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Gene knockout and transgenic technologies in risk assessment: the next generation
1Department of Genomics, Glaxo Wellcome Research, Inc., Research Triangle Park, North Carolina.
Abstract:
Transgenic and knockout mice have been proposed as substitutes for one of the standard 2-yr rodent assays. The advantages of using genetically engineered mouse models is that fewer mice are needed, the time to develop disease is greatly reduced, and the mice are predisposed to developing cancer by virtue of gain or loss of functions. The models currently being used have yielded a large amount of data and have proved to be informative for risk assessment; however, they are still far from ideal. In fact, they inherently do not reflect the complexity of mutation and carcinogenesis in humans. Recent advances in technology and the creation of new knockout mice may produce more useful and more sensitive models. This review covers two recent advances in technology--inducible and regulatable gene expression and targeted genetic modifications in the genome--that will allow us to make better models. I also discuss new gene deletion and transgenic mouse models and their potential impact on risk-assessment assays. These models are presented in the context of four basic components or events that occur in the multistep process leading to cancer: maintenance of gene expression patterns, genome stability and DNA repair, cell-cell communication and signaling, and cell-cycle regulation. Finally, surrogate markers and utility in risk assessment are also discussed. This review is meant to stimulate further discussion in the field and to generate excitement about working toward the next generation of risk-assessment models.
Insights
Genetically engineered mouse models offer faster, more sensitive cancer risk assessment than traditional rodent assays. Advances in inducible gene expression and targeted genetic modifications promise even more accurate human cancer modeling.
Area of Science:
- Toxicology
- Genetics
- Cancer Research
Background:
- Genetically engineered mouse models (GEMMs) are proposed alternatives to standard 2-year rodent carcinogenicity assays.
- GEMMs offer advantages like reduced mouse numbers, accelerated disease development, and predisposition to cancer via genetic alterations.
Purpose of the Study:
- To review recent technological advances in creating more sensitive and accurate mouse models for cancer risk assessment.
- To discuss the potential impact of new GEMMs on risk-assessment assays.
Main Methods:
- Review of recent advances in inducible and regulatable gene expression.
- Discussion of targeted genetic modifications, including gene deletion and transgenic models.
- Presentation of models in the context of key cancer-related events: gene expression, genome stability, cell signaling, and cell-cycle regulation.
Main Results:
- Current GEMMs, while informative, do not fully capture human cancer complexity.
- Inducible/regulatable gene expression and targeted genetic modifications enable the creation of improved mouse models.
- New GEMMs are being developed to better reflect the multistep process of carcinogenesis.
Conclusions:
- Technological advancements are crucial for developing the next generation of risk-assessment models.
- Improved GEMMs have the potential to enhance the sensitivity and utility of cancer risk assessment assays.
- Further discussion and development are needed to optimize these advanced models for regulatory use.