Experiments raise Hope of Replacing Brain Cells

By William J. Cromie

Gazette Staff

Fifteen years ago, it was dogma: dead brain cells can never be replaced in humans or other mammals.

But science is a dogma eat dogma business. About 10 years ago, cells were transplanted into the brains of people with Parkinson's disease to replace a missing chemical. The dogma went from "impossible" to "maybe."

Recently, Harvard Medical School researchers have found immature cells in the brains of mammals (mice) that can be coaxed into replacing dead or dying adult cells. "These immature cells apparently maintain their capability to develop into adult cells in the same way they do during development of the brain in an embryo," says Jeffrey Macklis, associate professor of neurology (neuroscience).

In other experiments, Macklis's research team has replaced dead and dying cells in the brains of adult mice with immature cells taken from mouse embryos or grown in their laboratory. Many transplanted cells now look just like those they replaced. What's more, the replacements have connected successfully with the correct cells in distant parts of the brain. They appear to have taken a working place in the brain's complex circuitry.

Humans possess the same kinds of cells as these mice, and such human cells are shaped by the same types of growth and development processes.

"In the next decade, it's reasonable to think we may be able to apply such transplants, or control dormant immature cells, to regrow nerves involved in spinal cord injuries," Macklis says. "Further away is the possibility of rebuilding entire brain circuits disabled by injury or disease."

The dogma has now gone from "impossible" to "adventuresome, but likely."

Reviving A Brain

Last year, Macklis, Evan Snyder, and their colleagues at Harvard-affiliated Children's Hospital in Boston activated molecules with a laser to selectively kill mouse cells that correspond to areas of reasoning and association in a human brain. These same kinds of cells degenerate in human diseases such as Alzheimer's, and in some types of stroke.

The researchers replaced the killed cells with what they call "multipotent precursors," all-purpose cells from embryos that have not yet developed a specialized function. Amazingly, the immature cells developed into the correct types of adult brain cells.

"This is the first time that precursor cells have successfully repopulated degenerated neurons [brain cells] in an adult mammalian nervous system," Macklis notes. "Recent experiments show that these cells grow extensions that connect them to other parts of the brain. Now, we're looking to see if these transplanted cells get activated by input from the senses and whether they communicate that information to other parts of the brain."

More recent experiments suggest that very immature cells recreate brain circuitry less efficiently than precursors taken from later stages of embryo development. Such precursors have already made some decisions about what types of adult cells they will become.

"More developed cells might be manipulated in more efficient, precise ways," Macklis speculates. "These older cells are more directed as to what they will become, but more restricted in what they can become. In trying to build new brain circuits, we think it might be wise to trade decreased flexibility for increased efficiency."

The researchers believe that more refined precursors might help them to do what some birds do naturally. Studies done by other researchers, including Fernando Nottebohm at Rockefeller University in New York, reveal that brain cells in some song birds, including canaries, die and are replaced every season. Specific brain cells dealing with song production die naturally; then, just as naturally, they are replaced by other cells that allow the birds to learn new songs.

Birds are lower down on the evolutionary ladder than mammals, but, says Macklis, "this is an intriguing result. It supports the idea that new neurons can make specific connections and take part in circuitry that changes behavior."

The birds don't receive transplants, so they must rely on cells already in place. Called "endogenous precursors," these are the immature cells recently found in mammals. They sit close to fluid-filled cavities near the deep center of the brain where new cell birth occurs in early development.

What happens, Macklis thinks, is that dying brain cells signal the precursors via molecules they release or by changes in their level of activity. It's like a 911 call saying: "Help, we need more of these song cells right away."

"The discovery of precursors inside the brain leads to a great deal of excitement," Macklis comments. "Instead of transplanting cells, we might be able to manipulate immature brain cells to become part of the working brain. And perhaps we can go one step further by taking precursors out and genetically engineering them to replace functions that are missing because of disease or injury. Such cells would then be re-implanted."

Death Leads to Life

Macklis collaborates with Nottebohm in experiments suggesting that the death of certain cells in a song bird's brain is directly responsible for the birth of new cells that take their place. Macklis thinks this also happens with mice and other mammals. Signals released by dying cells and by their normal neighbors make it possible for the transplanted precursors to survive and develop.

"If we could determine what these signals are and how they change precursors, then we might be in a position to manipulate the cells, either inside or outside the brain, so that we can grow new circuits in humans," Macklis points out. "That's a goal that we and other labs are pursuing."

"I have a gut feeling that this process recapitulates the development of a brain in the womb and immediately afterward," Macklis says. "This gives us great optimism that by manipulating precursors of various types and their environment we might be able to revive circuits in the brain that deal with such high-level functions as thinking and learning."

Macklis sees repair of spinal cord injuries as possibly the first application of these results. Such injuries often involve crushing or severing millions of nerve fibers.

"When patients have only a few percent of their axons (nerve fibers) intact, they still can regain a large amount of function," Macklis explains. "This tells us that reconstructing a relatively small percent of circuits could make a huge difference, perhaps the difference between being paralyzed or not. That's because exact reconnections are not as crucial as they would be for restoring language or cognition. Enough overlap in the spinal cord and plasticity in the brain exists for a patient to relearn lost motor functions."

"We're a decade away from attempting this," Macklis cautions. "Realistically, however, this is a place where these types of neuron transplantation and precursor control might have their first application."

Very specific classes of brain cells die in Alzheimer's; one of them is the same class that Macklis's team killed in mice and is attempting to restore. "The prospect of reconstructing some of this high-level circuitry drives much of our work," he says. "But any application would be even more futuristic than spinal cord work."

Could knowledge from this research be used to protect cells that die of aging?

"I wouldn't want to make that jump at this time, although it is implicit in what I'm saying," Macklis replies. "If we can understand molecules that support the survival and growth of brain cells that otherwise die, these molecules could potentially be useful in retarding the progressive degeneration due to aging."