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The eye as a window into the brain

Nature Network Boston

August 21, 2007

Brain and spinal cord tissue can’t regrow—a fact that is at the root of many neurological diseases. So researchers are figuring out how to coax neurons in the adult central nervous system to do what skin and blood do so easily: replace dead and damaged cells with new ones.

Studying regeneration in the bone-encased central nervous system can be difficult. So researchers at the Harvard-affiliated Schepens Eye Research Institute in Boston are using the eye as a handy stand-in for the brain. By studying the eye, they are beginning to figure out why central nervous system tissue doesn’t regenerate and what can be done to make it regrow. “The eye is a great model system,” says Schepens neuroscientist Michael Young, also an assistant professor at Harvard Medical School. “It’s accessible, and the readout of vision makes it so easy to test function.”

And because it’s easier to experiment on the eye than on other parts of the central nervous system, neural regeneration, if it’s going to work at all in restoring function, will likely be demonstrated first in the eye, says Dong Feng Chen, a Schepens neuroscientist who is working on optic nerve repair.

Retinal replacement

The retina—the light-sensing layer of cells lining the back of the eye—is a natural place to begin study; not only is it a model for the brain, it also falls victim to diseases like retinitis pigmentosa and age-related macular degeneration, which can lead to blindness. Regenerating the cells of the retina could be a way of treating or even curing these diseases.

In 2004, Young transplanted retinal progenitor cells—stem cells that can develop only into eye cells—into the degenerating retinas of mice and found that they integrated into the retina and became light-sensing rods and cones, which are crucial for vision, resulting in improved vision in the mice.

Young needed to know why the progenitor cells succeeded when other types of neural stem cells previously transplanted failed. In a Journal of Neuroscience paper this year, he and his team showed that retinal progenitor cells encouraged other cells to secrete a protein called matrix metalloproteinase-2 (MMP-2), which helps transplanted neurons integrate into the eye.

Young’s group is looking for other molecules that promote or inhibit regeneration in the eye so that their levels can be increased or lowered accordingly during a retinal transplant. He’s now working in pigs, whose eyes are similar to humans’. He says clinical trials could begin within five years.

New nerves

Even if the retina is intact, blindness can result from the degeneration of another part of the eye: the optic nerve, a rope of a million neurons that stretches from the retina to brain.

Chen and her lab have found that turning on a gene called bcl-2 in mice, which is normally active only in the peripheral nervous system and during early development, and inhibiting the formation of a certain type of neural scar led to the regrowth of the optic nerve from the eye all the way to the brain—the first time anyone has accomplished this in mammals, according to Chen. Still, the optic nerve stopped growing after about two weeks, so Chen and her team are looking for further factors that may be blocking its regeneration.

Both Young and Chen believe that the same inhibitory molecules they have found in the eye are also at work in the brain. Lowering their levels could stimulate regeneration in both, they say.

“The eye has provided a great deal of insight into the molecules and genes important for neural regeneration,” says Mriganka Sur, head of the Department of Brain and Cognitive Science at MIT. “The eye has a number of well-defined pathways, yet the principles are the same for regeneration in the central nervous system.”

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