GM Organisms

Impact of genetic manipulation on the fitness of Anopheles stephensi mosquitoes. Catteruccia, F. et al. Science 299, 1225–1227 (2003)

It has been argued that malaria could be controlled by introducing into natural populations transgenic mosquitoes that express genes which impair parasite transmission. For this strategy to be successful, the transgenic mosquitoes must be able to survive and reproduce competitively in the wild. However, this study shows that transgene expression, mutations introduced by transgene insertion, and inbreeding can result in a lower fitness of transgenic mosquitoes relative to wild type.

Mouse Models

Modification of ocular defects in mouse developmental glaucoma models by tyrosinase. Libby, R. T. et al. Science 299, 1578–1581 (2003)

Human primary congenital glaucoma (PCG) is often caused by mutations in the cytochrome P450 family member CYP1B1 and is associated with abnormal ocular drainage structures. This paper shows that Cyp1b1-deficient mice provide a good model for this type of glaucoma. Libby et al. used these knockout mice to show that tyrosinase gene deficiency increases the severity of the disease phenotype, and that this is alleviated by applying dihydoxyphenylalanine (L-dopa). This raises the possibility of new glaucoma therapies.

Technology

RNA interference targeting Fas protects mice from fulminant hepatitis. Song, E. et al. Nature Med. 19, 347–351 (2003)

RNAi can target and silence mammalian genes but can it prevent disease? Song et al. show that, in mice, RNAi can silence the gene Fas that codes for an important mediator of hepatocyte apoptosis. This indicates that RNAi could be used to prevent the adverse effects of hepatitis that are linked to cell death. The authors test this hypothesis in two models of Fas-mediated liver damage and show for the first time that siRNA can prevent disease in vivo.

Functional Genomics

Scanning the human genome with combinatorial transcription factor libraries. Blancafort, P. et al. Nature Biotech. 21, 269–274 (2003)

Blancafort et al. report a new technology that could be useful for studying and modulating gene function. They have constructed large libraries of artificial transcription factors that contain between three and six zinc-finger domains (TFZFs) that can either activate or repress gene expression. TFZFs can be applied to a cell line that is then screened for a desired phenotype. In this example, TFZFs were identified that were able to induce expression of the endothelial marker VE-cadherin in non-endothelial cell lines and to repress its expression when combined with a repression domain.