Key Facts:
Research from UNSW Sydney is changing the future of precision care for genetic and rare diseases, using children's own cells to build small organ models to test cystic fibrosis medicines on.
When UNSW Associate Professor Shafagh Waters explains cystic fibrosis (CF) to the children she works with, she asks them to imagine what is happening inside their own bodies.
"I tell them to picture an airport," she says. "There's a gate at the surface of every cell. It's meant to open so water and salts can flow through – just like planes leaving a gate.
"In cystic fibrosis, that gate might be stuck closed, built in the wrong place, or it could be so unstable that it falls apart as soon as it forms."
It's an image that captures the complexity of one of Australia's most well-known rare diseases.
"Cystic fibrosis is a genetic condition caused by changes in a single gene, CFTR," says A/Prof. Waters, who is stem cell and regenerative medicine researcher focused on paediatric lung and gut disorders.
"The CFTR protein acts like the airport gate at the top of the body's epithelial cells – the cells lining the lungs, gut and pancreas," she says. "When the gate opens, salts and water – the planes – flow out, to hydrate the mucus that traps bacteria in these organs and clear them out of the body."
But, with cystic fibrosis, the 'airport' can not only malfunction – sometimes it doesn't exist at all.
A/Prof. Waters' lab has spent years developing more personalised ways of matching children to the right CFTR modulator drug.
The lab method grows a patient's own stem cells and turns them into tiny replicas of their lungs or gut.
These 'organoids' – or, what A/Prof. Waters says to her patients are 'mini-mes' – can then be tested in the lab to see which drug best helps the individual patient.
How the disease works
In healthy lungs, the CFTR protein draws water into mucus, so it stays thin enough to sweep out bacteria.
"Bacteria grow in that mucus environment. And when water can't get to the mucus it becomes so viscous and thick – so sticky – that we can't move it outside of our lungs or out of our nasal cavity," A/Prof. Waters says.
Not being able to move this mucus out of the body means people with cystic fibrosis experience chronic inflammation alongside bacterial and viral infections. Over time, it's not just the lungs that are affected, but the gut, pancreas and liver too.
Two Australians die every four weeks from the disease.
One gene, many mutations
More than 2000 known CFTR mutations have been identified worldwide. The type of mutation a patient carries can alter everything from how severe their symptoms are to what drugs will work for them.
The CFTR modulator drugs are designed to address specific types of defects. Some help the gate open, while others help the protein reach the right location.
Yet, even among patients with the same mutation, the responses vary.
A/Prof. Waters says the diversity of genetic defects has pushed cystic fibrosis into the spotlight as a model for personalised medicine.
"When I first started, I thought, 'I only have one gene to deal with. How difficult can a monogenic disease be?'," she says.
"The reality is, although this is one gene, it's very complex and the patients are very heterogeneous in the way that they present. If I give you 100 patients with the same mutation and we give them the same medication, perhaps 40% respond.
"Some of them don't respond. And some of them actually get worse."
The first paediatric study of its kind
The varied responses mean patients can spend months on ineffective – and extremely expensive – medication, with doctors simply not knowing which one will work best for them.
In the past few years, A/Prof. Waters' team used organoid testing to guide treatment for children with ultra-rare CFTR mutations. These are patients who are excluded from clinical trials and left without access to CFTR modulator drugs. Yet, in multiple cases, testing a child's own cells demonstrated that a drug would work – enabling those children to receive therapies they otherwise could not.
The team's latest study takes that approach further, asking a more challenging question: can organoids also predict the drug response in children with common CFTR mutations, where genetics alone often fails?
To answer this, A/Prof. Waters and her team took nasal cells from 24 children, aged between five and 17 years old, and created lung organoids for each of them. In the lab, they then exposed every organoid to all four of the CFTR treatments currently available.
After this, they compared those lab results with each child's real-world outcomes: lung function, sweat chloride and overall response to medications.
The study showed the organoid responses closely aligned with a clinical response, supporting organoids as a practical way to predict which children are most likely to benefit from CFTR modulators.
"While patients are routinely transitioned between modulators, this is the first paediatric study to compare all clinically available CFTR modulators head-to-head in airway organoids – and relate those results to real-world clinical responses, as children transition between therapies," A/Prof. Waters says.
At the same time, the team ran whole-genome sequencing, hoping that a deeper dive into each child's DNA might reveal patterns that could predict drug response.
It didn't.
