When reviewers label a grant as a 'fishing expedition', it typically spells doom for a promising project; but a new school of researchers is turning the tables on this phrase and reimagining what it means to search for promising disease treatments.
Dr. Leonard Zon at Boston Children's Hospital is one such researcher, and a walk through his vivarium reveals not cages with mice and rats, but rows and rows of tanks filled with the small cyprinid Danio rerio, commonly known as zebrafish. His lab is interested in hematopoiesis, or the development of blood cells, and how these cells become cancerous in disease states like leukemia and lymphoma. His group has turned to zebrafish as a model organism, taking advantage of several technical benefits this species has to offer.
Their small size, rapid development times, and amenability to genetic manipulation make them an attractive model for large-scale in vivo studies. Likewise, zebrafish embryos, which grow outside their mother in the water, are transparent, allowing the research group to use advanced microscopy to image red blood cell development and differentiation in the intact organism.
Like all model organisms, zebrafish do have their limitations. The Zon laboratory also studies melanoma—a disease that typically befalls adults—and his group screens small-molecules for their potential anti-tumor activity. Applying these agents to adult zebrafish is difficult; dissolving them in water or mixing them in fish food does not provide a practical and rigorous approach to dosing. To overcome the hurdles of drug testing in adult zebrafish, the Zon lab developed a unique anesthesia regime and an oral-gavage technique for repeated dosing and longitudinal studies on melanoma progression (Dis. Model Mech. 9, 811–820; 2016).
As a proof of principle, the group tested multi-day dosing of Vemurafenib, an FDA-approved BRAFV600E inhibitor, in adult zebrafish with BRAFV600E melanoma tumors. The fish tolerated multiple bouts of anesthesia and gavage well, and tumors declined significantly in treated groups. Based on these results, the technique is an effective drug delivery system; just as important, the method can be adopted by most labs, potentially increasing the popularity and use of adult zebrafish for drug screening and toxicity studies. Basic technical developments like these, when combined with the inherent advantages of zebrafish, ensure that research with this model will continue to go swimmingly.
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Graham, D. An oral-gavage dosing method for zebrafish. Lab Anim 45, 315 (2016). https://doi.org/10.1038/laban.1094