IN SEARCH OF SIGHT

By J. MADELEINE NASH

Fifteen years ago, Dr. Terry Ernest, an ophthalmologist, had to tell his own father the news that he so dreaded giving his patients: Your eyesight is progressively deteriorating, and there is no cure for the condition. Despite tremendous medical progress in treating many forms of vision loss, Ernest could do nothing but watch as his father's eyesight slowly faded, eventually robbing him of the pleasure of pursuing the pages of his favorite books or seeing the smile on his son's face. "At one point, I actually apologized to my father for all the tuition he'd paid," says Ernest. "I had to say to him, 'I'm sorry. There's absolutely nothing I can do.' "

Earlier this year, a team of University of Chicago physicians led by Ernest and surgeon Dr. Samir Patel performed a complex operation on Pearl Van Vliet, a retired medical-center receptionist who was suffering from the same condition that had deprived Ernest's father of his sight. That disease is known as age-related macular degeneration, in which the eye's macula, a remarkably sensitive structure in the middle of the retina, gradually loses its ability to distinguish shapes and colors.

In a delicate procedure that lasted more than two hours, Ernest and his team tried a new and hopeful approach to macular degeneration. They first took cells from the retina of an aborted fetus, then surgically transplanted them into Van Vliet's severely impaired left eye. Since the operation, the transplanted cells have begun to proliferate, forming minute projections that stretch toward Van Vliet's macula. For Ernest, a large, affable man of 62, the weekly ritual of scrutinizing the eye scans that chronicle Van Vliet's recovery from surgery proved intensely satisfying, not only professionally but also because of his frustrating experience with his father, who died in 1992.

Even now, however, Ernest and his colleagues cannot be certain they are on the right track. Too many promising treatments for macular degeneration, they caution, have failed to produce discernible benefits. But if they--and other researchers around the world--are on to something basic, then eventually ophthalmologists will be able to help their patients, perhaps not to cure macular degeneration (that would be too much to hope for), but at least to stop its relentless progression.

To be sure, macular degeneration, which currently affects an estimated 10 million Americans, is not a fatal disorder. But it can be cruelly debilitating. For while the macula (named after the Latin word for spot) is no wider than a pencil, it is a hundred times more sensitive to small-scale features than the rest of the retina. Without a healthy macula, people cannot read a newspaper, recognize a friend, thread a needle, watch TV, safely negotiate stairs or see much of anything at all.

Until now, physicians have been able to offer only palliative care to patients with macular degeneration: more powerful eyeglasses; visual aids, such as machines that enlarge print; and, for a minority of cases--those that involve the invasive growth of blood vessels--laser therapy that sometimes slows down the disease, at least for a time. But only 10% of those in whom macular degeneration is diagnosed develop this more rapidly progressing, invasive form of the disease. For them, experts agree, intervention is needed earlier, before so much visual acuity is lost.

Macular degeneration is devastating because it kills off a small but critical patch of light-sensing cells that line the retina like the film in a camera. Known as rods and cones because of their telltale shapes, these cells record visual images as patterns of illumination and shadow, and relay that information, as electrical impulses, through the optic nerve to the brain. It is not that people with macular degeneration become completely blind; peripheral vision, which is handled by other areas of the retina, remains unaffected by the disease. But as damage to the macula builds up--probably a consequence of chemical damage that accumulates over a lifetime--central vision fades, and the external world dissolves into an indistinct blur.

The disease process does not attack the macula's light-sensing cells directly, most experts concur. It starts in the layer of tissue that lies just below them. The cells that constitute this tissue are known as RPE, or retinal pigment epithelium, cells. Like worker bees tending a hive, these cells provide the light-sensing cells with nourishment and dispose of their wastes. But in contrast to many other types of cells--skin cells, say--adult RPE cells cannot replace themselves through cell division. Thus when the RPE cells begin to sicken and die, so do the cells they support.

About five years ago, leading ophthalmologists began exploring the possibility of replacing the dysfunctional RPE cells with healthy fetal cells. In theory, says Columbia University ophthalmologist Dr. Peter Gouras, "it makes a lot of sense." The RPE cells form a single layer, rather like tiles on a bathroom floor, he observes. "So why not just go in and repave that layer with new tiles?" Fetal RPE cells seem ideal for the purpose. Unlike their adult counterparts, fetal RPE cells can divide and thus increase in number. Also, they are likely to continue functioning for a number of years. And, importantly, because they are immature, fetal cells should provoke little or no response from a transplant recipient's immune system, thus making rejection less likely. Or so experts reasoned.

But how would fetal-cell transplants work out in practice? In 1993--immediately after U.S. President Bill Clinton lifted the ban on fetal-tissue research imposed by the Bush Administration--Ernest, for one, launched a project designed to find out. In the beginning, he remembers, the technical challenges seemed overwhelming. He and his colleagues were not even sure whether fetal RPE cells could be kept alive in laboratory cultures long enough to make transplantation feasible. Then, after a young physician demonstrated that this could be done, the research team began a series of experiments to determine the best way of delivering fetal RPE cells to patients.

Early on, the researchers rejected the simplest method--suspending the cells in solution and injecting them into the eye--because cells handled in this fashion did not grow particularly well. The team found that it obtained much better results when it attached the cells to a sticky substrate like fibrinogen, a protein involved in blood clotting. "And then," says Ernest, "we made a serendipitous discovery." Dr. Karine Gabrielian, a physician on the team, had been struggling to fashion the thinnest possible slivers of fibrinogen. Checking on her samples one morning, she found that some of the slivers had curled up into spheres, each the size of a coarsely ground speck of pepper. Gabrielian added several of these odd-looking constructs to a culture dish that also contained fetal RPE cells. Within 24 hours, the cells attached themselves to these motes of material and started to grow. Then the researchers transplanted the spheres into the eyes of rabbits, positioning them just beneath the retina. The RPE cells did not stay put; instead they migrated throughout the eye. This suggested that it should be possible to position a transplant at a safe distance from the macula and still get therapeutic results.

But as his team made progress on one front, Ernest grew increasingly worried about the immune system's response to the transplants. Contrary to what many had supposed, fetal RPE cells did not behave as if they were immunologically neutral. In experiments in Sweden, for example, transplanted cells were rejected. And Ernest's team found that adding fetal RPE cells to laboratory cultures sent white blood cells, which attack transplanted tissue, into overdrive. Curiously, however, adding even greater numbers of RPE cells to the culture appeared to force the white blood cells into a quiescent state, thus lowering the chances of rejection. Pearl Van Vliet's transplant, accordingly, contained a souped-up 250,000 fetal RPE cells.

No one knows yet whether this hunch is right. Gouras and his Swedish colleagues have found that rejection of fetal RPE cells can occur months down the road. Moreover, slight differences in approach between Gouras' team and Ernest's may or may not prove to be significant. "It's an experiment," says surgeon Patel. "That's all it is. What we're trying to find out is whether there's a rationale for going to a larger study."

From the beginning, Ernest and his colleagues were also worried about the explosive ethical questions raised by the use of fetal tissue. Very early on, Ernest approached Dr. Mark Siegler, director of the University of Chicago's MacLean Center for Clinical Medical Ethics, for advice. As Siegler and many others saw it, there were no insurmountable barriers to the use of fetal tissue for medical purposes. After all, organs and tissue from brain-dead children and adults are donated for transplantation all the time. And while such deaths are tragic, they are caused not in order to obtain the organs but by events, such as automobile accidents, over which transplant teams have no control. Abortion, advised Siegler, could be viewed as another such tragic event.

Even more unsettling for Ernest has been the selection of appropriate patients. The first patient, of course, had to be someone in an advanced stage of the disease whom an experimental treatment could not harm and would perhaps help. "The problem is, patients with macular degeneration are desperate," Ernest observes, "and they are willing to let me do anything I want if I hold out any hope at all." Scanning his patient list, looking for people who were medically sophisticated enough to understand the trade-off of risks and benefits, Ernest almost immediately selected 80-year-old Pearl Van Vliet, a volunteer at the hospital for more than 20 years. Van Vliet, who is deeply religious and has always considered herself to be pro-life, sought advice from doctors in her own family as well as from her pastor and the congregation of the Calvin Christian Reformed Church of Oak Lawn, Ill. Everyone encouraged her to go ahead.

The operation on Van Vliet's eye went smoothly, but the aftermath was a bit rockier. A right-to-life group protested outside the University of Chicago Medical Center. Critical letters and phone calls flooded into Ernest's office. To one letter decrying his use of fetal tissue, Ernest responded, "I can only say I agree with you about the tragedy of abortion. [But] the use of human tissue obtained after death for transplantation has been a good thing in medicine, and I believe that with care and understanding, it will continue to be."

Conscientious and compassionate are words that colleagues use to describe Ernest--old-fashioned virtues that no doubt came from his youth in Sycamore, Ill., where his father was a postal carrier and he was a high school football star. His fascination with the eye, he says, began when he was a senior at Northwestern University and opted to do an honors paper on embryological development. "I went to the card catalog and opened up the file drawer, and the cards on embryology went the length of the drawer. In desperation, I narrowed the topic to the smallest part of the body I could think of, the eye."

As a research physician, Ernest straddles the twin worlds of biomedical research and clinical practice. His drive to explore new medical frontiers, he says, is rooted in a sense of urgency that comes from seeing 100 patients a week, many of them desperate and despondent. Indeed, when patients with macular degeneration complain about not being able to read, Ernest invariably thinks of his father and his love of reading. "My father was 93 when he died, and for the last 10 years of his life he was unable to read. We all take the ability to read for granted until it's gone."

Though macular degeneration has left an indelible mark on Ernest's life, there is no way of knowing whether it will be his team or some other group of researchers that will make the critical breakthroughs to alleviate the disease. When pioneering new treatments, observes Ernest, it is always prudent to expect the unexpected. "You often start out in one direction, but you end up going in another."