From the age of three, a child called Alan’s life was severely restricted by an immune disorder. It made bleeding almost impossible to stop and began to destroy his blood cells, threatening his life. Doctors suspected his disorder was genetic, but tests for known immune deficiency genes failed to identify the culprit.
Uncovering rare diseases
Realising time was running out, his doctor nominated him to take part in a study to better understand and diagnose rare immune conditions at the Garvan Institute of Medical Research. The study was run in collaboration with hospitals and Garvan’s Kinghorn Centre for Clinical Genomics (KCCG), the largest genome sequencing centre in the Southern Hemisphere.
KCCG’s genome sequencers are some of the most powerful on the planet, capable of sequencing more than 15,000 whole human genomes a year. Every day, KCCG generates at least four terabytes of data — equivalent to around 1,600 hours of high-definition video streaming.
Alan and his family gave blood samples, and their genomes — each one comprising over six billion DNA letters — were read by sequencers at the KCCG before being processed by supercomputers. KCCG bioinformaticians then used computational tools to analyse the data and prepare it to be interpreted by clinicians.
Working through the sequencing data for Alan and his family, the team’s clinical geneticist struck gold: a gene called LRBA. Alan’s genome contained two exceedingly rare disease-causing variants of the LRBA gene, one from each of his parents.
With the diagnosis, doctors could understand what was causing Alan’s condition: missing molecules that act as a brake on the immune system, causing it to ‘go rogue’ and attack normal body tissues.
As luck would have it, researchers in the US had recently separately identified a drug that mimics the function of the immune system ‘brake’, and his treating clinicians worked around the clock to get it approved for him.
Alan recovered rapidly in the weeks after starting the drug. When visiting, his medical team were surprised to find a boy so recently gravely ill completely transformed.
Of all the life sciences advances the world has witnessed over the last half a century, genomic sequencing has been among the most extraordinary.
Over a decade ago, it cost more than a billion dollars to sequence the first human genome; now it can be done routinely for just a few thousand dollars.
Alan’s story shows how genomic sequencing can transform the life of someone with a rare disease. And at a population level, genomics is also generating new insights into the causes of conditions that affect hundreds of millions of people — cancer, diabetes, heart disease and congenital disorders.
KCCG’s research is focused on improving the value, interpretation and translation of genomic information for patient care. Among numerous research projects, whole genome sequencing is being used at KCCG to identify kidney disease-causing gene variants; to understand how cancer tumours evolve; and to understand genetic risk factors for heart disease.
A/Prof Marcel Dinger, Head of the Kinghorn Centre for Clinical Genomics, explained that genomic sequencing at scale is also heralding the arrival of personalised medicine, where a simple blood test can identify susceptibilities to diseases like cancer and diabetes, help doctors make better choices for treatments, determine likely drug responses and motivate healthy behaviours.
“KCCG is uniquely positioned to translate the value of the human genome to realise the promise of precision healthcare,” said A/Prof Dinger.
Underpinned by technology
Behind the scenes at KCCG lies a high-performance computing environment that has been tailored for genome informatics. Housed within a Garvan IT data centre, the system comprises almost 2000 CPU cores with 512 Gigabytes of memory per node and 100 Gigabit per second network switches.
The data produced by whole genome sequencing is highly complex and goes through multiple stages of analysis and quality control. Some of this is done at Garvan, while other stages are run at scale at dedicated supercomputing facilities including the NCI supercomputer in Canberra.
Once processed, the data is accessed by national and international researchers who analyse it in a secure environment — either the NCI supercomputer or another high-performance cloud computing infrastructure.
AARNet partnered with UNSW IT and Garvan to design and deploy the network infrastructure required for the sequencing centre.
Dr Warren Kaplan, Garvan Chief of Informatics, explained that a recently implemented high-speed AARNet link connects Garvan to the NCI supercomputer for faster access to data than ever before.
“While in-house computing infrastructure is useful for prototyping and optimising, much of Garvan’s genomic research data is stored at the NCI in Canberra because its capabilities are wonderful for running at scale.”
“There are more than 80 Garvan bioinformaticians working with local and international collaborators on genomic data, and we have mind-bogglingly large amounts of genomic information that needs to be moved over the AARNet network for analysis and storage at the NCI. The volume of data is increasing exponentially so we also require a scalable network to meet our needs into the future.”
“We have mind-bogglingly large amounts of genomic information that needs to be moved over the AARNet network for analysis and storage at the NCI. The volume of data is increasing exponentially so we also require a scalable network to meet our needs into the future.”
The future of sequencing
Along with greater efficiencies, A/Professor Dinger explains that the next important step will be better integration of clinical research and practice to help us grow our knowledge of the human genome.
“We anticipate that translation of this new knowledge will lead to better health outcomes. This extends from our personal genomes informing our health care throughout our lives, to the sequencing of individual cancer cells in an effort to identify and tailor treatments.”