Jenni Laidman 2016-12-05 18:13:20
Since the 1950s, Massachusetts Lions have quietly funded groundbreaking research in eye disease. Lloyd P. Aiello was a young researcher in Boston interested in the blindness that can accompany diabetes when a cancer study drew his attention. He found the study so fascinating, he continued reading it as he walked down the hall and stepped into an elevator with one of his best friends, a cancer researcher. Talk about serendipity. Turning to his buddy in the elevator Aiello asked, “Have you ever heard of this thing called VEGF?” “Oh yeah!” his friend said. “We’re working on it in cancer!’” If Aiello wanted to investigate VEGF—vascular endothelial growth factor—in addressing diabetic retinopathy, the nearby lab at Dana Farber Cancer Institute had nearly everything he needed to get started. But how to pay for this work? It was smart, but it was still speculative. None of the big-gun funders—the National Institutes for Health, the National Science Foundation—put money into this kind of gamble. But the Massachusetts Lions Eye Research Fund (MLERF) did. A Breakthrough Throughout the last 60 years, MLERF has invested more than $32 million in foundational eye disease research. Funding comes from Lions clubs, the vast majority from Massachusetts. Nearly all the state’s clubs—as many as 250 in past years—support MLERF. Current support is about $1 million annually. All those pancake breakfasts, fish fries and lobster dinners translate into scientific gains. MLERF’s willingness to take chances on cutting-edge research has paid off spectacularly at times. “We are a little different than a lot of other Lions- based funding organizations,” said Martin Middleton, president of MLERF. “Our focus is providing seed money for institutions doing cutting-edge research. We specifically fund pure research. When a researcher has an idea, a way to a attack a problem, and they need to do the initial experiments, we will fund the start-up work.” If such preliminary Lions’ funded work succeeds, the researcher can take the results to the major grantors such as NIH. Aiello’s focus on VEGF is a case study on how MLERF’s support can make a crucial difference in a scientific breakthrough, leading to healthcare advances. In the early 1990s cancer scientists were eagerly investigating a signaling protein called VEGF. The protein, they had learned, signals blood vessel growth in tumors, and cancer researchers hypothesized that turning it off might starve cancer of oxygen. Aiello wasn’t interested in cancer, but he couldn’t help noticing the similarities between VEGF and the mysterious Factor X first postulated in diabetic retinopathy in the late 1800s. Factor X was theorized to fuel the growth of the leaky and malformed blood vessels that led to blindness in diabetic retinopathy patients—vessels that resembled the leaky and malformed blood supply of tumors. Might Factor X and VEGF be the same thing? Aiello’s fellowship adviser, George King, was quick to embrace the promise of investigating VEGF in diabetic retinopathy. King was the research director at the Joslin Diabetes Center, and his own research made an irreplaceable contribution to Aiello’s VEGF explorations. King had learned to grow retinal cells in the laboratory. While most labs relied on other types of eye cells for research, Aiello could conduct his VEGF experiments in the very cells he hoped to save. Aiello, now a professor of ophthalmology at Harvard Medical School and director of the Beetham Eye Institute at the Joslin Diabetes Center in Boston, had long had a special relationship to diabetic retinopathy. He is the third generation in his family to work on the disease that threatens the vision of nearly 30 percent of diabetic adults. His father, Lloyd M. Aeillo, was a leading eye researcher, as was his grandfather, William P. Beetham, for whom the institute Aiello directs is named. The family had already changed the face of diabetic retinopathy treatment in 1965 when Aeillo senior and his father-in-law, Beetham, developed photo laser coagulation therapy. Using lasers to zap the errant vessels in diabetic retinopathy reduced the risk of severe vision loss by 60 percent. It was a revolutionary change. But it wasn’t enough for Aeillo’s father. Dr. Lloyd Aiello made a key discovery about eye disease thanks to Lions’ funding “When I was growing up, he’d say, ’We’re just not very good.’ Even though [photocoagulation] saved all these people’s vision—it was more effective than penicillin! It was a major, major contribution. But it still destroyed the retina,” Lloyd P. Aiello says. Maybe VEGF would be the solution his father dreamed of. Almost from the start, VEGF looked promising. “I mean, the VEGF really has remarkable effects. These weren’t subtle,” Aiello says. Within two years—lightning quick in science—he and his team had published a paper in the New England Journal of Medicine painstakingly outlining VEGF’s role in diabetic retinopathy as the long-sought Factor X. Soon after, he published another paper in the Proceedings of the National Academy of Sciences demonstrating, among other things, how VEGF’s vessel-growing activities might be blocked. Turning those experimental results into a drug to safely treat patients, however, would require more than a decade and a half of clinical trials and U.S. Food and Drug Administration review. When, finally, clinical trials began to show that the new compound worked, Aiello couldn’t breathe a word about them. He couldn’t even tell his father. The day before the positive results were to be published, he spoke. “I said, ‘Dad, guess what? It works, and it’s better than laser,’” Aiello recalls. “And he looked at me and—he has a very dry sense of humor—he looked at me and he said, ‘Well, it took you long enough.’” The results more than fulfilled the MLERF’s mission. “The Lion’s gave us funding very early,” Aiello says. “It was a small amount, and yet it generated something that has now become the worldwide standard-of-care for three major conditions: diabetic retinopathy, age-related macular degeneration and central retinal vein occlusion.” A Quiet Start MLERF began inconspicuously—with a $5,000 grant to investigators at Harvard Medical School working on a problem often called “blind baby disease,” officially known as the retinopathy of prematurity. The grant came about because of a meeting of past Lions’ district governors at a New Hampshire farm. Talk at the farm even-tually drifted to the fact that two former governors had children who had lost their vision shortly after birth. Both infants were born prematurely, but sighted. Yet both lost their eyesight soon after birth. The seed grant from the Lions helped investigators learn that high oxygen levels in incubators caused blindness in some 2,500 premature infants annually. Other great successes followed. Just as Aiello focused on the retina to find a treatment for diabetic retinopathy, Michael Young, an associate scientist and director of Ocular Regenerative Medicine Institute at Harvard University’s Schepens Eye Research Institute, works on repairing the retina to undo the blindness caused by another disease, retinitis pigmentosa. Roxanne, star of TV’s “Beat the Clock” in the 1950s, examines a model eye with Massachusetts General Hospital’s Dr. William Stone, an early proponent of the Lions Eye Research Fund. Roxanne was in Boston to help Lions raise money for the fund The retina sits at the back of the eye, serving as the central switching station for visual information. When someone has one of the 100 or so mutations that lead to retinitis pigmentosa, the 100 million rod cells in the retina begin to die. Blindness strikes somewhere between the ages of 30 and 50, with some 50,000 victims in the United States, Young says. But what if those retinal cells could be replaced with cells that lack the genetic defect? That’s what Young set out to do. Although efforts to transplant mature cells into retinas failed time and again, about 15 years ago Young tried implanting a stem into a rodent retina. That was a game changer. The brain stem cells he employed in his initial experiments integrated into the retinas of adult animals without exciting an immune system attack. From brain stem cells, his team made the logical jump, demonstrating that retinal stem cells could also be successfully transplanted into the eyes of adult animals. Then they hit a wall. For five years he and his team tried to stop the stem cells from maturing too rapidly, which meant they would no longer divide and make more retinal stem cells. “We tried everything,” Young says. They grew the cells on different substrates. They grew them as spheres. They flooded the cells with growth factors. They fed them an expensive diet. Nothing worked. Then Young met Marie Csete at a conference in California. At the time, Csete was the head of California’s state-funded stem cell initiative, and she had a long history of working with stem cells in cancer labs. “I can remember the moment she said to me—it was kind of a throwaway comment—‘You should read my papers.’ I think she said, ‘You should try this. It will change your life.’” Csete had learned that stem cells in culture needed to live in a lower oxygen environment. While room air is about 20 percent oxygen, cells like no more than 5 percent. “She’s a smart woman. We took her advice very seriously.” ‘When a researcher has an idea, a way to a attack a problem, and they need to do the initial experiments, we will fund the start-up work.’ The result, he said, was astonishing. Not only did the retinal cells maintain their stemness, ever ready for transplantation, they kept dividing as stem cells. After letting the cell cultures divide and re-divide 20 times, he had enough cells for every retinitis pigmentosa patient in the world. The cells that grew from these cultures were far better cells then the ones grown at room oxygen levels. “They differentiate 1,000-fold better,” Young says. MLERF dollars helped him create a special substrate to study the new cells. He created a thin polymer scaffold like a wafer of rough tissue paper where cells could grow. Originally, the wafers were 100 microns thick—roughly the width of a table salt crystal; the ones they ultimately developed are no more than 10 to 15 microns—like a flake of skin. In April, a surgeon placed the retinal stem cells Young had labored over for so long beneath the retina of a patient with advanced retinitis pigmentosa as part of a trial. If the stem cells show promise after testing in a handful of patients, the hope is to move onto a full-scale trial with far more patients. “Support from the Massachusetts Lions Eye Research Fund has been vital to the work of Schepens Eye Research Institute and Massachusetts Eye and Ear Infirmary for more than 50 years. This has allowed us to pursue bold and innovative approaches to prevent and cure blinding diseases,” Young says. A Bionic Eye When Dr. Joseph Rizzo III, director of neuro-ophthalmology at the Harvard Medical School affiliate, Massachusetts Eye and Ear, put together the Boston Retinal Impact Team in the late 1980s, the journey to create a bionic eye combined a need for technical wizardry and surgical innovation in fields still in their infancy. “There was no foundation of knowledge to build upon,” Rizzo says. “We had to do everything from scratch.” “It was really brutally hard, to be honest with you,” Rizzo says. “And we didn’t really have a laboratory. We didn’t have equipment. We had to take a lot of baby steps and make a huge number of mistakes and really hang in there.” And in fact, after 10 years of working with the goal of placing the ultrathin electrode array that would replace the retina inside the eye, they were getting worried. Even as the team solved so many problems, the challenges that remained seemed even larger. “The retina is very delicate. It has the consistency of wet tissue paper,” Rizzo says. It’s also curved. Worse, the eye is a tiny sea in constant motion. The microelectrode retinal array needed to lie in contact with the curvature of retina to send signals to the nerves there. That meant it needed to be tethered against the tug of any turbulence. Tacking the array to the retina created a risk for scarring. Worse, it turned out, once the array was tacked down in one place, it popped up in another, requiring yet another tack. Now scarring seemed certain. After a year of discussion with the entire team, they changed course, deciding to tuck the retinal implant in the back of the eyeball, which created a different set of problems to solve, but problems that seemed more manageable. Such hairpin course changes are simply part of doing science, Rizzo says. “We were trying to create something that was dramatically different. I’m more than happy to admit large-scale ignorance, but you just feel like you’re continuing to learn.” Today, Rizzo and his team are preparing to place the implant in humans. They’re conducting pre-clinical trials through a company they formed called Bionic Eye Technologies Inc., with funding help through the NIH and the National Science Foundation. And they’re beginning an even more advanced bionic eye project, funded through the U.S. Department of Defense, that will work not only in people with damaged retinas, but also with nonfunctioning optic nerves. It’s quite a change. More than 20 years earlier, the whole program was considered massively speculative to the big funders. That’s where the MLERF stepped in. “Some of the very earliest money I ever received for this was from the Lions,” Rizzo says. “They helped me get going when there was no one else to turn to. It was an enormously valuable assistance in starting the project.” Extra Digital Content The Massachusetts Lions Eye Research Fund supports research for new laser techniques for earlier detection of cataracts and diabetes-related eye disease. Read the story from the April 1984 LION. Researchers Funded by MLERF Dr. Joseph Ciolino Assistant Professor of Ophthalmology and Investigator, Harvard Medical School, Massachusetts Eye and Ear Ciolino and colleagues are developing a novel contact lens that will gradually deliver medication to the eye to treat fungal keratitis, which can lead to blindness. The condition is currently treated by selfadministered drops, which in some cases must be hourly and are often done improperly by patients. Kip Connor, Ph.D. Assistant Professor of Ophthalmology and Assistant Scientist, Harvard Medical School, Massachusetts Eye and Ear Connor is investigating innate immune system components in the eye to treat retinal detachment. Surgery is the current treatment for the condition, but it often is completed after irreversible vision loss has occurred. Dr. Janey Wiggs Professor of Ophthalmology, Harvard Medical School; Associate Chief, Ophthalmology Clinical Research, Massachusetts Eye and Ear Wiggs (right) is conducting research to identify the genes that cause inherited eye disorders including inherited retinal degenerations and inherited glaucoma.
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