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FIRST ARTIFICIAL HUMAN CHROMOSOMES
By Sean Henahan, Access Excellence CLEVELAND (4/02/97) Artificial human chromosomes have been created for the first time. This feat will help scientists better understand what natural chromosomes do and how they do it, and could prove useful in gene therapy. "This opens the door to a whole new avenue of research in chromosome biology and gene therapy," said Huntington F. Willard, Ph.D., the senior author of the study, and chairman of genetics at Case Western Reserve University School of Medicine and University Hospitals of Cleveland. "While it's been known since the early years of this century that chromosomes carry genes, until now the complexity and size of normal chromosomes has limited our ability to analyze their structure and function. The synthetic microchromosome system now allows us to perform detailed studies on the nature of chromosomes -- essentially the next phase of the Human Genome Project which is to move from just mapping genes to actually understanding how they work and influence human disease." Natural chromosomes are consist of hundreds or thousands of genes, along with specialized elements that are believed to be important for chromosomal stability and function. Telomeres, which consist of DNA and protein, are located at the ends of chromosomes, protecting them from damage. Centromeres are specialized regions of DNA that are essential for the proper control of chromosome distribution during cell division. Human centromeres are believed to consist of large segments of highly repetitive DNA, called alpha satellite DNA, which is thought to play a significant role in centromeric function. "Our successful creation of functional centromeres and incorporation of them into artificial chromosomes were the critical achievements enabling the stability and normal behavior of the chromosomes throughout the cell cycle," noted Dr. Willard. He added that past attempts at producing synthetic chromosomes have failed because they lacked proper centromeres, and thus could not persist through multiple cell divisions. The research team created artificial chromosomes from normal human material using combinatorial genetic techniques. The researchers first synthesized arrays of alpha satellite DNA, then introduced the resulting centromeric material into human cells in conjunction with telomeres and genomic DNA. Inside the cells, the independent elements assembled to form miniature chromosomes, or synthetic microchromosomes, that were structurally similar to human chromosomes, but contained less genetic material. Analysis of the newly introduced artificial chromosomes demonstrated normal centromeric activity, genetic stability, and continued gene expression through repeated rounds of the cell cycle. "Synthetic chromosomes have the potential to overcome a major stumbling block in gene therapy," said John J. Harrington, Ph.D., a postdoctoral fellow at Case Western Reserve University. "The characteristic stability of our synthetic chromosomes enables, for the first time, the potential long-term expression of therapeutic proteins in target tissues of patients treated using gene therapy." The synthetic microchromosome remains independent within the host cell and functions essentially as an accessory chromosome. In contrast, most gene therapy systems currently under development utilize viral vectors, which often require the integration of the therapeutic gene into an existing chromosome and thus can result in chromosomal damage or interference with normal gene expression. Viral vectors can also induce immune responses that limit therapeutic efficacy. In addition, unlike other vectors, which lack many of the elements that control normal gene expression due to size constraints, the synthetic chromosomes could be engineered to contain all of the machinery necessary to promote and regulate the stable production of therapeutic proteins. The next step will be to refine the system and begin building an efficient vehicle for the introduction and stable maintenance of therapeutic genes in human cells. This might ultimately provide treatments for a wide variety of genetic disorders." The research was published in the April 1997 issue of Nature Genetics. Related information on the Internet
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