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Stem Cells: Their Potential for Treating PD

By Mark Noble, Ph.D.

It seems obvious that since Parkinson's disease (PD) is caused by a loss of cells in the brain, an attractive treatment strategy would be to replace these cells. This has been one of the great hopes in PD research. Recent scientific studies have suggested that one strategy may be found in stem-cell transplants. While there remain many significant problems to be solved, it is increasingly possible to envisage a cell-based approach to treating PD.

What are stem cells?
The goal of stem-cell research is to create or find a renewable resource of cells for transplantation. Among the sources under consideration are embryonic stem cells, tissue-specific stem cells and genetically-modified cells from other species. There is also considerable interest in discovering a way to stimulate stem cells in the brain to repair themselves, thereby eliminating the need for cell transplantation. Unfortunately, each of these potential sources comes with its own technical and/or ethical challenges.

Embryonic stem cells
The developmentally-earliest stem cells are called embryonic stem cells, or ES cells, and they are the source of all other cells in the body. The ability of these cells to generate all of the cell types of the body is why they offer such potential for scientific and medical purposes and why they are of great interest in the research community.

Blastocysts created by in vitro fertilization clinics
Embryonic stem-cell biology is marked by social controversy. A central issue is the definition of when human life begins. All species that reproduce sexually have a first stage in which sperm and egg fuse, followed by rounds of cell division that occur before any specific tissues appear. The fertilized egg generates a blastocyst, which is a simple ball of about 100 cells that is similar in all species at this stage of development. ES cells are derived from the cells in the blastocyst's center.

The blastocyst contains no nerve cells, no muscle cells, no gut cells, no bone cells and no blood cells. Nor does it contain any of the tissue-specific stem cells that are needed to make such cells. Its inner mass consists of a small number of cells that can be used to generate ES cells. The blastocyst does not develop further unless it implants in the wall of the uterus, which is the stage at which pregnancy begins. All species generate many more blastocysts than embryos that develop further. In humans, it is estimated that 40 to 80 percent of blastocysts never implant in the uterine wall and therefore do not result in pregnancy.

Human blastocysts may be readily obtained from in vitro fertilization clinics. When a woman undergoes in vitro fertilization (IVF), it often takes several tries before the doctors succeed in getting an embryo to implant itself successfully in the uterus. Because of this, doctors arrange to have multiple fertilized eggs in case the first attempts at pregnancy do not work. When success is achieved, the leftover blastocysts are eventually discarded. A reasonable estimate is that 100,000 blastocysts are discarded every year from IVF clinics, mainly because couples do not wish to pay for continued storage after a successful pregnancy. Many scientists believe that using some of these blastocysts to supply small numbers of ES cells for research that could enhance human health is more ethical than simply throwing them away.

The other major source of human ES cells involves a technique in which the nucleus of an adult cell from the patient's own body is transferred into an unfertilized egg from another source to generate ES cells. This is known as somatic cell nuclear transfer (SCNT). This procedure enables the nucleus of adult cells to be reprogrammed to express the properties of embryonic stem cells.

The opposition to such research involving both kinds of ES cells - those from blastocysts created by in vitro fertilization clinics and those derived through SCNT - is largely based on the belief that blastocysts should be treated as human beings because they have the potential to develop into a person. Those who disagree argue that personhood is not conferred until much later in the process - for example, after the blastocyst has become implanted in the uterine wall, or after pregnancy has developed to the stage at which the fetus has viability independent of the womb. The point is that there are multiple views on when exactly the beginning of human life is and no easy way of reconciling them. In such context, most people accept the notion of isolating small numbers of cells from blastocysts destined to be discarded from IVF clinics. Many also believe that it should be possible to use a patient's cells from his or her own body, through SCNT, to treat one's own diseases.

Tissue-specific stem cells
The second group of stem cells includes tissue-specific stem cells (often referred to as adult stem cells) which generate only the cell types that are found in a single tissue, such as the brain or the pancreas. For the treatment of PD, the tissue-specific stem cells with the most immediate potential therapeutic value are those that are isolated from the human brain. There is also considerable interest in learning whether stem cells from other tissues, such as bone marrow, can be used to generate brain cells.

Human brain cells
The use of the adult human brain as another potential source of stem cells is also an important avenue to explore. A 1992 claim that stem cells could be isolated from the adult brain of Parkinson's patients, followed by transplantation back into these patients, has not yet been confirmed by more detailed study.

Can tissue-specific stem cells not from the brain be used to make brain cells?
The possibility of utilizing stem cells from other tissues (such as the umbilical cord or bone marrow) to generate brain cells has attracted much scientific interest. There are no ethical considerations in harvesting such cells, since they are derived from whole tissues that have zero potential to create human life. Some people who are opposed to the use of ES cells claim that tissue-specific stem cells are all that scientists need to conduct successful transplantation, and that therefore there is "no need" to use ES cells. Such claims are highly controversial, and there do not appear to be any scientists with working expertise in the field of stem-cell biology who agree with that concept. In fact, those scientists who played the leading role in the discovery and utilization of tissue-specific stem cells from adults have been among the advocates for embryonic stem-cell research.

Research on how to generate brain cells from stem cells of other tissues remains very important, but the evidence available at present suggests that this approach is less likely to be of therapeutic use than the application of brain-specific stem cells or embryonic stem cells.

Cells from other species
Some researchers are trying to genetically modify brain cells from other species, such as pigs, to enable them to be transplanted into humans without being rejected by the immune system. The utilization of living cells from other species in human transplants remains a technology unproven in the medical arena. On the one hand, the signals that are involved in building a functional nervous system seem to be very similar among all mammals and, in many cases, perhaps even among all vertebrates. We also know that even tissue from a closely-related human being, such as a sibling, can be rejected by our immune systems. Using cells from another species to repair the human brain is an interesting scientific possibility, but we are still far from knowing whether this approach will ever develop into a medically-useful technology.

Enhancing repair without transplantation
Another area of research is focused on promoting repair by endogenous stem cells (stem cells that reside in the tissues of our own bodies). There are promising results with this approach in certain experimental situations, but its feasibility in treating PD has never been demonstrated. Of particular concern is the possibility that stem-cell populations become depleted and/or become less effective with increasing age. At the moment, the potential of using this approach to treat PD is only speculative.

What happens next?
What everyone is anxious to know is, "What will happen next in Parkinson's disease research?" Two critical goals are to develop diagnostic approaches that allow early recognition of PD and to find a way to slow the disease's progression. The development of effective and safe cell therapies is of critical importance, and scientists have multiple avenues to explore that require intensive research.

Dr. Mark Noble is a Professor of Genetics for the Center for Cancer Biology at the University of Rochester School of Medicine and Dentistry. His research is focused on stem-cell biology and regeneration in the central nervous system, among other neurological topics.