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Programmable cells open window of opportunity for gene therapy

Krawetz.jpg (18054 bytes) Dr. Krawetz has discovered the mechanism responsible for re-programming cells, which could make gene therapy a more immediate reality.

"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 Stephen Krawetz, PhD, who reported his findings in the December 1998 issue of Development.

In the fast-paced world of genetics research, Dr. Krawetz, associate professor in obstetrics and gynecology and the Center for Molecular Medicine and Genetics, 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 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 as "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.

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.

"What is most exciting in terms of differentiation is that cells can change their destiny," said Dr. Krawetz.

 

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