Gene Reveals How We See

William J. Cromie

Gazette Staff

The recent discovery of a gene that enables us to see could help prevent blindness in some people with genetic eye diseases.

The gene was found in mice by researchers at Harvard University, who collaborated with scientists at other institutions to show that the same gene causes a hereditary disease in humans known as CORD-2. That stands for cone-rod dystrophy-2, a progressive degeneration of the retina leading to blindness at age 10-20 years.

"We named the gene Crx, for cone-rod homeobox," says Connie Cepko, a professor of genetics at Harvard Medical School and a Howard Hughes Medical Institute investigator. "A homeobox is involved in switching on other genes. Genes thought to be turned on by Crx include opsin genes, which make light-sensitive pigments that enable mice and people to see."

Rhodopsin and cone opsin proteins allow rods and cones in the retina of the eye to convert light into chemical signals processed by the brain. Rods let mice and men see in dim light; cones make color vision possible in daylight and increase the amount of detail that can be resolved.

Mice and humans each have two Crx genes, one from their fathers and one from their mothers. Following their initial discovery, Cepko and colleague Takahisa Furukawa engineered mice so that they lack one Crx.

"We believe such mice provide an accurate model of humans with CORD-2, caused by one good and one bad copy of Crx," explains Cepko. "This leads to defective vision, which gradually results in blindness. There may be a way to turn up the amount of Crx protein that the good gene makes and so slow down, if not prevent, the blindness."

An Accessible Part of the Brain

Since Crx turns on at least five different genes, Cepko thinks it may be involved in other forms of blindness. One possibility includes some forms of retinitis pigmentosa, a disease in which rods start to degenerate in middle age. Crx might also contribute to macular degeneration, the leading cause of blindness in elderly people.

When both Crx genes don't work properly, a child can be blind from birth, a severe condition known as Leber's congenital amaurosis. Researchers at other institutions have found that Crx is mutated in some forms of Leber's. Crx-defective mice engineered by Cepko's team also mimic this disease, providing more basic information about the development of vision.

Cepko's interests go beyond the eyes to every cell in the brain. "The brain has an amazing variety of cells, which appear very similar in the womb," she notes. "I'd like to find out what decides their various fates - what they will be when they 'grow up.' "

Cepko sees the eyes as part of the brain. "They both develop from the same embryonic tissue," she says, "so they provide a simpler, more accessible piece of brain outside the skull."

Photoreceptors - cones and rods that bring sights of the world to the brain - are key parts of it. So Cepko, along with Furukawa and colleague Eric Morrow, looked for genes important for development of these light receivers. They were most interested in genes that switch on other genes.

The team found a number of them, but the one they eventually named Crx was the first switching gene discovered that works only in photoreceptors.

Crx is necessary for sight, but it probably doesn't work alone. "To turn on rhodopsin, the protein made by Crx needs to work with other proteins," Cepko says. "We suspect that some of these helpers are found in all cells, while the Crx protein is only expressed in photoreceptors."

Crx activity helps turn cells into both cones and rods, but the gene doesn't separate one from the other. That distinction evidently occurs through the action of other genes.

"We are studying what makes one cell a rod and another a cone in the retina of mice and rats," Cepko notes. "We have begun to get some clues, but we don't really understand yet how a cell becomes one or the other."

Looking for a Turn-On

Crx controls the making of opsins and other proteins in photoreceptors that sense light. But what turns on Crx?

"We don't know," Cepko answers. "But we think it's a combination of signals from the outside and things going on inside the cells where Crx will be expressed."

The outside signals might come from interaction with neighboring cells, rather than from a rigid genetic timetable of development. Presence of these neighbors, as well as conditions inside the cell, may set off the chain of events that turn it into a photoreceptor rather than some other kind of cell.

Once formed, cones and rods make up the retina at the back of the eye, the screen on which scenes of the world are presented to the brain. Light hitting that screen creates chemical reactions in nerve cells within the retina. Such signals travel to the back of the brain where other brain cells process them into a conscious understanding of what is being seen.

"The brain doesn't just receive dots and dashes of light, but whole patterns drawn by various combinations of cones and rods reacting to motion and to continuous changes of scene," Cepko says. "The brain is not just alerted to the sight of a tree, a dog, and a squirrel, but that the dog is moving from left to right and the squirrel is scampering up the tree."

Each human retina contains approximately 125 million photoreceptors, more than 90 percent of them rods. That's peculiar because cones do most of the work. While rods provide sensitivity, allowing you to see in dim light, cones provide color and the resolution that makes images sharper. Hawks boast more cones than humans; thus, their visual acuity is much greater. Rats and bats work at night, so their retinas are almost all rods.

No one knows why we have so many more rods than cones. "During evolution, humans may have improved their survival by developing an ability to spot predators and, perhaps, hunt prey at night," Cepko speculates. Humans have been running from bigger animals for hundreds of thousands of years, while electric lights didn't come into common use until about 120 years ago.

It's an intriguing mystery that Cepko and her colleagues are interested in solving, but for now their research is devoted to the new gene they discovered and how it might be used to reduce blindness.