Research
Harnessing the remarkable power of human pluripotent stem cells
Human pluripotent stem cells have the remarkable abilities to expand indefinitely and develop into every cell type in the body. The mission of our research group is to advance human stem cell research efficiently by the application of powerful new cutting edge technologies. Collaboration is key to our success; the scientists in our group work together to develop and master complex techniques and they freely share their results and ideas. We also have a large international group of trusted collaborators who strengthen our science by contributing their unique knowledge.
At the center of all of our research efforts is our unique database, called the Stem Cell Matrix. The Matrix is the repository for comprehensive datasets of molecular information on human stem cells and tissues. It currently contains more than 10,000 samples, and we are integrating genomic and epigenomic data from each sample. Our data include gene expression analysis, microRNA expression, SNP (single nucleotide polymorphism) genotyping, DNA methylation profiling, and genome and methylome sequencing, as well as phenotypic information about the cells and tissues. The data in the Stem Cell Matrix have taught us what makes a stem cell a stem cell, and the Matrix is the launching point for studies of genomic stability, epigenomic aberrations, differentiation, and the molecular basis of human disease. At the heart of the Matrix is its role in improving quality control of human stem cells that are to be used for clinical applications.
Stem cell projects:
Human disease: We have basic and translational projects studying several human diseases, using technologies that range from making disease-specific induced pluripotent stem cells (iPSCs) from patient skin biopsies to experimental transplantation strategies. Our most advanced translational project is development of a stem cell therapy for Parkinson's disease. We are also researching stem cell-based therapies for multiple sclerosis and autism.
Genomics: When we look closely at the genomes of pluripotent cells, we see that they acquire changes in their DNA sequence during expansion and differentiation. This is because some changes give cells a growth advantage, and it has raised concerns about the safety of cells used for transplantation. However, it is important to note that changes like these also occur in FDA-approved "adult" stem cells, so it is not a problem specific to pluripotent cells. We are identifying which genetic changes are benign and which should be avoided in cell therapy applications.
Epigenetics: Pluripotent stem cells are a great system to study control of gene expression. For example, we have completely sequenced the "methylomes" of undifferentiated and differentiated cells, to determine exactly what parts of genes are methylated and demethylated as the cells change. We have developed a new method to look for dynamic changes in DNA methylation and are investigating the role of epigenetics in developmental disorders like autism.
Single cell sequencing: Currently methods for genomic analysis require large populations of cells. We capturing single cells (like cancer stem cells in the blood or cells within a differentiated population in a dish) in order to better characterize and understand them.
MicroRNAs: MicroRNAs regulate the translation of mRNA transcripts. We are investigating the roles of microRNAs other non-coding RNAs in pluripotency, differentiation, and human disease.
Gene editing: Gene editing methods hold the key for correcting (or inducing) disease-causing mutations in pluripotent cells to understand how genetic mutations cause disease.
Improved drug development: One of the most important short-term applications for human iPSCs is in pharmaceutical drug development. Many drugs are toxic or ineffective in some people and not in others. We are building a large bank of ethnically diverse iPSCs to screen for toxicity of drugs that is caused by genetic/ethnic background. These will allow prescreening of drugs to determine what groups of people who would be least likely to have adverse side effects.
Endangered species: Pluripotent stem cells are not just useful for humans. In a collaboration with the San Diego Zoo, we have made induced pluripotent stem cells (iPSCs) from animal species that are on the verge of extinction. We are focusing on the Northern White Rhino; there are only 5 individuals still alive, and they will be extinct within our life times if we don't take extraordinary measures. We plan to try to make iPSCs into sperm and eggs so that we can revive the species. We call this "Jurassic Park without the scary parts."
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