Unclogging the Brain (11.01.02) - Just like traffic jams clog a city's roads, sometimes proteins in our body break down and clog up our cells. When this happens in our brain, it leads to devastating illnesses.
ENTER THE GENOME (2.10.01) - A special web project by ScienCentral News and Nature about the human genome, which has been called the greatest text in the history of the world. This is a series of articles with a plethora of multimedia content.
Knowing which gene causes Huntington's disease has so far not led to a cure or even a treatment. But as this ScienCentral News video reports, biomedical researchers have a powerful tool for stopping faulty genes from doing their damage.
Good Gene, Bad Gene
Huntington's disease is an inherited condition that can strike people as young as 30. Some symptoms include mood swings, depression, irritability, and involuntary movements which make it difficult for patients to drive and feed themselves. Concentration on intellectual tasks becomes increasingly difficult, and patients have trouble learning new things, remembering facts, or making decisions.
Humans have two copies of most genes. Huntington's disease is one of several degenerative diseases caused by an error in the DNA code of one copy of a gene. While the good copy tells brain cells how to build a needed protein, the bad copy results in a toxic protein that kills brain cells.
"In many diseases the normal gene plays a vital function, and it's important to keep that normal gene functioning," says Paulson. "If you were to eliminate that, as well as the diseased gene, that could cause problems itself. So our aim here is to keep the normal gene going with its normal vital functions, while eliminating this bad toxic gene."
To do that, Paulson and his team used a powerful new technique that interferes with messenger RNA, or mRNA for short, the middleman in the cell's process of converting the DNA code into proteins. "RNA is the intermediate step between the DNA, where the genes are, and the proteins that are produced by that DNA," says Paulson, who published the research in the June 10, 2003 issue of Proceedings of the National Academy of Sciences.
Scientists inhibit the production of the bad protein by creating a small piece of so-called "interfering" RNA, or RNAi, that matches only the bad gene. It tells the cell's natural machinery to find and destroy only the bad mRNA, so the toxic protein doesn't get produced.
"What we did in this study is to develop cell models of a couple of human neurological diseases similar to Huntington's disease and develop the RNA interference to suppress or silence expression of the disease, or the bad copy of the gene, while keeping the normal copy going. We can follow the expression of protein in these cells, and by doing that, we were able to show in a remarkably specific way we can eliminate the bad protein but keep the normal protein there."
The researchers are now trying to find the best way to deliver interfering RNAs into living brains, a difficult task since the brain has a strong mechanism for keeping 'unusual' things out. "Can we deliver [this RNAi] to the brain cells that are degenerating? For that we need something that can cross this very impenetrable blood-brain barrier and provide expression in the brain cells," says Paulson. "That's the next step in the process toward a therapy. We often don't understand at all how these diseased genes cause the brain cells to get sick and die, and this kind of technology says, 'We don't need to know. We know that it's a bad gene. Let's just eliminate expression of that gene'. I think there's a lot of excitement in the Huntington's disease community that this kind of technology might ultimately lead to a therapy."
Researchers have shown that RNAi's can silence genes in worms, flies and mice, so there is good reason to think it could also work in humans. RNAi is viewed by many genetics researchers as the most promising new tool in decades. Research is moving rapidly to test it against many other sorts of diseases.
"RNAi is a mechanism which every cell has," explains Nassim Usman, chief science officer of SIRNA, a biotechnology company. "In RNAi you can silence any gene you like. It's very robust. We have failed to find a target that we cannot knock down. We absolutely believe it could be used as a medicine."
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