Medicine: Light at the End of the Tunnel
Age-related macular degeneration affects thousands around the world, and Hadassah doctors are determined to treat this little understood disease.
They won’t use a cane or walk with a seeing-eye dog for several years yet. For the moment, peripheral vision around the widening blind spot in the center of each eye still allows them to keep to the sidewalk and cross the street.
But the world in which they live grows smaller every day. They can’t make out the face of the neighbor who says hello, so they don’t smile back. Nor can they drive a car, read a newspaper, watch television or even safely pour themselves a cup of coffee.
They are middle-aged and elderly men and women suffering a painless and incurable disease known as age-related macular degeneration (AMD). Longer life expectancy has made this disease the most common and fastest growing cause of irreversible blindness in the Western world today. Conventional medicine offers little help for AMD, though health professionals in the United States, such as Dr. Andrew Weil, director of the program in integrated medicine at the University of Arizona’s Health Sciences Center in Tucson, have suggested that dietary changes, sun protection and some supplements may slow the progress of this condition.
“Limited understanding in the scientific community as to why the macula degenerates and destroys sharp central vision in AMD is hampering the development of new and more effective treatments,” says Dr. Eyal Banin of the Hadassah–Hebrew University Medical Center’s Department of Ophthalmology. “We need to know a lot more about AMD’s causes and development.”
This need to know more is the background to Hadassah’s newly established Center for Retinal and Macular Degeneration, which Dr. Banin heads. He and his colleague Dr. Itay Chowers are bringing together their different and complementing expertise in a unique research initiative: Dr. Banin and his group are combining cell biology and electrophysiology to transplant new cells into the eye to restore degenerating retinas; Dr. Chowers and his team are hunting down the genes involved in AMD. Their shared aim is to uncover the origin and development of AMD and find ways to treat it.
The Banin team, working with Dr. Benjamin Reubinoff, head of Hadassah’s Human Embryonic Stem Cell Research Center, is trying to create and transplant healthy cells to replace failing retinal cells.
The focus of their work is both tiny and vast: the 137 million light-sensitive receptor cells that lie within the retina (the macula is at its center), an onion skin-thin layer of tissue covering less than a square inch at the back of each eye’s interior. Not only must researchers learn how to get the new cells in place, they must prevent them from growing wildly into tumors and ensure they work and interact with surrounding cells.
Two types of retinal cell are damaged in AMD: the retinal pigment epithelium (RPE), which covers the photoreceptors and are crucial to their functioning, and the photoreceptors themselves. Drs. Banin and Chowers are working with both. The raw materials with which they hope to support and replace the failing cells of AMD are human embryonic stem cells. These, the most basic form of human cell, are primed to convert an embryo into a fetus by specializing into the many different cell types that build the 200-plus human organs. Theoretically, they can replace any organ.
“Left to their own devices, stem cells will differentiate chaotically into any of the body’s cell types,” says Dr. Banin, who specialized in retinal degeneration and electrophysiological assessment of retinal function during a fellowship at the University of Pennsylvania and went on to study stem cell therapy during a sabbatical at The Scripps Research Institute in San Diego. “Our challenge is learning to direct their differentiation and turn stem cells into the cells we want.”
Dr. banin’s team has developed a two-step approach. They started by exposing stem cells to culture conditions in the laboratory to trigger their differentiation into neuronal and retinal cells—the photoreceptor cells. “This gets the cells out of their primitive state and reduces the risk of them growing uncontrollably,” he explains.
Next, they transplanted the photoreceptor cells into the eyes of mice and rats with retinal degeneration. As they had hoped, some of the transplanted cells have shown the potential to take over the job abandoned by the animals’ diseased retinal cells, or at the very least slow down degeneration. “Some of the transplanted cells express markers specific for photoreceptor cells, the cells that absorb light, which begins the process of vision,” Dr. Banin says. “This, to our knowledge, is the first time that human embryonic stem cells have ever shown they have this potential.”
A second important discovery has quickly followed the first. “We found that even when a stem cell doesn’t specifically differentiate into a retinal cell it has a beneficial effect on diseased retinal tissue,” he notes. “Why and how this happens isn’t yet clear, but the transplanted cells may somehow nourish the host cells or they may recruit and activate the host’s immune system, which helps the tissue function better. Or they may do both.”
Dr. Banin has also been trying to reproduce the other type of retinal cell affected in AMD—the RPE cells.
“It is these cells that probably fail first in AMD,” he explains. “In recent months, we have succeeded in differentiating stem cells into RPE cells and implanting them into the eyes of affected rats. It is too early, however, for results.”
Despite the progress made, there is still a long way to go, stresses Dr. Banin. While delivery to the much larger human eye will be easier (cells are injected under the retina through a very fine glass pipette) and advances in eye surgery have developed the necessary tools, many questions remain. Where, for example, is the right place to inject? Should cells be injected with factors known to promote cell growth or by themselves? And while stem cell therapy at its current stage can perhaps slow down degeneration of retinal cells, can it eventually replace a nonfunctioning retina, make the necessary connections with the brain and thus return vision?
“We’re looking at a decade, at the very least, before this technique comes into clinical use,” he says. “It’s a very new field, there’s a very large leap to be made from rodent to human eyes and there are many potential risks to be controlled before stem cells can be applied clinically.”
If stem cells mark one of modern medicine’s frontiers, molecular biology is another. Dr. Chowers and his fellow researchers are working on this second front, trying to identify the genes involved in AMD.
“[AMD is] clearly a disease with a genetic background,” says Dr. Chowers, who returned to Hadassah in 2003 following a three-year fellowship in molecular ophthalmology and vitreoretinal surgery at Johns Hopkins University School of Medicine in Baltimore. “A first-degree relative of an AMD patient is about four times more likely to contract the illness than an unrelated individual. We’re trying to identify the genes involved, pin down their function and target them for therapy.”
There are several probable culprit genes (one was found by researchers in the United States in 2005) and many more possibilities. In a state-of-the-art project initiated at Johns Hopkins and continued at Hadassah, Dr. Chowers and his group are tracking these genes with a new molecular biology-computational technique that allows them to compare tens of thousands of genes from healthy and AMD retinas in both humans and mice.
“When a disease process is ongoing, expression of the involved genes is altered, and this helps us find them,” explains Dr. Chowers. “We use a 1-by-2-inch slide, similar to a microscope slide, on which 10,000 tiny points of DNA material are printed, like pixels on a television screen. Each point represents a section of a different gene. Next, we take a sick retina and mark its genetic material (RNA) with fluorescent dye. A scanner combines the two to produce a picture, which shows where gene expression is higher or lower than normal. Abnormal expression can mean the gene is involved in the disease.”
Within the next two to three years, the team expects to firmly identify several culprit genes. “When we know which genes play a role in AMD, we can work on altering their expression and thus slow progression of the disease,” says Dr. Chowers. “Slowing the disease at its outset will reduce its impact. When treated in its late form, it’s difficult to save useful vision. Since it takes years, even decades, for AMD symptoms to appear, delaying onset would, in effect, constitute a cure.”
Alongside the research on genes in cadaver eyes from the United States, the team is also hunting closer to home. “Nothing is known about the genetics of Israel’s population with regard to AMD, so we’re taking advantage of our very busy retinal clinic at Hadassah,” says Dr. Chowers. “We’re collecting blood samples from patients and analyzing them to see, first, whether the known gene is involved in our population and, second, whether there are other mutations, too.”
To date, samples have been collected from over a hundred patients and the same number of matched controls. One early result is that several of the candidate genes identified are associated with iron. “Iron is potentially toxic and can cause free-radical injury,” says Dr. Chowers. “We’re joining with Eyal Banin’s group to study iron’s role in AMD and ways of reducing the damage it can cause. One possibility is medication that reduces iron content in the tissues.”
While the AMD epidemic is the research focus of Drs. Chowers and Banin, it is likely that many of their findings will also be relevant to other blinding diseases involving retinal and macular degeneration, among them glaucoma and retinitis pigmentosa. And with the retina a highly accessible part of the central nervous system, their work may help in the study of degenerative diseases such as Parkinson’s and Alzheimer’s.
Meanwhile, the emphasis remains on halting or curing AMD. “Vision is a very highly prized constituent of our quality of life,” says Dr. Banin. “The eye may be a very small organ, but it gathers 80 to 90 percent of the knowledge we absorb.”