Jan. 29, 1999 DETROIT -- "Any cell can be reprogrammed, and this process is reversible. You do not need to start with the stem cell." These remarks and the research behind them, which could have a profound impact on gene therapy, come from Wayne State University researcher Stephen Krawetz, Ph.D., who reported his findings in the December issue of Development.
In the fast-paced world of genetics research, Dr. Krawetz, associate professor of obstetrics and gynecology and the Center for Molecular Medicine and Genetics at the WSU School of Medicine, has begun to unravel the mechanism that is responsible for the direction each cell takes in its development from the generic cells of the embryo to the specific cells of each tissue.
His findings also provide an insight into the previously unknown mechanism behind the creation of Dolly, the first animal cloned from adult cells. "They knew the cells were reprogrammed, but they had no idea of the mechanism," Dr. Krawetz said. He has identified the mechanism and has learned how it works. The ramifications for gene therapy are tremendous, he remarked. "It is our expectation that by using this new technology, we may be able to selectively open and express genes, or close and silence genes in populations of differentiating and/or replicating cells. Harnessing this potential to specifically change cell type will resolve some of the problems faced in bringing gene therapy from the bench to the bedside."
To discover the mechanism responsible for cell reprogramming, he studied the spermatogenesis pathway, which creates sperm cells, and the point at which the genes in the cell are available for expression. He described this process is "naturally expressive," because it readies a select subset of genes from the genome for expression. The fate of the cell, then, is determined by the repertoire of these readied, or "potentiated" genes.
Dr. Krawetz's main task was to determine how this mechanism "potentiation" arises. He began to look at several genes that he could show were exclusively activated at specific and different times. These genes included those from the protamine locus, which are only expressed in males and the phosphoglycerate kinases PGK1 and PGK2.
Upon further examination, he found that the switch between the genes was controlled by the state of their chromatin domains on each chromosome. Dr. Krawetz found that the domains could take on two conformations: one that closed off all but a few genes for expression, and another that opened up the genes, making them available for expression.
"There are multiple times that potentiation can occur during development, therefore there are multiple points of entry," he said. In other words, a cell's destiny is fine-tuned with each successive opening and closing of the gene-containing chromatin domains. In his resulting research paper, Dr. Krawetz concluded, "These results are key to understanding how differentiative pathways are controlled and cellular phenotypes determined."
By understanding the mechanism behind "natural" potentiation, Dr. Krawetz theorized, scientists might then be able to access any cell's genetic makeup and turn off or turn on specific genes. Shutting down tumor genes, or creating additional bone cells or brain cells would not be unthinkable, he noted. In summarizing the work on a more informal level, he remarked, "What is most exciting in terms of differentiation is that cells can change their destiny."
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