The zebrafish:scalable in vivo modeling for systems biology

Abstract

The zebrafish offers a scalable vertebrate model for many areas of biologic investigation. There is substantial conservation of genetic and genomic features and, at a higher order, conservation of intermolecular networks, as well as physiologic systems and phenotypes. We highlight recent work demonstrating the extent of this homology, and efforts to develop high-throughput phenotyping strategies suited to genetic or chemical screening on a scale compatible with in vivo validation for systems biology. We discuss the implications of these approaches for functional annotation of the genome, elucidation of multicellular processes in vivo, and mechanistic exploration of hypotheses generated by a broad range of 'unbiased' 'omic technologies such as expression profiling and genome-wide association. Finally, we outline potential strategies for the application of the zebrafish to the systematic study of phenotypic architecture, disease heterogeneity and drug responses.

Next-Generation Genome-Wide Association Studies

“…This new wave of clinical investigation will exploit translational research facilities and major population studies such as the NHLBI-funded Framingham Heart Study, ideally capturing multiple phenotypic axes in parallel. Many different phenotypes might potentially be used in downstream integrative studies, but the feasibility of translation to and from model systems is likely to be a critical attribute for the empiric definition of genetic architecture and for pathway entry or exploration 29 .…”

Pluripotent stem cell-derived hepatocyte-like cells

“…Similarly, zebrafish models have been employed as a higher-throughput system to examine numerous genetic variants but given the significant developmental, structural, physiologic, and metabolic differences between species, the value of these models is less clear [29-30]. Consequently, cell culture systems have been employed, despite the observation that although no single cell type tested to date fully recapitulates hepatocyte morphology, phenotype, and function [31-33]. In contrast, iPS cells offer the potential to establish patient-specific cell types such as iHLCs, thus facilitating in vitro modeling of rare diseases, and may one day enable personalized medicine [18-19].…”

Preclinical testing of drug delivery systems to bone

“…The main route of drug delivery is through the larvae's skin [119], but microinjections are also possible [120]. Recently, zebrafish are used as an in vivo model for systems biology [121]. Testing drug delivery systems for bone regeneration is feasible as zebrafish are vertebrates with a developmental osteogenesis similar to humans [122,123].…”