Model organisms in genetics research: the zebrafish
Ben Stockton finds out how the zebrafish came to be a model organism
We have an extensive knowledge of a select group of animals, plants and microorganisms that are used in labs around the globe. The results of studies in these so-called ‘model organisms’ are used to help us understand biological phenomena in humans and animals.
It would come as no surprise if you hadn’t heard of the zebrafish – and no, it’s not just a black-and-white striped seahorse. These small, slender fish, characterised by white and neon blue stripes running down their flanks and fins, have become crucial model organisms over the past four decades or so. Despite being unknown to many people, these animals are of massive significance in a vast number of genetics labs.
Where did the zebrafish come from?
Known as Danio rerio in Latin, the zebrafish is native to the slow streams and rice paddies of East India and Myanmar. In these waters, they rarely grow larger than 4 cm long. This once-quiet existence has now been replaced by scientific stardom. Zebrafish have a far shorter relationship with science than many other animals: they were first used in research in the late 1960s. By 1976, the USSR [the Soviet Union] had launched a zebrafish into orbit on the Salyut 5 space mission.
Despite their meteoric rise in use by scientists, many people know the zebrafish as just a popular pet. Marketed by pet shop owners as ‘hard to kill’, they continue to inhabit the tanks of many (possibly slightly neglectful) exotic fish owners.
Who were the pioneers in zebrafish genetics?
Hailed as the father of zebrafish genetics, George Streisinger – who worked at the University of Oregon – began the fish frenzy. A fish hobbyist himself, Streisinger was the first to recognise the potential for using zebrafish in the lab in the late 1960s.
In order to develop the zebrafish as a model animal for research, Streisinger had to create new techniques to study their genetics. At the time, Aaron Novick was the director of Oregon’s Institute for Molecular Biology, and Streisinger was able to take the time he needed to work on zebrafish thanks to Novick’s ability to see the long-term potential of the study. Amazingly, despite receiving funding for the whole period, Streisinger didn’t publish a single paper on zebrafish in the 1970s. This would be unheard of in a modern research environment, where scientists are under pressure from research funders and universities to publish their work. But Novick trusted Streisinger, and he was right to do so.
The big breakthrough came in 1981 when Streisinger and his colleagues created cloned zebrafish. The paper on this work made the front cover of ‘Nature’, one of the most prestigious scientific journals. As zebrafish research began to make significant gains, Streisinger sadly died from a heart attack while scuba diving.
But, like many scientific pioneers, Streisinger inspired a generation to continue his work. One such individual was Charles Kimmel, a colleague of Streisinger’s, who continued to study zebrafish throughout the 1980s and remains at the forefront of zebrafish developmental genetics today.
Why are zebrafish suited to genetics research?
Given his own experiences, Streisinger knew why zebrafish were popular among fish owners: they were hardy and easy to maintain. In the wild, they live in small freshwater pools – conditions that are easy to replicate in a tank. In addition, zebrafish are vertebrates, unlike other popular genetics model organisms such as fruit flies and nematode worms. This, along with the fact that zebrafish embryos develop outside the body and are almost completely translucent, means they are ideally suited for studying vertebrate development.
The embryos can be manipulated genetically to alter the expression of certain genes as they grow, and 84 per cent of known disease-causing genes in humans have counterparts in zebrafish. As a result, zebrafish are not just useful to developmental biologists but are also useful in studying disease states.
A pair of zebrafish can produce up to 300 fertilised eggs a week. This extraordinarily high fecundity (the ability to produce lots of offspring) allows scientists to have vast numbers of samples. Within a matter of months, these eggs will have developed into adult fish. A short generation time (the time between two generations of offspring) means that scientists can complete studies quickly and that the costs of rearing zebrafish are lower than for other organisms.
Have zebrafish been used in any landmark studies?
Zebrafish genetics had firmly established itself in Oregon in the 1980s, but it was the work of scientists outside the university and outside of the field of zebrafish genetics that really brought the field to the fore.
Christiane Nüsslein-Volhard had worked on screening fruit flies for mutations that affected their development. By looking at the mutant flies, it was possible for Nüsslein-Volhard and her colleagues to identify genes that were important for development. This work, which was carried out at the end of the 1980s, later won her the 1995 Nobel Prize in Physiology or Medicine.
By the early 1990s, fruit-fly genetics was far more advanced than that of vertebrates. To establish the significance of her work in flies, Nüsslein-Volhard turned her hand to zebrafish. The resulting project – looking for developmental mutations in zebrafish – was led by Nüsslein-Volhard at the Max Planck Institute in Germany and an ex-student of hers, Wolfgang Driever, in Massachusetts, USA. It became known as ‘The Big Screen’ and culminated in the publication of 37 papers in a 1996 volume of a publication called ‘Development’, in which around 4,000 mutations were identified.
How are zebrafish bring used today?
The Zebrafish Mutation Project at the Wellcome Trust Sanger Institute, Cambridge, now has funding to study 8,000 mutant zebrafish. It aims to find the function of every protein-coding gene in the zebrafish genome. This, in turn, could reveal the function of 80 to 90 per cent of human genes. Currently, the Institute has sequenced about 3,000 zebrafish genomes. Once sequenced, the data are made publicly available, and samples of the mutant zebrafish sperm are kept frozen.
Allowing other scientists to access the data and the sperm from these experiments means they can create the mutant strains themselves. Researchers can treat the mutant strains with potential drugs to develop new therapies for genetic diseases. As the project continues, subsequent work will no doubt reveal novel treatments for a variety of diseases.Lead image:
Annie Cavanagh, Wellcome Images CC BY NC ND
Questions for discussion
- List at least three advantages and three disadvantages of using zebrafish instead of mice in research. Think about the facilities needed to raise each animal and how similar the animals are to humans.
- Why do you think it’s important for scientists to make their research findings publicly available? Think about who might be funding the research and how other scientists might benefit. Who or what might be blocking the release of such information?