next checkup is two months away—long enough for her kids to take her to Puerto Vallarta. “I’ll be able to see the turquoise water and white sand!” she says, giddy as an Oscar winner.
The bleeding could start again at any time, of course.
But Apte’s keeping a close eye on her.
