Replacement of degenerated tissues by stem cells is a dream shared by victims of incurable disease, their families, and the scientists who devote their careers to advancing medical research. One of the greatest challenges for developing stem cell replacement therapies is to develop stem cell lines that won't be rejected by the patient's own immune system. The best solution for this problem would be to turn the patient's own cells- skin cells or bone marrow cells, for example- into a more useful cell type that can be used to repair other tissues such as brain, heart, or pancreas. There have been recent advances in several laboratories around the world that indicate that this will be possible. In several laboratories, skin cells have been "reprogrammed" so that they become more like the stem cells that can be turned into many different kinds of tissues. The successful strategy to convert skin cells to stem cells is based on a scientific technique called "phenocopying," in which the molecular composition (proteins, DNA, RNA) of one cell type is changed in specific ways that make it more similar to another cell type.
The application of this approach so far has been through genetically engineering the skin cells so that they make a different set of "transcription factors", which are proteins that turn on the production of many other proteins. The transcription factors selected by the researchers come from a list of such proteins that are abundant in human embryonic stem cells. This list was generated in large part by work of our laboratory and our collaborators, and we have far more information about pluripotent cells than is currently available in the scientific literature. Analysis of our database of more than 500 samples of human embryonic stem cells, adult stem cells, and non-stem cells (like skin cells) has given us insight into the inner workings of pluripotent cells. We have discovered that pluripotent cells are unique not only in their transcription factors, but also in other types of molecules that are termed "regulatory molecules" because they control the production of many other molecules. In our search for the ideal way to phenocopy pluripotent cells, we have decided that using a higher level regulatory molecule would be more powerful than using transcription factors. The molecules we decided to use are microRNAs, which are recently discovered small molecules within cells that are powerful regulators of other molecules, including transcription factors. Based on our discovery of a unique set of microRNAs that are characteristic of human ES cells, we propose to reprogram skin cells (and other non-pluripotent cells) by phenocopying the microRNA profile of pluripotent cells. Since these molecules are small, we do not necessarily need to use viruses to introduce them, and we will not require any cancer-causing genes. Thus our approach may make this method safer for patients receiving transplants.
California has a large and diverse population that poses challenges for the future of medical care. A major goal for California's supporters of stem cell research is development of stem cell-based products that have broad medical use. Stem cells have the potential to improve the health of all Californians, but they are especially important for research and development of treatments for diseases that have no cure. Neurological diseases are especially difficult to treat with classical medicines, and these diseases are increasing in prevalence.
This proposed project is designed to convert an individual's skin or bone marrow cells into stem cells. It focuses on three neurological diseases that affect a wide range of people of all ages and ethnicities, and are increasing in the California population: autism, amyotrophic lateral sclerosis (ALS), and Alzheimer's disease (AD). Autism is a severe developmental disorder that is becoming more prevalent in California, affecting 10-12 people in 10,000. There is very little known about the causes of autism, although there is evidence for genetic predisposition, and there is no effective treatment. Stem cells will help researchers understand the causes of autism, and guide development of treatments. ALS, commonly called Lou Gehrig's disease is a progressive degenerative disease of nerve cells that control muscles. For most of the cases there is no known cause, but the some cases appear to be inherited. There is no treatment available for ALS, and life expectancy after onset can be as little as 2- 5 years. Stem cells can be used to screen promising drugs, and for cell therapy to reverse the degeneration. AD is another neurological disease that is increasing exponentially. AD is the most common form of dementia, currently affecting more than half a million Californians. The number of AD cases is expected to triple by 2050, and it is no longer just a disease of the aged. There is a growing number of cases of early-onset AD (occurring before the age of 65). AD, like autism and ALS, is untreatable with conventional drugs. Stem cells can be used to test potential AD drugs, and to deliver supportive molecules to the brain. Development of treatments for these incurable diseases will increase the quality of life for all Californians.