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Stem Cell Science & Ethics. Opponents of embryonic stem-cell research have objected to two basic scientific techniques: harvesting stem cells from 5-day-old human embryos donated by fertilization clinics and creating human embryos using either somatic cell nuclear transfer (SCNT), replacing the DNA in an egg with DNA from another organism, or in vitro fertilization. In all cases, the embryo is ultimately destroyed.
Opponents have maintained that scientists should abandon research that destroys embryos and redouble their efforts in other medical research fields, such as non-controversial adult stem-cell studies. Adult stem cell research involves stem cells found in only certain human tissues — blood, umbilical cord blood, and bone marrow — that have the capacity to regenerate only the tissues from which they originated.
Scientists argued that adult stem-cell research was no substitute for embryonic studies, because the undifferentiated cells in embryos had the unique capacity to develop into pluripotent cells that can make up any organ tissue in the body. In recent research, scientists created what they say appear to be pluripotent cells by coaxing or “reprogramming” adult skin cells to revert to an embryonic stem-cell-like state referred to as induced pluripotent cells. The new skin-cell technique produces stem cells with the same DNA as the donor, and some scientists believe it renders SCNT moot.
In 1998, a team lead by James Thompson at the University of Wisconsin (UW) was the first to successfully harvest pluripotent stem cells from embryos donated by fertilization clinics. Since then, scientists have developed some 400 embryonic stem-cell lines using private and public research funds. Thompson’s lab houses the majority of federally-approved stem-cell lines and his skin-cell research — considered non-controversial from the outset. The lab was funded in part by the US National Institutes of Health (NIH).
In addition to avoiding the ethical controversy over creating and destroying embryos, scientists point out that further refinements to the the new technique may avoid the cumbersome process of acquiring donated eggs and embryos.
Jerusalem, Israel. While it has long been known that embryonic stem cells have the ability to develop into any kind of tissue-specific cells, the exact mechanism as to how this occurs has heretofore not been demonstrated. Now, researchers at the Hebrew University of Jerusalem and elsewhere have succeeded in graphically revealing this process, resolving a long-standing question as to whether the stem cells achieve their development through selective activation or selective repression of genes.
Global Transcription in Pluripotent Embryonic Stem Cells. Sol Efroni, Radharani Duttagupta, Jill Cheng, Hesam Dehghani, Daniel J. Hoeppner, Chandravanu Dash, David P. Bazett-Jones, Stuart Le Grice, Ronald D.G. McKay, Kenneth H. Buetow, Thomas R. Gingeras, Tom Misteli, and Eran Meshorer. Cell Stem Cell 2008 2: 437-447.
This permissive expression includes lineage-specific and tissue-specific genes, non-coding regions of the genome that are normally "silent," and repetitive sequences in the genome, which comprise the majority of the mammalian genome but are also normally not expressed. The research findings appear in the latest issue of the journal Cell Stem Cell.
An embryonic stem cell labeled with a DNA-binding dye (blue, left) and a red probe which signals expression of normally silenced repetitive elements (red, right).
When embryonic stem (ES) cells differentiate into specific cell tissue-types, they undergo global genetic silencing. But until this occurs, the ES cells maintain an open and active genome. This might very well be the secret of their success, since by maintaining this flexibility they maintain their capacity to become any cell type. Once silencing, or genetic repression, occurs, this ability is gone.
Thus, one can say that the ES cells stand at the ready until the "last minute" -- prepared to engage in selective activation into specific cells — holding "in abeyance" their ability to become any kind of cells at the point and time required. To reveal the process as to how this occurs, the researchers created the first full-mouse genomic platform of DNA microarrays.
The microarray is a tool consisting of a small membrane or glass slide allow simultaneous detection of thousands of genes.
Microarrays contain a very large number of genes in a small space. This makes them useful when studying a small sample or conducting a quick survey of a large number of genes. Microarrays for DNA are small, solid supports — the sequences from thousands of different genes are immobilized, or attached, at fixed locations.
The microarrays used in the study were not confined to specific genes only but spanned the entire genome.
Hundreds of such microarrays were required in the study to cover the entire genome in different time points during stem cell differentiation. It was by observation of these sequences that the researchers were able to establish exactly how and at what point the stem cells developed into specific tissue cells and when the silencing occurs.
Global Transcription in Pluripotent Embryonic Stem Cells. Sol Efroni, Radharani Duttagupta, Jill Cheng, Hesam Dehghani, Daniel J. Hoeppner, Chandravanu Dash, David P. Bazett-Jones, Stuart Le Grice, Ronald D.G. McKay, Kenneth H. Buetow, Thomas R. Gingeras, Tom Misteli, and Eran Meshorer. Cell Stem Cell 2008 2: 437-447.
Summary. The molecular mechanisms underlying pluripotency and lineage specification from embryonic stem cells (ESCs) are largely unclear. Differentiation pathways may be determined by the targeted activation of lineage-specific genes or by selective silencing of genome regions. Here we show that the ESC genome is transcriptionally globally hyperactive and undergoes large-scale silencing as cells differentiate. Normally silent repeat regions are active in ESCs, and tissue-specific genes are sporadically expressed at low levels. Whole-genome tiling arrays demonstrate widespread transcription in coding and noncoding regions in ESCs, whereas the transcriptional landscape becomes more discrete as differentiation proceeds. The transcriptional hyperactivity in ESCs is accompanied by disproportionate expression of chromatin-remodeling genes and the general transcription machinery. We propose that global transcription is a hallmark of pluripotent ESCs, contributing to their plasticity, and that lineage specification is driven by reduction of the transcribed portion of the genome.
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