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On Again, Off Again
A gene comes with a handy switch

Context: Good health requires more than the right genes; those genes must also be able to switch on and off at the right time. In research involving animals or cell cultures, fi guring out a gene’s function is much easier when scientists can turn it on at will. Led by Richard Mulligan, a group of researchers at Harvard Medical School and Children’s Hospital in Boston have crafted genes that come with an easily controlled on/off switch – a powerful research tool that has the potential to off er a new kind of gene therapy.

Methods and Results: The switch consists of a ribozyme, an enzyme made up of RNA. Laising Yen, a postdoc in Mulligan’s lab, and colleagues inserted a ribozyme sequence into a gene that coded for an easily detectable protein. Cells with the altered gene made long stretches of messenger RNA; part of the RNA made the ribozyme, while the rest carried instructions for making the protein. The researchers tinkered with diff erent ribozymes, eventually creating ones that were able to chop up the RNA before the protein it coded for could be made. In the cell cultures and living mice containing the ribozyme sequence, protein production dropped to nearly undetectable levels. What’s more, the researchers were able to deactivate the ribozyme using certain drugs – essentially turning on the inserted gene by turning off the off switch. Such treatments succeeded in restoring gene expression by up to 50 percent.

Why it matters: The researchers imagine creating genetic therapies in which the onset of a physiological condition would activate the genes necessary to manage it. Genetically engineered cells might be able to secrete insulin in accordance with glucose levels, freeing diabetics from constant blood monitoring and insulin injection. For the moment, however, such dreams are far from reality. Closer at hand and still very exciting are discovery techniques that would allow researchers to monitor the effects produced by several genes in a single animal, or to analyze how a gene adjusts to an organism’s aging or to different stages of a disease.

Source: Yen, L. et al. (2004) Exogenous control of mammalian gene expression through modulation of RNA self-cleavage. Nature 431:471-6.

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Tagged: Biomedicine

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