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Brain cells are coaxed into repair duty

by Richard Saltus, Globe Staff

June 2000

Boston scientists say they have succeeded in activating an overlooked self-repair system that enables animal brains, and potentially those of humans, to make new nerve cells and heal themselves from the inside. The remarkable finding topples long-held beliefs that the brain has no way to fix itself, and could open a new route to treating everything from Alzheimer’s disease to strokes. For now, researchers cannot try the strategy in humans: They had to kill brain cells in the experimental mice in order to switch on their brains’ nerve-generating capacity. But the researchers are hunting for other methods, such as drugs, that could turn on the hidden maintenance kit in the brain. The discovery is "enticing," said researchers commenting on the work.

"There is a long way to go," wrote Drs. Anders Bjorklund and Olle Lindvall of Lund University in Sweden, but learning how to switch on the repair system "might eventually lead to a powerful tool for brain repair in human disorders of the central nervous system." The prominent Swedish brain researchers made the comments in an article accompanying the report in today's issue of the journal Nature. The report is by Dr. Jeffrey Macklis, an associate professor of neurology and neuroscience at Harvard Medical School and Children's Hospital, and his colleagues, Sanjay Magavi and Blair Leavitt. Magavi, a graduate student, should be credited as the "motive force" in the study, Macklis said.

The findings are the latest in a string of intriguing discoveries in the past few years about "neural stem cells," previously unrecognized immature cells that can generate all the major types of cells in the brain. Already, scientists have cured mice of some severe brain disorders by implanting neural stem cells into their brains.

It had been long thought that the brain was incapable of changing or repairing its nerve circuits once it had fully developed. In fact, people were thought only to lose nerve cells as they aged. Scientists believed that was a product of evolution in which the brain was prevented from making new nerve cells, or neurons, after childhood because cell growth would increase the chances of making harmful neural connections.

"We now know that this view isn’t correct," Macklis said. Several years ago, researchers showed that neurons could make connections. More recently, neural stem cells that can generate all kinds of neurons were discovered and isolated. Macklis said in an interview that in two areas of the more primitive part of mammals’ brains, neural stem cells are known to generate new neurons, though not in great numbers, in response to damage. But it seemed the cells could not make neurons in the higher-function parts of the brain, like the cerebral cortex. The researchers attempted to see whether the neural stem cells, also called neural precursors, could move to the cerebral cortex and generate neurons to fix damage there. To test this idea, Macklis and his colleagues injected a light-sensitive chemical into a certain area of brains of adult mice. Two weeks later they opened the skulls and shined a light on that tiny area, and the activated chemical caused hundreds of thousands of neurons to commit suicide, a process called apoptosis. The death of these neurons caused the neural stem cells to become active, to migrate to the damaged brain area, to turn into the correct type of neurons, and make long-distance connections to the proper places, Macklis said. Their repair route took them only a fraction of a millimeter, "but that’s a long way for a nerve cell" in a mouse brain, he added. The goal now, Macklis said, is to discover what signals are received by the neural stem cells to summon them. That might enable scientists to design drugs that would recruit the neural stem cells and, it is hoped, make it possible "to do the repair from the inside" of the brain rather than needing cell implants.

Dr. Paul Sanberg, chairman of neuroscience at the University of South Florida, termed the work "very important." But he added, "the question will be how much neurogenesis will you see in response to large injuries in clinical studies." Neurogenesis is the creation of neurons. Bjorklund and Lindvall in their commentary, said, "These cells might represent a dormant capacity for neuronal repair," but they pointed out that in the mouse experiment only a small fraction of damaged neurons were replaced by the stem cells. "It is inconceivable" that such a small number of nerve cells "would allow significant functional recovery.

This story ran on page A18 of the Boston Globe on 6/22/2000.