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Stopping Mad Cow Disease with RNA Interference

Researchers at Cold Spring Harbor Laboratory and Texas A & M have demonstrated that they can eliminate the production of infectious prion proteins in livestock by using RNA interference (RNAi). The technique could enable scientists to genetically engineer livestock that are resistant to prion-caused diseases such as mad cow disease (bovine spongiform encephalopathy or BSE). A similar strategy might be used to protect animals against influenza, foot-and-mouth, and other diseases.

“ Although careful monitoring of animal health and appropriate safety precautions are a current approach to containing such diseases, there is theoretical potential for creating genetically engineered strains of animals with a natural resistance to numerous diseases. However, genetic methods for altering livestock have thus far been lacking,” write the authors in an article published on March 20, 2006 in the Proceedings of the National Academy of Sciences (advance on-line edition).

Abnormal, pathogenic prion proteins can misfold themselves into forms that can induce misfolding of normal prion proteins. In mammalian prion infections, these misfolded, insoluble proteins trigger protein clumping that can kill brain cells. In humans, prion clumping causes fatal brain-destroying diseases such as Creutzfeldt-Jakob disease and kuru, and in animals it causes BSE and scrapie.

The new study extends the use of RNAi beyond mice to larger animals for the first time. The researchers say that the success of the technique suggests that manipulating genes with RNAi in plants and livestock may be an important alternative to traditional breeding or genetic engineering techniques to enhance production of meat, dairy, or fiber products. Current techniques can be costly, inefficient, and time-consuming.

“ This is very much a research effort, however, given the ability to manipulate these organisms in this way, I think it will be possible to do more quickly what selective breeders have been doing for a long time -- creating animals with disease resistance and more advantageous properties for agriculture,” said Howard Hughes Medical Institute investigator and Cold Spring Harbor Laboratory professor Greg Hannon, one of the senior authors of the study.

Hannon and first author Michael C. Golding, who are at Cold Spring Harbor Laboratory (CSHL), collaborated on the studies with senior author Mark E. Westhusin of Texas A & M.

RNA interference shuts down targeted genes by interfering with the messenger RNA they produce. Due to recent advances in RNAi from Hannon’s lab, the researchers suspected it might be possible to apply the approach to agricultural challenges.

Several factors have, until now, limited the use of RNAi to smaller animals. But in the new collaborative study, the researchers were able to use techniques developed in Hannon’s laboratory to design genes that would produce interfering RNAs that could then be introduced into goat cells. The researchers conducted their experiments with goats because they are susceptible to the prion disease scrapie, which requires less stringent precautions than for those for studying BSE in cattle.

“ In many ways, this is a simple proof of principle,” said Hannon. “Our objective was to ask whether we could generate a large animal through a cloning procedure in which our RNAi technology could be used to knock down gene expression. This is very much a basic experiment, and cows have been cloned before, but it seems that the leap from what we've done to practical application could be rather short,” he said.

Hannon said that his laboratory, however, will continue to concentrate on the basic development and use of RNAi techniques in mice to understand cancer biology. For example, he and his colleagues are continuing to explore findings they published last year in which they reported that a specific cluster of microRNAs can spur tumor progression in mice, and probably humans.

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