Parkinson's disease, according to most recent findings, has a strong environmental exposure component for one form of the disease. The nature of the agents and the timing of the exposure remain unknown at present. The use of human pluripotent stem cell cultures will permit screening for the subtle effects of candidate environmental toxicants and toxicant mixtures on specific cell types in the developmental stages of the cell lineage comprising the nervous system cells and tissue associated with the brain region compromised by the disease. Such explorations may yield powerful insight into the biological mechanism(s) underlying human susceptibility to the epigenetic form of this disease with onset after age 50, as well as the genetic-based "early" onset form of the disease.
It is possible that studies using the opportunities afforded by human pluripotent stem cell research will lead to molecular markers or surrogate markers or combinations of these that can be utilized for population-based studies of gene-environment interaction in disease etiology. Using the power of human pluripotent stem cell toxicity screening coupled with DNA micro-array technology, it may be possible within a decade to construct complex matrices of reporter molecules that report a "signature" characteristic of very high risk for the development of a complex source human disease. Applied to newborns and children, the most vulnerable of our population, maximum opportunities for medical health planning for intervention and prevention of disease in sensitive individuals would be possible.
On Aging
Human pluripotent stem cells hold enormous potential for cell replacement or tissue repair therapy in many degenerative diseases of aging. For disorders affecting the nervous system, such as Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis, and spinal cord and brain injury, transplantation of neural cell types derived from human pluripotent stem cells offers the potential of replacing cells lost in these conditions and of recovery of function. Human pluripotent stem cells have several critical advantages over stem cells of more mature derivation. The problem of rejection following cell therapy may be easier to overcome with pluripotent stem cells than with more mature stem cells. They can differentiate into virtually any cell type in the body and are capable of generating large numbers of cells. In addition, human pluripotent stem cells can provide a model for studying fundamental molecular and cellular processes important in the understanding of aging and age-related diseases.
Use of pluripotent human stem cells for cell therapy in Alzheimer's and Parkinson's diseases: Human pluripotent stem cells could be grown in culture and then transplanted to brain areas either as pluripotent stem cells or after being treated to become a specific type of neural cell. Work in animal models of human nervous system diseases, such as demyelinating disorders and spinal cord injury, has provided evidence that mouse pluripotent stem cells can survive, differentiate, and give some degree of functional recovery following transplantation to the affected region of the nervous system. In addition, stem cells could be stimulated to eventually develop into a cell type that uses dopamine to transmit signals between nerve cells. These cells could then be grown in culture to provide a potentially unlimited supply of cells that could be transplanted into the brains of Parkinson's disease patients to replace lost dopamine-producing neurons. Similar approaches could be developed to replace the dead or dysfunctional cells in cortical and hippocampal brain regions affected in patients with Alzheimer's disease. Human pluripotent stem cells could also be used to replace certain kinds of glial cells, particularly those that maintain the myelin sheath around nerve fibers, in age-related conditions characterized by loss of this protective sheath.
Use of stem cells as vectors for delivering genes or other therapeutic substances, such as neurotrophic or growth factors, to defined brain regions: Human pluripotent stem cells offer the potential to deliver therapeutic molecules to regions of the brain that are undergoing cell atrophy as seen in aging or cell death in Alzheimer's disease. Stem cells or stem cell-derived neural cells could be genetically modified to express certain proteins, such as neuronal growth factors, and then transplanted into affected brain regions where they could provide local delivery of the critical therapeutic factor(s). Animal studies using genetically modified cells have provided strong evidence for the feasibility of this approach.
Use of stem cells to study basic biologic processes: Human pluripotent stem cells can allow investigators to study basic molecular and cellular processes. For example, they can be used to study how the expression of the telomerase gene gets turned off during differentiation, which has critical importance for understanding both aging and cancer. Additional studies could help to define the factors that control the self-renewal capacity of pluripotent stem cells or the differentiation of pluripotent stem cells into various cell types when grown in cell culture or when transplanted into human tissue. Other studies are needed to understand those factors leading to optimum therapeutic benefit, including determining the best type of cells for transplantation and what happens when cells are transplanted into hosts of different ages or into hosts with different diseases. A better understanding of the fundamental, biological properties of human pluripotent stem cells can lead to their successful use in cell transplantation and tissue regeneration therapies in age-related disorders.
On Arthritis and Musculoskeletal and Skin Diseases
Generation of replacement cells and tissue to treat diseases: Because stem cells constitute a self-renewing population of cells, they can be cultured to generate greater numbers of bone or cartilage cells than could be obtained from a tissue sample. Equally important, if a self-renewing population of new stem cells can be established in a transplant recipient, it could effect long-term correction of many diseases and degenerative conditions in which bone or cartilage cells are deficient in numbers or defective in function. This could be done either by transplanting the stem cells from a healthy donor to a recipient, or by genetically modifying a person's own stem cells and returning them to the marrow. Such an approach holds great promise for genetic disorders of bone and cartilage, such as osteogenesis imperfecta and the various chondrodysplasias. In a somewhat different application, stem cells could be stimulated in culture to develop into either bone or cartilage-producing cells. These cells could then be introduced into the damaged areas of joint cartilage in cases of osteoarthritis, or into large gaps in bone that can arise from fractures or surgery. This sort of repair would have a number of advantages over the current practice of tissue grafting.
Improve understanding of normal and abnormal development: The ability to isolate and manipulate stem cells in culture will provide experimental access to the processes that regulate the differentiation of bone and cartilage cells. This will enable investigators to identify the molecules that control the proliferation of stem cells, or induce or inhibit stem cells' progression to mature functional cell types. In turn, testing for the presence and activity of these regulatory molecules in healthy and diseased tissues will indicate conditions in which defects of stem cell regulation or differentiation underlie pathology.
