The promise of stem cell research is very real, but to realize the potential of stem cells for treating nervous system diseases, we must overcome significant obstacles. We don't yet know how to control the survival and specialization of stem cells adequately. Just delivering cells to the appropriate sites within the human brain is an extremely difficult task. All of these factors argue for intensified efforts to understand the basic biology of stem cells in the nervous system and to apply what we know to treating disease.
Infectious Diseases Research
Transplantation: Research on human pluripotent stem cells could lead to cures for diseases that require treatment through transplantation, including autoimmune diseases. (Autoimmune diseases include multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, and type-I diabetes). The most feasible example over the short term is treatment of type-I diabetes by transplantation of pancreatic islet cells or beta cells produced from autologous human pluripotent stem cells -- that is human pluripotent stem cells found in the person who would be receiving the transplant. While much research is needed, including research on whether stems cells can be found in children or adults, the promise is considerable. Gene transfer into pluripotent stem cells could obviate the need for immunosuppressive agents in transplantation and the ensuing susceptibility to other diseases. Moreover, ultimately, human pluripotent stem cells might be used to create transplantable cells, tissues, and organs of any type. In addition to eliminating the need for immunosuppressive drugs, this would address problems ranging from the supply of donor organs to the difficulty of finding matches between donors and recipients.
Primary Immunodeficiency Diseases: Human pluripotent stem cells might be used in treatment of virtually all primary immunodeficiencies. There are more than 70 different forms of primary (congenital and inherited) deficiencies of the immune system. Primary immunodeficiency diseases are characterized by an unusual susceptibility to infection and are sometimes associated with anemia, arthritis, malabsorption and diarrhea, and certain malignancies. They can involve considerable pain and suffering, numerous hospitalizations, high medical costs, and even death. Almost all of these diseases are rare. Because these diseases are genetic, gene replacement is an important area of investigation in the search for effective treatment. The transplantation of human pluripotent stem cells reconstituted with a normal gene might result in development of healthy cells of the types affected by the missing or damaged genetic material in the immunodeficiency disease. As a mechanism for gene replacement, based on research with animals, there is reason to believe that human pluripotent stem cells will have proliferative advantages over currently available alternatives, such as peripheral blood or bone marrow derived hematopoietic stem cells. Other hypothetical advantages include greater susceptibility to genetic transduction. The hope is for greater potential for engraftment, long-term survival and reconstitution of normal cellular functions.
HIV/AIDS: Research on autologous human pluripotent stem cell transplants (transplants to and from the self) could make restoration of immune function a viable option for treating HIV disease. Such transplants could regenerate all the components of the immune system that have been damaged by HIV infection. Research would need to demonstrate that autologous human pluripotent stem cells could be found in HIV-infected patients. Experiments in animal models point to significant advantages with the use of these cells. Primarily, the human pluripotent stem cells are easily transduced with new genetic material, such as anti-HIV genes, so that the daughter cells are resistant to HIV infection. Thus, this combination of gene therapy and stem cell research could result in the immune reconstitution of AIDS patients with cells that are resistant to HIV.
Human Development Research
The fundamental question in biology is how a single fertilized egg develops into a complex adult organism with many different specialized cell types performing specific functions. This development follows a program directed by precisely timed turning on and off of many genes. Learning how this process works is basic to the mission of NICHD in promoting the birth of healthy offspring through research on human reproduction and development. Since pluripotent stem cells can develop into many different cell types, the study of how pluripotent stem cells can develop into many cell types may provide new knowledge of how fertilized eggs develop into organisms. Also, pluripotent stem cell research will allow scientists to, among other things, direct the development of these stem cells along a certain path to become liver, blood, brain, or any type of cells which then can be used in transplantation and for other purposes. Within NICHD's area of interest, these cells could be used to replace organs or tissues that are defective as a consequence of birth defects. For example, one such condition is biliary atresia, in which part of the liver does not develop correctly. Human embryonic stem cells could potentially be directed to form liver tissue or to replace the damaged organ and save the life of the affected infant.
Gene Expression: The differentiation potential of pluripotent stem cells make them important candidates for studies of alterations in gene expression profiles. Being able to examine the genes that are turned on and off during the differentiation process of these cells using newly developed microarray technology could supply very useful information about normal and abnormal cell development. This information could have promising application to a whole host of disease areas.
Parkinson's Disease (PD): PD is caused by degeneration of neurons in a region of the brain, the substantia nigra, leading to severe abnormalities in movement. The cause is largely unknown, although in a few rare families with early onset disease, mutations in the gene for alpha synuclein are known to be responsible. As with other neurodegenerative disorders, replacement of damaged nerve cells with nerve cells generated from pluripotent stem cells is one avenue of possible therapy. Current experiments using fetal cells for replacement have provided very mixed results, especially in the long-term. One possible explanation for the less than complete replacement is that the cells being transplanted are too far along in path of development and differentiation to be able to take up residence in the substantia nigra, make all the correct connections, and replace the damaged cells. Using even less differentiated cells, such as human pluripotent stem cells, is a possible alternative.
Gene Therapy: Almost any genetic disease where cell and tissue transplantation protocols exist could potentially benefit from the application of human pluripotent stem cells in gene therapy. For example, patients with genetic disorders of immunity might benefit greatly from studies involving gene transfer using specially derived pluripotent stem cells. Studies involving these cells may also be useful in immune reconstitution or engineering viral resistance for HIV infected individuals.
Blood Disorders/Sickle Cell Disease: The epsilon globin gene is expressed only in red blood stem cells. This gene recently has been shown to block the sickling of the sickle cell hemoglobin. Research involving human pluripotent stem cells could help answer questions about how to turn on the epsilon globin gene in adult blood cells and thereby halt the disease process. Stem cell research may also help produce transplantable cells that would not contain the sickle cell mutation.
Environmental Health Sciences
Human pluripotent stem cell research offers great promise for use in testing the beneficial and toxic effects of biologicals, chemicals and drugs. Such studies will lead to fewer, less-costly, better-designed human clinical trials yielding more specific diagnostic procedures and more effective systemic therapies. Human pluripotent stem cell research also offers powerful new research approaches for clarifying the complex association of environmental agents with human disease processes. It also makes possible a powerful new means of conducting detailed investigations of the underlying mechanisms of the effects of environmental toxicant or mixtures of toxicants. Cancer is not the greatest health hazard of environmental toxicants at the common exposure levels with which we encounter them. Of greater concern are their subtle effects on the developing embryonic and fetal development tissue systems responsible for maintaining strong post-natal health. For example, the human embryo and fetus may be very susceptible to long-term impairments of immune or nervous system functions from the in utero effects of toxicant exposure. Similarly, dioxin, an environmental toxicant, is now present virtually everywhere in the environment, including in humans. How dioxin behaves in humans is poorly known with respect to its toxic effects on subtle embryonic, fetal, or neonatal developmental processes whose damage may take further decades to result in overt disease expression. The use of human pluripotent stem cell cultures may allow the identification of the specific early cell types at greatest risk of dioxin effects, the mechanism of the toxic effect(s) and the temporal nature of its harbored effects in the progeny of the cell lineage(s) established from such stem cells.
