Engineering pluripotent hESC-like cells by genetic reprogramming of differentiating cells
Nearly every cell nucleus in an adult human contains the complete instructions (i.e., all the genes) to make an entire human. Thus, we each carry about 100 trillion sets of the genetic instructions that could make a genetically identical human. Cells in early embryos, and human embryonic stem cells (hESCs) are able to read all of our genes and therefore are able to produce all the cells of a human. However, during our development, cells become progressively more specialized and lose their ability to read some of these instructions. Each specialized adult cell (a “differentiated” cell) is locked down in such a way that only a subset of the genes can be read; each type of cell uses a different set of these instructions. The process is normally inexorably driven in one direction: the process is not reversed, and one type of differentiated cells does not change into another type. However, experiments in other animals demonstrate that the locks in mature cells can be completely reset in the laboratory, in particular by transferring a nucleus containing the genetic instructions into a fertilized egg. Thus, it is possible to reverse the normal process that creates the locks on the genetic instructions, allowing the instructions from a specialized adult cell to be unlocked and used to generate all other cell types in an individual.
Our goal is to develop technologies for directly changing differentiated adult human cells into cells that behave similarly to human embryonic stem cells (hESCs), without the need for transferring nuclei into human embryos. To do so, we propose to identify the genes that code for the locks that prevent genetic instructions from being read in specialized cells and to investigate methods for resetting these locks. We have devised a system that allows us to look through nearly the entire genome of a model animal for such genes. Many of the genes we have found are equivalent to genes in humans that perform the same functions. We will test whether these human genes turn hESCs into differentiated cells whose genetic instructions are locked down. With the goal of resetting the locks, we will also inactivate these genes in mature, differentiated cells and will ask whether this causes these cells to become capable of reading instructions that they normally cannot read and makes them behave similarly to hESCs.
Critical for the success of this project are hESC lines that are prohibited under current federal guidelines. This research may make it possible to create better stem cells and could lead to technologies that make it possible to create new hESC-like cells from virtually any cell in a patient without the need for harvesting human embryos or relying on the difficult task of transferring cell nuclei. Because these hESC-like cells would be genetically identical to the other cells in the patient, they would not be rejected when transplanted.
The driving long-range goal of this research is to develop new ways to create hESC-like cells. Successful application of these methods would make it possible to produce hESC-like cells from mature tissue of any patient that could be used to treat a large variety of diseases and injuries.
As this research is designed to reveal how cells in embryos are able to produce many different types of adult cells (for example, cells of the brain, spinal cord, heart, muscle, liver, pancreas, etc.) the results of this research will be immediately informative to scientists studying the biology of stem cells and other areas of human development. Thus, this research could spur further discoveries by California scientists in many areas of human health. Our findings will first be communicated to scientists at conferences within the state and will therefore have a direct immediate impact on California science.
Developing methods for creating better stem cells (capable of producing a greater variety of replacement cells), or generating new stem cells from mature tissue, will have a dramatic impact on medicine and biotechnology in this state. California would be the state in which centers that use these technologies are first established and clinical trials are first carried out. The citizenry of California would have early access to new clinical treatments for a wide variety of diseases ameliorated by stem cell therapies.
Discoveries from the proposed studies might well lead to intellectual property claims, and royalties derived from licensing of the new methods could generate substantial revenue for UC through the UCSB Office of Technology & Industry Alliances. These discoveries could spawn new ventures in the biotechnology industry that would contribute to the California economy. The successful application of this research would make California a focus for a new direction in stem cell research and therapies, which would draw scholars and clinicians, as well as investors, from outside the state.
Finally, there are potential ramifications of this research that could benefit the political climate in California. Methods for creating new hESC lines that circumvent the need for human embryos would quell the enduring political conflict between advocates of hESC research and the significant fraction of the electorate opposing such research on moral and religious premises. While hESC-based therapies promise to change the course of human medicine and health, there can be little question that legal challenges, such as those currently obstructing use of the funds earmarked by the passage of Proposition 71, will continue as long as human embryos are needed for such research. If the ultimate goal of this research is achieved, the pace of stem cell-based research and medicine would become limited not by resolution of political and legal conflicts, but instead by the availability of resources and human ingenuity.