Disease on demand
Diphtheria toxin is so poisonous to humans that a single molecule may be enough to kill a cell. However, biotechnology researchers have harnessed that toxicity to develop a model of hepatitis, a fatal disease of the liver that affects millions of people worldwide: They have shown that a transgenic mouse containing the human receptor for diphtheria in its liver can easily be induced by the toxin to replicate the symptoms of hepatitis-an approach that will aid efforts to understand and treat liver disease (Nature Biotechnology, Vol. 19, No. 8, 01 Aug 2001).
Scientists often try to selectively kill specific types of cells in mice in order to see whether the resulting effects mimic certain diseases, but current methods for doing this have serious limitations: Removing cells using surgery or lasers, for instance, cannot target cells at the molecular level, and chemicals that home to specific cell types are rare. And while some researchers have attempted to use genetic engineering to induce specific tissues to express protein toxins, cell death occurs early in the life of the animal and cannot be controlled experimentally, with these methods. The new strategy, however, developed by Kenji Kohno and colleagues in Japan, allows researchers to destroy mouse liver cells at will by injecting the mice with diphtheria toxin.
Diphtheria toxin can enter a cell only by fitting into a specific receptor molecule on the cell's surface, like a key into a lock. Mice are naturally resistant to diphtheria toxin because their receptor is a slightly different shape than that in humans. So the researchers genetically modified mice to produce the human diphtheria toxin receptor in their livers, making their liver cells susceptible to diphtheria toxin: When these transgenic mice were injected with toxin, their liver cells were selectively killed and the mice developed liver disease, while unmodified mice were unaffected.
By redirecting expression of the diphtheria toxin receptor to different tissues, it is likely that this strategy could be used to model diseases in other organs.
Research and Education Center for Genetic Information
Nara Institute of Science and Technology
(News & Views)
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University of Washington
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(C) Nature Biotechnology press release.
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