Skates resemble speckled, smaller versions of the giant rays that have roamed the oceans for more than 400 million years. The animal's mouth is on its underside. On its top, a pair of eyes with scalloped pupils protrude from either side of its pancake-like head.

Those remarkable looking eyes are among the most thoroughly studied organs in Woods Hole, due to an oddity in their cellular construction. Alone, so far as biologists know, among the back-boned creatures on earth, the skate (Raja erinacea) has a retina that is all rods and no cones.

Biologists trying to unravel the puzzles of night blindness and a collection of inherited eye disorders known as retinitis pigmentosa have been studying the skate's retina for nearly three decades. The goal, explains Harris Ripps, a University of Illinois (at Chicago) neurobiologist and long-time MBL summer investigator, is sorting out the molecular mechanisms by which our eyes adapt - or fail to adapt - to changes in light intensity.

Sunlight on the beach at high noon is 10 billion times brighter than the faint light by which we row across the pond on a moonless night. To operate in such varied conditions, our eyes must lose sensitivity in bright light and regain it in the dark - a trick they can accomplish in a matter of minutes, as anyone who comes in from the beach to the darkened Lillie Auditorium can see.

But for more than 100,000 Americans with retinitis pigmentosa, the light/dark adaptation is impaired or absent altogether. Usually beginning in adolescence or young adulthood, retinitis pigmentosa is a degenerative disorder that can progress from night blindness (a diminished ability to see in the dark) to tunnel vision, and, eventually, to total blindness.

When biologists began exploring Raja's eyes around 1970, the mechanisms underlying retinitis pigmentosa were unknown and the treatment, Ripps says, "was go home and prepare yourself for blindness."

Unraveling the molecular web of vision

Our retina has two types of photoreceptor cells: cones and rods. The cones detect color and perform well in bright light, while the more sensitive rods detect dim light. In 1969 Ripps and John Dowling, a Harvard biologist who also works at the MBL in the summers, were studying the light/dark adaptation in rods. Elasmobranchs (sharks, skates, rays, and their relatives) were reputed to have rod-dominated vision, which meant the picture in the retina would not be com-plicated by information about color and high-intensity light.

Ripps and Dowling tried dogfish, which have a few cones, and then settled on skates, which turned out to have no cones. The skate proved to be a good model for other reasons as well. The individual cells in the retina are large, with some stretching a whopping 100 microns from tip-to-tip, explains Paul Malchow, a biologist who collaborates with Ripps. The large cells enable biologists to use a variety of experimental methods to measure the movement of ions and molecules in and out of cells.

Additionally, the different cell types in the skate retina are easy to identify and hardy enough to live in culture for a week or more, says Malchow, who came to the MBL as a Grass Fellow in 1989 and then worked as a post-doc with Ripps before establishing his own lab at the University of Illinois (at Chicago).

Over the years, Ripps and Malchow and other colleagues - principally Richard Chappell (at Hunter College, CUNY) - have explored a variety of cells in the skate retina, including the light-detecting rods, the "second order" neurons that process the signal generated by rods, and the glial cells (non-nerve cells that form supporting tissue in the retina and elsewhere in the nervous system).

A disease with dozens of faces

The effort to piece together a picture of how retinas adapt to changing light and the abberations that cause abnormalities in the adaptive process has been complemented, in recent years, by a search for the genetic defects that cause retinitis pigmentosa.

Scientists use a patch pipette and two puffer pipettes to dispense neuroactive agents into a skate retinal cell.

It turns out that retinitis pigmentosa may be caused by many different genetic mutations, Ripps says. Already more than 75 mutations have been identified in genes that code for the protein rhodopsin, the molecule found in the retinal rods that actually detects light. Some people have normal rhodopsin but nonetheless suffer night blindness and retinal degeneration. This suggests that retinitis pigmentosa can also be caused by defects in other proteins in the rods or in retinal cells other than photoreceptors. "We haven't even touched the inner retina yet," Ripps points out.

Retinitis pigmentosa serves as a reminder that finding a disease gene is not synonymous with finding a cure. With the genes in hand, the challenge remains to figure out exactly how defective proteins cause disease. One approach to that puzzle is through the use of "knockout" mice - lab mice that do not have the normal gene (it has been knocked-out through genetic engineering). At his Chicago lab, Ripps is studying knockout mice that do not have the normal gene for making a protein (called IRBP) that is needed to move that light-detecting rhodopsin molecule to its proper place in the retina.

The other approach is to keep piecing together the picture of how vision works in a normal, healthy model system.

"Thirty years ago," Ripps says, "nobody had a clue how the electrical signal from the photoreceptor is generated or how the rhodopsin is recycled." Today, those parts of the light/dark adaptation story are being worked out in exquisite detail at the MBL and elsewhere.

The progress has not yet produced a cure, but it points the way to some stop-gap measures - the possibility that minimizing exposure to light may slow the pace of vision loss in some forms of retinitis pigmentosa, for instance. The gathering appreciation of how retinas work is also laying the foundations for gene therapies or, possibly, for transplantation of rod and cone cells.

Those therapies are a ways off, but the prospects for people afflicted with retinitis pigmentosa has already changed. "Go home and prepare for blindness" has been replaced by, "Hang in there, we're starting to figure out how this works."