Continuum, Winter 1997-98

THE EYES HAVE IT

Geneticists at the University of Utah train their sight on a gene defect that causes macular degeneration, the leading cause of legal blindness in people over 65.

by Elaine Jarvik

In the center of his vision, where once there were words and numbers and the details of his wife's face, Sylvan Alcabes, 73, now sees something muted and vague. It's as if the world has been repainted by a watercolor painter with a clumsy hand and a very large brush.

Like an estimated one million Americans, Alcabes suffers from age-related macular degeneration, a kind of blindness that doesn't leave its victims in total darkness but can lead, in the disease's more advanced stages, to the next worst thing: either an uncorrectable blurriness or what seems like a black hole smack in the middle of one’s eyesight.

Macular degeneration is the leading cause of legal blindness in people over age 65. By the time a person is 75, in fact, there is a one-in-three chance he will have some stage of the disease.

For centuries it has been a disease without a treatment or a cure, or even a known cause. Doctors have understood macular degeneration basically by what the doctors themselves can see: as people age, the cells in the macula of the eye – a tiny portion in the center of the retina – can become coated with debris.

But the disease is now coming into sharper focus, following the discovery of a gene defect that may cause the most common “dry” form of the disease in up to 25 percent of cases.

A research team from the University of Utah's Department of Human Genetics and the Moran Eye Center helped track down the gene, in collaboration with scientists from the National Cancer Institute, Harvard Medical School and Baylor College of Medicine.

Exploring the molecular landscape for genes and gene mutations is, of course, nothing new at the U’s Eccles Institute of Human Genetics. But the macular degeneration gene marks another kind of first – the discovery of a specific genetic cause for a common eye disease.

The more common the disease the harder the search for a gene that might cause it, explains U of U genetics professor Mark Leppert, who headed up the macular degeneration team.

A common disease – arthritis, for example – is more likely to be caused by a multitude of factors and a number of genes. In the case of age-related macular degeneration, those factors could include exposure to sunlight, cigarette smoke, alcohol consumption, and nutritional deficiencies or excesses – as well as a genetic inevitability or a genetic predisposition.

Looking for an age-related macular degeneration gene is also complicated by the fact that the disease typically appears in a person’s 70s, which means that the patient's parents – and therefore their DNA samples – have already died.

So sleuthing the gene related to age-related macular degeneration actually began with a search for a rarer form of the disease – an inherited disease called Stargardt that usually surfaces in childhood or adolescence.

Like the disease that creeps up on older people, Stargardt causes a loss of central vision. As with age-related macular degeneration, its victims are left with a disconcerting ability to see out of the periphery of their eyes, although this peripheral vision is never as clear as healthy central vision.

The hunt for the Stargardt gene took 10 years. As with all genetic detective work, it began with a list of names – in this case the names of patients with Stargardt and their family members.

Scientists already knew that Stargardt was caused by a recessive gene – that is, a gene that must be inherited from both parents. The parents, who each carry just one copy of the gene, do not have the disease.

At the University of Utah, the search for the Stargardt gene took place in the sun-filled laboratories of the Eccles Institute of Human Genetics, with their stunning views of mountainsides and big expanses of sky. The hallways are lined with coolers – similar to the kind you might find at a convenience store – only these are full of tiny vials of DNA. It is from these vials of clear liquid that researchers’ detective work began.

First, researchers narrowed their search to a particular short region of a chromosome by linking the disease to molecular “markers” – chemical street signs that let scientists know where they are on the genetic map.

Ordinarily, researchers would then have to examine hundreds of genes in that region until they found the one gene they were after. In the case of Stargardt, however, the hunt was simplified when they learned that the region contained a previously identified gene associated with the retina.

Stargardt turned out to be caused by a mutation of a gene known as an ABC transporter. Such transporters code for proteins that work as one-way delivery trucks, taking important molecules in or out of a cell membrane. Usually each transporter delivers just one particular kind of molecule.

Researchers believe that the gene in question for Stargardt is supposed to truck something out of the eye's rod cells, although they don't know yet what that something is. Apparently, though, the build-up of this molecular substance in the rod cells eventually damages the eye's cone cells – that part of the eye that enables perception of detail and color.

After announcing the Stargardt gene discovery last March, Leppert, his colleagues Nanda Singh PhD’92 and Andy Peiffer, and scientists at NCI, Harvard and Baylor, then turned their attention to the similar but more common disease of age-related macular degeneration.

“If you look at the retina of Stargardt individuals, it looks very similar to the retina of people with the “dry” form of macular degeneration,” explains Singh. “We hypothesized that the same gene might be mutated” in both conditions.

It took only six months to discover that this hypothesis was right. Of 167 unrelated macular degeneration patients tested, 16 percent turned out to have mutations of the Stargardt gene. Most of the mutations occurred in people with the “dry” form of the disease. (The dry form is caused by the accumulation of yellowish deposits known as drusen; a wet form of the disease is caused by leaking blood vessels).

If only dry-form patients had been tested, says Leppert, the percentage of patients who have the mutated gene would probably have risen to 25 or 30 percent.

The findings of the collaborative research team were published in the September 19 issue of the journal Science. That same week, ophthalmologist Paul Bernstein from the U Moran Eye Center was in Scotland attending an international conference on macular degeneration – where, he says, news of the gene discovery was heralded as “the most important finding in macular degeneration in 100 years.”

The disease has always been a mystery. But, “for the first time, we have the hope that we can get to the root of the problem,” notes Moran ophthalmologist Norman Zabriskie. Understanding the role of the ABC transporter could eventually lead to a successful therapy.

Meanwhile – probably within the next two years, says Zabriskie – doctors will be able to provide genetic testing for the gene. Young people who have inherited it would then at least know to take precautions – to wear proper sunglasses, to not smoke, to pay attention to their diet.

Based on epidemiological studies, says Zabriskie, it appears that people with diets rich in carotenoids – the phytochemicals found in green leafy vegetables such as spinach and kale – have less incidence of macular degeneration.

“I'm not saying megadoses,” says Zabriskie, who has modified his own diet after discovering that his mother has the disease. No one knows yet how much spinach might make a difference, or whether it really makes a difference at all. These are the kinds of strategies that still need to be studied.

In the meantime, patients can sometimes augment their vision with special binocular-like glasses. Some patients, like Salt Lake cardiologist Wallace Jenkins BA’50 MD’55, have learned to compensate for their central vision loss. Dr. Jenkins, who still treats patients despite his disease, has learned that by turning his head five or 10 degrees he can look out the corner of his eye and see well enough to practice medicine.

“If I want to look at a patient's nose,” he explains, “I look at the ear. And if I want to look at the ear, I look at the nose.” He relies on his medical partners to read the tiny squiggles on cardiograms.

Val Green BS’52, 70, of Layton still plays golf, despite his macular degeneration. The whole golf course looks pretty much the same to him – a fuzzy green – but he relies on his friends to tell him where the ball is.

About 90 percent of people with macular degeneration have the dry form and 10 percent have the wet form of the disease. The wet form sometimes can be halted (but not reversed) by laser surgery.

A form of radiation therapy is currently being tested for dry-form macular degeneration. But this, and other techniques, are still in the experimental stage, says Bernstein.

In the meantime, geneticists at the Eccles Institute are going back to their DNA vials to look more closely at the gene that causes macular degeneration. Are there specific mutations that cause the disease to progress slowly or quickly? Why do some people not get symptoms till they are 80? Do some mutations make people more susceptible to damage from the sun?

And maybe there is a second gene, or several other genes, that causes the disease. Meanwhile, doctors suggest coping strategies but often can only feel frustrated by a disease that often just gets worse. Sometimes, says ophthalmologist Zabriskie, he and his patients “just have to sit there and watch it happen.”

– Elaine Jarvik is a feature writer for the Deseret News. Her cover story on human genetics appeared in Continuum’s May 1991 premiere issue.