Inside the human brain, branching neurons grow beside, around and on top of one another like trees in a dense forest. Scientists used to think that any neurons that wilted and died from injury or disease were gone forever because the brain had no way to replace those cells. By the 1990s, however, most neuroscientists had accepted that the adult brain cultivates small gardens of stem cells that can turn into mature neurons. Researchers are still trying to determine exactly how often these stem cells become new neurons and how well these differentiated cells survive and join established brain circuits. Some evidence suggests that the brain’s neural stem cells help the organ heal itself in modest ways—helping to replace small populations of neurons that suffocated during a stroke, for example. But this minimal self-repair does not restore the millions of neurons lost to stroke, traumatic brain injury and neurodegenerative diseases such as Alzheimer’s and Parkinson’s. Twenty years ago neurosurgeons tried to overcome the brain’s limited regenerative ability by slicing up sheets of fetal brain tissue and grafting them onto a diseased brain to replace dead neurons with new ones. The resulting clinical trials were disappointing, but some investigators think they have now worked out how to make the treatment safer and more reliable. Instead of relying on fetal tissue, scientists can grow millions of young neurons from stem cells in the laboratory and inject the juvenile brain cells directly into patients’ brains. Although few expect the therapy to be widely used for another decade or two, early studies toward that end have begun. The most promising work so far focuses on Parkinson’s, which seems to be particularly responsive to grafting. Parkinson’s, which affects about 10 million people (including one million Americans) worldwide, results primarily from the death of dopamine-secreting neurons in the substantia nigra, a section of the midbrain important for controlling movement, among other functions. Symptoms include shaking, stiffness and difficulty walking. In the early 1980s researchers harvested immature brain tissue from rat fetuses and transplanted it into the substantia nigra of rodents whose dopaminergic neurons had been killed to mimic Parkinson’s. Despite the transplanted neurons surviving the procedure, they largely failed to form functional neural circuits. Usually, as the brain develops in the womb, neurons in the substantia nigra extend branches to another region of the brain called the striatum, where they squirt out the neurotransmitter dopamine to communicate with striatal neurons. In the fetal brain, the distance between the substantia nigra and striatum is not that large; in an adult brain—even an adult rat’s brain—the distance is considerably greater. In those early experiments, the transplanted neurons could not bridge the gap. In follow-up studies, researchers instead tried grafting the immature neurons directly into the striatum. It seemed to work. The cells survived, wove themselves into existing neural circuits and began to secrete dopamine. In subsequent experiments with rodents and monkeys, such transplants have restored dopamine to nearly typical levels in the brain and improved motor functions—the animals do not quiver as much and gain better control of objects in their grasp. Researchers have speculated that the treatments work not only because the transplanted neurons release dopamine but also because they secrete substances called growth factors that protect and nurture dopamine-receptive cells in the striatum. Because the transplanted neurons are living cells that continuously produce, secrete and absorb neurotransmitters, they may balance dopamine levels in the brains of Parkinson’s patients more effectively than pharmaceutical treatments, such as l-dopa. By the early 1990s four people with Parkinson’s had received transplants of fetal brain tissue in Sweden—pioneering work that paved the way for two larger clinical trials of 40 and 34 people, respectively, in the U.S., funded by the National Institutes of Health. In both trials, half the patients received transplants, and half underwent sham surgery. The results were discouraging: treatment groups did no better than the sham groups, except for some patients younger than 60 in one of the trials. Whereas many researchers viewed these trials as complete failures, others saw reasons to question the data and try again. First, transplants of fetal tissue are notoriously difficult to standardize—patients often receive tissue samples of varying quality from multiple donors. Second, Anders Björklund of Lund University and other researchers argued that the trials expected improvements too soon. Transplanted neurons are so immature that they will likely require several years to fully integrate themselves into the brain. A follow-up study to one of the nih-funded trials found that two and four years after receiving grafts, some patients had improved. Lorenz Studer of the Memorial Sloan-Kettering Cancer Center has focused on a different way of replacing cells lost to Parkinson’s—a strategy that solves the issue of standardization. In the lab, he exposes embryonic stem cells to a series of molecules that mimic the kind of chemical signaling the cells would receive in the fetal brain, nudging them toward a specific stage of development equivalent to about two months in utero—just after their last cell division but before they have grown any long or intricate branches. Because he carefully guides their growth and development in the lab, he can generate millions of nearly identical young neurons for transplantation. Injecting undifferentiated embryonic stem cells into the brain—or any organ—risks the formation of tumors, because stem cells can grow uncontrollably; shepherding stem cells toward an adult form in the lab greatly reduces that risk. So far Studer has published promising results with rodents and monkeys—both sets of animals showed improved motor control—and he hopes to start clinical trials in humans in three to four years. “This research addresses a broader issue: how to help the brain repair itself,” Björklund says. “Parkinson’s is a very good test bed for this new approach to therapy. If we can make stem cell therapy work for Parkinson’s, this opens up the possibility of treating a wider spectrum of central nervous system damage and disease.” Learn more about regenerative medicine at ScientificAmerican.com/apr2013/regenerative-medicine
Researchers are still trying to determine exactly how often these stem cells become new neurons and how well these differentiated cells survive and join established brain circuits. Some evidence suggests that the brain’s neural stem cells help the organ heal itself in modest ways—helping to replace small populations of neurons that suffocated during a stroke, for example. But this minimal self-repair does not restore the millions of neurons lost to stroke, traumatic brain injury and neurodegenerative diseases such as Alzheimer’s and Parkinson’s.
Twenty years ago neurosurgeons tried to overcome the brain’s limited regenerative ability by slicing up sheets of fetal brain tissue and grafting them onto a diseased brain to replace dead neurons with new ones. The resulting clinical trials were disappointing, but some investigators think they have now worked out how to make the treatment safer and more reliable. Instead of relying on fetal tissue, scientists can grow millions of young neurons from stem cells in the laboratory and inject the juvenile brain cells directly into patients’ brains. Although few expect the therapy to be widely used for another decade or two, early studies toward that end have begun.
The most promising work so far focuses on Parkinson’s, which seems to be particularly responsive to grafting. Parkinson’s, which affects about 10 million people (including one million Americans) worldwide, results primarily from the death of dopamine-secreting neurons in the substantia nigra, a section of the midbrain important for controlling movement, among other functions. Symptoms include shaking, stiffness and difficulty walking.
In the early 1980s researchers harvested immature brain tissue from rat fetuses and transplanted it into the substantia nigra of rodents whose dopaminergic neurons had been killed to mimic Parkinson’s. Despite the transplanted neurons surviving the procedure, they largely failed to form functional neural circuits. Usually, as the brain develops in the womb, neurons in the substantia nigra extend branches to another region of the brain called the striatum, where they squirt out the neurotransmitter dopamine to communicate with striatal neurons. In the fetal brain, the distance between the substantia nigra and striatum is not that large; in an adult brain—even an adult rat’s brain—the distance is considerably greater. In those early experiments, the transplanted neurons could not bridge the gap. In follow-up studies, researchers instead tried grafting the immature neurons directly into the striatum. It seemed to work. The cells survived, wove themselves into existing neural circuits and began to secrete dopamine.
In subsequent experiments with rodents and monkeys, such transplants have restored dopamine to nearly typical levels in the brain and improved motor functions—the animals do not quiver as much and gain better control of objects in their grasp. Researchers have speculated that the treatments work not only because the transplanted neurons release dopamine but also because they secrete substances called growth factors that protect and nurture dopamine-receptive cells in the striatum. Because the transplanted neurons are living cells that continuously produce, secrete and absorb neurotransmitters, they may balance dopamine levels in the brains of Parkinson’s patients more effectively than pharmaceutical treatments, such as l-dopa.
By the early 1990s four people with Parkinson’s had received transplants of fetal brain tissue in Sweden—pioneering work that paved the way for two larger clinical trials of 40 and 34 people, respectively, in the U.S., funded by the National Institutes of Health. In both trials, half the patients received transplants, and half underwent sham surgery. The results were discouraging: treatment groups did no better than the sham groups, except for some patients younger than 60 in one of the trials.
Whereas many researchers viewed these trials as complete failures, others saw reasons to question the data and try again. First, transplants of fetal tissue are notoriously difficult to standardize—patients often receive tissue samples of varying quality from multiple donors. Second, Anders Björklund of Lund University and other researchers argued that the trials expected improvements too soon. Transplanted neurons are so immature that they will likely require several years to fully integrate themselves into the brain. A follow-up study to one of the nih-funded trials found that two and four years after receiving grafts, some patients had improved.
Lorenz Studer of the Memorial Sloan-Kettering Cancer Center has focused on a different way of replacing cells lost to Parkinson’s—a strategy that solves the issue of standardization. In the lab, he exposes embryonic stem cells to a series of molecules that mimic the kind of chemical signaling the cells would receive in the fetal brain, nudging them toward a specific stage of development equivalent to about two months in utero—just after their last cell division but before they have grown any long or intricate branches. Because he carefully guides their growth and development in the lab, he can generate millions of nearly identical young neurons for transplantation. Injecting undifferentiated embryonic stem cells into the brain—or any organ—risks the formation of tumors, because stem cells can grow uncontrollably; shepherding stem cells toward an adult form in the lab greatly reduces that risk. So far Studer has published promising results with rodents and monkeys—both sets of animals showed improved motor control—and he hopes to start clinical trials in humans in three to four years.
“This research addresses a broader issue: how to help the brain repair itself,” Björklund says. “Parkinson’s is a very good test bed for this new approach to therapy. If we can make stem cell therapy work for Parkinson’s, this opens up the possibility of treating a wider spectrum of central nervous system damage and disease.”
Learn more about regenerative medicine at ScientificAmerican.com/apr2013/regenerative-medicine
