Zebrafish: The New Lab Rat?

The zebrafish is a small freshwater fish that is often kept in home aquariums. Despite its unassuming appearance, in recent years it has played an important part in medical research due to some surprising characteristics.

Upon first glance, the zebrafish seems an odd choice for a research model, with few obvious similarities to humans. However, they share over 80% of their DNA with humans, and use many of the same proteins and cellular pathways as mammals, including humans. This making them a useful animal to model the effects of a drug or disease in humans. Zebrafish also share some developmental characteristics with humans. These similarities have been studied in depth, allowing advances in our understanding of development. Zebrafish models of specific mutations have been used to understand the pathology of congenital defects, particularly in the heart (1).

Although the similarities between zebrafish and mammals make them extremely useful, the differences also make them superior in some aspects to other animal models. One of the characteristics that makes zebrafish so useful for research is that their larvae can survive without a functioning cardiovascular system. Research into heart conditions such as dilated cardiomyopathy has been limited as the defect is often fatal in mammals. However using zebrafish models for this has allowed significant advances in our understanding of this condition (2).

The majority of animal research today is conducted on rodents, usually mice or rats. However compared to zebrafish there are several drawbacks due to their physiology and development. For example, from birth it usually takes around 6 weeks until mice can be used for testing, and few offspring survive to maturity. In contrast, zebrafish can be ready for testing after as little as five days following fertilisation of the embryo. Along with the shorter growth time, zebrafish also give rise many more offspring.

A common issue in science is the costs associated with research. Animal models are expensive to run and research facilities are always looking for opportunities to reduce costs. Zebrafish, due to their small size and lower handling costs are significantly cheaper than mice to care for throughout the testing process.

In addition to the practical reasons for using zebrafish, another important aspect is the ethical considerations associated with animal work. A huge amount of regulations are in place to limit harm caused to animals during research, and all practical steps are made to reduce the stress on the animals. Compared to mammals such as mice, zebrafish, especially the larvae have very limited cognitive processing of stressful stimuli, and do not have the same emotional response to pain or discomfort as do mammals. This is another reason why they are a popular model, as it can help reduce suffering of animals while still allowing important scientific research to be conducted.

So have there been any breakthrough discoveries made by using zebrafish?

In 2012, researchers based at the Huntsman Cancer Institute, in Utah, USA, used genetically modified zebrafish to screen for possible anti-drugs. They focused on a common childhood cancer called T-cell acute lymphoblastic leukaemia (T-ALL) (3), where T-cells replicate uncontrollably.

The study used genetically modified zebrafish that had been induced to have T-ALL, and were tested with over 26,000 compounds. They identified a single drug they called lenaldekar that slowed growth of the T-cells without affecting other cells. This specificity could then help reduce side effects compared to other cancer drugs by limiting the damage to other cells.  

Lenaldekar is currently still under development, however it has shown to be effective at treating human T-cells in some models and appears to be specific towards T-cells, which could help to reduce the side effects associated with other cancer treatments. Although it is still in its preliminary stages, lenaldekar could potentially become a newer and safer cancer treatment.

The discovery of lenaldekar using zebrafish screens shows they can be used to identify new drugs. It also highlights how although they are seemingly very different from humans and other mammals, they are more like us than we might expect, and offer an exciting opportunity for future scientific advances.

By Luke Boothman

References:

  1. Noel ES, Momenah TS, Al-Dagriri K et al. 2015. A Zebrafish Loss-of-Function Model for Human CFAP53 Mutations Reveals Its Specific Role in Laterality Organ Function. Human Mutation. 37(2): 194-200
  2. Bakkers, J. 2011. Zebrafish as a model to study cardiac development and human cardiac disease. Cardiovascular Research. 91: 279- 88
  3. Ridges, S; Heaton, WL; Joshi, D et al. 20120. Zebrafish screen identifies novel compound with selective toxicity against leukemia. Blood. 119(24): 5621-31

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