Imagine each time you injured yourself – whether a simple cut, or a broken limb – your body’s natural healing mechanisms turned damaged muscle into bone.
It sounds like science fiction, but this cruel twist on recovery is real.
It’s a rare genetic condition known as fibrodysplasia ossificans progressiva (FOP) – sometimes referred to as Stone Man Syndrome – that locks people in a second skeleton as they age.
Yesterday, a team of our researchers based at The Institute of Cancer Research (ICR) in London revealed a remarkable genetic link between FOP and a devastating type of childhood brain tumour, publishing their findings in the journal Nature Genetics.
And the discovery could offer new ways to treat children with the disease, which up until now has proved incurable.
Harry Eastlack and the frozen skeleton
The story starts in Philadelphia in the US back in 1938, when five year old Harry Eastlack broke his leg.
Suffering problems during his recovery, Harry’s knee and hip stiffened as bone began to form on his thigh muscles.
As he grew the condition spread around his body, freezing up his muscles and joints.
Attempts to remove the excess bone only made it worse, growing back quicker and stronger than before.
Harry had FOP and sadly died just shy of his 40th birthday, but his legacy lives on through research.
Studying rare diseases – including rare forms of cancer – can be tough. Funding can be scarce and with only a handful of people affected around the world, accessing samples for research and enrolling enough people in clinical trials can be a struggle.
But interest in Harry’s skeleton kick-started research into FOP.
And it’s through that research that our scientific stories align today – research that could now benefit children with a rare and devastating type of brain tumour called diffuse intrinsic pontine glioma, or DIPG for short.
From bones to brains
Dr Chris Jones and his team at the ICR are scanning reams of genetic data that could provide new ways to target a variety of childhood cancers.
Among these is DIPG, which affects between 20 and 30 children in the UK each year. It develops from early ‘precursor cells’ that during normal development would go on to form specialised brain cells, called ‘glial cells’.
Due to their location in the brain, these tumours cannot be removed by surgery, meaning the outlook for patients with DIPG is poor. On average, children with DIPG survive for less than a year and there are no effective treatments to target the disease.
That’s why Dr Jones and his team are focussed on learning more about DIPG and translating this into potential new ways to treat it.
Their latest study, which is part of our Genomics Initiative and is funded through our Catalyst Club – a pioneering venture to raise £10 million to aid research into personalising cancer treatment – is starting to piece together the genetic puzzle of DIPG.
By finding the key gene faults driving the disease, Dr Jones hopes to lay the foundations for future cures.
A surprising genetic crossover
The team scoured the DNA code of 26 unique samples from children with DIPG.
“Finding that the same few spelling mistakes are shared between two rare and drastically different diseases is remarkable” - Dr Chris Jones
They found that in just over a quarter of these samples a cluster of genetic faults were cropping up in a precise portion of a particular gene that had not previously been linked to DIPG.
In fact, when they ran these faults through a vast database of known cancer-linked errors they saw that no other tumour type carried these faults with the same high frequency.
This was a striking result.
“Less than one per cent of the many thousands of samples present in the database matched the faults we saw so frequently in these DIPG patients,” said Dr Jones.
“It really shows how important these faults could be in pinpointing a subset of patients that could benefit from treatments in the future,” he added.
But even more striking was the discovery that these same genetic faults matched those responsible for FOP.
“When you think that the human genome – the complete set of genetic information found in our cells – is over 3 billion letters in length, finding that the same few spelling mistakes are shared between two rare and drastically different diseases is remarkable,” Dr Jones said.
Turning stone into treatments
The gene Dr Jones and his team identified is known as ACVR1 and it produces a key protein in cells called ALK2.
If the faulty gene is present in all cells at birth then that child will develop FOP. But it’s extremely rare, affecting just one in two million people.
And now it would seem it’s possible that if the faulty gene is present only in the early precursors to the specialised glial cells then this could lead to DIPG.
The faulty version of ACVR1 produces a hyperactive form of ALK2 that permanently switches on a set of signals in cells.
In FOP these signals seem to be responsible for the tell-tale bone growths characteristic of the condition.
The precise role these signals play in DIPG is not yet known, and more research will be needed to pin down the molecular miswiring that may be responsible for the disease.
But thanks to research into FOP there are potential drugs already being developed that target the faults in ACVR1. And these could be repurposed as a new treatment for children with DIPG in the future.
It’s early days, but when Dr Jones took a selection of DIPG cells that carry the faulty ACVR1 gene and treated them with one of these promising compounds in the lab he saw that it was effective at killing the cells.
“These compounds aren’t quite at the stage of being ‘drugs’ we could give to people. But our first sets of experiments have shown promising early results,” Dr Jones said.
“The big challenge will be turning these into compounds suitable for treating DIPG patients.
“This will require some complicated chemistry to find ways of getting these potential drugs into the brain, which can be a real challenge and has been one of the major stumbling blocks when developing treatments for DIPG – and other brain tumours – in the past.”
Research feeds research
This study is a fascinating example of how two drastically different, but equally devastating, diseases can be brought together by the genetic events that fuel them.
And how two research communities, previously unknown to each other, can now work together to widen the benefit of their research for the patients who rely on it.
Whether peering at Harry Eastlack’s overgrown skeleton, or decoding vast swathes of data from childhood tumour samples, genes are genes.
And whether research like this is aiming to stop muscle turning to bone or improve the outlook for children with brain cancer, it’s all adding to our understanding of biology and underpinning the treatments of the future.
FOP skeleton image from Wikimedia Commons.
- Taylor K.R, et al. (2014). Recurrent activating ACVR1 mutations in diffuse intrinsic pontine glioma, Nature Genetics, DOI: 10.1038/ng.2925