Cardiovascular Research The National Heart, Lung, and Blood Institute (NHLBI) believes that human pluripotent stem cell research can develop exceptional new tools to address many important public health problems. The broadest potential application of stem cell research is the generation of cells and tissues that could be used as therapies. If scientists can learn how to control stem cell conversion into new, functionally mature cells, then physicians might be able to cure many cardiovascular diseases for which therapy is currently inadequate. For example, stem cells could potentially be used to repair the failing heart when it can no longer pump, to generate growth of heart chambers when infants are born with malformed hearts, and to repair vascular damage resulting from high blood pressure and atherosclerosis. Preliminary work in mice and other animals has demonstrated that healthy heart muscle cells transplanted into the heart successfully repopulate the heart tissue and work together with the host cells. These experiments show that stem cell transplantation is feasible. Stem cell research could also have ramifications for lung disorders and could lead to methods to correct defects in lung development or promote tissue repair following injury to the lung.
Diabetes and Digestive and Kidney Diseases Research Human pluripotent stem cells offer the potential for treating a number of major diseases of concern to all of our NIDDK programs. Because of their special plasticity, these cells offer the possibility to differentiate into highly important tissue specific cells. For example, there is an intense effort underway to understand the genetic rules by which an undifferentiated cell becomes a beta cell of the islet of the pancreas, which is capable of secreting insulin. For this to happen, it is important to understand the genes that are expressed temporally that are not only related to the growth of this type of cell, but also related to its important differentiated function of recognizing glucose concentrations and responding by secreting insulin. Isolated cells of this type are used for transplantation studies and, to a limited extent, in human therapeutic approaches to treat type 1 diabetes. The human pluripotent stem cell could offer an unlimited supply of these cells once the rules of differentiation are known. Other examples include attempts at cellular therapy to replace diseased liver tissue. In this case a cell would need to differentiate along the lines of a functional liver cell. Again, a similar set of rules are necessary for this to happen, but again the plasticity of the human pluripotent stem cell would form an excellent base for this to occur. Other examples could include various forms of kidney cells or potentially bladder cells. At the present time, there are a number of studies underway in an attempt to grow bladder cells that could be used to reconstruct a human bladder. There are numerous other examples in addition to diabetes, liver failure, kidney failure, and urologic diseases in which human pluripotent stem cells may have a major therapeutic role. It would also be important to try and understand the genetic rules of development so that these important cells may be applied to important therapeutic uses.
Neurological Disease Research In no area of medicine is the potential of stem cell research greater than in diseases of the nervous system. The most obvious reason is that so many diseases result from the loss of nerve cells, and mature nerve cells cannot divide to replace those that are lost. In Parkinson's disease, nerve cells that make the chemical dopamine die. In Alzheimer's disease, cells that make acetylcholine die. In amyotrophic lateral sclerosis the motor nerve cells that activate muscles die. In stroke, brain trauma, and spinal cord injury many types of cells are lost. There are many more disorders that affect both adults and young children in which nerve cells die. It might seem hopelessly optimistic to think that supplying new cells to a structure as intricate as the brain would do any good. Can new cells become well enough integrated to restore function? The encouraging preliminary results from fetal tissue transplantation trials for Parkinson's disease argue that they can. Here, the difficulty of obtaining enough cells of the right type杢hat is, dopamine producing nerve cells--limits success. This year, in animal experiments scientists developed methods to isolate neural stem cells and coax them to proliferate for several generations in cell culture, and then, on cue, to specialize into mature dopamine nerve cells. A large supply of "dopamine competent" stem cells will remove the barrier of limited amounts of tissue. When these cells were implanted into the brains of rodents with experimental Parkinson's disease, the animals showed remarkable improvements in their movement control. In other experiments, scientists inserted the gene for a crucial enzyme into stem cells, then transplanted these cells into animals with experimental Tay-Sachs disease, again with very encouraging results. Experimental cell replacement therapies are underway for other chronic diseases and for acute disorders like spinal cord injury and stroke. Transplant therapies for intractable epilepsy are also not out of the question. The potential for cell transplant therapies using cells derived from stem cells is enormous. Because stem cell therapies have been proposed for so many neurological disorders, it is important to note that stem cells might be used to do very different things to treat different disorders. For example, in some diseases stem cells might specialize and replace a particular type of nerve cell--a different kind of nerve cell for Parkinson's than for Alzheimer's than for amyotrophic lateral sclerosis and so on. For other disorders, like multiple sclerosis, it is not nerve cells, but supporting cells, the glial cells that wrap electrical insulation around nerve fibers, that stem cells might help replace. In other problems, for example brain trauma or stroke, we could speculate about using stem cells to regenerate regions of brain tissue, with many integrated types of brain cells. In the many devastating disorders in children where a single enzyme is missing, the ability of stem cells to migrate widely in the brain and supply the needed enzyme might be the key. There are several other strategies that might rely upon stem cells, such as using stem cells to supply neurotrophic factors, the natural growth and survival signals of the nervous system. Stem cells have important uses beyond cell transplant therapy. Other possibilities include drug development and drug screening methods. One enticing possibility follows from some surprising results that were reported just last year. Contrary to a longstanding belief that nerve cells in the adult human brain cannot be replenished, scientists found neural stem cells in one part of the brains of adult, even 60 year old, humans. If we can identify the natural signals that control the proliferation and specialization of stem cells, and understand how best to encourage these restorative reactions, we may be able to help the brain repair itself in certain vulnerable regions. 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.
Human Genome Research 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. 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 pluri
