A defect in newborn babies is present in one in every 5,000 births
PAEDIATRIC surgeon Reshma Doodnath made the big switch some months ago. She put away her surgical gloves and gown and donned a lab coat to take up a PhD research project which now includes feeding and taking care of small, striped fish, common in home aquariums.
This is not trivial work. Through experiments at Trinity College Dublin using these zebrafish ( Danio rerio), Dr Doodnath will shed light on the genetics behind a bowel defect that affects one child in every 5,000 Irish births.
The disease was identified in the 19th century by a Danish physician who noted deaths in newborns with swollen bellies. Scientists now know that babies suffering from Hirschsprung’s disease lack nerve cells in their large bowel, to varying degrees.
“If a baby doesn’t have a dirty nappy within the first 48 hours, our first index of suspicion is Hirschsprung’s disease,” says Doodnath, who has performed surgery on such babies. “Their belly gets extended and they start to vomit.”
Many experiments on the disorder are not feasible in humans, and it is also difficult to study in mammals such as the mouse. Zebrafish, however, come up trumps. They are early developers, with all organs present in five-day-old fish.
Their millimetre-sized embryos form a functional gut within days, and the gut can be observed through a microscope because the embryos are transparent, says Dr Michael Wride, lecturer in zoology and project supervisor. Such observation will enable Doodnath to view normal and abnormal development of the gut’s nervous system in the tiny fish.
Moreover, the gut nervous system in fish and humans is remarkably similar. The gut is a very old organ, since every animal needs some kind of gut, and the genetic network controlling its development is also very old and therefore conserved, says Dr Ralf Dahm, a leading expert on zebrafish at the Spanish National Cancer Research Centre.
Dahm, who recently visited Dublin and offered advice, says: “The majority of genes in humans, perhaps 95 per cent or more, also exist in zebrafish. And the vast majority of these genes perform the same or a similar function.”
Doodnath’s project will look at the way six genes influence the gut nervous system. The researchers want to know where and when these genes are expressed, notes Wride, and what they are doing at various points during the development of the gut’s nervous system.
The enteric nervous system (Ens) of the gut is a complex network with more nerve cells than the entire spinal cord, says Prof Prem Puri, consultant paediatric surgeon and president of the Children’s Research Centre in Crumlin hospital and project co-supervisor.
The Ens in humans contains around 500 million neurons and can direct digestion without input from the central nervous system.
The network forms when stem cells migrate from an area called the neural crest to the bowel wall in the growing embryo. Hirschsprung’s disease occurs when the migration or development of these cells goes awry.
The Trinity researcher will visualise cells as they move through the fish embryo and will see what happens when she turns the genes on or off.
The Children’s Research Centre, which is funding the project, has been actively involved in research into enteric plexus disorders of the bowel for decades and is a leader in the field of Hirschsprung’s disease and related disorders. Puri has written the only book on the disease.
“The six genes we are studying are just a small fraction of the genes involved,” notes Doodnath. “In the long term, we would hope for a treatment for Hirschsprung’s disease with something like stem cell therapy.”
First, though, basic research must increase our understanding of the genetics involved, she adds.
Many people were surprised at the fish part of her research, says Doodnath, since it’s a relatively new model for a human disorder. But Dahm says Doodnath’s project is a fantastic example of the potential to use fish to study human diseases. He says lots of medical researchers now use zebrafish, including cancer researchers. Zebrafish facilities are cheaper than those for mammals, and a female fish can produce hundreds of embryos each week.
Doodnath says she may one day return to surgery. “This is pure science, but it is nice to be able to relate this to clinical medicine,” she adds. “I’ve seen what the parents go through, what the kids go through, and this does make a big difference.”
