Introduction
Wandering through your local fish shop, you might not give a second glance to the humble zebrafish. Small, silvery, and unassuming, to pale in comparison to the vibrant betta fish or the exotic knife fish. Yet, behind their simple appearance lies a biological powerhouse, one that has revolutionised biomedical research. These tiny freshwater fish hold the keys to unravelling fundamental questions about human development, disease, and evolution.
Zebrafish (Danio rerio) is now the second most widely used animal model in British research (1), with over 3,250 institutions across 100 countries relying on them for scientific studies (2). While the exact number of zebrafish used in research each year remains uncertain, estimates suggest it could exceed five million.
But how did such a small, seemingly ordinary fish become an indispensable tool in biomedical research?
Zebrafish: A Model Organism for Modern Science
Zebrafish possess several advantages, making them a preferred model for studying human biology. They share approximately 70% of our genes, they are easy to house and breed, produce large numbers of offspring, and develop rapidly. Furthermore, they have transparent embryos that allow scientists to observe early-stage development in real-time without invasive procedures, a feature particularly valuable for developmental biology and toxicology studies. These features make them an ideal system for studying protein structure and function in a living organism.
Featured Structure: THEM2 and Its Role in Cellular Function
Beyond their role in genetics and embryology, zebrafish are now a key link between protein structure and biological function. One example is their use in studying Thioesterase Superfamily Member 2 (THEM2), a protein essential for cell proliferation. THEM2, part of the hotdog-fold thioesterase superfamily, breaks down acyl-CoA molecules, which are crucial for metabolism, by hydrolysing thioester bonds. While its enzymatic activity is known, its precise role in living organisms was for some time unclear.To explore its function, researchers in the Zhou lab used zebrafish and determined the crystal structure of zebrafish THEM2 (fTHEM2) at 1.80 Å resolution (3), this allowed them to show the zebrafish’s protein’s strong similarity to the human version (hTHEM2), with a rmsd of an incredibly close 0.5 Å (4). Previous studies suggested a role for hTHEM2 in lipid metabolism, but its connection to development and disease remained unknown.
Due to the similarities between the proteins, it was possible to then use the zebrafish as a model for the human THEM2 to explore the function of this enzyme and to provide insights that would be difficult to obtain from human studies. Functional assays confirmed that zebrafish THEM2 hydrolyses palmitoyl-CoA, identifying its enzymatic activity in vitro. When morpholino oligonucleotides—synthetic molecules that block gene expression—were used to reduce fTHEM2 levels in zebrafish embryos (an experiment not feasible in humans), researchers observed delayed cell division, developmental abnormalities, and increased mortality rates, suggesting a crucial role in early development.
These findings highlight zebrafish as a powerful model organism for linking protein structure to biological function. By uncovering THEM2’s developmental role, this research provides valuable insights into its potential involvement in human health and disease.
Future Research with Zebrafish
The versatility of zebrafish extends far beyond this study. Their contributions to structural biology and drug discovery continue to grow, with several promising research directions emerging:
- AI-driven Structure Prediction � The AlphaFold DB provides high-accuracy predicted structural models of all , enabling cross-species comparisons and functional predictions.
- Live Imaging of Protein Dynamics � Their transparent embryos allow researchers to observe protein folding, trafficking, and interactions in real-time, offering unprecedented insights into cellular processes.
- Drug Screening Applications � Zebrafish facilitate rapid, in vivo testing of potential drug candidates for protein-related diseases, accelerating the path from discovery to therapeutic application.
From their natural aquatic habitat to high-tech research labs, zebrafish have proven to be indispensable allies in the quest to understand protein structure and function. Their ability to model human diseases, combined with their suitability for large-scale studies, cements their place as a cornerstone of modern biomedical science.
As we celebrate World Water Day, let’s take a moment to appreciate these small yet mighty fish, not just as creatures of rivers and aquariums, but as essential tools unlocking big answers for human health.
About the artwork
The artwork captures the interplay between protein structure, metabolism, and development, illustrating how scientific disciplines interconnect to reveal biological function. The central elements—a zebrafish embryo, a molecular structure, and metabolic pathways—merge organically, symbolizing their intrinsic link. The composition uses fluid, layered forms to reflect the complexity of biological systems, while the contrast of soft and defined edges conveys the balance between structural precision and dynamic life processes. A blend of digital painting and hand-drawn elements creates depth, echoing the layered nature of scientific discovery.
View the artwork in the .
Structures mentioned in this article
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Sources
[1]
[2] Lidster K, Readman GD, Prescott MJ, Owen SF. International survey on the use and welfare of zebrafish Danio rerio in research. J Fish Biol. 2017 May;90(5):1891-1905. doi: 10.1111/jfb.13278. Epub 2017 Feb 20. PMID: 28220489.
[3] Yu S, Li H, Gao F, Zhou Y. Crystal structure and potential physiological role of zebra fish thioesterase superfamily member 2 (fTHEM2). Biochemical and Biophysical Research Communications. 2015 Aug;463(4):912-916. DOI: 10.1016/j.bbrc.2015.06.034. PMID: 26067557.
[4] Cheng Z, Song F, Shan X, et al. Crystal structure of human thioesterase superfamily member 2. Biochemical and Biophysical Research Communications. 2006 Oct;349(1):172-177. DOI: 10.1016/j.bbrc.2006.08.025. PMID: 16934754.
