The emergence of The Zebrafish (Danio rerio) Model for biomedical research began in the 1960s at the University of Oregon in Eugene, largely due to the pioneering work of George Streisinger and coworkers. They systematically determined the conditions necessary to adopt this new model (originally from small rivers in India) for the laboratory environment. The foundational techniques were also established for genetic manipulations and imaging that were critical to expand the imaginations of the next generation of scientists. For the next ~30 years, the vast majority of global zebrafish research efforts focused on understanding the processes of normal vertebrate embryonic development. The use of forward genetics [starting with a phenotype (trait), then proceed to identify the gene(s) that is/are responsible], and reverse genetics (first select a gene, disrupt that gene, and then observe the phenotype) –– coupled with careful in situ hybridization methodologies –– dominated the field. As authors of the two brief reviews [attached] describe, soon it soon became possible to elucidate vertebrate gene functions in the transparent early-life stage zebrafish at unprecedented economy and speed (in large part. due to zebrafish’s short generation-time).
A group (including Jonathan Knight and Monte Westerfield) was appointed at the 1994 Cold Spring Harbor “meeting on zebrafish genetics and development” to establish ZFIN, an online database of information (genetics, cellular, anatomical, physiological, and ultimately genomics similarities with mammals) –– that continues vibrantly today –– for zebrafish researchers. Intriguingly, it was discovered that much of this information could be extrapolated quite readily from the zebrafish genome to the human genome, and, hence, its value in discovering the cause of, and to develop treatments for, human diseases. The continued and accelerated acceptance of zebrafish has truly been amazing.
Toxicology, by definition, is a deeply applied science that is tightly constrained by the need to focus research efforts on disease prevention. Practical questions –– such as whether a specific chemical is safe, or a given disease is caused or influenced by a specific chemical exposure –– are at the core of the discipline. These questions are often difficult to answer with certainty, presenting a dilemma for individuals tasked with making policy decisions about Risk Assessment and chemical safety. By the mid-1990s, molecular toxicology and environmental genetics began moving the toxicologist away from predominantly describing dose-dependent endpoint relationships, to, instead, discovering chemical (and drug) targets and molecular pathways associated with the development of specific endpoints.
Today, the developmental characteristics of zebrafish are strategically being used by scientists to study topics –– ranging from high-throughput toxicity screens to toxicity in multi- and trans-generational studies. High-throughput technology today has obviously increased the utility of zebrafish embryonic-toxicity assays in screening of chemicals and drugs for toxicity, or downstream effects. In addition, advances in behavioral characterization and experimental methodology allow for observation of recognizable phenotypic changes after exposure to foreign chemicals including drugs. Future directions in zebrafish research are predicted to take advantage of CRISPR/Cas9 genome-editing methods –– in order to quickly create models of disease and interrogate modes of action and mechanisms of action with fluorescent reporters or tagged proteins. Zebrafish has many advantages as a toxicologic model. New methodologies and areas of study continue to expand the usefulness and application of the zebrafish.
Toxicol Sci May 2o18; 163: pp 3–4 and pp 5–12