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Zebrafish make a difference

Dr Don Love and his team are using zebrafish as a research tool to study heritable diseases such as Duchenne muscular dystrophy.

What is muscular dystrophy?

Duchenne muscular dystrophy (DMD) is a neuromuscular disease. It results in muscle degeneration, or wasting. First, the voluntary muscles become useless. Later, involuntary muscles like the heart and diaphragm stop functioning. There is currently no cure and the disease is fatal.

DMD is caused by a defect in the gene coding for dystrophin protein. Dystrophin is produced inside muscle cells and provides structural support by anchoring the internal cytoskeleton to the cell membrane.

The dystrophin gene is found on the X chromosome and is recessive. This means that only males are affected (males receive only one X chromosome at fertilisation, and so the recessive allele cannot be “overridden” by a normal allele on a second X chromosome, as would happen in a female. A daughter would only get the disease if her father was affected and her mother was a carrier; this is highly unlikely).

DMD affects approximately 1 in 3000 live male births.

Using fish to study human muscular dystrophy

Dr Don Love and his team at Auckland University are using zebrafish as a tool to study gene expression in heritable diseases such as DMD.

Fish can naturally develop a version of muscular dystrophy. These fish, called sapje mutants, have been used to study muscular dystrophy in the past. Although their symptoms do not precisely mirror the human disease, these mutant fish do offer insight into certain disease outcomes that have received little attention in human DMD patients.

Working with zebrafish models of DMD such as the sapje mutants has implications for the development of suitable treatments for the human disease.

Giving a fish muscular dystrophy

In order to study the human version of the disease in an animal model (because it would be impossible to experiment on humans), Dr Love and his team have to find a way of giving zebrafish the same version (or allele) of the gene that causes the disease in humans. Scientists have several strategies to do this, some more effective than others.

Leaving a gene intact, but preventing the protein product from being expressed (or made) is called down-regulation. Down-regulating the expression of the dystrophin gene causes a decrease in the production of dystrophin protein. This has the same overall effect as a cell which has the DMD allele and consequently does not make dystrophin.

A relatively new technique, based on RNA interference (RNAi) looks promising.

RNAi works by creating an RNA molecule which binds by complementary base pairing to the RNA transcript produced from the dystrophin gene. This results in the formation of a double-stranded RNA molecule, which is degraded by natural processes within the cell.

RNAi leads to cellular breakdown (cleavage) of the dystrophin RNA transcript so that it can’t be translated, and the dystrophin protein is not made.

Get video: The dystrophin gene sequence

In order to down-regulate a targeted gene you need to know the base sequence of that gene (so that you can create a DNA sequence which will code for a complementary RNAi sequence).

Figuring out DNA sequences is still a lot like trying piece together a large puzzle, as PhD student Daniel Lai is finding out.

Recognising the mutants

The diseased fish are created by causing mutations in their DNA. But finding out if you have been successful in creating a mutation is not as easy as you might think.

Get video: Recognising mutants

The zebrafish model

Once the fish is expressing the DNA code the scientists want in the way they want (in this case, it is replicating the effects of muscular dystrophy) it becomes a model which scientists can use in order to better understand the pathways of the disease.

It also provides a useful system in which to test the effectiveness of potential treatments.

But even if the treatment works in zebrafish, how useful will the research be to humans?

Get video: But can you really compare humans to zebrafish?

The ethics

Giving a zebrafish a human disease, such as DMD, is subject to strict ethical monitoring. Getting approval for their work is a vital first step in any project Dr Love and his team plan to carry out. This is a requirement under the Animal Welfare Act, 1999.

Get information sheet: The ethics of zebrafish in research

Zebrafish in the lab

Zebrafish, Danio rerio, are native to the slow, warm fresh waters of the Ganges River. Keeping them safely in the lab requires these conditions to be mimicked.

Get video: Looking after zebrafish

The rapid and manipulable zebrafish life cycle is a great asset to scientists, and means that these fish are such a useful research tool.

Get video: The zebrafish lifecycle

Spawning is the process by which fish lay their eggs. Keeping track of which eggs are fertilised by which sperm is an important in zebrafish research, so it is useful to be able to control this reproductive process.

Zebrafish in the classroom

Zebrafish are available from most pet shops. They are inexpensive, and much of the embryonic development that Dr Love and his team of scientists observe in their research is visible with the average school light microscope.

Having zebrafish in the lab for scientific purposes requires ethical approval. To find out more about getting ethical approval for using animals in your classroom, go to www.royalsociety.org.nz/Site/teachersstudents/ethics/.

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