Stem cells are the building blocks of the human body. They play a major role in the regeneration of tissues, and in the development of the human embryo. Stem cells are now at the center of world attention, since it has become evident that they possess the potential to change the face of medical research and human health. In our own research we have studied human embryonic stem cells for many years, and we have made seminal discoveries in the field. We were pioneers in the demonstration of both spontaneous and directed differentiation of human embryonic stem cells in culture into a dozen different cell types. In addition, we were the first to demonstrate genetic manipulation of the cells, to analyze their immunogenicity, and to suggest ways to overcome their tumorigenicity. In addition to our research on the potential of human embryonic stem cells for transplantation, we have been pioneers in establishing models for human diseases using human embryonic stem cells. Derivation of human embryonic stem cell lines which harbor specific genetic defects has great value for modeling human inherited disorders and for finding new drugs for many of these diseases, especially in cases where no good animal model exists. We have already created models for two genetic disorders. By creating a specific mutation in human embryonic stem cells, we have generated a model for Lesch-Nyhan syndrome, a fatal kidney disease resulting from accumulation of uric acid. The mouse model failed to recapitulate the symptoms of this devastating disorder, but our human embryonic stem cells did accumulate uric acid. Moreover, we showed that a specific drug can reduce the levels of uric acid produced by the cells. In addition, we have created a model for the most common cause of hereditary mental retardation, namely fragile X syndrome. The molecular basis of this disease could not be demonstrated in animal models. We have isolated a cell line carrying the fragile X syndrome after pre-implantation genetic diagnosis for this disease, and characterized its molecular basis. We aim to continue creating such models for various genetic disorders, and will now concentrate on chromosomal aberrations, the number one cause of spontaneous miscarriages. Our research will yield a repository of many different cell types for our own research and for the research of other investigators in California and the rest of the world. This proposed research will enable us to define the earliest stages that lead to embryonic death during the first trimester of pregnancy.
Statement of Benefit to California:
California in now in a special position to lead research on stem cells for years to come. Research with human embryonic stem cells has the capacity to change the face of medical research. Our own study will focus on the number one cause of spontaneous abortions, namely an abnormal number of chromosomes in the embryo. If the embryo survives an abnormal number of chromosomes it will develop abnormalities of the body and brain, dependent on the specific chromosomal excess or deficiency . The most known such disorders are Down Syndrome which results from an extra chromosome, and Turner Syndrome which results from a lack of a chromosome. Our research will be beneficial to the state of California and its citizens in various ways. First, in our study we will create a repository of human embryonic stem cells that are missing a chromosome or that have an extra chromosome. Such a repository will be extremely important for our research, but also will serve other investigators in California. We have vast experience in research with human embryonic stem cells and their derivation, so we expect to have a substantial repository in the near future. Second, our research is aimed at the very important clinical issue of spontaneous abortions. Most early abortions occur during the first trimester, and most of them result from chromosomal aberrations. The reasons for the developmental arrest are not fully understood, but now we have a unique opportunity to study developmental arrest using materials that were not previously available. In this regard, this research proposal is aimed at the study and potential methods of prevention of spontaneous abortions. The third level of benefit is basic understanding of human embryogenesis. Our research will touch the most crucial aspects of early human development and the molecular events that are involved in this process. Thus, our research will serve as a unique source of materials and knowledge for stem cell research in California.