Healing the brain from the inside out

June 20, 2000

Researchers find existing brain cells -- not transplants -- may replenish dead counterparts

Boston, MA -- June 22, 2000 -- Healing a human brain from the inside out was supposed to be impossible. The evolutionary choice for mammals was believed to be between a brain that was fixable and a brain that was too complex to tinker with after it was formed, especially from the inside. Now comes the discovery from a Children's Hospital research group, published today in the journal Nature, that our brain's nerve cells or neurons could one day be induced into healing themselves.

The paper from Jeffrey Macklis, Harvard Medical School associate professor of neurology at Children's Hospital, and his associates Sanjay Magavi and Blair Leavitt, flies in the face of a century of neuroscience conviction that in mammals the brain and particularly the cerebral cortex is incapable of healing itself‹a dogma that a series of recent experiments has shaken.

"Somewhere during evolution it was believed," Macklis says, "our brain, unlike the brains of other lower vertebrates, decided it would no longer do self-repair. The assumption has been that because we as mammals build a very complex brain, we don't want to mess around with it. We know now that this view isn't correct."

The Macklis group was able to induce stem cells deep in the cerebral cortex of adult mice to replace damaged neurons. These new neurons grew from already present immature precursor cells into fully formed, connected, and mature replacements. These home grown neurons demonstrate for the first time that the brain can heal itself from the inside out, without transplantation.

This breakthrough in fundamental neural cell biology is a long way from clinical application but Macklis says that if the mechanisms at work here can be understood and controlled, it may open a new avenue someday for treatment of degenerative brain diseases and central nervous system injuries.

Until recently, neuroscience held that neural precursor cells, active during fetal development, shouldn't exist in adults and yet recent research uncovered them in the forebrains of mice. Other work has shown that precursors can form new neurons in two limited areas of the brain. The dogma said that diseased or damaged neurons in the cerebral cortex can't be replaced and yet Macklis's lab has had success with injecting lab-grown neural precursors into the cortex of mice and watching them replace dying cells. Still even while working with transplantation, the investigators proceeded along another route, pursuing what Macklis calls "the futuristic idea that one might be able to activate neuronal repopulation and repair from the inside out."

The trick was to reopen the genetically controlled pathway that once allowed nerve cells to change. Macklis and his colleagues reasoned that, even suppressed, the instructions for the pathway must still be encoded in DNA. But how to signal them?

Macklis's team found the signals by using biophysical targeting to convince certain neurons to undergo apoptosis, or cellular suicide. Then they introduced chemical labels revealing whether or not existing precursor cells in the cortex were multiplying and taking their places as new neurons.

The investigators found that the endogenous neural precursors already were multiplying, as evidenced by the appearance of labeled BrdU, a marker of DNA replication. Then they spotted Doublecortin, a protein expressed only by migrating neurons, Hu, an early neuronal marker, and NeuN, a marker expressed only by mature neurons, indicating the precursors were progressively developing into mature neurons. Confirmation that the replacements were projecting their axons to make connections with other neurons came from additional anatomical labeling with dyes.

Macklis warns that this experiment is merely a first crude step in exploring the pathway of neural regeneration. "Not for a moment would any of us suggest that to repair the brain we want to go around inducing cell death. Rather, it's that we want to use this as an experimental tool to dissect out what the controls are. Our approach of targeted apoptosis, or cell death, has given us a crude external lever over a whole program of genes that we're investigating now. What we've done in this study is to turn on the whole program, all at once. What we'd really like to do is to define what the sequence and combination of the individual molecules is."

"Now comes the hard work," says Macklis.
This work was supported in part by grants from the National Institutes of Health, the Alzheimer's Association, and the Human Frontiers Science Program.

Children's Hospital is the primary pediatric teaching affiliate of Harvard Medical School, home to the world's leading pediatric research enterprise, and the largest provider of health care to the children of Massachusetts.

Harvard Medical School

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