9 - The zebrafish as a model for human disease

Publisher Summary This chapter discusses the achievements of the zebrafish in modeling human disease including cancer, hematopoietic disorders, and cardiovascular disease. The zebrafish has been a useful cancer model for several reasons. Like humans, zebrafish develop tumors spontaneously. Comparison of the zebrafish and human genomes revealed that most oncogenes and tumor suppressors are evolutionarily conserved. The zebrafish has enabled the application of forward genetics to cancer research, in part because a large number of animals with cancer can be generated. The relative transparency of the zebrafish significantly helps in identifying events involved in carcinogenesis and tumor progression. Cancer onset and progression usually require activation of oncogenes. Most zebrafish cancer models express mammalian oncogenes. Unlike mammals, zebrafish embryos develop externally and are optically transparent. This allows direct visualization of circulating blood cells and the beating heart with a simple dissecting microscope. Pioneering forward genetic studies have generated many interesting zebrafish mutants with hematopoietic phenotypes that mirror human diseases. The chapter also discusses several approaches that are available to zebrafish researchers to generate models for human disease and examines the expanding field of chemical screening in zebrafish. Screens utilizing zebrafish are guided by the desired phenotype. In these screens, thousands of embryos are arrayed in multi-well plates, and are treated with chemicals during certain developmental stages. The embryos are allowed to grow and then scored for the desired phenotype. Phenotype-based screens enable drug discovery without knowing the specific molecular targets and mechanisms. This approach overcomes the problem of complex diseases involving several targets.