Our approach

This discovery pipeline approach has been proven to enable the understanding of individual diseases, target therapy and inform development of new diagnostics that expand our ability to deliver precision medicine. The ANU team has recently described a new syndrome in two families with a previously undiagnosed immune deficiency1. This research provided proof-of-principle of this pipeline for discovery. In another hallmark paper recently published, the ANU team have demonstrated the same approach can stratify lupus, a complex disease2. This is significant progress because it validates how the ANU genomics-phenomics pipeline can lead to precision medicine for genetically complex disease. This approach is now being applied to help patients with severe, chronic and difficult to treat diseases from across Australia. The steps in genomic medicine pipeline are shown in Figure 1 below:

Figure 1. Genomics-Phenomics Discovery pipeline (‘M’ number refers to one of the 7 PTI Milestone numbers)

1 Cardinez et al., Journal of Experimental Medicine (2018) 215:2715 &


2 Jiang et al., Nature Communications, (2019) 10(1):2201

Steps in the Genomic-Phenomics Discovery pipeline

Patient. Clinicians identify patients with a genetic cause of disease.

Clinical Assessment (patient phenotyping). Clinicians collect data from the patient. For patients with immune disease this includes a detailed analysis of their white blood cells and serum markers.

Rare Gene Variant Discovery. DNA is extracted from the patient’s blood, then undergoes DNA sequencing to map the whole genome for that patient. Bioinformaticians use sophisticated data analysis to identify rare variations in the genome that are suspects for contributing to the disease. Sometimes the rare variant is located in a gene where the function is well known but the impact from the particular variation may not be well understood.  Often the rare gene variant is in a gene that is not obvious and further research work is required to identify and understand how it works.

Functional Validation of gene variant. Once identified, researchers use CRISPR/Cas9 genome editing technology to insert the suspect gene variant precisely into the DNA of mouse and human cell lines in the laboratory (M2).  Using these models, researchers test the function of the specific rare gene variant in isolation from other variants in the patient (M4).  This research shows whether the gene variant causes similar disease traits in mice and abnormalities in cell processes. This work is referred to as ‘functional validation’. By understanding exactly how the gene variant affects cells and molecules, researchers can discover the molecular pathway that leads to the disease.

Test Pathway Specific Medicines. Once the pathway is understood, researchers seek medicines or treatments that can specifically address the pathway that has been disrupted. Medicines can be tested on the mouse models that have been created with the specific rare gene variant (M5). This is called ‘Preclinical testing’. Sometime there are medicines already available for the pathway identified and the mouse model can demonstrate that it will be beneficial for patients.

Treat Patient. Once drugs are shown to be safe and successfully used to treat the disease through trials, they can be made available to other individuals with disease where the same pathway is affected.