How cutting-edge paediatrics research gets implemented

RNA is the new DNA, according to Professor Sandra Cooper, and the implications are revolutionary.

Cooper, a neuroscientist specialising in functional genomics, is Scientific Director of the Kids Neuroscience Centre at the Children’s Hospital at Westmead, where she leads the Genomic Medicine Groups.

“My research focuses on identifying the genetic basis and mechanism of disease in children with genetic neurological disorders,” she says.

The ability to study and sequence RNA has opened up new possibilities for diagnosis and, eventually, therapeutics. But the research is running so far ahead of current practice that its benefits can only be unlocked and implemented once the medical world has agreed on a framework for its use.

And then comes the question of how to make sure that the whole population benefits.

The challenge

The Human Genome Project, an international collaboration to map the human genetic blueprint, was declared complete in April 2003. This led to an explosion of scientific breakthroughs which fed back into an understanding of the genome; the map was truly completed in May 2021.

And while scientists were unlocking DNA, they were simultaneously working on messenger RNA – the molecule that puts the DNA instructions into action.

The way Cooper explains it, where DNA is like an encyclopaedia of everything needed to bake any type of cake: different flour types, ingredients, oven temperatures, pan types, how long to cook it etc;  RNA is the recipe for a specific cake. Understanding it is challenging because the same DNA gene code can result in multiple different RNA recipes – like optional chocolate chips in a banana cake.

“New methods to sequence DNA, called massively parallel sequencing, are imminently transferable to RNA. We published one of the first papers in 2017 about using RNA sequencing for diagnosis of rare genetic conditions,” says Cooper. “It’s a new genetic frontier.”

Cooper says that because her group at Westmead has a collaboration with the Broad Institute of MIT and Harvard, it was one of the first in Australia to benefit from the diagnostic benefits of RNA sequencing.

While an international rule book for interpreting genetic results exists – the ACMG-AMP guidelines, named for the American College of Medical Genetics and Genomics and Association for Molecular Pathology – nothing existed for RNA. Cooper realised RNA was so complex that clinically interpreting RNA sequencing results would need input from multiple disciplines.

“We brought a lot of genetic experts together from a lot of different disciplines,” she says. “We would propose a methodology, gets lots of feedback and do surveys.” Solving a mystery of this magnitude, she adds, requires “cross-talk between the research community, the pathology community and the clinical genetics community – hearing all the voices, to bring RNA into the clinical realm”.

In 2019, Cooper set up a group called SpliceACORD, the Australian Consortium for RNA Diagnostics, whose function is to bring everyone who works in this area together to create the rule book for how to bring RNA genetic testing into clinical practice and pathology testing. Those efforts resulted in guidelines for testing built by consensus. “In Australia, we’ve literally created the first standardised guidelines to use RNA diagnostics in clinical practice,” Cooper says.

Now, she is working with NSW Pathology to turn RNA testing into “an accredited pipeline of testing, and trying to coordinate across the nation as quickly as possible”.

Research in the real world

Raghu Lingam is Professor in Paediatric Population Health and Health Services Research at the University of New South Wales and a Consultant Paediatrician at the Sydney Children’s Hospitals Network. Lingam has set up the Population Child Health Research Group, which aims to develop and evaluate equitable models of care for children across New South Wales, nationally and internationally.

Lingam and his team are not involved in Cooper’s research, but are currently working on over 20 research projects aimed at population level medicine. “For example, we’re doing a trial at the moment called ‘Strengthening care for children’ with our colleagues in Melbourne.” It involves paediatricians going into GP practices and helping improve their paediatric skills, so that GPs can deliver “a value-based care, so that children can be seen quickly in the community rather than sitting on waiting lists for hospitals”.

In another study, his team is working with four rural health districts across NSW on the question of how to improve the management of children with complex and chronic illnesses. “Our new model consists of a care coordinator helping families locally, using existing members of staff.”

Lingam says the approach can also be used for children with rare diseases. “If you put all the children with rare diseases together, then it’s not one or two, but 1.2 million children across Australia.” He says that if the principles of care are right, then they can be implemented regardless of whether the child has a more common condition like diabetes, or an extremely rare cancer. What’s key is thinking in terms of systems.

“You would have a nurse specialist that could help you navigate the system. That person could help you liaise with doctors locally, but also make your appointments at a central children’s hospital, and to help you have a telehealth appointment in your home, rather than having to travel to Sydney.”

The results so far have been promising. “We’ve found there is a huge cost savings in terms of children not needing to come into hospital all the time. And they were getting much better care, delivered closer to home. UK data has shown that reduction in admissions was about 40% – quite staggering.”

Putting such systems in place also mean that even families living in remote regions will be able to benefit from the increasingly sophisticated treatments that are on the horizon.

The right system equals better outcomes

Cooper says that once the SpliceACORD had guidelines in place, they tested 100 families from across Australia who were affected with a rare disorder or had inherited cancer predisposition. “We provided our RNA testing results to the pathology labs and they interpreted it. We got diagnostically informative results for 95% – we ended up being able to provide a diagnosis for 75% of the cases enrolled.” For the first time, these 75 families had a diagnosis. For some of them, it resulted in targeted treatments, while for others, it meant being able to join a clinical trial.

Cooper believes that this is only the beginning of what understanding RNA will offer, from diagnostics through to using RNA to deliver the crucial proteins that are missing in disorders like cystic fibrosis for precision genetic therapeutics.

She’s very proud of what has already been achieved, but adds, “with RNA vaccines being administered across the globe to combat COVID-19, I feel like there is going to be an avalanche of RNA therapeutics. We are entering an extremely exciting time for RNA, to diagnose and potentially cure families with rare genetic disorders”.

For Lingam too, the importance of having the right systems and processes in place to support interventions is paramount. For many interventions: “We have to find out whether it works, how well it works, and whether it’s cost-effective in the real-world health system.” If it does work, it can then be rolled out across Australia, with minor adaptations for local conditions.

He says that when it comes to applying new and cutting-edge treatments, “the most important thing is you have to test out your novel models of care in the real world”.