HARVARD GAZETTE ARCHIVES
Nerve Cell Clones Repair Brain Damage
By William J. Cromie
Clones of human brain cells are being used in laboratory experiments aimed at repairing, even re-creating, brain areas damaged by injury, disease, and birth defects.
The cells, related to fetal stem cells that develop into every tissue and organ in the body, give rise to different types of brain and other nerve cells. Experimenters at Harvard have transplanted these neural stem cells into mice and shown that the implants will replace missing or deficient brain cells. These new cells can migrate to parts of the brain where they are needed and differentiate into apparently normal cells.
When cloned, such cells can also be genetically engineered to produce proteins that correct -- in the laboratory -- inherited diseases like Tay-Sachs. Introduced into a laboratory culture of Tay- Sachs cells, neural stem cells secrete a missing protein, reversing the disease process.
Other potential targets of this stem-cell therapy include strokes, spinal cord injuries, brain tumors, Parkinson's disease, multiple sclerosis, and a host of inherited disorders.
"In a way, we're trying to re-create areas of the brain by going back to stem cells, the source of original development," explains Evan Snyder, a neurologist at Harvard Medical School. "A colleague compares it to 'reseeding' a lawn. A birth defect is analogous to not putting down sod right in the first place. An injury may be like a period of bad weather or people tramping over the same spot repeatedly. If you want to start over, you plant new seeds; the seeds for regrowth of the brain are neural stem cells."
A Mysterious Journey
A tiny cluster of stem cells in a human embryo sires every tissue and organ -- heart and liver, blood and bones, skin and stomach. As these cells mature, they apparently develop into more specialized stem cells, such as those that become bone marrow, which in turn beget blood cells.
"The developmental journey from original stem cells to those that develop into more specialized organs and tissues is one of the most mysterious in biology," Snyder admits. "We just don't know how it happens."
Since the 1980s, Snyder and a small group of other researchers around the world have experimented with stem cells that give rise to various brain cells in mice. Their experiments raised the question of whether humans have the same type of cells and if these cells can regenerate a human brain the way they do in rodents. Ongoing research suggests that they can. Snyder described the research on Monday at a meeting of the American Association for the Advancement of Science in Anaheim, Calif.
A team headed by Snyder and working at Harvard-affiliated Children's Hospital in Boston extracted neural stem cells from the brain of a 15-week-old human fetus and transplanted them into the brains of developing mice.
The cells came mainly from an area in the center of the brain where the nervous system first starts to form. The scientists were able to grow these cells, freeze then thaw them, and transplant them into mice. They showed that these cells could grow into any of the three major types of brain cells and do so in different regions throughout the brain.
"We cloned cells once from a single fetus, then expanded their numbers," Snyder notes. "If we can continue the expansion indefinitely, and if the cells can be grafted into humans, that could eliminate the need for cells from aborted fetuses, or from excess embryos discarded by fertility clinics."
When transplanted into the brains of newborn mice, these cells migrated to various regions, following the same routes that cells take during normal development of a mouse brain.
The transplanted cells inserted themselves into the proper areas, formed the appropriate types of specialized cells, and integrated their activities with other brain cells.
"This migration and differentiation demonstrated that, despite freezing, thawing, and other manipulations, stem cells seem to replace those missing in a brain," Snyder points out. "They follow normal developmental patterns after implantation into the brain."
Looking ahead to humans, such clones could, in theory, rescue brain and spinal cord cells that have lost a protective sheath of fatty material known as myelin. Destruction of myelin causes several disabling diseases, including multiple sclerosis.
Other researchers are investigating the feasibility of treating Parkinson's disease with fetal cell transplants. The hope is that the fetal cells will produce more of a chemical called dopamine, lack of which leads to the tremors and stiffness that characterize the disorder. If this approach works, physicians may be able to use stem-cell clones instead of tissues from aborted fetuses.
Adding Genes to a Brain
Snyder's group has also demonstrated the feasibility of introducing new genes into a malfunctioning brain to make chemicals the organ needs to function normally. At first, the researchers engineered cells to carry marker genes that trace the movement of cells after transplantation. Such genes reveal the final destination of the implanted stem cells when the mouse is killed and its brain is examined.
Next, the team tried this with mouse cells engineered to carry a gene to treat a mouse version of Tay-Sachs, an inherited childhood disease. When this was successful, the researchers put human neural stem cells containing such genes into mouse brain cells in laboratory dishes. The genes carry blueprints for making a protein, lack of which causes the disease. The human cells functioned as predicted, raising both protein levels and hopes that this approach someday may successfully treat this lethal disease.
Snyder and his colleagues are now transplanting into mice a variety of human genes involved in genetic disorders. They include Krabbe's disease, in which absence of a gene causes deterioration of myelin sheaths around nerves -- a condition that can lead to blindness, deafness, paralysis, and death within one year.
"We have already implanted cells with mouse genes into the brains of mice affected with the human equivalent of such disorders," Snyder notes. "The mice appear to respond favorably in most cases. Now we're ready to try implanting human cells with human genes into mice. If that turns out to be safe and effective, we'll try the same kind of therapy with monkeys. We've already started some tests with monkeys but have not analyzed our results yet."
If such transplants prove to be safe and effective in monkeys, a next step could be to attempt stem-cell transplants in human patients with particular types of untreatable or fatal brain disease. Such a possibility contains what Snyder refers to as "an enormous number of 'ifs.'" However, he adds, "the field as a whole is moving rapidly ahead."
Besides replacing missing or faulty genes, stem-cell transplants might be used to boost the performance of genes needed to regrow nerves after spinal cord or head injuries, or to replace cells destroyed by diseases or strokes.
"Our research is not driven by the goal of finding cures for diseases but by the desire to learn about human development," Snyder explains. "We want to understand how stem cells take up specific functions and form different tissues and organs. What signals, for example, guide a neural stem cell to a certain part of the brain and cause it to become a particular type of nerve cell? Then we can ask ourselves what happens, in a fundamental sense, when something goes wrong. New treatments, and even new diseases, will fall out of such knowledge."
Snyder speculates that scientists will eventually find stem cells that dictate the development of other organs such as heart, stomach, lungs, etc. "If so, researchers could apply the same methods we are now using for the brain," he says.
Since stem-cell clones can "reseed" a brain, would it be possible to replace an entire brain that is being destroyed by cancer or Alzheimer's disease, or even to build a new brain from scratch?
Snyder answers with a smile: "That's an intriguing, almost Faustian, question."
Copyright 1998 President and Fellows of Harvard College