Mar. 27, 2005 Development of the brain involves a babel of messages that must speak to the formation and integration of hundreds of different types of nerve cells. If such messages could be separated from the "noise" of other brain activity and clearly understood, researchers would be closer to repairing damage caused by a number of nervous system diseases, paralyzing injuries, and combat wounds.
Researchers at Harvard Medical School and Massachusetts General Hospital in Boston have actually done this with mice. They managed to isolate distinct types of nerve cells, then identify the genes and molecules responsible for their development. This feat sets the stage for using nervous system stem cells to repair nerve cells damaged by spinal cord injuries or affected by diseases such as amyotrophic lateral sclerosis (ALS, or Lou Gehrig's disease). For example, some of the genes and molecules might be manipulated to enhance the survival of damaged motor cells in the brain, or to coax stem cells into replacing nonfunctioning nerve cells.
Both treatments might someday help disabled people walk again. Those like deceased actor Christopher Reeve, who lost the use of his arms and legs as the result of a horseback-riding accident, might regain some use of their limbs. The potential number of people who might be helped increases every day as paralyzing injuries among troops and civilians in Iraq and Afghanistan continue to increase.
"Until now, almost nothing was known about how specific types of brain cells form from unspecialized stem cells," notes Jeffrey Macklis, associate professor of surgery at Harvard Medical School and Massachusetts General Hospital. "Our new approaches are being viewed by those in the field of brain development as opening up an entirely new ability to dissect the nervous system apart one cell type at a time. We have already done this for three important nerve types, and we are working on more."
Macklis' group worked specifically with nerves that carry movement signals from the cortex of the brain to the spinal cord. He and his team isolated such nerves at several stages of development in mice. The researchers also purified two closely related nerve cell types, allowing them to understand precise signals that distinguish one from the other. Then they found the genes active in these cell types during their growth. This was done with the help of special devices, called gene chips or microarrays, which can measure the activity of thousands of genes simultaneously.
The result enabled the researchers to identify the specific genes vital for the maturation of critical brain-to-spinal cord connections. The Macklis team includes Paola Arlotta, an instructor in surgery, and Bradley Molyneaux, a graduate student at the Center for Nervous System Repair at Massachusetts General Hospital and Harvard Medical School.
Birthing new nerve cells
There are so many nerve cells and genes involved in body movements, the investigators had to be sure that the pathways they identified were the ones that controlled connections from the brain to the spinal cord. To do this, they employed genetically engineered mice with one of the critical genes they identified "knocked out," or inactivated. This resulted in the complete elimination of the connections between the brain and spinal cord needed by the brain to control normal movements. That left no doubt. The missing genes control the development and hookup of nerve cells that carry the signals necessary for getting around. Now the signals for each type of nerve cell can be heard over the rest of the brain's incessant babel.
These nerve cells and their connections are important to humans because they are one of the two types of cells that degenerate in ALS and other paralyzing diseases. ALS causes weakness and wasting of muscles. Sufferers often die when the disease progresses to the muscles involved in breathing and swallowing. No cure is known.
Because ALS involves the death of the very brain cells that the Macklis group has been working on, he says, "there is solid reason to think that these might be repaired or protected if we can figure out what goes wrong with them, or how to make these specialized cells from adult stem cells already present in the brain."
Animal research in the Macklis lab already provides intriguing evidence that brain cell losses in both ALS and traumatic injuries can be replaced with carefully grown stem cells. "We hope that unspecialized human stem cells, present in the adult brain, possess the potential to be coaxed, with the right combination of molecules and growth factors, into custom-made replacements," Macklis says.
This might be accomplished by raising the right type of nerve cells in a laboratory dish, then transplanting them into patients. Macklis also thinks that replacement might be done "by recruiting adult stem cells that already exist in the brain." If he is correct, the latter technique would avoid the furor associated with growing human embryos to obtain the necessary starter cells.
Macklis, who heads the neuroscience program of Harvard's Stem Cell Institute, is a pioneer in this new business of birthing new nerve cells. His latest results add to four years of searching for - and finding - molecules and genes in the nervous system unknown before. The work has been supported by the Christopher Reeve Paralysis Foundation, the ALS Association, the National Institutes of Health, and others.
"We've established a basic foundation that allows us to think seriously about replacement of certain nerve cells in humans," Macklis says. "But we still have much basic research to do first."
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