Massachusetts Daily Collegian

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A free and responsible press serving the UMass community since 1890

Massachusetts Daily Collegian

A free and responsible press serving the UMass community since 1890

Massachusetts Daily Collegian

Fishing for a cure

Wikimedia Commons
Wikimedia Commons

Researchers at the University of Massachusetts developed a model for the study of a rare metabolic disorder with the help of an unlikely ally: Danio rerio, otherwise known as the zebrafish.

Neurobiologist Gerald Downes and colleagues identified the gene and regulation in Maple Syrup Urine Disease (MSUD) by disrupting an amino acid sequence’s metabolic breakdown, disrupting the normal function of a gene. They created a model that will be used to do further research with what researchers say might be the perfect test subject: the mutant zebrafish.

Every gene has a specific function, such as eye or hair color, and the only way to discover the function is to turn each gene on and off. Downes and his lab worked with point mutations to alter amino acids, altering the gene. Then they observed the embryo and hatched fish to analyze what was wrong with it.

He compared the process to a car in an interview with the Collegian. Every part of the car works together to make a functioning machine; when you remove a component part – a headlight, for example – it is possible to determine that the headlight is related to light production.

The research team was looking into 10 mutations that affect the fish’s ability to swim, using the lab’s 7,000 tiny zebrafish. After years of research and breeding generations of a zebrafish mutant called “questschkommode” – which means “squeezebox” in German – Downes found the gene that affects one of the mutations and said “it was a total surprise” that the specific mutation resulted in Maple Syrup Urine Disease.

This discovery allowed Downes to create an accurate model for future research. He and his research team are positive the mutation is the Maple Syrup Urine Disease gene because in wild fish they were able to alter the same gene and get the same results.

Maple Syrup Urine Disease is a rare genetic disorder. Approximately 1 in 185,000 infants are affected worldwide, but in certain religious populations, such as Old Order Mennonites, incidence is much higher, according to the National Institutes of Health. MSUD causes disease by interrupting the normal metabolic breakdown of the amino acids, isoleucine, leucine and valine, which are found in protein-rich foods, such as eggs, milk and meat, said Downes.

The build-up of the amino acids causes urine and all other body fluids to smell sweet, like maple syrup, but it also leads to brain damage, uncontrollable and abnormal twisting of body parts known as dystonia, coma and eventual death, said Downes.

In the mutated zebrafish the same effects were found, minus the smell. The affected fish do not swim normally: Instead of a standard left to right fin action, their bodies act like an accordion in what Downes thinks may be a dystonia seizure, making it nearly impossible for the fish to swim. The fish live only about five days because of this inability to swim as it would normally.

Mutant zebrafish have become the ideal test subject for gene testing, said Downes. They are cheap, can be housed thousands at a time and are transparent. Transparency, in particular, is a useful trait, because researchers can observe transitions in a fish’s systems without having to dissect the fish every step of the project, according to Downes.

Downes said that the embryonic development is equally important, as the embryos are also transparent, giving the same advantages. Fish embryos develop outside of the mother, unlike in mice, another animal often used in testing, so the embryos require no dissection. The fish embryos also develop much faster than mice, making more fish available to different mutations and different attempts to cure the mutation, according to Downes.

“It’s fantastic to solve this mystery,” said Downes, expressing his pleasure at the results his team gathered after five years of study. “[To finally have a] useful model to benefit human treatment is incredibly satisfying.”

The new model will be used to test compounds that could be used as treatments to regulate the disease. The standard treatment is a strict diet consisting mostly of shakes and some food with no protein – or a liver transplant. But Downes and his lab have already started testing 10 compounds on the fish trying to strengthen the immune system, protect the nervous system from damage and allow more protein in the diet. If trials are successful, then the treatments will be tested on mice and then potentially on people.

Downes has been accepted to speak at the 16th Biennial MSUD Family Support Group Synopsis in Philadelphia in June 2012.

“I’m thrilled that our work might be helpful to people in a direct way,” he said.

Claire Anderson can be reached at [email protected].

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