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November 8, 2019

Disease Week: Zebrafish Model Organism

Zebrafish first emerged over three decades ago as a promising animal model to better understand embryonic development in vertebrates. Recently, it has gained a foothold as a model to study human diseases and for drug discovery. Despite the vast amount of evolutionary time separating fish from humans, we share important similarities including most of our major organ systems as well as 70% of our genes. As such, many diseases can be modeled and studied in zebrafish. Unlike mammals, adult zebrafish have a nearly unparalleled regenerative capacity to replace and repair injured tissues including heart, spinal cord, and brain. Understanding how zebrafish can recover from conditions that would irreparably harm us could open the door to improved treatments.

The use of zebrafish as a model organism was pioneered to overcome some of the difficulties that plague other vertebrate model organisms such as in utero development, low offspring number, lack of genetic tractability, and high maintenance costs. Zebrafish entered the field at a time when many molecular biology techniques including mutagenesis and cloning of genes had already been developed in other model organisms. As such, these molecular techniques and other advances were quickly adapted and developed in zebrafish. Today many transgenic lines exist that enable one to look at a specific organ or a subset cell population. Many mutants with define phenotypes have also been created and characterized, allowing one to better understand the molecular mechanism underlying the genetic anomaly. The advent of CRISPR technology allows genome editing with the precision that one could only have imagined to be possible just less than 10 years ago. Finally, the advent of ever more sophisticated imaging techniques have made the zebrafish, which are transparent as larvae, a more popular research subject.

When I entered graduate school in 2008, behavioral studies and small molecule screening in zebrafish were at very early stages. Today, however, mechanisms underlying behavioral aspects of many complex neurological diseases have been elucidated using this model organism and many therapeutic compounds have already been identified from studies in zebrafish. With increasing demands to reduce our reliance on research animals, a vertebrate like the zebrafish can potentially bridge the gap between cell culture models (which lack the complexity required to study many diseases) and more traditional animal models like mice and rabbits. Furthermore, zebrafish is the only vertebrate model organism that has the potential for high-throughput screening for toxic and therapeutic compounds. Combining this with precise genome editing, it is not so hard to imagine that zebrafish could play a large role in personalized and precision medicine.    

The use of zebrafish in research offers promise to better understand and treat renal diseases. While much pioneering work has been done in order to study the kidney in zebrafish (some of which were discussed earlier in the week), there is still much to do and refine. Zebrafish allow us to study the kidney in different contexts: the embryonic zebrafish kidney (pronephros) allows one to study a simpler structure; the adult zebrafish kidney (metanephros) allows one to study more complex phenotypes. I am beyond excited to be a part of a group that will work toward developing zebrafish models that will aid in identifying novel diagnostics and therapies for kidney diseases.