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Biology’s next top model: Zebrafish

The developmental and empirical potential of zebrafish in drug testing
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The many similarities of zebrafish with mammals make them an ideal organism for disease modelling. COURTESY OF OREGON STATE UNIVERSITY/CC FLICKR
The many similarities of zebrafish with mammals make them an ideal organism for disease modelling. COURTESY OF OREGON STATE UNIVERSITY/CC FLICKR

It’s not a hybrid of a zebra and a fish; instead, Danio rerio, commonly known as the zebrafish, is a small freshwater fish found in tropical climates. The zebrafish is characterized by its slim body and bright stripes, and is well known for its unique biological properties — properties that have made it a favoured organism for modelling research in genetics, embryological development, and medicine. 

‘Model organisms’ like zebrafish are particularly significant for scientists and researchers to learn and discover mechanisms of biological processes.

The history of zebrafish as model organisms

In the 1960s, zebrafish began to be used as model organisms in various biological studies. Their small size, low-maintenance care requirements, short prenatal period, and other unique features make them ideal candidates for research. 

Zebrafish eggs develop outside the mother’s body. Given that the embryos are transparent, it’s possible to easily observe early embryological developments in zebrafish and the sequential growth of their internal structures. Zebrafish are highly similar to mammals in terms of their important anatomical and physiological features. Classified as vertebrates, they also share a remarkable number of similarities with humans specifically — they have the same major tissue systems and organs as we do, and share many common features with humans’ muscles, blood, kidneys, and eyes, in particular. 

These commonalities are also present at the genetic level: zebrafish and humans share around 70 per cent of their genes. Eighty-four per cent of genes linked to human diseases are shown to have a close correspondence to their zebrafish counterparts. Research performed with zebrafish as a model organism, therefore, holds great potential to unlock new pathways for medicine and resolutions to human diseases, allowing us to better understand the molecular mechanisms behind how and why we get sick.

The genetics of zebrafish

Advancements in genetic engineering technology and new zebrafish facilities at many institutions around the world have allowed zebrafish to become a widely used model in genetic studies. Zebrafish are the favoured organism for this area of research due to their easily accessible genes, the low cost of providing for them, and the less numerous ethical restrictions on zebrafish research compared to mammalian organisms. In the past few decades, zebrafish have been used both in forward and reverse genetic screens, with highly impactful results.

‘Forward genetics’ involves examining the genetic cause of a mutation, which helps scientists identify a number of different variations of the same gene. In the 1990s, a group of scientists attempted to identify many genes essential to organ system development by conducting a massive screening of zebrafish. This was the first time that scientists conducted this type of screening on a vertebrate species, and it resulted in a lot more information about the genetic causes of different diseases. The screening identified 1,500 mutations in 400 different genes responsible for developmental defects through observation, which was made possible by the fact that zebrafish embryos are nearly transparent and grow very quickly. 

‘Reverse genetics’ involves altering a particular gene of interest and observing the consequences. Although rodents are the usual go-to model organism for reverse genetics studies, they require scientists to inject target genes into unfertilized egg cells, which can be difficult. It is much easier, therefore, to conduct reverse genetics analyses in embryonic and larval zebrafish. 

Early zebrafish embryos can be injected with genetic materials so scientists can observe whether there is a temporary change in how the target gene is expressed, or if there’s an absence of genetic response. This method allows researchers to study early zebrafish development in a manner that permits close scrutiny of how genes affect an organism at a place and time in the development process that researchers choose. This disease modelling is how scientists search for effective therapies for certain genetic conditions.

Researchers usually have an easier time conducting these forward and reverse genetic analyses on zebrafish larvae than on some other animals, which gives zebrafish a clear advantage. The genetic research we have been able to conduct using zebrafish has allowed us to model and gain insight into some of the most prevalent and dangerous illnesses of our time, such as cancer. 

The regenerative abilities of zebrafish 

In order to learn more about how zebrafish are used as model organisms, The Varsity interviewed Ian Scott, a professor of molecular genetics at U of T and senior scientist at the SickKids Foundation. Scott has been conducting research using zebrafish as model organisms for years. 

Scott talked about the incredible regenerative abilities of the species, explaining that zebrafish are able to repair or regrow many parts of their body if injured, including severed spinal cords and damaged hearts. While the driving mechanisms behind these regenerative processes are not yet fully understood, we know that they involve cells entering a different state where they are able to undergo the necessary transformations. Scott believes that in the distant future, it may be possible to activate these same kinds of regenerative processes in people who have experienced severe injuries.

Professor Ashley Bruce from U of T’s Department of Cell and Systems Biology, who is also an expert in embryonic development, wrote to The Varsity in an email that this line of research has long-term potential for health care. Bruce added that, in situations such as the aftermath of a heart attack, it could be used to develop “approaches in humans to stimulate heart regeneration.”

How zebrafish aid in drug discovery 

Ultimately, the objective of disease modelling is to improve existing diagnostic methods and therapies by developing new drugs to treat different conditions. To this end, zebrafish also serve as an ideal model for testing libraries of chemical molecules in search of new drugs designated to treat genetic diseases. 

In the context of pharmacology, it’s necessary to observe physiological changes in live organisms — instead of stem cells — to accurately evaluate how much of the administered chemicals are able to take effect, and whether they have any potential adverse effects. Intact animal models are particularly important in neuroscience drug discovery. Due to the complexity in the functioning of the nervous system, even undifferentiated stem cells obtained from patients are not as well-suited for drug discovery as fully intact organisms like zebrafish.

Most zebrafish organs have similar physiological functions to corresponding human organs. There are even some characteristics where zebrafish physiology resembles humans more than rodent models — namely, the electrical properties of cardiac cells. According to a Nature article, Zebrafish larvae are known to have “[a] functional liver, kidneys and blood-brain barriers,” which enable insight into how zebrafish respond, early in their development, to chemicals administered by scientists. 

Promising chemical compounds tested on zebrafish are also directly transferable to other mammalian model organisms without extensive pharmacological modifications. Although, when tested on zebrafish, some chemical compounds may not display all of the pharmacological properties we need to observe, the dose-response relationships obtained from observing zebrafish still serve as valuable references that point out a direction to future drug development. 

Foreseeable challenges and opportunities for zebrafish 

Despite promising prospects for drug discovery and disease modelling using zebrafish, there are many challenges in the field for scientists to overcome. 

Researchers are yet to determine the details of how different ‘behavioural phenotypes’ correspond to potential therapeutics. In order to standardize behavioural responses to chemical compounds in humans, it’s necessary to thoroughly screen the behaviours induced by novel chemical compounds. This massive undertaking requires not only scientific expertise, but also a substantial increase in financial investment. 

Rapid advances in genome engineering and genome editing technology will most likely make it easier to reconstruct numerous human genetic mutations in zebrafish models. At the moment, chemical screenings have demonstrated the usefulness of zebrafish in identifying compounds that can counteract disease-causing genetic mutations. 

Regardless of all the challenges that genetic research may face in the future, there is no doubt that the zebrafish is one of the emerging biological supermodels of our time.