NIH: What would you hope to achieve from human pluripotent stem cell research?
Institutes and Centers
Answers to the Question:
"What would you hope to achieve from human pluripotent stem cell research?"
National Cancer Institute
April 26, 2000
Pluripotent stem cells have the ability to divide without limit and give rise to many specialized cells in an organism. There are several reasons why human pluripotent stem cells may be important to cancer research and reducing the cancer burden. First, pluripotent stem cells may be used to treat the tissue toxicity brought on by cancer therapy. Bone marrow and peripheral blood multipotent stem cells (which are more committed stem cells) are used already to restore patients' hematopoietic and immune systems after high dose chemotherapy. However, pluripotent stem cells may have greater potential for returning the complete repertoire of immune response to patients undergoing bone marrow transplantation, thus contributing to the development of other treatments such as immune/vaccine therapy. Other tissues damaged by cancer therapy also may benefit by replenishing their stem cell pools, e.g., injection of pluripotent stem cells into the heart may permanently reverse cardiomyopathy caused by certain chemotherapeutic agents, injection of pluripotent stem cells that have been differentiated into neural cells may restore brain function after cancer treatment.
A second reason why stem cells may be important to cancer research is based on the finding that cancer cells may have certain stem cell properties, specifically, the ability to renew themselves. The isolation and characterization of stem cells and in depth study of their molecular and cellular biology may help scientists understand why cancer cells survive despite very aggressive treatments. Once the cancer cell's ability to renew itself is understood, scientists can develop strategies for circumventing this property.
A third and final reason for studying stem cells lies in the field of gene therapy, where a gene that provides a missing or necessary protein is introduced into an organ for a therapeutic effect. One of the most difficult problems in gene therapy studies has been the loss of expression (or insufficient expression) following introduction of the gene into more differentiated cells. Introduction of the gene into stem cells to achieve sufficient long term expression would be a major advance. In addition, the stem cell is clearly a more versatile target cell for gene therapy, since it can be manipulated to become theoretically any tissue. A single gene transfer into a pluripotent stem cell could enable scientists to generate stem cells for blood, skin, liver, or even brain targets. Applications to cancer might include engineering replacement cells that are resistant to chemotherapeutic assault or that express antibodies against cancer targets.
National Heart, Lung, and Blood Institute
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.
National Institute of Dental and Craniofacial Research
Pluripotent human stem cells offer an important new tool and resource in biomedical research. Research using animal pluripotent stem cells is already helping to improve our understanding of the complex events of tissue development and regeneration. In addition, it is providing new approaches for the development and testing of new drugs and therapies and is contributing to the development of new technologies for the repair and replacement of organs, which have been damaged by disease or injury.
This is but a glimpse of what promises to become a rapidly expanding research portfolio at NIDCR. Stem cell research should better allow us to understand the biology of inherited craniofacial anomalies such as cleft lip and cleft palate and also the way normal cells can become malignant in orofacial and pharyngeal cancer. This should provide new information to prevent and treat these diseases. In addition, stem cell research could lead to the engineering of specialized cells such as bone, cartilage and salivary cells, which can be used as replacement for organs damaged by disease or injury. Examples include the treatment of temporomandibular joint disorders (TMDs), the replacement of skeletal elements lacking or damaged in diseases such as fibrous dysplasia of bone using cells grown in special natural or synthetic scaffolding materials, and the replacement of salivary cells damaged by disease (Sjögren's Syndrome) or radiation for head and neck cancer.
National Institute of Diabetes and Digestive and Kidney Diseases
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.
National Institute of Neurological Disorders and Stroke
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 typeï¿½that 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.
National Institute of Allergy and Infectious Diseases
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.
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.
National Institute of General Medical Sciences
Human pluripotent stem cells could make a significant contribution to applied trauma and burn research, such as research devoted to the development of "artificial skin." Such a biomaterial would enjoy wide application in the field of burn therapy. Initial studies, begun in the early 1980s, led to the development of a model for cultivating skin cells from burn patients. The method, which is being tested on patients today, consists of combining a biopolymer sponge made of collagen with actual skin cells from burn patients. Conceivably, human pluripotent stem cells could also be used as a source of "skin" to build such a graft, especially for severely burned patients with limiting amounts of remaining intact skin.
National Institute of Child Health and Human Development
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.
National Eye Institute
Treatment of Retinal Degenerations:
Some promising results have been obtained transplanting retinal cells and tissues in an effort to "treat" animal models of retinal degeneration. However, the results have been mixed and many questions remain. The immunologic issues governing transplant survival are complex and only partially understood. Possible strategies for overcoming these problems are suggested from ongoing investigations of the development and maturation of the normal retina. Cell lineage analysis has shown that retinal cells are generated from progenitor cells throughout development. The cell types generated in vitro can be influenced by the environment, and certain growth factors added to retinal cell cultures can lead to shifts in the types of cells produced. Growth factors can also influence the survival of retinal cells in vitro or in vivo. In addition to the effect of extrinsic cues, intrinsic properties of progenitor cells contribute to the genesis of retinal cell types as well. These types of experiments may lead to more effective strategies whereby manipulation of these progenitor cells could be exploited for retinal transplantation therapies. However, these experiments may also reveal insurmountable difficulties associated with this limited approach. In which case, use of pluripotent stem cells would become essential to overcome the immunological or other potential problems that may be encountered.
Treatment of Ocular Surface Disorders:
There is a significant clinical need for improved techniques to promote conjunctival and corneal healing during disease or after injury. Conventional surgery is not consistently successful in treating persistent corneal ulcers, chemical or thermal injury, bullous keratopathy, and various cicatrical diseases. Transplantation with pluripotent stem cells could provide a means of facilitating epithelialization of the ocular surface, reducing inflammation, vascularization, and scarring.
National Institute of 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.
National Institute 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.
National Institute of 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.
Improve development and testing of drugs:
A detailed understanding of stem cell regulation and the molecules that affect it would provide new targets for pharmacological interventions. Stem cell culture systems would also make possible rapid and economical testing of candidate agents for both effectiveness and safety.
National Institute on Deafness and Other Communication Disorders
Stem cell research offers the possibility of potentially replacing the sound-detecting hair cells in the inner ear that are often lost due to genetic, infectious, traumatic, or pharmacologic causes. Many scientific advances must occur before it would be rational to attempt to use pluripotent stem cells generate lost hair cells, including research advances that would prevent immune rejection of such stem cells. In addition, research advances will be needed to define the molecular events that lead human pluripotent stem cells to a differentiation pathway that generates highly specialized hair cells, and not other specialized cells. Having noted these caveats, an opportunity would be lost if investigators were unable to obtain NIH support to determine the full potential of human pluripotent stem cells for replacing differentiated cells that are lost or damaged.
National Institute of Mental Health
There is good evidence that many of the mental and behavioral disorders such as schizophrenia, autism, manic-depressive illness and memory disorders, result from permanent disruption of brain circuitry or brain chemistry.
The National Institute of Mental Health (NIMH) is currently supporting many research grants to determine exactly where and how such brain disruptions may occur, and is encouraging a vigorous program of research, including stem cell research with animals, to develop disease models and understand basic neuronal processes. For example, scientists are using non-human primate models to explore the hypothesis that schizophrenia is the result of damage to brain cells that mature at a particular stage of human development. If this hypothesis is supported, pluripotent stem cell research might provide a window into what goes wrong in the brain in schizophrenia, as well as potential interventions to remediate this devastating illness. Similar hope may apply to the severe developmental disorders, such as autism.
In another arena, investigators are examining stress- and toxin-induced loss of cells in a brain structure important for memory, the hippocampus. Animal studies have shown that natural replacement of cells in the hippocampus, via stem cells, results in improved memory performance as long as another important structure for memory, the cerebral cortex, is largely intact. Human pluripotent stem cells might ultimately be important to the development of replacement cells in the hippocampus of humans suffering from memory loss caused by selective damage to the hippocampus.
National Institute on Drug Abuse
Refinement of human pluripotent stem cell technology will provide an additional tool for scientists to study drugs of abuse. For example, although we are currently not supporting any stem cell research, NIDA-supported researchers can potentially use stem cells to reverse some of the long-term effects of drugs. Pluripotent stem cells offer a potential means of replacing neurons destroyed by drug abuse. This will be especially useful for individuals who have abused drugs such as methamphetamine, MDMA (ecstacy) and inhalants which have been shown in animal and some human studies to cause long-term, possibly permanent damage to selected areas of the brain. For example, recent research has shown that methamphetamine can have significant toxic effects on dopaminergic and serotonergic neurons in the brain. This is of particular concern because of the spreading use of this drug and may be related to the dramatic behavioral effects, including the development of psychotic-like behavior patterns that methamphetamine can have in some people. Pluripotent stem cells stimulated to develop into dopaminergic, serotonergic or other types of neurons, could offer a potential means of replacing neurons destroyed by drug abuse. In this way, we may be able to eventually reverse some of the debilitating behavioral effects of drugs such as methamphetamine.
Pluripotent stem cells can also lead to the development of valuable tissue sources for screens to study the effects of drug exposure on specific cell types. This could help researchers determine whether in utero exposure to drugs such as methamphetamine is neurotoxic and which cell types are particularly vulnerable. In this way, researchers will better understand the effects that prenatal exposure to drugs of abuse have upon the developing fetus, thereby gaining knowledge critically important to the improvement of the public health of neonates, infants, and children which cannot be learned through studies on humans themselves.
National Institute on Alcohol Abuse and Alcoholism
Pluripotent stem cell research offers significant potential for advances in the treatment of alcohol-associated organ pathology and in preventing or treating fetal alcohol syndrome. The value of pluripotent stem cell research would be in elucidating mechanisms of cellular differentiation. With this knowledge, scientists would have the potential to selectively differentiate cells into various tissues. The following examples demonstrate the potential utility of this type of research to the alcohol field:
Alcohol is a major source of damage to organs, such as the liver and brain, that may or may not regain function with abstinence from drinking. Development of medications that accelerate recovery in organs damaged by alcohol would be a major breakthrough. Such an advance would lessen human suffering and the economic burden associated with alcohol-induced organ damage. Human pluripotent stem cell research could provide a cost-effective means of discovering mechanisms that underlie alcohol-related pathology and that could be targets for new medications. For cases of irreversible organ damage, human pluripotent stem cell research could be used to facilitate generation of new organ tissue.
Fetal alcohol syndrome (FAS):
Human pluripotent stem cells would provide FAS investigators with a tool to study how alcohol disrupts cellular differentiation. Findings from this research would contribute to the design of potential interventions for FAS.
National Center for Research Resources
Many scientists believe that it one day may be possible to grow replacement tissues from cells that have been specifically programmed. Already, skin is routinely grown in large sheets and used to replace skin destroyed by burns or other types of injury. But before complex tissues from the brain, heart, pancreas or liver can be reliably reproduced, years of research lie ahead. Studies on human pluripotent stem cells can provide important information on how the different organ systems in the body develop and how this development can be controlled and put to good use. Unfortunately, stem cells still are difficult to isolate and culture. NCRR will support the development of a nonhuman stem cell resource to facilitate this important research. Such stem cell studies may eventually lead to effective treatments for Alzheimer's and Parkinson's disease and possibly other degenerative brain disorders as well as to the production of insulin-producing pancreatic beta cells to treat diabetics who no longer can make their own insulin. It may also be used to generate replacement heart valves and functional liver tissue.
National Institute of Nursing Research
Nursing research will benefit from the technological advances from human pluripotent stem cell research. For example, investigators in our Intramural Wound Healing Laboratory could grow skin tissue to be used for grafts in chronic wounds. When stem cell clinical applications involve patient care, nursing research studies will contribute to the science base for health care professionals, especially nurses.
National Human Genome Research Institute
The National Human Genome Research Institute is using the tools produced by the Human Genome Project to study the fundamental mechanisms of development and the contributions of genetic factors to disease. NHGRI investigators have identified the following as potentially promising areas of study involving pluripotent stem cells:
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.
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.