A veterinary scientist from the University of Sydney has been instrumental in an international research effort that has discovered an animal model of a disease of the developing liver. This disease is the most common reason for liver transplantation in children.
The findings confirm the importance of documenting unusual disease episodes in animals as they may offer potentially valuable scientific discoveries, including models of poorly understood human diseases.
‘This is an excellent example of how field investigations of spontaneous livestock disease can uncover new mechanisms of human and animal disease’, said Emeritus Professor Peter Windsor, from the University of Sydney’s Faculty of Veterinary Science.
In 1990 the then Dr Windsor was a veterinarian working for the NSW Department of Agriculture and reported an outbreak of a disease that was killing lambs and calves. Affected animals were from mothers that had been restricted to grazing the pigweed plant (Dysphania species) on the banks of the Burrinjuck Dam in NSW during drought.
‘The Australian livestock outbreaks were always suggestive of a toxic cause and we were keen for a group of chemists and experimental pathologists to take an interest in and pursue this unique finding’, said Emeritus Professor Windsor.
Recurrence of the disease in 2007 enabled Dysphania to be collected by the district veterinarian Stephen Whittaker and colleagues and sent to a research team in the US. This resulted in an unlikely collaboration which has made several surprising discoveries.
The international team of gastroenterologists, pediatricians, natural products chemists, and veterinarians established that the chemical found in Dysphania provides insights into the cause of a debilitating disorder affecting newborns – biliary atresia – a failure of development of the ducts of the liver that excrete bile.
Their findings are published in Science Translational Medicine this month.
Biliary atresia (BA) is the most common indication for a liver transplant in children. The incidence of BA in humans is one in every 10,000 to 15,000 live births. It occurs worldwide and is one of the most rapidly progressive forms of liver cirrhosis and liver failure. While a life-saving surgical procedure is available to babies, most will later develop cirrhosis of the liver and ultimately liver failure, leading to the need for a transplant either in infancy, childhood or adolescence.
At the University of Pennsylvania the research team isolated a plant toxin with a previously uncharacterised chemical structure that causes BA in zebrafish and mammals.
Peter Windsor had joined the University of Sydney’s Faculty of Veterinary Science in 2002 and as Professor of Livestock Health and Production, he participated with the research group,advising on outbreak epidemiology, comparative pathology and the original livestock disease’s origin and development.
One of the perplexing qualities of the plant toxin is why it only acts on large bile ducts outside the liver. To better understand this the researchers examined various zebrafish mutants, with the hope of finding one that might be either more sensitive or resistant to bile duct injury.
Remarkably, the group was able to identify a mutant that was sensitised to the toxin, and this mutation mapped to a region in the zebrafish genome that is similar to an established human BA susceptibility region found previously. This provided further evidence that the Dysphania BA syndrome will be important for understanding human BA.
Taken together, these findings provide direct evidence that BA could be initiated by prenatal exposure to an environmental toxin.
While it is clear that humans do not consume the pigweed or related plants implicated in the livestock BA outbreaks, a non-toxic, structurally related compound is found in beets, chard and other consumable plants.
The team is currently studying whether gut bacteria can convert this inactive compound into the active toxin.
The research team is now attempting to synthesise a large enough quantity of the toxin to study its effects in mice, which have a liver and biliary system more closely related to humans than fish.
In addition it will work with the models that they have already established in their respective laboratories to determine the toxin’s mechanism of action and understand how this can be used to prevent and treat BA.