Pathogen genomics research transforms disease control

Written by Professor Vitali Sintchenko
Westmead Clinical School and Institute of Clinical Pathology and Medical Research, Westmead Hospital

For many years, communicable disease outbreaks have been managed using a number of time-consuming investigative tactics. Tracing the cause of the epidemic involved investigating the characteristics of the people affected, doing detective work to identify the causative pathogen, working out the mechanics of the spread and then introducing control measures.

Researchers at the University of Sydney and Westmead Hospital recently developed a faster, more accurate and potentially more economical approach to disease control by studying the genome of affected people using body fluid samples, such as blood or respiratory secretions.

Following this breakthrough, NSW Health Pathology officially launched a state-wide public health pathogen genomics service designed to assist communicable disease control. This service will be offered at the Institute of Clinical Pathology and Medical Research (ICPMR) at Westmead Hospital where a new unit has been formed.

Established in July 2019, this landmark development is the culmination of a decade of translational research led by Professor Lyn Gilbert AO and Professor Tania Sorrell AM.

The research brought together microbiologists from the University of Sydney School of Medicine, as well as specialists in public health, epidemiology, microbiology and genomics.

More specifically, it was a long-term collaboration between clinicians and scientists from the Centre for Infectious Diseases and Microbiology-Public Health (CIDM-PH) at Westmead Hospital, NSW Health Pathology-ICPMR, the Westmead Institute for Medical Research and Westmead Clinical School. 

The team recognised that next-generation sequencing technology enabled high-resolution, genome-wide examination of pathogens unequalled by other contemporary methods using gene-by-gene comparisons. They also realised the significance of applying this genomic technology to public health laboratory surveillance and outbreak detection.

In addition, they realised that for genomics to be truly transformational, it must generate the diagnostic data sufficiently and rapidly to support public health action, so a capacity for rapid sequencing and analysis of pathogens was required. 

The work began in 2012 when a next-generation benchtop gene sequencer was procured as a result of a generous donation from the Raymond E Purves Foundation. This enabled researchers, for the first time, to develop and evaluate testing and analysis pipelines where all pre‑analytical, sequencing and post-analytical steps were controlled and adjusted to maximise the clinical and public health value of results.

This new capability supported several successful National Health and Medical Research Council (NHMRC) grants and was utilised by three NHMRC Centres of Research Excellence (CREs): the CRE for Critical Infectious Diseases (led by Professor Jonathan Iredell at Westmead), the CRE for Tuberculosis Control and Prevention (Professor Warwick Britton AO, Centenary Institute of Cancer Medicina dn Cell Biology), and the CRE for Emerging Infectious Diseases (Professor Sorrell).

The team of clinicians and researchers involved in applied genomics research grew in numbers and expertise. From the beginning, researchers have recognised the importance of cross-disciplinary engagement to maximise the power of genomics and the critical role of informatics.

This has emerged as a critical element of translational biomedicine due to rapid advances in bacterial genomics, pathology informatics and molecular diagnostics. Epidemiologists from NSW Health Protection have also become essential partners in the research.

The establishment of the Marie Bashir Institute for Infectious Diseases and Biosecurity (MBI) by the University of Sydney in 2013 has provided a powerful boost to the agenda of communicable disease control.

The partnership between MBI, CIDM-Public Health and NSW Health Pathology-ICPMR has led to further enhancements in the pathogen genomics capability across campuses.

The NSW Pathogen Genomic Initiative put forward by this partnership attracted $1 million of infrastructure funding from the NSW Ministry of Health. 

This enabled the upgrade of next-generation sequencing equipment and led to multiple collaborative projects with staff from Royal Prince Alfred Hospital, the Woolcock Institute of Medical Research, St Vincent’s Hospital, the Prince of Wales Hospital and the University of New South Wales.

Activities of MBI and CIDM-PH have provided evidence and examples which led to the recognition of pathogen genomics in the NSW Health Genomics Strategy as an important case study for implementation.

The appointment of Professor Edward Holmes as Professor of Evolutionary Biology in the University’s School of Life and Environmental Sciences has broadened the scope of research and facilitated evolutionary approaches to the analysis of microbial genomes.

This has demonstrated that ongoing genomic surveillance can identify determinants of transmission, monitor pathogen evolution and adaptation, ensure the accurate diagnosis of infections with epidemic potential, and refine strategies for their control. Critically, the evolutionary analysis of pathogen genome sequence data allowed epidemiological hypotheses to be tested, often in real time.

The real milestone in the transition of pathogen genomics from bench to practice was the award of the NSW Health Translational Research grant in 2016, aimed at translating pathogen genomics into improved public health outcomes. 

The grant was led by Professor Jonathan Iredell and myself. The findings provided justification for the establishment of the NSW state-wide public health pathogen genomics service, which is a node of the Communicable Disease Genomics Network.

The research has helped the NSW Health Protection, NSW Food Authority and OzFoodNet to identify the point sources of transmission sooner and with greater precision than before, and to determine the magnitude of outbreaks.

We have applied genomics approaches to the analysis of strains, allowing us to separate clusters of infections transmitted locally from multiple independent importations of drug-resistant strains from overseas.

In addition, researchers have played a key role in the development and implementation of standard operating procedures and laboratory protocols for bacterial genome sequencing and staff training, leading to accreditation of the ICPMR laboratory for genomics surveillance and drug resistance testing by the National Association of Testing Laboratories.

An example of the application of pathogen genomics is the tularaemia bacterium, which was first identified at the Westmead laboratory as the cause of ulcerative human skin infections in Tasmania. The infections were found to have been acquired through close contact with ringtail possums that carried the same strain.

Genomics also enabled researchers to find missing links in a chain of person-to-person tuberculosis transmission in NSW, finding individuals who were ‘silent’ transmitters and helping to stamp out the infection.

Experience of pathogen genomics research has confirmed the wisdom of “looking within for value and beyond for perspective”. Pathogen genomics has not only improved public health response to disease outbreaks, but has also revolutionised our understanding of the mechanisms of disease transmission.

It has moved from the simplistic view that the spread of diseases is determined mainly by the mechanics of human contact or of contact between a sick animal and a human body. Rather, we now understand that transmission is an evolutionary event that can have a major effect on the extent and structure of genetic diversity as it flows through the population.

Overall, it is clear that the insights provided by pathogen genomics have fundamentally changed our collective understanding of the long-term global and short-term local spread of communicable diseases.