Professor Stephen Robertson and his team of crack DNA detectives tackle genetic disorders that few of us have ever heard of. For the families they help, their work is life-changing. Jamie Morton reports.
Robert Chalmers-Wilson, to anyone who’s met him, is a happy, thriving boy.
On the inside, mum Louise says, things are a little more complex.
The Invercargill 8-year-old was born with a condition so remarkably rare that just a few hundred cases have ever been reported globally.
Currarino syndrome - which has an estimated prevalence of one in 100,000 - involves spinal defects that left him missing vertebrae and a tailbone.
It’s meant plenty of time in hospitals, including urgent surgery to untether his spine when he was six months old, and a life of severe bowel problems.
For an hour, each day after school, Robert needs to flush fluid directly into his colon and takes medications that also help prevent blockages.
It’s a life few of us could comprehend, but Louise says her brave boy doesn’t know any other way.
“He knows he has something incredibly rare, and he thinks that is pretty special.”
Had it not been for the earlier loss of his brother, Jackson, from complications with the same syndrome, and the efforts of their pediatrician who suggested the cause, it may have taken months or years before the family knew what they were up against.
“He would have been passed off as a child with chronic constipation and possibly gone on to have some life-threatening infections, with no idea why.”
Recently, after eight years, Robert at last got a molecular diagnosis that confirmed the syndrome.
It didn’t come from scientists at some sprawling research institute in California or Germany, but a small team at Otago University, just a few hours up the road.
“We found it,” Professor Stephen Robertson gleefully told Louise over the phone.
Most of us have likely never heard of Currarino syndrome, reflex sympathetic dystrophy, macrophagic myofasciitis or facio-oculo-acoustico-renal syndrome.
Scientists believe there exist between 7000 to 10,000 of these disorders which, while extremely uncommon, collectively touch the lives of several hundred million people worldwide.
The vast bulk of them, including Currarino, remain without approved drug treatments.
Around three-quarters are genetic so they can be present throughout a person’s life even if their symptoms don’t appear straight away.
But, as with Robert, a large number do, and around half the people known to be affected by them are children.
These unique patients are a focus of Robertson, a world-renowned researcher, and his team of DNA detectives at Otago’s Laboratory for Genomic Medicine.
Their job is to hunt out the hidden causes of single-gene disorders which, as you’d expect, couldn’t be more complex.
Within the genetic jigsaw that makes up each of us are some three billion base pairs of DNA – and it’s within this human haystack that the scientists must find their needle.
Proving they’ve got their causative gene is another feat and often involves lab experiments and models.
Standard genetic tests, which often focus on common variants, typically can’t pick up these disorders.
As specialists explained to Louise: if these tests were like skim-reading a page just to get the important bits, then finding the cause of her son’s Currarino was like trawling an entire novel for an out-of-place full-stop.
But find it they did, using a decoding process called whole genome sequencing, perhaps best known by Kiwis for its role in matching and tracking strains of coronavirus during the pandemic.
Two of Robertson’s colleagues - medical student Em Jameson and bioinformatician Dr Ben Halliday – managed to pin-point a genetic factor buried near a known causal gene for the syndrome.
“All I could think was, wow, that is amazing for them, what a career milestone,” Louise said.
Then she realised what that meant for her boy.
“Should Robert decide to have children, he’ll have greater options to be informed [of the child inheriting Currarino] at birth, or even beforehand.”
Along with the rewarding feeling of working with families like this, Robertson admits he loves the challenge – and the rush - of genuine scientific discovery.
A board member and medical adviser for the charity Cure Kids, Robertson and his team have now established the cause of more than 50 genetic conditions, most of them affecting children.
Asked if he’s our own answer to Hugh Laurie’s genius diagnostician Dr Gregory House, Robertson laughs.
“To be honest, I lean on so many others,” he said.
“Very often, our research begins with some very thoughtful and often inspired insight from a clinical colleague.”
His own run of breakthroughs stretch back to 2002, when he discovered a rare disorder afflicting a Māori whānau from Auckland he’d met while working as a trainee paediatrican nearly a decade before.
“At that time five boys had died, the offspring of three sisters,” he said.
“Their mother had also lost a son to the same condition in the remote past. The condition was not accurately diagnosed - let alone a cause identified.”
Inspired by the whanau – who’d initially put their misfortune down to mākutu, or a curse – he refused to give up searching for an answer.
Nine years later, he revealed the gene responsible and developed a diagnostic test for the disorder.
The offending gene also turned out to be implicated in a raft of congenital syndromes, surprising many geneticists internationally.
“I stay in close contact with this whānau to this day, and our work together really sparked my other research.”
In 2018, Robertson was part of a global collaboration that discovered a new gene for a rare and mysterious neurological disorder, characterised by malformations of specific structures in the brain.
People affected with the condition – visible on MRI scans – could have seizures, while others could have intellectual disabilities.
“We have been searching for the full range of causes of this condition for over 15 years and have contributed to the identification of half a dozen other genetic explanations for its appearance,” he said.
“The long-term view with this work is that understanding the genetic regulators of successful healthy brain development could have far-reaching benefits for many neurological disorders.”
Another major study revealed the root of another condition called recessive spondylocarpotarsal synostosis syndrome, which leads to the fusion of bones in the spine and limbs.
His group’s latest success came just this month, when PhD candidate Amy Jones revealed the cause of another incredibly rare condition known to cause seizures and delayed development.
Working with kids from 10 unrelated families around the world, their study revealed how specific genetic variants could produce a stabilised enzyme, which in turn created the small molecule glutamine in an unregulated way.
“Typically, genetic disorders result from genetic variants that disable a gene, so it was surprising that in this case there was an increase in stability of the enzyme,” Jones explained.
“In some ways these variants can be thought to be taking the handbrake off the enzyme and letting it free wheel in an unregulated fashion.
“This tells us that the production of glutamine needs to be maintained within a very tight specific range during brain development – both too much and too little damages the developing brain.”
Roberston described Jones’ discovery as “an excellent example of finely tuned precision medicine”.
“All of these children were previously treated according to their symptoms, rather than from an understanding of the cause of their condition.”
There’s a term for the painful years that families spend in the dark trying to find the cause of a mystery ailment: the “diagnostic odyssey”.
It often comes with multiple misdiagnoses and wrong treatment plans, all while symptoms became tougher to manage.
With the advent of genomic sequencing, things are improving – but not as quickly here as in other countries like the US and Australia.
Robertson’s team have been helping paving the way for this to become part of our clinical landscape, with a major project that tested the genomes of more than 100 Kiwi kids and their families.
From those tests, mostly carried out at Canterbury Health Labs, about a third achieved a diagnosis.
One mum who received one, and declined to be named, told of her son having had bad seizures from the time he was just a few days old.
That led to a year spent in and out of hospital and half a dozen possible diagnoses over 13 years – none of which fitted.
“We knew testing was available overseas, in European countries, but never here in New Zealand; I had conditioned myself to never expect a diagnosis,” she said.
“It has been a journey of grief, and the unknown is the hardest part.”
Robertson saw plenty of reasons for New Zealand to catch up with the rest of the world.
“In health, the faster it is to a diagnosis, the better the outcomes for the patient and the cheaper it is for the system,” he said.
“With misdiagnosis, there are corresponding treatment plans that don’t work and may cause more complications for the patient and stress on the health system.”
Merely bringing our diagnostic services onshore, rather than relying on overseas labs at high cost, would be a major win.
“Presently we are exporting our opportunities - there is a huge opportunity to innovate in this space.”
Professor Mik Black of Genomics Aotearoa, which funded the effort, saw the project as a “blueprint for DNA testing on the ground”.
“We can use the pathways put in place to integrate this into New Zealand’s healthcare system, saving money, increasing professional capabilities, and supporting families in difficult situations.”
Rare Disorders NZ was similarly excited by the work.
The umbrella group recently published a white paper showing that more than half of those with rare disorders took more than a year to diagnose; nearly two in 10 took more than a decade.
Its chief executive, Chris Higgins, said early diagnosis could mean the difference between the negative effects of a rare disorder being eliminated, or going on to cause problems.
“This is the way of the future,” he said of the new project.
“The numbers are small, but this is just the start.”
Looking to the future, Robertson has much to be optimistic about.
There’s a strong pipeline of talented researchers, like Jones and Jameson, coming up through the system.
“The modern face of genomics in medical practice sits comfortably in the hands and minds of our emerging scientists.”
We also now have the high-end computing power to crunch the data.
“We have sequenced the genomes of nearly 2000 people for our science now – that equates to datasets that are huge. The collective size of this dataset is around 600 terabytes, the entire storage capability of 5000 smartphones.”
Health New Zealand is developing a framework to better coordinate how rare disorders are detected, diagnoses and cared for, while smart new treatments are beginning to emerge.
They include drugs – like the ground-breaking Trikafta for cystic fibrosis – and organ-specific gene editing and gene therapy.
There’s growing potential for disorders to be picked up much sooner – such as with quick heel-prick tests for newborns to screen for spinal muscular atrophy, which affects one in 10,000 of us.
Within a few decades, Robertson figures genomic sequencing itself will become cheap, fast and locally accessible to families in need of diagnosis.
“This will be particularly useful where the child is very ill, or the person has an acute illness for which treatment needs to start straight away,” he said.
“Having your genome sequenced early in life could become a foundational component of your individualised healthcare.”
Doctors might come to attack diseases in an entirely new way.
For those like cancer, he said, doctors could refer to a person’s genomic profile, rather than what they see down a microscope, for the best approaches for treatment.
And for rare disorders, researchers will have a much deeper understanding of their molecular mechanisms – opening the door to a host of new therapies.
In the shorter term, Robertson sees plenty more breakthroughs lying ahead for his team.
“There are more unexplained problems than the small number I have solved... and there’s always the next unsolved challenge to turn to.”
Louise, meanwhile, couldn’t be more grateful that her boy’s was among the cases Robertson’s team cracked.
She still remembers what it was like to be standing in a room, with a very sick child, and having New Zealand’s best doctors tell her they didn’t know what was causing the problem.
Now there’s the possibility of helping spare other families the same pain.
“The fact we can be a small part of this discovery has been exciting, emotional and feels a bit like coming full circle.”
Jamie Morton is a specialist in science and environmental reporting. He joined the Herald in 2011 and writes about everything from conservation and climate change to natural hazards and new technology.
The 5-year-old died on Saturday night at Lower Hutt's Avalon Park.