Thanks to an Australian-based scientist and a zebrafish tank, two tiny babies born on opposite sides of the world have avoided treatment that would cost millions of dollars.
A boy from New South Wales and a girl from Germany were born in 2023 with an unusual mutation in the gene that causes spinal muscular atrophy (SMA) during newborn screening.
Neither newborn had a family history of the disease, which affects an estimated 1 in 10,000 babies worldwide.
Both babies were born with mutations previously unknown to science, so it was impossible for doctors to know whether they would develop the condition.
Jean Giacomotto, a biomedical scientist at Griffith University, holds up a tank of zebrafish in her laboratory at the Biomedical and Glycomics Institute. (Provided by: Griffith University)
That created a dilemma. Should the specialist initiate treatment, risking unnecessary intervention with potential side effects, or delay treatment, risking irreparable harm?
The Australian Functional Genomics Network, set up to improve our understanding of genetic variation, turned to Griffith University biomedical scientist Jean Jacomot and his zebrafish to find out.
Spinal muscular atrophy is caused by mutations in the SMN1 (survival motor neuron 1) gene, resulting in a deficiency of a protein necessary for motor neuron survival.
In the past, children with SMA type 1, the most common genetic disease, died before the age of two.
But in the past decade, three treatments have emerged, including the one-time gene therapy drug Zolgensma, which costs about $2 million.
To avoid irreversible motor neuron death, everything must start before symptoms appear, and the long-term effects of treatments are unknown.
Dr Giacomotto, from the Griffith University Biomedical and Glycomic Institute, used zebrafish to show that the SMN1 mutation in both babies does not cause the disease.
Dr. Giacomott injected baby SMN1 mutants into zebrafish embryos that had been bred without the gene. (Provided by: Griffith University)
He did it within six weeks and reproduced the results.
Zebrafish are popular fish for home aquariums because of their eye-catching striped patterns. However, it has also proven to be a useful tool for researchers studying neurological conditions such as spinal muscular atrophy.
Dr. Giacomott said zebrafish raised without the SMN1 gene developed a type of neuromuscular disease that resulted in spinal degeneration, progressive loss of motor function, and premature death.
A normal zebrafish’s lifespan is about two years, but they die within about six days.
But when they used precision injection techniques to introduce baby SMN1 mutants into zebrafish embryos raised without the gene, they found they survived.
“We were able to functionally test each baby for the exact mutation and show that it was not harmful,” Dr. Giacomott said.
A side view of a developing zebrafish. Muscle fibers are in red and motor neurons are in white, helping researchers track disease progression and study the effects of genetic mutations. (Provided by: Griffith University)
“This study is the clearest demonstration to date that zebrafish can play a crucial role in interpreting clinical variants, especially in newborns flagged by expanding genomic screening programs.”
“As genome sequencing increases around the world, clinicians are encountering increasingly uncertain variants.
”This little fish provides a quick and affordable way to help solve these cases and alleviate the suffering for families.”
The children at the center of the study were over 2 years old and developing normally.
Dr. Giacomott’s research is featured on the cover of the latest edition of the scientific journal EMBO Molecular Medicine.
Michelle Farrar, a pediatric neurologist based at the University of New South Wales, also participated in the study and described it as a “game changer”.
Zebrafish in the laboratory. (Provided by: Griffith University)
“This is really the first time this model has been used in a timely way to actually support clinical decision-making to provide the best management for the child and certainty for the family,” Professor Farrar said.
She said gene therapy for infants with spinal muscular atrophy was only subsidized in Australia by the Pharmaceutical Benefits Scheme for children with a confirmed diagnosis.
“This study was very important because our newborn screening guidelines say that if the result is uncertain, it should be followed up until it becomes clear,” she said.
The luminescent bodies of zebrafish larvae make it easier for researchers to observe certain characteristics. (Provided by: Griffith University)
Researchers suggest that zebrafish could be a “valuable model” for testing genetic mutations of uncertain significance, not just for spinal muscular atrophy but for human diseases in general.
“There is an explosion of new genetic variants associated with a variety of diseases,” the researchers wrote in the journal Science.
“Identifying their functional impact poses a significant challenge, and this problem will continue to grow with the development and need for precision/personalized medicine.
“Zebrafish can help address this translational need.”
Loading…
Peter Currie, head of research at the Australian Institute of Regenerative Medicine, who was not involved in the study, described the milestone as a “huge success story for modern medicine”.
Professor Curry, who uses zebrafish to study muscular dystrophy, said zebrafish share 70 per cent of their genes with humans and that zebrafish are a “well-established” model for studying human diseases.
Zebrafish embryos are translucent, allowing scientists to study internal biological processes such as neuromuscular development.
Professor Peter Currie, head of research at the Australian Institute of Regenerative Medicine, uses zebrafish to study muscular dystrophy. (Supplied)
The Monash University-based researchers described Professor Giacomott’s zebrafish work as a “very clever way of using models to speed up the diagnostic process”.
Professor Currie said zebrafish are also a useful model for screening experimental drugs for the treatment of human diseases, including cancer.