Stem Cell Transplants

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The discovery that the mature human brain possesses neuronal stem cells that yield new neurons into advanced age was groundbreaking and has provided major impetus to research into the potential of stem cells to definitively treat degenerative disorders, including Alzheimer's disease. Researchers hope that stem cells might be able to restore damaged brain functions by replacing cells that were destroyed. Stem cells might also be able to slow or stop 190, further damage by helping to bathe neurons in protective chem icals that the stem cells themselves transport and express. Most experiments involve transplanting stem cells directly into the brain through imaging-guided needle injection, but some researchers are using intravenous infusions of stem cells mixed with a drug that can cross the blood-brain barrier.

When neuronal stem cells have been implanted into the brains of animals and humans, they have taken root, so to speak, proliferating and connecting to preexisting neurons. In one experiment, laboratory-grown human neuronal stem cells were transplanted into the brains of aged rats, resulting in improved performance in an experimental learning paradigm. The old rats were able to learn and remember a route through a water maze as well as their younger counterparts. These findings are encouraging. They offer hope that stem cells might one day be able to repair brain damage from trauma, stroke, or other brain diseases.

Preliminary findings on the use of stem cells in treating the depletion of dopamine-producing cells in Parkinson's disease have produced mixed results. Clinical trials here and abroad have found the stem cell implants significantly improved symptoms in some patients—to the point where they no longer needed dopaminer-gic therapy; however, the symptoms worsened in other patients. As with any type of organ transplant or tissue graft, one of the major obstacles to overcome with stem cell transplants is to prevent a rejection response in which the body's natural immune defense attacks the new cells.

Early experiments with neural stem cell transplants have yielded a wealth of basic information about stem cells and the work that needs to be done before stem cell transplantation can become a viable therapy. To be effective, the transplanted cells need to be rendered specific to the task at hand. If the therapy calls for an increase in dopamine, for example—as in Parkinson's disease—then stem cells capable of becoming dopaminergic neurons must be used.

Unfortunately, stem cells don't come to the laboratory presorted. The challenge here is to find a way to separate out the specific stem cells that are needed from all the others in a batch or to ,191

genetically manipulate stem cells to make them develop into the desired cell type. Another challenge is to develop a reliable way to produce these cells in sufficient quantity for treatment.

Stem cell research has generated controversy because the primary sources of stem cells are discarded fertilized eggs from in vitro fertilization procedures and aborted fetuses. After federal funding support was restricted to a small subset of cell lines that had been in existence prior to September 2001, research continued to be funded privately. In November 2004, Californians voted in favor of a $3 billion initiative to support stem cell development and research; other states are likely to follow. Private institutions, including Harvard, have created funding and infrastructure in support of this work.

Alternative methods of producing stem cells are also being developed, including using tissue from neonatal umbilical cords. The use of adult stem cells is also a major focus of research.

The Search for an Alzheimer's Disease Marker i_

In order to prevent Alzheimer's disease, we must first be able to identify at-risk individuals either before or very early in the preclinical phase, the period during which disease activity (deposition of beta-amyloid) is occurring but has not yet reached a level sufficient to produce clinical symptoms.

We do not currently have a true preclinical marker for early identification of the vast majority of people who are destined to develop Alzheimer's disease; development of early detection strategies is a major focus of research. Although Alzheimer's susceptibility genes, such as ApoE, offer partial information on risk, additional tools will be needed, including brain imaging studies, blood tests or other biochemical assays, and more sensitive neuropsychological testing than we have today. Ultimately, early detection of Alzheimer's disease will probably be based on some combination of these methods.

Although stem cells from adults do not possess the perfect plasticity of embryonic stem cells—that is, the potential to become any cell type in the human body—methods are being developed to coax a greater range of specialized cell types out of adult stem cells. Another line of research is focusing on drugs that can stimulate the brain to grow its own new stem cells.

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