Fishing for Clues in Rare Genetic Diseases, by Dr. Andrew Grierson

November 15, 2012

Fishing for clues in rare genetic diseases

Zebrafish are increasingly popular ‘model organisms’ used by scientists to investigate the causes of diverse human diseases, and to test new treatments. Zebrafish are vertebrates, which means, like us, they have a spinal cord that transmits messages between the brain and the rest of the body. In addition, adults are small enough to maintain in large numbers at a very low cost in the laboratory; a single tank of 40 adult zebrafish is sufficient to produce hundreds of young every week for research.

A versatile model 

Zebrafish have copies of almost all human genes. There are two main ways to model human disease in zebrafish. Firstly, we can inject a small piece of synthetic DNA called a morpholino, which can ‘switch off’ a gene for a few days, offering a small window to look at the disease in young zebrafish embryos. Secondly, we can introduce a mutation into the zebrafish copy of the gene. Male zebrafish are treated with a powerful chemical that randomly mutates DNA, and after allowing time for recovery they are bred with females to generate thousands of offspring, each of which contains many different mutations. Exome sequencing is then used to find and catalogue the mutations in the thousands of offspring. The mutations can be stored in libraries of live fish, or for convenience, sperm samples can be frozen and stored until they are needed, at which time they can be used for in vitro fertilization. The Sanger Centre (Cambridge, UK) has already generated mutations in over 25% of all zebrafish genes and these are available free of charge for research. Morpholinos and stable mutants offer major opportunities for generating models of human rare diseases in zebrafish.

Zebrafish are increasingly utilized by scientists for studying rare disease.


Curing Fish?

Drug development programs use a number of approaches, but typically it takes years before testing new drugs in a living organism. Because of their small size and availability in large numbers, zebrafish offer a unique opportunity to turn this approach around, and potentially test thousands of drugs for efficacy in a vertebrate model. One particularly attractive study design is to take a collection of known drugs and test them all in a zebrafish model. Any positive results allow us to identify new uses for old drugs- a process called drug repurposing. A further advantage of this approach is that these are drugs that have been previously tested in humans, which means the path to clinical use in the rare disease under investigation could be much more rapid.

Zebrafish are most suitable for studying early-onset disorders because their embryos offer the best opportunity for drug screening on a large scale.  If you or your rare disease organization is interested in having a particular gene studied through research in zebrafish, please contact [email protected].  To learn more about other opportunities for researchers to partner with families to study rare diseases and available free research services, reagents and consulting, check out the Rare Disease Science Challenge – applications are open until December 15th.


Dr. Andrew Grierson, PhD is the Senior Lecturer in Neuroscience at the University of Sheffield (UK). Research in his laboratory involves identifying the molecular mechanisms underlying the regulation of axonal transport in health and disease. In particular, they are investigating the involvement of axonal transport in diseases including motor neurone disease (MND) and hereditary spastic paraplegia (HSP). In addition, they are developing and characterising novel vertebrate models of neurodegeneration in zebrafish and mouse. With support from the NC3Rs we are refining the widely used SOD1G93A model of motor neuron disease.


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