A miracle in the making

The discovery of neural stem cells that are capable of replacing damaged brain cells raises hopes of effective treatment for degenerative diseases such as Alzheimer's and Parkinson's.

FOR decades, certain facts in medical science have been accepted without question. One such fact was that brain cells are constant and not regenerated. Medical doctors and scientists alike accepted as a matter of faith, that the neurons, or brain cells one was born with are all the brain cells one would ever have. So, any damage to these cells would cause one to lose that part of the brain and its function.

However, Fred Gage, a neurobiologist at the Salk Institute for Biological Studies in La Jolla, California, showed in a groundbreaking experiment that brain cells are born even in adult brains. This discovery forced scientists to rethink some of their most basic ideas about how the brain works.

The cells that are responsible for this are not simple brain cells or neurons. Known as `neural stem cells' (NSCs), they are progenitor cells or master cells that can take up any form and function of brain cells. They have the ability to morph into any type of brain cell, depending on the chemical signals they receive as they grow. Researchers have shown that these cells are most commonly seen in the memory centres (called hippocampus) and in other deeper areas of the brain called neurogenic areas. Gage and his team have shown that a part of the hippocampus contains actively developing NSCs. They can be pressed into function by a simple but timely addition or subtraction of a few key growth factors in the brain's chemical soup.

The discovery of a `fountain of youth' for brain stem cells could lead to their use in treating degenerative brain diseases such as Parkinson's disease, and Alzheimer's disease. They can also be useful in certain cases of traumatic brain injuries. A big effort is already under way to find out their usefulness in spinal cord injuries. The basis of these experiments is that the neural stem cells are immature cells that can develop into many of the different types of specialised cells that make up the brain. In neurodegenerative diseases such as Alzheimer's and Parkinson's, normal brain function is impaired because of progressive brain cell death. If neural stem cells could be coaxed into replenishing these brain cells, they could restore a damaged or destroyed brain tissue.

Parkinson's is a disease where cells in certain regions of the brain (Substantia Nigra) die. As these cells die, the chemical they produce (dopamine) is in a short supply. The shortage of dopamine leads to the malfunctioning of the various neuronal circuits in the brain. This results in the dreaded symptoms of the disease: tremors, rigidity and slow progressive deterioration of spontaneous movements. Drug therapy for this problem is effective initially. Slowly, the drugs become ineffective and cause multiple side-effects. New surgical treatments like deep brain stimulation are effective but expensive in the Indian context. Moreover, they do not correct the basic abnormality.

So, in a disease like Parkinson's, from a conceptual perspective, the perfect treatment would be to replace the cells lost. The challenge is to find a suitable cell that is not rejected by the organism of the patient, survives for a long period within the brain and integrates well into the brain structures so that they comply with a series of functions. This is where the NSCs come into the picture. These cells are a subtype of primitive brain cells that are capable of self-renewal and multilineage differentiation. The use of NSCs thus becomes an appropriate therapeutic tool as they provide an endogenous source of brain repair. The number of NSCs in an adult brain is very low and hence will not be sufficient for repair. Therapeutic efforts are directed at stimulating the production of endogenous NSCs or transplanting the exogenous ones.

Endogenous NSCs can be isolated through simple surgical techniques. NSCs thus harvested can be used in autologous neural stem cell transplantation, that is, the cells harvested directly from the brains of Parkinson's disease patients could be transplanted back after differentiating them into stable and self-renewable brain cells that secrete dopamine. NSCs can also be transplanted as undifferentiated cells and then stimulated with specific chemicals so that they undergo a subsequent site-specific differentiation. Alternatively, they could be pre-differentiated in the culture into a desired neuronal type. Studies have shown that human embryonic and fetal neural stem cells can be induced to generate dopamine-producing neurons.

Using endogenous NSCs as a source of repair has certain advantages. Since these are patients' own cells, the immunological consequences of transplantation are completely avoided. Ethical and political concerns that shroud the use of fetal tissue are conveniently circumvented. In a different role, NSCs also constitute a very useful tool to deliver important genes with therapeutic value because they locally disperse after grafting, integrate in the host adult brain and differentiate into multiple, stable phenotypes. NSCs can thus be used as vehicle for gene therapy.

This research is a major step towards healing the brain, a difficult organ to treat. A majority of brain diseases are untreatable because of the basic limitation that brain cells do not grow. The discovery of neural stem cells and the research on the possibility of using them to replace damaged brain cells is a major step in modern medicine. Though in the experimental stages yet, this therapy definitely has the potential to grow into a modern miracle.

Milind Deogaonkar is a Research Fellow at the Department of Neurosciences, Cleveland Clinic Foundation, Ohio, United States.

References:

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