Jeremy Nathans spent much of the past 17 years focusing on just one aspect of vision: how we see colors.

"If a bright red beach ball comes whirling toward you, you see its color, shape, and motion all at once—but your brain deals with each of these characteristics separately," he explains.

Neurons are relatively slow computing machines, says Nathans, an HHMI investigator at the Johns Hopkins University School of Medicine. "They take several milliseconds to go from input to output. Yet you see things in a fraction of a second—time for no more than 100 serial steps. This is why the system needs parallel processing."

Nathans became interested in how we see in color the day he heard of new discoveries about how we see in black and white. It was 1980, and he was a student at Stanford Medical School, he recalls, when Lubert Stryer and Denis Baylor, both of Stanford, described their remarkable findings about the workings of rod cells.

Rod cells—one of two kinds of photoreceptor cells in the retina—enable us to see by the muted starlight of a hazy night. "Baylor showed that rod cells achieve the ultimate in light sensitivity—that they can respond to a single photon, or particle of light," says Nathans. "It was a beautiful experiment." (Baylor's work was done in collaboration with Trevor Lamb and King-Wai Yau.)

Then Stryer explained how rhodopsin, the light-sensitive receptor protein in the disk membranes of rod cells, announces the arrival of this tiny pulse of light to the signaling machinery inside the cell. Stryer had found that rhodopsin could do this only with the help of an intermediary, called a G-protein, which belonged to a family of proteins that was already known to biochemists from their study of how cells respond to hormones and growth factors.

Nathans immediately realized this meant that the structure of rhodopsin itself might be similar to that of receptors for hormones. His mind began racing with possibilities. "And I ran—literally ran—to the library and started reading about vision," he says.

Until then, Nathans had been studying the genetics of fruit flies. But as he read a paper by Harvard University biologist George Wald—a transcript of Wald's 1967 Nobel prize lecture on "The Molecular Basis of Visual Excitation"—Nathans set off on a different course. He determined to do what Wald himself had wished to do 40 years earlier: find the receptor proteins in the retina that respond to color.

Rod cells function only in dim light and are blind to color. "Get up on a dark moonlit night and look around," suggests David Hubel of Harvard Medical School, a winner of the Nobel prize for his research on vision. "Although you can see shapes fairly well, colors are completely absent. It is remarkable how few people realize that they do without color vision in dim light."

But the human retina also contains another kind of photoreceptor cell: the cones, which operate in bright light and are responsible for high acuity vision, as well as color.

Rods and cones form an uneven mosaic within the retina, with rods generally outnumbering cones more than 10 to 1—except in the retina's center, or fovea. The cones are highly concentrated in the fovea, an area that Nathans calls "the most valuable square millimeter of tissue in the body."

Even though the fovea is essential for fine vision, it is less sensitive to light than the surrounding retina. Thus, if we wish to detect a faint star at night, we must gaze slightly to the side of the star in order to project its image onto the more sensitive rods, as the star casts insufficient light to trigger a cone into action.

— Geoffrey Montgomery

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The intricate layers and connections of nerve cells in the retina were drawn by the famous Spanish anatomist Santiago Ramón y Cajal around 1900. Rod and cone cells are at the top. Optic nerve fibers leading to the brain may be seen at bottom right.

Illustration: Santiago Ramón y Cajal ca. 1900, Instituto Cajal, CSIC, Madrid

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