Eyes Confess the Secrets of the Brain

The face is the mirror of the mind, and eyes without speaking confess the secrets of the heart.
St. Jerome

Neurobiologists do it.
So do sensory physiologists.
And biophysicists.
Even behaviorists.

Scientists from a wide range of disciplines study vision. Beginning with Selig Hecht in 1917 and continuing with his student George Wald and on through three more generations of biologists, the MBL has hosted a long and successful effort to unravel the physics and chemistry of vision.

Why study vision? One reason is that vision is our favorite sense. When we step out on the deck in the morning, we look at the light coming to the sky. The dog, meanwhile, scurries about sniffing the ground. The possum that passed through the yard in the night and left such an exciting trail of odor for old Daisy's chemoreceptors is non-existent, for us. Seeing, we say, is believing. But the generations of scientists who have spent their careers studying the secrets of nature's photoreceptors have other reasons for studying vision, too.

The retina is a good model for learning how the vertebrate nervous system works, points out Paul Malchow, a young biologist who studies vision in skates. The retinas of many marine animals are accessible. The whole tissue and isolated, individual cells can function for a long time in the lab.

And the natural stimulus - light - is easily controlled and readily quantified. All of which makes the eye a good organ in which to study the cellular and sub-cellular principles of both data gathering and data processing.

The MBL was less than 30 years old when Selig Hecht kicked off the century-long effort by showing that an animal's responses to light can be analyzed and explained in terms of physics and chemistry. That simple truth may seem self-apparent now, but it was the necessary first step in unraveling the cellular and molecular mechanisms of vision. Hecht, a biophysicist at Columbia and long-time summer MBL investigator, went on to explore many aspects of vision, including light/dark adaptation.

One of Hecht's students, George Wald, identified many of the molecular components of vision and demonstrated the role that Vitamin A plays in detecting light. Wald, a Harvard scientist who spent many summers working at the MBL, was awarded the Nobel Prize in 1967 for his work on the biochemistry of vision.

Wald shared the prize with H. Keffer Hartline, another MBL summer investigator (from the 1920s through the 1960s) who studied the eyes of horseshoe crabs and frogs. Hartline uncovered many of the basic mechanisms of vision, including lateral inhibition, one of a number of strategies retinal cells employ to process information from the photoreceptors before passing it along to the brain.

Other pioneers in vision research at the MBL included Stephen Kuffler, founder of the Department of Neurobiology at Harvard, and Edward MacNichol, Jr., who directed the year-round Laboratory of Sensory Physiology at the MBL in the 1970s and early '80s. MacNichol built the world's best photon-counting microspectrophotometer and did pioneering work on the biochemistry of color vision.

The vision work at the MBL continues today, carried on by Grass Fellows at the beginning of their careers and veteran biologists whose careers overlapped with Nobelists Wald and Hartline. The Laboratory of Sensory Physiology founded by MacNichol is directed now by Ferenc Harosi, who has continued to refine the art of microspectrophotometry and who has been described by a leading neurobiologist as "an international resource for the vision research community."

The ambitious effort to unravel vision has come far enough that scientists who study nature's eyes have been stalking bigger quarry for some time now. The poet may believe the eyes reveal secrets of the heart, but the scientist thinks eyes provide a window to the brain. Some neurobiologists even speak of the eyes as if they are part of the brain. In talking about how far vision studies have come, for instance, Harvard neurobiologist and MBL veteran John Dowling says, "We know more about the retina than any other area of the brain."

One example of non-vision lessons learned in the retina comes from a team of MBL summer scientists, including Harris Ripps and former Grass Fellow Haohua Qian who recently discovered that skates may use zinc to increase nerve cell responses to GABA, a common neurotransmitter. Interestingly, the same type of GABA receptor in the human brain is involved in our response to a class of therapeutic drugs that includes Valium®.

Zinc was not known as a neuromodulator capable of increasing GABA responses before the recent discovery in skate retinas. Following-up on this lead, other investigators so far have found the same regulating mechanism in just one other group of animals: primates, which includes human beings.

"At some point, this little experiment (using zinc as a neuromodulator) was done by the genetics of both systems," says Richard Chappell, a Hunter College, CUNY researcher and long-time MBL summer investigator who is also one of the principal investigators on the skate retina study. "Skates may have different reasons for having it, but the fact that it is there means we can study the mechanism" - and possibly point the way to improved management of Valium® and related drugs in humans.

Closer to the original target, vision studies are promising to shed light on how organisms process information about the world.

"We're studying vision, but the real goal is understanding how the brain works," says Robert Barlow, a State University of New York neurobiologist who studied for his Ph.D. with Hartline. "We're really looking for the neural basis of behavior."

The search, for Barlow, has centered on the horseshoe crab, a contemporary of the dinosaurs whose lateral eye has roughly 1,000 clusters of photoreceptors (compared to the human retina, with its more than one hundred million photoreceptors). Coming to the MBL every spring to study the horseshoe crab during its mating season, a team led by Barlow has mounted a camera (dubbed CrabCam) on male crabs to record what they see underwater while they search for mates. Simultaneously, an electrode attached to the animal takes a reading of the response of a single nerve fiber.

On a computer in Syracuse, Barlow has built a model horseshoe crab eye, based on the detailed knowledge of the eye that Hartline and Barlow and others have pieced together over the years. When he shows the computer eye a digitized version of the underwater film taken with CrabCam, the computed firing pattern of the optic nerve fibers contains robust signals about objects resembling potential mates - especially when they are moving. The image of a female Limulus virtually pops out of the background, Barlow says. The accuracy of the computer eye's response is confirmed by comparing the response of a single optic nerve fiber in the computer eye with a corresponding nerve fiber in the animal's eye. The responses of the real fiber and the fiber in the model eye match so closely that the investigators are convinced they are learning how to listen-in on conversations among neurons. "We think," Barlow says in early 1997, "we've found the neural code for vision, at least in the horseshoe crab."

After 80 years of intense study, the eyes are confessing ever deeper secrets of the brain.