The Best Australian Science Writing 2014 (33 page)

Years later, floating weightless in the International Space Station, Colonel Chris Hadfield, a Canadian astronaut, says you can't live a worthwhile life without taking risks – it is only in
this way that dreams and fantasies are turned into reality. He spoke about overcoming his fears via a satellite link-up to William Shatner, aka
Star Trek
's Captain Kirk.

‘You have the opportunity to go around the world every 90 minutes with the view of Earth from your window. All you have to do is flip yourself upside down and suddenly the rest of the universe is right there at your feet.'

Turning things on their head is exactly what Stephen Damiani has done in the worldly sphere of personalised or genomic medicine. A friendly, unassuming guy, who sports glasses with bright red frames, he has no college-level medical training. From his home-base ‘Mission Control' in Elsternwick (the same suburb I grew up in during the '60s) Damiani has been the architect of a complex family genetic project, organising to have his wife Sally's, son Massimo's and his own genomes – the complete set of genetic material (DNA) carried within each cell of the body – mapped and compared. Inspired by his childhood astronaut heroes, Stephen was driven by the need to find a diagnosis for his son's unknown genetic condition, which became apparent after his first birthday when his development deteriorated rapidly. He was presumed to have some form of leukodystrophy that is characterised by a disorder of myelin, the substance that coats nerve fibres and enables transmission of electrical impulses throughout the nervous system.

‘Like any small boy I was always fascinated with aviation, aerospace and all things pointy and fast,' says Damiani. ‘I remember staying up late to watch the first space shuttle launch when I was in grade four and was in awe from that point. The space program always seemed to be at the cutting edge of science, technology and engineering, going further, faster, higher and into new frontiers with every step. It was an era when science was inspired by imagination and anything was possible. When we reached the end of the road in trying to diagnose Massimo in
December 2009 we needed to engineer a miracle. If we were to achieve a diagnosis we needed to separate science from finance and allow researchers to be inspired by imagination, rather than be hindered by ivory tower ethics, bureaucracy and budgets.' He set up a charitable fund called ‘Mission Massimo'.

Stephen follows in the footsteps of parents like Augusto Odone, whose story inspired the 1992 film
Lorenzo's Oil
, starring Nick Nolte and Susan Sarandon. Augusto was told 20 years ago that his son Lorenzo suffered from a rare, crippling genetic disease called adrenoleukodystrophy (ALD) and had, at most, two years to live. He and his wife were determined to find a cure for him despite being told this may be impossible – 50 per cent of leukodystrophies remain undiagnosed. They were warned that with no medical training they would be unable to understand the specialised medical literature and, like the Damiani family, that there was little hope for their son.

‘I cast my mind back to the start of perhaps one of the most extraordinary periods of advancement in science, technology and engineering, the 1960s space race,' says Stephen. ‘President Kennedy's challenge to the American people of landing a man on the Moon and returning him safely to the Earth before the end of decade. The Apollo program may have been politically motivated, to some degree, but it united a nation into achieving a common goal and the results were nothing short of spectacular. Massimo needed an Apollo program.'

What Stephen Damiani has achieved in just over three years is nothing short of the wildest science fiction. The discovery of Massimo's defective gene – a mutation in the DARS gene which is thought to prevent the formation of myelin, a protective coating around nerve fibres in the brain and spinal cord, as well as causing leg spasticity – and coming up with a more specific diagnosis than had been possible before, together with the parent-driven nature of this advance; all this marks a huge turning point in
medicine, no less monumental than landing a man on the Moon. Fitting that Massimo's favourite toy is a NASA Space Shuttle.

Dr Adeline Vandever, a paediatric neurologist who specialises in leukodystrophies at the Children's National Medical Center in Washington DC, is part of the international team involved in finding the gene causing Massimo's illness.

‘Before genomic medicine, the patient and their family were very isolated,' she says. ‘Several times a week I get an email from someone out there who has a child with an unsolvable leukodystrophy. This is all played out in Massimo's story. Once the gene responsible for his condition was found, we started looking at a series of images in other patients.' The man responsible for the discovery is Dr Ryan Taft, a genomics researcher then working at the University of Queensland's Institute for Molecular Bioscience.

‘We asked Ryan to analyse their genomes too and immediately found two patients who also had the DARS gene defect. Instantaneously, we had a domino effect, with a whole cohort of patients. Since the paper was published in the
American Journal of Human Genetics
, even more are coming out of the woodwork. Genomics, coupled with the link-up and collaboration around the world made this possible. This shrinks the isolation of these families, from Michigan and Colorado to Melbourne.'

Before we look to the future though, she emphasises that we need to look back at the past to see how far genomics has come.

‘I've been doing this work for ten years. At first only a handful of diseases were identified, there was a creeping-forward in disease discovery. Now it's galloping and diagnoses occur weekly, whereas once they were only occasional. Of course, the main reason for this is genetic advances, but there are less tangible advances too. I remember when I was pregnant with my second child, eight years ago, when Professor van der Knaap, my colleague in Holland, came to visit. I would wheel in a huge rolling cart of printouts of MRI scans and pin them up on the white
board. It took us three days just to look through all the results. Now, everything is digitised. I can upload the same amount of information on Dropbox and share it with her instantly. Nowadays we spend all our time doing virtual second opinions. Sometimes we can make the diagnosis on image alone. We have quicker diagnoses by virtue of advances in information technology.'

From my notes in Massimo's file: ‘Having Baclofen at night to prevent muscle spasms. Awaiting genetic testing results.'

From my notes in Massimo's file: ‘Genome ready in a few weeks. They have pushed finding a genetic diagnosis with one aim in mind – to find a treatment or cure for Massimo.'

* * * * *

It took 11 years and billions of dollars for the first complete human genome to be read back in 2001. The Human Genome Project set out to decipher the code of human DNA – our genetic blueprint, comprising over 25 000 genes and three billion letters of DNA – with the ultimate goal of identifying how each gene might contribute to disease. To date, there are around 8000 known genetic diseases. However, the faulty gene responsible for a particular disease has been identified in only 40 per cent and of these known genetic causes, only a fraction can be treated in some way. Statistically, you are probably more likely to find a needle in a haystack than an unknown gene that is causatively linked to a disease.

‘If each letter of Massimo's raw genome data was one centimetre [long]… it would stretch to the Moon and back 4.6 times,' Stephen Damiani says. ‘We were searching for two letters and found a compound heterozygous variation in the DARS gene.'

Genomic medicine, also known as personalised medicine, where whole genome sequencing and various other screening technologies are employed, is rapidly changing the future of
health care. Researchers in the field are using the vast amount of data that can be gathered on an individual's genetic make-up to tailor prevention, diagnosis and treatment plans for various diseases.

Technology enables researchers to take shortcuts in gene sequencing, focusing on a specific region of DNA – called an exome – that specifies the genetic code for proteins. Although exomes account for only 1 per cent of the entire human genome, they are thought to be implicated in more than 80 per cent of mutations that cause disease. The estimated number of rare disease sufferers in the world is as high as 250 million. The exciting thing about personalised medicine is that as these methods are refined and become cheaper, much earlier diagnosis for hitherto unknown diseases is being brought out of the realm of what was once science fiction. This enables clinicians to better predict the course of a genetic disease and aim for earlier and better treatment options. Or simply give parents a name for their child's mystery illness, so they know what they are dealing with.

‘This is the future of medicine,' says Dr Ryan Taft, who led Massimo's team of doctors from around the world – including paediatric neurologists and MRI experts from the Children's National Medical Centre in Washington DC, Royal Children's Hospital in Melbourne and VU Medisch Centrum in Amsterdam. They worked collaboratively to diagnose Massimo's condition.

‘It is a complex area and brave new ground for all involved,' says Taft, whose expertise is in bioinformatics, a field that lies at the intersection of computer science and biology. ‘Although in this new age of genomic medicine we are getting better at finding mutations, translating these discoveries into specific treatment is still a huge leap, especially when it comes to a newly recognised genetic disorder in a gene like DARS, the one we found responsible for Massimo's disease, that has previously not been described as being associated with any disease.'

Taft became involved with the Damiani family by happenstance. I was having coffee with his wife who had recently edited a piece I'd written about how physicians have a tendency to develop ‘tunnel vision of the soul', an inability to read the nuances in a patient's narrative. I was telling her about the Damianis as a case in point, and of some genetic specialists who were tending to dismiss their ideas for further investigation of their son as science fiction, when she casually mentioned that her partner was a genetic researcher. I look back on this moment now and like to think that in my previous incarnation I may have been the village matchmaker, floral scarf and all. Taft soon became involved in the Damianis' search for a diagnosis, working on the project during his free time, often through the night and on weekends, without any pay. It was a steep learning curve for him, with many ups and downs.

‘This whole journey was amazing and I feel honoured to have been a part of it,' says Taft. ‘It's very rare for a basic research scientist to be on the receiving end of a call from the father of a sick child, asking, “can you help us?” Knowing there was even a remote possibility that I could have some small effect on someone's life was hugely motivating. Then, to actually get what I thought was “It”, was incredible. I convinced Illumina [a US biotechnology company specialising in the field of genomics] to take a shot with sequencing Sally and Stephen's genomes. Once we had the findings, it took a couple of weeks before the clinicians reacted and then months went by before we could really validate everything. Soon after though, the team in Amsterdam independently identified two more patients with mutations in the DARS gene and within 48 hours, 18 months of hard work was completed. It felt surreal. We got to discover a new disease. Who gets to do that?'

In a recent
New York Times
article on pushing forward gene sequencing technology that can afford rapid diagnosis of genetic
illnesses in a neonatal intensive care unit, Dr Stephen Kingsmore, director of Children's Mercy Center for Pediatric Genomic Medicine, reiterated the hardship a family goes through when it ‘embarks on a terrifying diagnostic odyssey. When a baby has a mysterious disease, test after test is performed,' he said. ‘Some tests are invasive; the child is suffering. The child is getting worse and worse – most spend their entire lives in the hospital, and there is no answer.' Just knowing the answer can be a comfort. ‘Providing a definitive diagnosis somehow brings closure,' Kingsmore said. ‘It is something they can name.'

Adeline Vanderver says recent advances in genomics have completely changed her life as a physician working in the field of paediatric leukodystrophies. ‘In one way a diagnosis robs parents of the hope that there's nothing wrong, the lingering thought that maybe the doctors are misguided in their bleak prognostications. But most find a huge sense of relief at the end of their diagnostic odyssey. The end of this trip is only one leg of the journey over, it is particularly treacherous – it is difficult for parents to 100 per cent trust their doctors because they don't know what the future holds.'

As to whether there is any imminent treatment breakthrough in sight, Vandever muses: ‘That's why I get up every morning. We are searching for a global cure for leukodystrophies, looking at replacing defective cells in the body with normally functioning ones. We are hoping to minimise the disease process for sufferers and improve their symptoms, hopefully improving their life expectancy. But we are still a long way away from this.'

How does working in this field affect her personally?

‘I keep a stack of condolence cards in my desk drawer. I have to use them far more often than I would like. There are days when that's really hard. I go to patients' funerals if I think it's meaningful for the families to have me there. We have palliative care paediatricians attached to our unit, disguised as what we
call “complex care” doctors. Together with grief counsellors, they help both the families and the medical team to cope with accepting that often there is nothing we can do to save these children. Everyone's life has an arc – a beginning, middle and end – but even though these children's arcs may be much shorter, they can still be packed with meaning.'