Nathan Palpant

Finding the genetic causes of inherited heart disease

Inherited cardiovascular diseases such as cardiomyopathies can have devastating consequences for patients and their families, yet genetic testing often identifies rare DNA variants whose clinical significance remains uncertain. This creates a major challenge: a genetic change may be detected, but clinicians may still not know whether it causes disease, how it alters heart function, or what it means for other family members. Our laboratory is interested in closing this gap by studying which rare genetic variants truly cause cardiovascular disease, how do they disrupt cardiac biology, and can those effects ultimately be reversed.

This HDR project will investigate candidate disease-causing variants identified through clinical genetics and genomic studies. Our program has already examined variants in genes including HOPX, TPM1 and TNNC1, using functional evidence to connect genotype with cardiac phenotype. This work identified HOPX as a novel cardiomyopathy-associated gene and contributed to reclassification of the TNNC1 E96del variant from a Variant of Uncertain Significance to Likely Pathogenic, providing clinically actionable information for diagnosis, family screening and patient management.

A major strength of the project is the ability to recreate human genetic disease experimentally. Depending on the variant and student interests, the work may combine patient-derived or genome-engineered human pluripotent stem cells, cardiomyocyte differentiation, genome editing, single-cell genomics, cardiac functional phenotyping and molecular biology. These systems allow candidate variants to be introduced or corrected in controlled genetic backgrounds, making it possible to determine whether a variant is causal and define precisely how it changes cardiomyocyte development, structure, contractility or stress responses.

The project can also extend beyond diagnosis to ask whether disease-associated phenotypes are therapeutically reversible. Once the underlying mechanism is established, candidate interventions can be tested in human cardiac models, creating a pathway from genetic diagnosis to mechanism-based therapeutic development. This reflects the laboratory’s broader strategy of linking human genetics with experimentally tractable disease models rather than treating variant interpretation as a purely computational problem. Our stem-cell and single-cell studies have already established platforms for defining cardiac developmental trajectories and genetic mechanisms of disease (Cell Stem Cell 2018).

The work also sits within a broader national effort to improve rare-disease genomics. Through the Australian Functional Genomics Network, this research area has contributed to evaluation of nearly 250 variants of uncertain significance, including variant reclassifications, new gene–disease associations and resolved diagnoses.

The longer-term goal is to move from variant discovery → biological mechanism → clinical interpretation → therapeutic opportunity, improving the value of genomic testing for patients and families affected by inherited cardiovascular disease.

Building more realistic human models of cardiovascular disease

Cardiovascular disease does not result from a single genetic change or environmental stress. It emerges from interactions between genetic background, cell state, ageing, metabolism, comorbid disease and environmental exposures, yet conventional laboratory models often isolate these factors rather than recreating their combined effects. Our laboratory is interested in building human models that better reflect the biological complexity that determines disease risk and treatment response.

This HDR project will develop and apply advanced human pluripotent stem-cell models to study cardiovascular disease in a more realistic and population-relevant context. A major focus is the “village-in-a-dish” approach, which enables many genetically distinct human induced pluripotent stem-cell lines to be cultured and analysed together. This creates a scalable system for linking inherited genetic variation with cellular phenotypes and for testing why different individuals respond differently to the same biological stress or therapeutic intervention (Nature Communications 2023).

The project will also build on our work to improve the maturation and physiological relevance of human cardiomyocyte models. Depending on the student’s interests, this may include manipulating metabolic environment, contractile state, tissue architecture or exposure to clinically relevant stresses such as hypoxia, acidosis and reperfusion injury. The aim is to move beyond simplified cell culture systems towards models that better reproduce adult cardiac physiology and disease-associated vulnerability.

A second major theme is comorbidity modelling. Cardiovascular risk is strongly influenced by conditions such as diabetes and metabolic dysfunction, but these factors are rarely incorporated into preclinical models in a systematic way. Our laboratory has shown that glycaemic variability can directly impair cardiomyocyte function and increase susceptibility to myocardial injury, providing a framework for modelling how metabolic instability contributes to cardiovascular risk (Nature Communications 2026).

The project may combine stem-cell differentiation, population-scale cellular models, genome engineering, single-cell genomics, metabolic profiling, electrophysiology, contractility assays and high-throughput phenotyping. There are also opportunities to integrate experimental findings with human genetic and clinical datasets.

The longer-term goal is to create human disease models that are sufficiently realistic to predict patient biology, helping explain variation in disease severity, identify mechanisms of vulnerability and improve how new cardiovascular therapies are developed and tested.

Revealing the hidden biological subtypes of complex disease

Common diseases such as diabetes, cardiovascular disease and inflammatory disorders are usually treated as single diagnoses, yet patients with the same condition can have very different underlying biology, clinical trajectories and responses to treatment. A central question for our laboratory aims to understand whether inherited genetic risk be decomposed into distinct biological mechanisms that reveal meaningful disease subtypes.

This HDR project will investigate how the epigenomic programs that govern cell identity can be used to interpret the enormous number of genetic variants associated with complex disease. Our laboratory has identified conserved regulatory principles that organise coding and non-coding regions of the genome and help connect genetic variation with the genes, cell types and biological processes it affects (Cell Systems 2020; Nucleic Acids Research 2025). These discoveries provide the conceptual foundation for EpiCops, a computational framework designed to resolve complex genetic risk into distinct regulatory programs rather than treating all associated variants as contributing to a single homogeneous disease process.

The project will use large-scale human genomic and clinical datasets to ask whether genetically defined regulatory programs correspond to different disease mechanisms, tissue and cell-state dependencies, clinical outcomes or therapeutic responses. Initial applications are focused on cardiometabolic diseases such as type 2 diabetes and myocardial infarction, but the framework is disease-agnostic and can be extended across a wide range of complex traits.

Depending on the student’s interests, the project may combine statistical genetics, machine learning, epigenomics, regulatory genomics, polygenic risk modelling, single-cell data analysis and clinical cohort studies. There are also opportunities to integrate computational predictions with experimental validation using human stem-cell models and functional genomics, allowing disease subtypes identified in population data to be linked back to measurable cellular mechanisms.

Related genomic platforms developed by the laboratory have already attracted more than A$1 million in commercial research partnerships with HAYA Therapeutics, Merck, CSL and Sanofi, supporting applications in therapeutic target discovery and genetically informed patient stratification.

The longer-term vision is to move beyond broad diagnostic labels towards a mechanism-based classification of complex disease. By linking inherited genetic variation with regulatory biology, cellular context and clinical outcomes, this project aims to identify patient groups who share common disease mechanisms, reveal new therapeutic targets and ultimately improve how patients are stratified for prevention and treatment.

Why does the heart become damaged when its blood supply is interrupted?

Heart attack remains a major cause of death and disability worldwide because restoring blood flow does not completely prevent irreversible damage to heart muscle. During ischaemia, loss of oxygen forces cells to rely on anaerobic metabolism, causing lactate accumulation and a rapid fall in tissue pH. Our laboratory is interested in a fundamental question arising from this process: how does tissue acidosis become a signal for cell injury and death, and can these mechanisms be targeted to protect the heart?

A major focus is the acid-sensing ion channel ASIC1a, which our laboratory identified as an important mediator of cardiomyocyte death during ischaemia-reperfusion injury. Blocking ASIC1a preserves cardiomyocyte viability and improves cardiac recovery in experimental models, discoveries that established ASIC1a as a first-in-class cardioprotective target and have progressed into clinical development through Infensa Bioscience (Circulation 2021; European Heart Journal 2024).

This HDR project will investigate the broader biology of acid-sensitive stress responses in cardiovascular disease. Key questions may include: Which cardiac cell types activate acid-sensing pathways during ischaemia? How do the magnitude and duration of acidosis determine whether cells recover or die? How do genetics, metabolism and comorbidities modify these responses? And can acid-sensitive mechanisms be exploited not only therapeutically, but also as biomarkers of evolving tissue injury?

Depending on the interests and background of the student, the project can combine human pluripotent stem-cell-derived cardiomyocytes, genome engineering, functional genomics, high-content cellular phenotyping, transcriptomics, human genetics and experimental models of myocardial infarction. There are also opportunities to investigate the spatial and temporal activation of ASIC1a during tissue injury and to evaluate new peptide-based probes and inhibitors as diagnostic or therapeutic tools. The broader research program is examining these mechanisms across multiple ischaemic settings, including myocardial infarction and organ transplantation.

The project sits at the interface of fundamental cardiovascular biology and therapeutic translation. Its longer-term aim is to identify the molecular events that determine whether ischaemic tissue survives or progresses to irreversible injury, and to use that knowledge to develop new strategies for protecting patients from the consequences of heart attack and other forms of acute ischaemia.