Published in Griffith Review, July 2013
AS soon as the midwife placed my newborn son on my belly, moments after a twenty-three-hour labour brought him into the world, I started counting his fingers and toes. I checked his fontanelle wasn’t too big. Or too small. Or bulging. Or sunken. I looked closely for a squint, unusual lumps on his ears, a receding chin, any sign of respiratory distress. I ran my hand slowly along his spine. Most parents I have spoken to over the years describe the first meeting with their baby as it emerges into the word in radiant or spiritual terms; a moment of exaltation. I, on the other hand, spent those precious moments at the starting line of our life together, scanning my son’s tiny 2.9 kilogram body for imperfections.
It’s how I roll. I have dedicated much of my working life to routinely checking newborn babies. I always set aside a half-hour slot so I have time to examine them thoroughly. Sometimes because of this I can run quite late, keeping the next set of young parents anxiously waiting. I hate it when this happens. Not only are they often shattered by lack of sleep, but they are also weary from Baby Tourism – that endless stream of relatives and friends popping in to visit, staying way too long, expecting to be served cake and coffee, oohing and aahing as they peer into the crib – ‘he has Uncle Freddy’s nose’, or ‘she has Grandma Zelda’s earlobes’. The truth is though, most parents are anxious as they wait to see the doctor because they want the security of knowing their baby is healthy.
One wintry day back in 2008, Stephen and Sally Damiani walked into my office, proudly holding their first newborn son. It was particularly frantic at the clinic, so I bypassed the chit-chat and went straight over to little Massimo. There is a fixed routine for examining a neonate head to toe. You need to completely undress the baby. First weigh them. Measure length and head circumference. Check the colour – pink is good, blue is definitely not. Palpate the fontanelles, look for symmetry of the face, insert a gloved finger into the mouth and use a torch to make sure there is no cleft palate, feel the tiny space between the skull bones, listen to the rapid lubdub of the fledgling heart. Feel for clicks in the hips as you splay their legs out like a frog. The stepping reflex is always good for a laugh – I tell parents their baby is a genius who already knows how to walk. Leave the Moro reflex for last, because as you hold the baby’s hands together and then let go, it will inevitably startle and let out a shriek. In essence, when you examine a baby, always look for something you don’t want to find.
Irish author Anne Enright writes in Making Babies (2004) of ‘the anxiety of reproduction, the oddness of it – and how it feels like dying, pulled inside out.’ Up until recently I’ve been in the habit of breathing a sigh of relief at the end of a normal examination, as I say to the parents, ‘Your child is perfect.’ It rolls off the tongue so easily and is the quickest way to engender beaming grins all around. But lately I’ve been thinking about this seemingly innocuous phrase and have substituted the watered-down, ‘Everything seems to be okay’. I remember as a young paediatric resident working at Prince of Wales Children’s Hospital in Sydney, calling a senior consultant once when I had found some abnormality during an examination. He told me to check for two more imperfections – ‘Things come in threes with FLKs.’ In those days we used this coded term when the parents were present beside the crib, for a baby who in some way seemed unusual and warranted further investigation. FLK: Funny Looking Kid.
Massimo Damiani had a two-millimetre skin tag at the base of his spine. I remembered my professor’s warning of the Trinity of Affliction and so spent time scouring the baby’s body for any other signs or anomalous structures. The rest of his examination was thankfully unremarkable, but an x-ray revealed unusual tethering at the base of his spinal cord, a malformation that would most likely need surgery further down the track. Stephen and Sally were devastated. None of us realised then that it was only the start of this little guy’s journey into the world of the unknown.
Notes in medical record: Parents have been trawling the internet for information. They have multiple questions I cannot answer.
WHEN THE EAGLE landed in Tranquility Base in 1969, I was a little girl seated on the rug in our living room, watching the live broadcast on a black and white TV screen. For a kid who had never travelled much beyond the sleepy Melbourne suburb of Elsternwick, let alone been able to imagine a voyage into space, watching Neil Armstrong step down from his lunar module onto the moon’s surface, I felt anything was now possible.
Years later, floating weightless in his space shuttle, Colonel Chris Hadfield, a Canadian astronaut who has flown in two missions, 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 recently, via a satellite link-up to William Shatner, aka Star Trek’s Captain Kirk. ‘You have the opportunity to go around the world every ninety 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 which is characterised by a lack of myelin, the substance that coats nerve fibres, enabling 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 twenty 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 it may be impossible as 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, 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, which we called Mission Massimo.’
What Stephen Damiani has achieved over the past three years is nothing short of the wildest science fiction. The discovery of Massimo’s defective gene, the coming up with a more specific diagnosis than had been possible before, together with the parent-driven nature of this advance, 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 from 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 digitalised. 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.’
Notes in Massimo’s medical records: Having Baclofen at night to prevent muscle spasms. Awaiting genetic testing results.
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 ELEVEN 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 twenty-five thousand 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 eight thousand 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 by one centimetre 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 able to 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 [Griffith REVIEW deputy editor Erica Sontheimer], 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, 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 is 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 Damiani’s 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 biotoechnology company specialising in the field of genomics) to take a shot with sequencing Sally and Stephen’s genome. 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 forty-eight hours, eighteen 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.’
Identifying a child’s genetic illness is a relief for most parents, Vanderver maintains.
‘It is always better to fight an enemy you can name.’
As to whether there is any imminent treatment breakthrough in sight, she 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 Vanderver 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 patient’s 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.’
When she looks at her own children, now aged five, seven and ten, she appreciates all the things they are capable of. ‘When my healthy five-year-old acts like a pill, I simply enjoy the fact that she can.’
WHAT TO DO with potential findings that are unrelated to the focus of the search, caught up in the drift net as you trawl through masses of information? The ethical considerations raised by genome sequencing are enormous. One of the pitfalls of sequencing and analysing a child’s entire DNA is that researchers may find aberrations leading to conditions that only become evident later in life. For example, would a parent want to know that their sick child carries a gene that increases the risk of Alzheimer’s as they age?
‘As scientists in the lab, we don’t look at these incidental findings, but it becomes a thornier issue when rolled out in the clinic. For example, how do we deal with insurance companies who may look at the genetic readout of a potential client and refuse to insure them? There is a revolution on our doorstep and most people don’t know it,’ Taft said.
The Beijing Genomics Institute Shenzhen (BGI), the biggest genetic research centre in the world, is aiming to become a major player in this space. They have initiated a Cognitive Genetics Program, sequencing and collecting entire genomes of two thousand of the world’s smartest people in an attempt to identify the genes which determine human intelligence. They are explicit that they are looking for IQ markers that are unique.
Mining human genetic material can potentially uncover a huge bioethical earthquake. China is not widely known for its ethics when it comes to clinical research. Tests on a mother’s blood or urine in early pregnancy can detect foetal DNA, which shows the sex as early as seven weeks. These foetal sex determination tests have a dark side that goes way beyond what one company advertises on its website – a marketing pitch that describes the kit as ‘a curiosity application for the parents who would like to know the gender of the baby’. This ‘curiosity’ to know the gender of a baby has purportedly led to a rise in the number of abortions of female foetuses in China, where traditional preferences are for sons. China now has a sex ratio bias towards boys, creating a gender gulf of more than 30 million more men than women who will enter the mating game by 2020. This gender shopping is commonplace in India as well. In fact, with the identification of IQ markers, a couple will most likely soon be able to screen their frozen fertilised eggs for intelligence and select the one to implant that will be the smartest of the lot. The project isn’t such a big step away from becoming blatant eugenics and rings alarm bells for me, not only as a physician, but also as the daughter of a survivor of Auschwitz.
China passed a so-called ‘Eugenics Law’ in 1994 – the Maternal and Infant Health Care Law: ‘This law regulates support for maternal and child health and also requires physicians to recommend a postponement of marriage if either member of a couple has an infectious, contagious disease or an active mental disorder. If one member of a couple has a serious hereditary disease, the couple may only marry if they agree to use long-term contraception or to undergo sterilisation. If prenatal tests reveal that a foetus has a serious hereditary disease or serious deformity, the physician must advise the pregnant woman to have an abortion, and the law states that the pregnant woman “should” follow this recommendation.’
There are more nuanced ventures than this though – several companies are currently offering non-invasive prenatal testing. They take a blood sample from the mother containing circulating foetal cells, to identify the most common genetic syndromes such as Down syndrome and Trisomy 18. It does away with the need for amniocentesis, a more invasive test used currently. Yet where do we draw the line as to what is okay to know? What happens when technology improves to the point where we can get a full foetal genome simply by sampling maternal blood and parents can elect to abort if, say, the child’s eyes aren’t blue, or he won’t be tall enough to play basketball?
Another area of deep concern is in the area of gene patents. In a recent article published in the journal Genome Medicine, the alarm was raised about companies laying claim to the human genome for profit. It showed that forty thousand patents already exist on human DNA molecules, which in effect limit clinicians and researchers from studying particular genes in order to develop new drugs or diagnostic tests.
‘If these patents are enforced, our genomic liberty is lost,’ says the study’s lead author, Dr Christopher Mason.
‘The future of genomics is full of promise, but there are still issues to be resolved,’ says Taft.
‘There has been an explosion in personalised medicine. Current genetic testing is faster and cheaper and will soon replace old diagnostic protocols. We are looking at the genetic structure of the genome and testing drugs using this technology that will work for the individual. In principle, a private hospital can already sequence every newborn born in their labour ward, with view to prevention and tailored treatment from the beginning of a person’s life. What concerns me most is that the public doesn’t understand this is happening.’
How do you start to lock this down, protect the rights of individuals to the privacy of their own, or their child’s genome?
‘The horse left the barn a long time ago,’ Taft says. ‘We need more public discussion about genomics and its impacts. It’s going to affect everyone. The technology is out there and both public institutions and private companies are already using it. We need to ensure data security – how do you maintain your genome in a safe place? Do you carry it around with you on a chip, attached to your keyring? The cost has come down from $3 billion in 2001 – in theory today your genome can be sequenced in seventy-two hours for $3,000. Currently most clinicians use an MRI for diagnosis, which costs around $1,500. Within eighteen months to two years they will almost certainly be looking at a patient’s genome as well.’
There is a sleek kit available now from a company called 23andMe, based in California, which is in part subsidised by Google. They offer direct-to-consumer genetic testing kits for $99 based on saliva samples, to create a ‘SNP Chip’ of data. In their waiver, they say that by agreeing to having this test done, a potential client will give them permission to mine the data and have the right to patent any genetic information obtained as a result. They are able to patent a biomarker of disease from the patient’s sample, essentially excluding researchers and clinicians from doing further tests on this gene.
Where does Australia stand in this international genomics revolution? When I was a young child, watching Neil Armstrong take that Giant Leap for Mankind, I remember feeling so proud when the TV commentator spoke of the support role of Australia’s Radio Telescope at the Parkes Observatory in relaying communications from the Apollo Mission to NASA. Sadly, we seem to be lagging behind in this new frontier of exploration and research.
‘It is a huge opportunity for Australia,’ says Taft. ‘We have the potential to do it right. We have a socialised medical system, a well-educated, mainly middle-class population and some of the world’s leading experts in the application and use of this technology. If we don’t step up now, we may not be able to compete internationally.’
In the United States it is possible to have a sick child’s exome sequenced within seventy-two hours nowadays. In Europe, this procedure has become a standard of care for suspected paediatric genetic disorders. In Australia, funding is scarce and the pull for top scientists to enter private industry is financially far more attractive. As the Damiani’s GP, I have witnessed the family’s ongoing struggle from the outset as they have negotiated with various high-level players, trying to enlist their assistance and backing in finding a diagnosis for Massimo. They ended up paying for a lot of the testing themselves, although the US company Illumina gave pro-bono help with the reagents used in sequencing the family’s genomes. I have been ashamed at times to see the turning-up of some of my genetics peers’ noses, the unwillingness to take risks into the unknown, or to simply keep up with state-of-the-art research and development happening in the field of genomics. Like many other visionaries, Stephen has met with a fair amount of resistance along the way. Thankfully, he is a stubborn and determined man and has followed those who were able to see beyond the tremendous obstacles, to have faith in his ability to facilitate the process.
The journey towards a cure has just started for little Massimo Damiani. What has been the hardest thing all along, according to his parents Stephen and Sally, is living with the uncertainty of their son’s future. From here on in they take solace in knowing they are not alone. The Damianis are realistic in their expectations, but determined to take another leap into the unknown towards developing a therapy and maybe a cure for their son, and for others around the world with this condition.
‘We have something tangible to fight now that the disease has a name.’