The final frontier

TELEVISION WAS MY babysitter. As a child growing up in the ’60s, I would race home from school, grab a plate of biscuits and a glass of milk, and spend the afternoon on the couch watching back-to-back American cartoons and sitcoms. Several decades later, I can still sing the theme songs to Mr Ed, Gilligan’s Island and Super Chicken, if asked nicely. Though my favourite by far was Milton the Monster, in which the diminutive Professor Montgomery Weirdo from Horror Hill, and his anaemic, lanky assistant Count Kook, concocted a grotesque son out of primordial soup. As well as ‘six drops of the essence of terror and five drops of sinister sauce’, they spilled way too much ‘tincture of tenderness’ into the cocktail they titrated in their secret laboratory. As a result, Milton was born a gentle giant instead of a terrifying monster. 

By the time the early ’70s rolled around, I’d moved on from heroic dumbclucks and mad scientists to become a Trekkie, an ardent follower of the sci-fi series Star Trek, set in the twenty-third century. I recited the opening monologue of each episode, along with the earnest and often bolshy Captain James Kirk: ‘Space: the final frontier. These are the voyages of the Starship Enterprise. Its five-year mission: to explore strange new worlds, to seek out new life and new civilizations; to boldly go where no man has gone before.’ 

Star Trek was certainly a major inspiration for my career choice to become a doctor – to boldly go where no woman in my family had gone before. I watched avidly as his curmudgeonly shipmate and friend, Dr Leonard ‘Bones’ McCoy, wielded technological wizardry to save an entire planet from the deadly Saurian virus. Using a contraption called a hypospray, by which medication is forced under the skin through a high-pressure delivery system, emitting a soft pffft – no needle required – he administered painless inoculations to the entire Dramian population. 

Back here on planet Earth, in real life, around the same time that Neil Armstrong took that first giant leap for mankind, a device called a jet injector, invented by Aaron Ismach, was being employed to administer mass inoculation as part of a successful program to help eradicate smallpox in Africa. The device – a gun-shaped, air-powered injector that breaks the barrier of the skin – fell out of favour when concerns were raised regarding the likelihood of cross contamination. Recently though, it seems to be making a comeback. In fact, the jet injector is only one of a myriad of technical advances in medicine that may very well see physicians being made redundant. Leveraging of enormous advances in genetic and molecular science, development in cross-disciplinary technology and the widespread availability of information over the internet have begun to drive a monumental shift in the world of medicine. In addition, narrowing differences in knowledge and power between doctor and patient have served to advance patient advocacy. And an increasing body of knowledge itself will inevitably shift the framework from one-size-fits-most to a more targeted model, although the element of cost-effectiveness in relation to this is unknown. In my nightmares, the examination of my patients is performed by my Smartphone, and my entire skillset has been superceded by Dr Data. Abraham Verghese, a well-respected physician and writer, fears that the patient is becoming no more than a data point. He laments the loss of doctors’ powers of observation as well as the vanishing of the traditional skill of bedside examination. Human touch, and all it entails, is already being replaced by CT and MRI scanners, and genomic medicine may be the nail in the coffin of traditional medicine. Verghese laments: ‘We’re losing a ritual that I believe is transformative, transcendent and is at the heart of the patient-physician relationship.’ 

DISEASE PAYS MY mortgage; I make my living from patients’ illnesses, although of course my job is to try to cure them, or at very least to mitigate their symptoms and alleviate their pain. As a family physician, I work at the coalface of death. It’s not unusual for a patient to walk into my consultation room feeling fabulous, only to leave after half an hour, mortality suddenly jumping out from nowhere, cruelly dangling its grey web before them. Mine is a sobering profession that has slowly taken its toll on me over the years, leaving me with a chronic trembling fear of which hideous illness I will eventually succumb to.

At the tail end of 2014, I was invited to attend a Key Opinion Leaders Summit organised by Illumina, a San Diego-based company on the cutting edge of genomics research. As part of the lead-up to this event, the offer to have my own genome sequenced was put on the table. Before the meeting, I received a report about what my own Scrabble tray of genetic letters held. Even though my Ashkenazi Jewish heritage ominously implied I might possess the worst of the letters, the Zs, Xs and Qs, I had somehow been knotted together with DNA that wasn’t too frayed. I’d won when it came to the genetic crapshoot – for now, that is. The known disease-causing genes I was tested for are a mere drop in the ocean compared to those that remain to be discovered. 

Experts from various disciplines had come together at the Illumina summit to talk about the future possibilities of personalised medicine. If the genome is our individual book of life, then everyone seated in the room were its publishers. Bold letters emblazoned on a sign hanging in the main conference room announced: Innovation is in our DNA. Below it, an unassuming urn rested on a table, a piece of cardboard propped against it, with Homemade apple cider and choc-chip cookies scrawled in black felt pen. We were told that only five hundred and fifty people in the world were privy to having had their entire DNA blueprint clinically interpreted to date. And I was one of them.

‘The future has arrived,’ announced Ryan Taft, Illumina’s director of scientific research. Back in 2009, while he was a postdoctoral bench scientist working at the University of Queensland, I had introduced Ryan to Stephen Damiani, the father of one of my paediatric patients. Baby Massimo was suffering from a mystery genetic disease, which saw him lose the ability to walk and swallow, soon after his first birthday. Stephen and Ryan teamed up and went on to find a novel gene mutation, hitherto unknown, by using a new technique in which both the parents’ and the child’s genomes were sequenced and analysed in tandem. This was no mean feat, especially as Stephen had no prior medical training and feverishly upskilled himself in both genomics and bioinformatic science. He was driven by sheer determination to try to save his son. ‘Children with rare diseases are now being diagnosed every day using whole genome sequencing,’ Taft says. ‘We need more public discussion about genomics and its impacts. It’s going to affect everyone.’ 

The Human Genome Project, the mapping of our collective DNA, was completed on 14 April 2003, after thirteen years and $2.7 billion dollars. Nowadays, the technology to unravel a chunk of your genetic map will set you back around $1,000.

On the shuttle from our La Jolla hotel to Illumina headquarters, I sat next to Sharon Terry, a petite, silver-haired former nun and unassuming mother of two adult children who were born with pseudoxanthoma elasticum (PXE), a rare disease affecting the elastic tissue of blood vessels and skin, which can lead to blindness. As president of Genetic Alliance, a network of over ten thousand organisations that includes many powerful patient advocacy groups, Terry lives and breathes genomics. Even her next-door neighbour happens to be Francis Collins, the current National Institutes of Health director and head of the Human Genome Project. During several heated discussions on the day, Terry held her own against the other high flyers in the room, which included Jeff Huber, senior vice-president of Google, and Jeanette McCarthy, a top educator and associate professor of medicine at University of California, San Francisco. She certainly occupies a front row seat among this group of people who are quietly changing the world. ‘My job is to empower people to move the science faster,’ Terry said. ‘Up until recently, the patient and their family have been inaudible. We are busy putting systems in place now so people don’t have to reinvent wheels. Parents are going to be the army that gets things done for their kids.’ 

Stephen Tucker, a quietly spoken specialist oncologist based in Singapore who is an expert in medical technology and digital health, chatted to me over a healthy lunch of salad and sushi. ‘My goal is to put myself out of business,’ he said, referring to patient-powered research networks like Genetic Alliance. These advocacy groups have not only become well-respected curators of information and knowledge, but have collectively evolved into a powerful driving force in the world of personalised medicine. ‘Genomics is not a test, it’s a resource. Anyone who is proud of traditional medicine hasn’t looked at the data. We don’t need to cure disease, we just need to stop killing people.’

At the concluding session, Michael Hultner, chief scientist at Lockheed Martin, asked rhetorically: ‘Why’s the guy from the airplane company that builds fifth-generation stealth fighters here to talk to you about genomics? As consumers drive medicine to a new culture, we need to prepare the IT structure that underpins it.’ And it seems Lockheed is lined up to do just that. It has forged a strategic alliance with Illumina to assist countries such as Qatar to launch projects in which every citizen’s genome is mapped, with the hopeful vision that in the near future they will be able to integrate genomics into the national health system. The collaborative mission statement asserts: ‘…analysing a person’s DNA sequence data can provide a better understanding of health risks (such as how susceptible a person is to a particular disease or if they may react to a certain type of medication), resulting in more precise and proactive medicine. By aggregating genomic data across large populations, public health and wellness officials can more effectively address health concerns, reducing health care costs and improving quality of life.’

The final words went to Howard Jacob, director of human and molecular genetics at the Medical College of Wisconsin. Bearing a striking resemblance to the original Star Trek’s Captain Kirk (the young William Shatner), he summed up our meeting enthusiastically, his face beaming: ‘You are the first set of explorers. I can think of no other diagnostic thing we do in medicine that has benefit from the day you are born to the day you die. We are entering a new era of discovering the genetic underpinnings of disease.’ When I asked him why there has been such a slow uptake of genomic medicine among medical professionals – many are downright hostile to the idea, while others are at best sceptical, if indeed they have even heard of it at all – he stared at me with piercing blue eyes. ‘The king never calls for revolution.’

THE WORD ‘BESPOKE’ has always sounded like something out of a Jane Austen novel to me. First cited in the Oxford English dictionary in 1607 – ‘ordered, commissioned, arranged for’ – it is often interchanged with the term ‘custom made’, which I used to hear thrown around my father’s tailoring workshop when I was a little girl – each client’s waist, chest and arm length measured carefully, secret numbers jotted down like code in a tattered but sacred notebook he hid in his shirt pocket. The garments he made were individually cut, lined with the finest silk, and painstakingly hand-stitched. The most important thing to him was the fit, and he would bring the customer back several times to ensure everything was perfect. Father used to complain bitterly when companies started manufacturing clothes on a large scale. ‘Shpimbedegingeh!’ he would cry, resorting to Yiddish, his mother tongue, to decry the rise of shoddy craftsmanship, running his thumb over the frayed edges of mass-produced garments – ‘And no overlocking either. 

In those days, a regular protagonist of my after-school TV binge watching was Marcus Welby MD – the medical equivalent of my father. Like my tailor father, this old-fashioned doctor carried with him values of caring for the bespoke, the individual. This set him apart from the decades of physicians who have administered treatment to patients with a formulaic approach, focusing on diagnosis through taking a history of symptoms. From this gathering of information across a multitude of patients’ records, guidelines were formed and standards of care and treatment applied to patients across the board. The problem, though, is that guidelines look backwards and audit what was, in order to determine what will be. The other stumbling block is that, up until recently, medicine has been reactive, formed on the precept that doctors fix what is broken. Benjamin Franklin’s famous aphorism, ‘an ounce of prevention is worth a pound of cure’, is the premise that the world of genomics now seems to be focused on.

Our current model of healthcare is built around limited knowledge; despite differences, many people have a lot of things in common. Modern healthcare systems accommodate the majority, in both diagnosis and treatment, a one-size-fits-all approach. Yet throughout history, medicine has always aspired to be a personalised gig. Even as far back as Hippocrates, the ideal course of treatment for each patient was based upon the four humours of phlegm, black bile, yellow bile and blood. Nowadays these have been replaced by four tiny proteins – adenine, thymine, cytosine and guanine – the building blocks of DNA that through their sequence make each of us unique. These, coupled with newly-identified biomarker proteins in the blood, may lead genomics and its offshoots to become the equivalent of a soothsayer’s crystal ball in enabling more accurate health predictions, not only at the earliest stages of illness, but also by pre-empting disease before it occurs. Not only will we be able to predict the likelihood as well as the timeframe in which an individual may develop a certain disease, we will also be able to check whether they will respond well to treatment, preventing avoidable serious drug reactions along the way. 

The body is a highly complex system of networks we do not fully understand. If doctors aren’t sure exactly what it is they are trying to prevent, they rely on watchful waiting before they act. Often, this is too late for the patient, as the disease process has progressed beyond the stage where modern treatments are effective. With the recent advance of genomics, digitalised medicine can rapidly augment the current model of medicine and begin to allow health professionals to design tailor-made treatments based on an individual’s specific genetic makeup. 

The personalisation of things – from what we choose to eat and wear, through to bespoke designer furniture and curated travel – has become a prime feature of consumer culture. We use all sorts of gadgetry to monitor everything from our calorie intake and hydration level to the number of steps we have taken and how our heart rate responded to this. It is only a matter of time before the annual routine check-up at the doctor’s will be replaced with ongoing self-monitoring of the body’s physiology and metabolism, predicting individual risk factors beyond sweeping general guidelines. 

All these individual indices and measurements will then be added to a universal database to pool information. Innovation is rooted in the recording and siloing of these parameters. Precision medicine offers new possibilities of treating cancers according to a genetic profile unique to each individual. No longer will the stab-in-the-dark approach work. Breast cancer and melanoma will cease to be global terms that encompass a preformed set of rules for treatment; rather, a patient’s genetic profile will provide the data for a specifically designed treatment to target the unique type of breast cancer or melanoma they have, or are even just prone to develop. 

The advent of pharmacogenomics, which identifies how genes affect responses to drugs, means that deciding which medication a patient is likely to respond to will no longer be left to guesswork. Pre-prescription geno-typing will inevitably become a widespread practice, leading to fewer if any side effects and adverse reactions.

The Cancer Genome Atlas, completed at Johns Hopkins University in 2015, is a compilation of the known genomic changes in all cancers. It is used to inform individualised cancer treatment. The artificial division of cancers into regions of the body will become anachronistic as sequencing the genes of specific tumours, irrespective of their anatomical origin, and the use of precision therapy are becoming the norm. Gene editing, which uses new technologies such as CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) to remove a faulty DNA sequence, is a rapidly growing area of research. In much the same way that you hit the delete button on your keyboard to remove a typo, CRISPR operates like a genetic scalpel to change or replace genes inside the cell. 

By contrast, gene therapy, an experimental and novel technique that uses the transfer of genetically modified stem cells to add in a gene copy, opens up potential treatment for hereditary conditions such as cystic fibrosis, immune disorders and even some cardiovascular diseases. The potential risks posed by these therapies beg the breadth of our imagination. There is already concern among sports physicians that the potential use of genetic enhancement or ‘gene-doping’ in athletes – something that, unlike anabolic steroid use, could pass by authorities undetected – could open up a veritable Pandora’s box. The International Summit on Human Gene Editing issued a statement after its December 2015 meeting, emphasising that it would be ‘irresponsible’ to proceed with clinical application of germline gene editing until issues of efficacy and safety are sufficiently addressed. 

Epigenetics – linking DNA and environmental factors – is another area that is causing a buzz in research. Studies of external factors, such as certain viruses, chemical exposure, diet and even the experience of trauma, have shown tentative evidence that these insults are somehow able to modify how a gene is expressed. These changes seem to play a role in the development of disease, and may even be passed on to subsequent generations. 

Eric Topol, professor of genomics at the Scripps Research Institute, calls personalised medicine ‘panoramic’ in its scope. Rather than being population based, it draws on information from individuals in real time – the data generated by patients themselves rather than doctors. Also rapidly disappearing are the days when doctors own their patients’ histories and hide case notes away in confidential files. Precision care is relevant at all stages of the life cycle – from preconception to death and, in the case of tracing ancestry, often beyond the grave. It is rapidly becoming the new status quo. In the same way as the first computers were clunky and the neonatal form of the internet viewed with trepidation, so too genomics has as many doubters as it does proponents. If we do indeed come to a point where we are able to find a cure for all maladies and prolong each person’s longevity to afford a two-hundred-year healthy lifespan, what in essence have we really achieved?

At the dinner table one evening, my teenage son asked me to pass the salt. As I handed him the shaker, I dutifully delivered a mini lecture on the health benefits of a low-salt diet. This was followed immediately with him asking why I’d chosen a career in medicine. As he seasoned his meal, I kvelled with pride at what a noble profession being a doctor was – ministering to the sick, sometimes even saving people’s lives. I hoped like mad that some of my enthusiasm would rub off on him so he might consider donning a white coat in the future, following proudly in my footsteps. He chewed his food slowly.

‘Surely, disease is nature’s regulatory system?’ He stabbed a mushroom with his fork. ‘It’s life’s way of keeping the fragile ecosystem on our planet in place. By fighting disease so avidly, you doctors disturb this fine balance. It’s unsustainable.’ It was an uncomfortable, unpleasant thought, and I shoved it away as soon as he raised it by asking if he’d like another helping of lasagne.

‘THERE HAVE BEEN three revolutions in genetics,’ says Professor John Mattick, scratching his neatly trimmed, greying beard. As head of the prestigious Garvan Institute of Medical Research in Sydney, he is at the forefront of the tornado that genomic medicine promises to be. ‘Discovering the double helix structure of DNA allowed us to see what a gene looked like. Then came cloning – which provided us with a window into gene complexity. Now we have genomics – an unrecognised seismic shift in the world.’ 

Mattick is a genius. At four he was already reading Longfellow’s The Song of Hiawatha. He topped Year 2 at St Mary’s in the Sydney suburb of Concord and still has the copy of Black Beauty he received as a prize. He went on to dux almost every class, embarrassed to admit he even came dux in religion. The price he paid was that throughout his entire school life, he had to endure the kids teasing him. His nickname was ‘four-eyes’.

‘I spent a lot of my time trying to convince them I was human,’ he says, pushing his wire-framed spectacles back up onto the bridge of his nose. ‘I was a dopey kid socially. I had no idea what I wanted to do in life. I dug ditches for the Sydney water board, worked in the post office, drove taxis late at night in Kings Cross. I thought about becoming an actuary. I didn’t want to do medicine; the idea of looking down people’s throats didn’t thrill me. Besides, I was already a natural radical – the established order had little value for me.’

He’s not sure where all the school bullies ended up, but Mattick, despite skipping dull lectures during first year university to go sailing on Sydney Harbour, went on to pursue an illustrious career as a scientist, eventually running the Institute of Molecular Biology at the University of Queensland, where he became mentor to two outstanding young researchers – Marcel Dinger, who went on to become head of the Kinghorn Centre for Clinical Genomics, and Ryan Taft, the scientist who ended up finding the cause of little Massimo Damiani’s mystery illness. Not having had a gifted mentor himself as a young scientist, Professor Mattick took on an important behind-the-scenes role during the diagnosis of Massimo. He plays it all down: ‘It was mentorship by neglect. I just sheep-dogged around the edges. But the intellectual environment at the institute in Queensland was super and we all wanted to prove the world wrong about “junk DNA”. We showed them that junk wasn’t rubbish.’

Taft maintains it was this freedom to pursue his own creative ideas, coupled with Stephen Damiani’s enthusiasm and drive, that helped him find the pathway to discovering a new disease.

The Garvan Institute’s five-year goal is to develop a simple, routine diagnostic test for rare and inherited diseases using next-generation sequencing technology, which incorporates characterising the development of cancerous tumours such as pancreatic cancer. Mattick believes that precision genomic medicine ‘will have a transformative impact on personal health and wellbeing, health economics and national productivity’. Funding from the National Health and Medical Research Council was recently allocated to the institute for a major multidisciplinary initiative entitled ‘Preparing Australia for Genomic Medicine’.

Years ago, Mattick, Taft and Dinger had already envisioned a future in which everyone will have their genome sequenced as part of a routine health record. ‘Look, there’s an iPhone app called Face2Gene in which you can upload a patient’s photo, and use facial recognition technology to match facial features to a database of genetic dysmorphic syndromes for diagnosis,’ muses Marcel Dinger. ‘That, and the iPhone app FaceFusion could make dating etiquette interesting: one snap and a peek at what the kids might look if you partnered up with the person seated opposite you in that romantic restaurant may cut the date short, prompting a “maybe I’ll call you” followed by a quick getaway.’

THE INTEGRATION OF patients’ medical and genomic information is key to the success of cutting-edge research, as well as advancement in the clinical arena. This requires investment in building the necessary infrastructure that will accommodate enormous electronic databases. Scientific and medical communities worldwide are beginning to seize the transformative opportunities of personalised medicine, although its rapid development has left most providers feeling underprepared. Headway is also being made at local research facilities such as the Centre for Comparative Genomics at Murdoch University in Western Australia, and the Menzies Institute for Medical Research at the University of Tasmania. But in order to become a key player on the global stage, and convince the Australian community to embrace the potential of genomics while feeling confident they are protected in terms of privacy and data security, a lot more investment and innovation needs to occur.

Elsewhere, these opportunities are being embraced. US President Barack Obama’s ‘Precision Medicine Initiative’ has added momentum to the inte-gration of genomics into the clinical setting. The ‘100,000 Genomes’ project is well underway in the UK, which aims to sequence the genomes of children with rare disease and their parents, as well as a broad range of oncology patients. It is the largest genome-sequencing project in the world and aims to kick-start a UK genomics industry, with the protection of genomic data as one of the key areas of focus. This new need for absolute security is itself emerging as its own unique field of research. Alongside the potential misuse of gene editing, many opinion leaders emphasise our need to be mindful of ensuring that the dark history of human genetics of the first few decades of the twentieth century not be repeated. 

One arena of personalised medicine that holds enormous promise is pharmacogenomics, the study of how an individual will respond to drugs, thereby affording a tailored approach to prescribing. The genotyping of certain metabolic enzymes that chemically alter drugs in order to eliminate them from the bloodstream has already lead to improvements in the administration and calculation of dosages of medications for a wide range of conditions, including depression, heart disease and cancer. Minimising deleterious side effects and blind, trial-and-error prescribing has seen dramatic improvements in the management of a broad range of patients. 

Implications of genetic technology for the pharmaceutical industry are particularly important. The shift towards targeting drugs to specific, segmented populations changes the entire dynamic of drug development. This has the potential to affect all levels of the industry, from research and development through to dispensing and costs. It could be incremental or entirely disruptive, given the rate of its evolution. 

Since the mapping of the genome more than a decade ago, these rapid developments have left a gap not only in the infrastructure and education required to support personalised medicine, but also in the public debate over policy, which includes bioethical considerations as well as new business models. The enthusiastic proponents of genomic medicine foresee a future filled with promise, in which the healthcare system undergoes a huge paradigm shift. Others imagine a Gattaca-like world, populated by mutant monsters and zombies created by mad scientists bent on genetically engineering human life at any cost. In this dystopian vision, nascent regulatory guidelines will become impossible to police and the entire spectrum of molecular medicine, including the metabolome, the proteome and the epigenome, will run amok.

The naysayers of genomic medicine raise concerns regarding the storage of sensitive data and information as well as the environmental and bioethical considerations around new techniques of gene editing, stem cell treatment and gene therapy. However, as testing becomes quicker and cheaper, personalised medicine is slowly coming to replace the drawn-out and often excruciating odyssey of old diagnostic protocols. The shift in medicine is from an emphasis on symptoms and reaction to methods of prevention. Although the future of this new technology is full of promise, issues at both a bioethical and data security level need to be vigorously debated in public forums and ultimately resolved. 

For most humans, life expectancy has increased by three months for every year over the last hundred and sixty years, despite the plague, Spanish flu and countless wars. The radical increase in longevity that personalised medicine promises changes nature’s game plan for the planet. I thought about my son’s harsh yet prudent criticism over the dinner table after naively singing my profession’s praises for prolonging life – out of the mouths of babes. It’s crucial for us all to keep in mind that personalised medicine is still only a map for a better future, and not a definitive promise. 

BACK IN THE mid-1960s, the flat-topped Milton the Monster, puffs of white smoke blowing from his empty head, was designed to do his master’s bidding. The accidental spillage of too much ‘tincture of tenderness’ into the mould scuppered Professor Montgomery Weirdo’s evil designs of ‘monstrous glory’. His grotesque son was instead filled with empathy and understanding for his fellow ghouls. At the end of every episode, the heart-of-gold Milton, missing the obligatory fierceness of monsterdom, inevitably saved the day, bringing compassion and kindness to Horror Hill despite his father’s dastardly plans. 

My glass of milk resting empty on the floor, a plateful of Arnott’s Teddy Bear biscuits devoured, I always sang along to the closing refrain:

Now all of us must take that creepy 

trip down Horror Hill.

Beware the dangers along the way

Or you may take a spill.

I understood it signalled the time for me to settle down and get to work on my homework, in preparation for the important lessons the next day would bring.

Listen to Leah Kaminsky discuss genomic medicine and her book We're All Going to Die with Phillip Adams, on ABC RN's Late Night Live.


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