29 August 2016
Genomics has come of age. The massive reduction in DNA sequencing costs, approximately one million-fold since the completion of the first draft of the human genome 15 years ago, has brought this once elite field into the practical realm, not only to enable research into human health but also, increasingly, for productive applications in healthcare.
Our inherited and acquired genetic idiosyncrasies affect every aspect of our biology. They encompass our physical and to a substantial extent our psychological characteristics. They underlie the genetic disorders estimated to affect around 6-8% of our community, including 2% of children but also appearing, often without warning, later in life (for example in cardiac conditions), inherited risks for cancer and other complex diseases, responses to drugs, and susceptibility to infections, among many others.
To date, medicine and healthcare has been mainly and necessarily targeted at the average person, and usually at the point of crisis, with little knowledge of the underlying genetic variables, which has made it difficult to disentangle the synergistic relationship between genetic and environmental factors in the aetiology of disease.
The potential for genomic information to transform medicine and healthcare is being recognised in other jurisdictions, notably England (and soon the entire UK) through its NHS-overseen 100,000 genomes project, the United States through its Precision Medicine Initiative announced last year by President Obama, and most recently France, which has made an initial commitment of €670m.
Just over two years ago NSW became one of the first three places in the world to acquire the technology to enable the whole human genome sequencing for a base cost of ~$US1,000. While the actual costs of obtaining and interpreting the sequence information are substantially higher, they will decline rapidly, due to improvements in the technology and the impact of competition, as well as increasing automation of the analytical pipelines.
Thanks to substantial gifts from the Kinghorn Foundation to acquire the technical infrastructure and build the software systems, and major investment in developmental research projects by the NSW Government, NSW is well placed to lead the region and partner with the world in the realisation of the benefits of genomic medicine.
The Kinghorn Centre for Clinical Genomics, led by Associate Professor Marcel Dinger at the Garvan Institute in Darlinghurst, is now sequencing, for both research and clinical purposes, over 1,000 genomes per month, and rising, placing it among the leading centres internationally.
NSW Government investment, through the Ministry of Health and OHMR, totals some $34m, which has provided the ability to capitalise on the opportunity, and now lead the nation.
This includes $24m across the three programs of the Sydney Genomics Collaborative, comprising: a Medical Genome Reference Bank– a resource containing approximately 4,000 whole genome sequences from healthy, aged people to be used as a broad-spectrum risk-depleted comparison control for disease-specific genomic research; a Genomic Cancer Medicine Program – a research program applying genomics to the understanding of inherited risk factors, early detection, prevention and management of cancer; and NSW Genomics Collaborative Grants – funding for researchers to undertake whole-genome sequencing to improve understanding of the genetic causes of disease, which has powerfully engaged the clinical community and already funded seven major projects across the state, including at Westmead Hospital, Royal North Shore Hospital and the Hunter Medical Research Institute.
It also includes a $6m NSW contribution to the US-led Cancer Moonshot Program, funding an integrated cancer proteogenomics program at the Children’s Medical Research Institute at Westmead and Garvan.
[At this juncture I hasten to point out I use the term ‘genomics’, which is the most widely recognized word in the public eye, to include other ‘omics’ such as epigenomics, transcriptomics and proteomics, which all have considerable potential and whose technical and implementation challenges are being overcome.]
A philanthropic study to sequence children with unexplained disorders is also being conducted at Liverpool Hospital to demonstrate the utility of whole genome sequencing for children born with severe developmental and/or intellectual disability. Indeed the current diagnostic returns from whole genome sequencing are around 55%, tripling pre-existing rates, and rendering other expensive and usually unproductive diagnostic tests unnecessary.
These programs are also leveraging other investment, including a major NSW role in the $25m NHMRC-funded national research project – the Australian Genomic Healthcare Alliance (AGHA)– to investigate the best means of introducing genomic medicine, including assessment of the health economic implications led by Professor Deborah Schofield at the University of Sydney. They have also led directly to a $4m grant from Lions for a Kids Cancer Genome Project, involving the Children’s Cancer Institute and Sydney Children’s Hospital at Randwick, together with the Garvan and paediatric cancer centres around Australia.
New software suites are also being developed, to allow genomic analysis to be done at scale and be integrated with other forms of medical data; genomic information is sterile without it. To this end Garvan has recently developed software called Patient Archive, which enables the automatic conversion of clinical notes into standardized terminology that enables machine learning and cross-institution patient matching, is being trialed across Australia through AGHA as well as in Japan, and is included in an MOU with Genomics England. Another is Seave, which largely automates the difficult task of pathogenic variant identification and prioritisation, to optimise the process of genomic-driven disease diagnosis.
Most recently, the Garvan announced, with the support of NSW Health Pathology and SydPath at St Vincent’s Hospital, the establishment of the first clinical genomics company outside of North America, Genome.One, with NATA (ISO15189) accreditation, enabling clinicians to obtain diagnoses by whole genome analysis, initially of children and others with severe undiagnosed, likely genetic, disorders, and soon other affected groups such as renal and cardiac patients.
Indeed research at St Vincent’s and Garvan has shown that whole genome sequencing solves one of the longstanding difficulties in accurately diagnosing polycystic kidney disease. Garvan has also established a cardiogenomics program in partnership with the Victor Chang Cardiac Research Institute. Other programs, to sequence cancer biopsies and circulating tumour DNA, to inform treatment options and monitor progression, are being developed.
There is little doubt that genomics, aided by its intersection with clinical data and machine learning, will transform medicine, and improve the quality and efficiency of healthcare. Not as obviously, but in fact equally powerfully, it will make a contribution to the economic growth of the state and the nation, indirectly through the reduction in the burden of chronic disease, and directly through the establishment of next-generation health information industries (which have major export potential). This will require a new generation of clinical specialists, and the Royal College of Pathologists of Australasia is ramping up its training programs accordingly. It will also require large numbers of genetic counsellors, many of which are currently being trained at Royal North Shore Hospital.
NSW has made a great start, and leads the nation. It is important now that we work together to realise the benefits of genomics in medicine and health, and to both manage and accelerate its introduction into the fabric of the healthcare system in Australia and beyond.
By John S Mattick, AO FAA (Executive Director, Garvan Institute of Medical Research)