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TITLE The Dangers of Mitochondrial DNA Heteroplasmy in Stem Cells Created by Therapeutic Cloning ABSTRACT In therapeutic cloning, a patients cell is combined (fused) to an enucleated donated egg (oocyte) from an unrelated woman or from another animal. It is hoped that cellular factors in the egg cytoplasm will reprogram the patients cell nucleus making it capable of generating replacement cells for the patients body. Thus, if a patient is suffering from Parkinson Disease due to loss of brain cells, these cells could be replaced with differentiated, individualized, nuclear-transplantation, embryonic stem (ntES) cells. While this strategy should generate ntES cells with the patients nuclear DNA (nDNA), it overlooks the fact that another part of the cell, the mitochondrion, also has DNA, the mitochondrial DNA (mtDNA). While the nDNA contains the blueprints for assembling the structure of the cell and body, analogous to carpenters plans for a house; the mtDNA contains the blueprints for the cellular electrical system, the wiring diagram of the house. It is universally agreed that mixing the nDNAs from two different cells would be destructive, yet the potentially disastrous effects of mixing different mtDNAs has been overlooked. In electricity, randomly mixing the components of two different integrated electrical circuits will result in short circuits. The same appears to be true for the cell. In mice in which we artificially mixed two mtDNAs, the resulting mice aged and died prematurely, had a striking increased frequency of cancer, and an increased mtDNA mutation rate. Moreover, in human studies, the accumulation of mtDNA mutations has been associated with aging and the development of cancer. Therefore, to document what happens to the mtDNAs during the creation and growth of htES and hES cells, we propose to create ntES cells
PI Douglas Wallace INSTITUTE University of California, Irvine STATE California AMOUNT $2,530,000.00 AWARD DATE 2007 March GRANT TYPE Comprehensive