The Nervous System's Fountain of Youth?

If neurons could somehow be made young again, damage to the central nervous system (CNS)--such as actor Christopher Reeve's severed spinal cord--might be reversible. Now scientists at the Massachusetts Institute of Technology (MIT) have taken a first step toward designing such a treatment: They have identified a protein that stimulates regrowth of severed eye-brain connections in mice, according to a report in tomorrow's issue of Nature.

The protein, called Bcl-2, is already famed among biologists for its ability to block "apoptosis," or cell suicide, the process by which damaged or obsolete cells destroy themselves. Dong Feng Chen and Nobel laureate Susumu Tonegawa, both of MIT's Center for Learning and Memory, and MIT biologist Gerald Schneider found that nerve cells' production of Bcl-2 is turned off after about the 18th day of a mouse embryo's development--the same time that axons, or nerve extensions, of cells in the embryonic mouse retina lose the ability to grow back after injury. That suggested that unchecked cell death, perhaps due to loss of Bcl-2, may somehow strip the mouse CNS cells of their ability to regenerate.

But the researchers discovered that Bcl-2's regenerative powers seem to reside in a different, unknown mechanism. Chen removed the retinas from mice engineered to produce extra Bcl-2. When these retinal "explants" were placed next to mouse brain tissue, new axons sprouted--even in explants from adults, long past the age when nerves are supposed to be able to regenerate. And in transgenic pups whose optic nerves were surgically severed 4 days after birth, retinal axons grew around the gap, finding their way to the proper target areas in the brain. Chen observed no such growth, however, when she treated retinal explants from normal mice with a compound that blocks apoptosis. "The neurons stayed alive longer, but they didn't extend axons," Chen says. "That means survival and nerve growth are probably two different activities of neurons." She's now searching for other proteins and genes through which Bcl-2 may act to spur regeneration, and for the genes that regulate Bcl-2 production itself.

According to Tonegawa, the find suggests a new avenue for treating victims of brain or spinal-cord injuries. For instance, Tonegawa says, researchers might be able to develop a drug that stimulates Bcl-2 production or a gene therapy that provides extra, active copies of the Bcl-2 gene. And on the basic research front, says William Snider, a neuroscientist at the Center for the Study of Nervous System Injury at Washington University in St. Louis, the results "are really going to broaden people's thinking about the functions of Bcl-2 and its family members."