The recent discovery of a method to turn non-stem cells into stem cells represents a major leap forward for stem cell based regenerative medicine. These new stem cells, termed induced pluripotent stem (iPS) cells, open doors to new, patient specific stem cell therapies in the future. In theory skin cells from any patient—for example those with Alzheimer’s or Parkinson’s diseases as well as cardiac, liver or spinal cord injury—could be isolated and turned into iPS cells, then given back to the patient as a therapy. However, two major hurdles stand in our way for the use of these cells: safety and efficiency of generation. At this time, these exciting new stem cells cannot be used due to risk of the transplanted iPS cells giving the patient cancer and current methods are very inefficient as well, likely to most often fail in patients. Our goal is to solve these problems with innovative new approaches to making human iPS cells.
In order to develop these methods we must identify new genes that can give the process a boost and also find substitutes for some of the currently used genes, particularly Myc, which is one of the most common genes mutated in human cancer. This one gene paradoxically is also required for strong efficiency of iPS generation. Here we propose to discover new pluripotency and self-renewal modifiers via unbiased, global screening methods. We will also tackle the complex role of Myc in iPS formation, with the objective of finding ways to replace Myc or finding a lower level of Myc that eliminates the cancer causing ability of iPS cells, while retaining or replacing its positive role in the process.
If the aims of this proposal are achieved, we will have made several key contributions. We will have generated new iPS cells lines available to the stem cell field for further study with distinct and improved properties compared to existing iPS cells. We will have identified novel inducers as well as suppressors of iPS formation using unbiased global screens. The use and manipulation of these new regulators may play key roles in improved iPS protocols, paving the way for the production of yet additional new and further improved iPS lines. The goal of discovering iPS suppressors is a very innovative but logical approach. This novel strategy may pave the way to safer, non-genetic ways of efficiently inducing pluripotency using pharmacological inhibitors of these iPS cell suppressors such as drugs or growth factors. Finally, we will have also determined how to best deal with Myc’s role in iPS formation, a key step toward safe and efficient iPS methodology.
Our overall goal is to produce the next generation of iPS cells that are efficient to make and safe to use. Longer term our goal is to work with our neural (Alzheimer’s disease, Parkinson’s disease, and spinal cord injury), cardiac, and liver disease teams to generate safe and effective iPS cells tailored for each patient.
Statement of Benefit to California:
The proposed studies will provide new induced pluripotent stem (iPS) cell lines and methods for generation of iPS cell lines. Such cells hold great promise for treating patients here in California, benefiting the state both in terms of improving the lives of patients as well as enhancing the knowledge of the stem cell field. It will also further the development of regenerative medicine leading to a new, valuable biotechnology. California should be a leader in developing safe, effective regenerative medicine.