Overview
Background
Career Summary: 2009: PhD, University of Michigan, USA with training in cardiac physiology, modelling myocardial ischemia in vivo and in vitro, and development of therapeutic approaches for myocardial ischemia; 2009–2015: Postdoctoral Research Fellow, University of Washington, Institute for Stem Cell and Regenerative Medicine, USA with training in stem cell biology, genomics, genome editing, and cell therapeutics for ischemic heart disease; 2015–current: Group Leader, University of Queensland (UQ), Institute for Molecular Bioscience; 2022-current: Associate Professor, UQ; 2018–2021 and 2023-2026: National Heart Foundation Future Leader Fellow. Dr. Palpant’s research team has expertise in human stem cell biology, computational genomics, and cardiac physiology, which enables them to translate outcomes from cell biology and genomics to disease modelling, drug discovery, and preclinical modelling.
Availability
- Associate Professor Nathan Palpant is:
- Available for supervision
- Media expert
Fields of research
Qualifications
- Doctoral Diploma, University of Michigan
Research interests
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Developing new drugs for heart disease
Our work aims to prevent organ damage associated with ischemic injuries of the heart. There are no drugs that prevent organ damage caused by these injuries, which ultimately leads to heart failure, making ischemic heart disease the leading cause of death worldwide. This project aims to identify new molecular targets coupled with development of a novel pharmacological inhibitors as novel therapeutics to promote rapid and more effective recovery following an acute cardiovascular event. Development of new cardiovascular drugs will address a major clinical area of unmet need, thereby decreasing mortality, improving recovery and quality-of-life for survivors, and drastically reducing the burden of these diseases. Conditions caused by obstruction of blood flow to the heart are the most common emergency manifestation of cardiovascular disease. Although acute reperfusion therapies have improved patient outcomes, mortality remains high and heart attacks are one of the largest attributable risks for heart failure (HF). Myocardial sensitivity to ischemia-reperfusion injury (IRI) therefore remains a primary point of vulnerability underlying cardiovascular disease, which is the leading cause of morbidity and mortality worldwide. Despite decades of preclinical therapeutic development, there are no drugs in clinical use that block the acute injury response to cardiac ischemia. My research group has discovered a new therapeutic drug to prevent injuries of the heart, a peptide (Hi1a) isolated from venom of the Fraser Island funnel-web spider. Hi1a is a safe and potent therapeutic that we have shown improves heart recovery after myocardial infarction (MI) and greatly enhances the performance of donor hearts procured for transplantation. These remarkable therapeutic properties stem from Hi1a’s ability to protect heart muscle cells from ischemic injury by inhibiting an ion channel known as acid-sensing ion channel 1a (ASIC1a). More broadly, my research program is advancing studies on Hi1a alongside development of other novel therapeutic drugs that reduce the scope and spread of organ injury to the heart after ischemic injuries. These research projects integrate information from diverse sources to establish rationale and mechanism including population statistical genetics methods (e.g. GWAS), CRISPR genetic perturbation studies in iPSCs, functional studies in cell models, and animal models of disease.
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Building tools to predict how the genome controls cells
This work focuses on development of disease-agnostic, high throughput and scalable functional genomics methods that integrate computational predictions and disease modelling to study mechanisms controlling cell differentiation and genetic causes of disease. Genome sequencing is a powerful tool for studying the biological basis of disease, yet out of millions of data points, finding the underlying cause of disease can be difficult. Current protocols for classifying variants from patient DNA data largely rely on prior knowledge about normal and abnormal gene variation contained in large public databases, known disease-causing gene panels, or identifying variants causing amino acid changes in proteins (which only comprise 2% of the genome). Despite these powerful approaches, studies indicate that classifying variants as pathogenic occurs in only a minority of cases and among variants reported in ClinVar, a public archive of relationships between human variation and phenotype, wherein a large proportion (37%) are classified as variants of unknown significance (VUS). New approaches are needed to improve variant prioritisation and classification from genetic data. My research group is developing unsupervised, genome-wide computational analysis methods to reveal genetic mechanisms of development and disease. For example, our recent work developed TRIAGE which uses epigenetic modification of DNA-binding histone proteins to identify regions of the genome that are critical determinants of cell decisions and functions. Using data from >800 cell types, we identified genomic “hot-spots” that, when mutated, are associated with diseases, including neurological and cardiovascular diseases, multi-organ syndromes, and cancer. Our data show that TRIAGE regions of the genome are enriched for pathological variants (especially those causing congenital diseases), intolerant to mutations, have significantly increased effects on complex trait phenotypes, and encode genes that are key determinants of cell differentiation and morphogenesis. This area of my program focuses four design criteria in developing and implementing computational tools to facilitate novel discovery in cells. Simplicity: We are building methods that help organise genomic information in an unsupervised manner across the human genome. These methods can be used to analyse orthogonal data (e.g. patient genetic data) to identify genetic causes of disease or development and/or reveal relationships between gene groups that inform programs controlling cell decisions and functions. Versatility: We aim to develop methods that can be used with any genomic data that maps to genes or a chromosomal address including analysis of patient genetic data or any genomic data type (GWAS, SNPs, RNAseq etc). Furthermore, these methods are ideal models to weight regions of the genome in genetic analysis tools such as polygenic risk scores or machine learning algorithms. Disease-agnostic: Using a systems level approach, these methods enable broad implementation in data analysis pipelines for any data sample from any cell, tissue, disease, or individual. Efficient functional screening: These prediction methods provide robust rationale for wet lab cell biology to functionally test novel hypotheses derived from computational prediction methods in functional genomics studies.
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Harnessing control of stem cell decisions and functions
Cell differentiation is a process involving the continuous coordination of gene expression programs that guide undifferentiated cells into specific, functional cell types. The mechanisms controlling cell differentiation are not well understood. Recent advances in stem cell biology and tissue engineering have highlighted this fundamental knowledge gap. For example, cells derived from pluripotent stem cells (iPSCs) are often heterogeneous, display physiological properties reminiscent of fetal cells and fail to fully mature towards an adult functional state. Our inability to accurately guide cell differentiation pathways currently limits the utility of iPSC-derived cell products in research, tissue engineering, and drug discovery. Despite these profound limitations, the stem cell market is forecasted to grow to nearly $6B USD by 2025. The anticipated impact of the stem cell sector is dependent on precision control of cell differentiation into cell types that model human physiology. Efforts to dissect cell differentiation mechanisms and recapitulate human development using iPSCs have encountered the following major challenges: 1) we lack fundamental understanding of human developmental biology, 2) we lack sufficient scale of data mapping gene expression changes controlling cell processes over time, 3) among the thousands of genes expressed in cells, we lack the ability to efficiently identify genes (especially non-transcription factors) responsible for guiding specific cell differentiation processes, and 4) we do not understand how and when to effectively perturb these specialised gene programs to customise cell differentiation decisions or functions. My group is developing the data, tools, and cell biology perturbation and phenotyping strategies to address these limitations, positioning us to establish new insights into cell biology of differentiation. Using our expertise in stem cell and cardiovascular developmental biology, we are studying how gene programs change as cells move across the cell developmental lineages and identifying genetic on/off switches that control cell choices and functions during differentiation.
Research impacts
Advancing stem cells toward clinical testing: Work by Dr Palpant on iPSC genome engineering and differentiation protocols led to him receiving the 2015 Young Investigator Award from the International Society for Heart Research. This work resulted in a licensed patent (US Patent 10,612,002; 2020) on derivation of hPSCs-endothelial cells. This patent and seminal studies on regenerating the mammalian heart with iPSC-derived heart muscle (Nature x2) formed the basis for Sana Biotechnology (USA; USD $700M series A VC investment in 2019). Dr Palpant has an ongoing collaboration with Sana CSO Professor Charles Murry (including publications and a 2017 UQ Global Strategy and Partnership Award) to advance discoveries for commercialisation by Sana.
Genomic innovation for drug discovery: Dr Palpant has been at the forefront of research into innovative genomics algorithms and sequencing methods. His work developing a computational method to identify genetic features controlling cells resulted in the Lorne Genome Millennium Science Award (2019) and led to current funded collaborations with HAYA Therapeutics (Switzerland; USD $16M series A VC investment, 2020), Merck (Germany), and ConcR (UK) resulting in >$600K in industry funding for early access to these discovery platforms.
New drug therapeutics for cardiovascular disease: Dr Palpant has led development of Hi1a as a novel cardiovascular drug. These discoveries stemmed from his expertise in using human pluripotent stem cell biology and disease modelling of acquired heart disease. This work was recognised by the Cardiac Society for Australia and New Zealand Ralph Reader Prize and resulted in a provisional patent on ASIC1a-knockout iPSCs (PAT-02408-US-01). The clinical impact of this work has resulted in a UQ spinout company, Infensa Bioscience to commercialise Hi1a for clinical testing. He is scientific co-founder and on the scientific advisory board of Infensa Bioscience.
Publication Impact Metrics: Dr Palpant's expertise in pluripotent stem cell biology, cardiac muscle cells, and genomics has resulted in publications cited 7-fold higher than the field average (Topic E 4031 FWCI of 7.37, SciVal). His research has been featured on the ABC, Newsweek, The Guardian, and The Washington Post.
Professional Standing: Since 2019, Dr Palpant has been involved in national initiatives including as co-chair of the Queensland Cardiovascular Research Network and advisory member of the Precision Medicine Flagship for the Australian Cardiovascular Alliance. His expertise is reflected in his role on the steering committee for the Australian Functional Genomics Network. Dr Palpant has given seminars and presentations throughout Australia, USA, Europe, Singapore, China, and Japan. He reviews for journals including Science, Nature Methods, Cell Stem Cell, and JCI Insights.
Works
Search Professor Nathan Palpant’s works on UQ eSpace
2008
Journal Article
Molecular Cardiology in Translation: Gene, Cell and Chemical-Based Experimental Therapeutics for the Failing Heart
Turner, Immanuel, Belema-Bedada, Fikru, Martindale, Joshua, Townsend, DeWayne, Wang, Wang, Palpant, Nathan, Yasuda, So-chiro, Barnabei, Matthew, Fomicheva, Ekaterina and Metzger, Joseph M. (2008). Molecular Cardiology in Translation: Gene, Cell and Chemical-Based Experimental Therapeutics for the Failing Heart. Journal of Cardiovascular Translational Research, 1 (4), 317-327. doi: 10.1007/s12265-008-9065-6
2008
Journal Article
Single histidine-substituted cardiac troponin I confers protection from age-related systolic and diastolic dysfunction
Palpant, Nathan J., Day, Sharlene M., Herron, Todd J., Converso, Kimber L. and Metzger, Joseph M. (2008). Single histidine-substituted cardiac troponin I confers protection from age-related systolic and diastolic dysfunction. Cardiovascular Research, 80 (2), 209-218. doi: 10.1093/cvr/cvn198
2007
Journal Article
Non-canonical Wnt signaling enhances differentiation of Sca1+/c-kit+ adipose-derived murine stromal vascular cells into spontaneously beating cardiac myocytes
Palpant, Nathan J., Yasuda, So-ichiro, MacDougald, Ormond and Metzger, Joseph M. (2007). Non-canonical Wnt signaling enhances differentiation of Sca1+/c-kit+ adipose-derived murine stromal vascular cells into spontaneously beating cardiac myocytes. Journal of Molecular and Cellular Cardiology, 43 (3), 362-370. doi: 10.1016/j.yjmcc.2007.06.012
Funding
Current funding
Supervision
Availability
- Associate Professor Nathan Palpant is:
- Available for supervision
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Available projects
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Projects in Stem Cell Biology, Genomics, Cardiovascular Development, and Cell Therapeutics
As outlined in the research interests of my lab, there are numerous projects available for students covering a range of topics. These projects are continuously changing. The following areas cover topics I use to develop projects for incoming students:
- Use stem cells, genome engineering, and single cell RNA-sequencing to study how cells differentiate into cell types of the heart
- Modify stem cells to generate cells with custom engineered functions to create synthetic cell states
- Use bioinformatics approaches to analyse large scale genomic data to study what features of the genome control cell decisions
- Study novel genes that control how heart cells respond to stress like ischemia and work with chemists to develop novel drugs that could be used to treat patients who have heart attacks
- Use computational genomics and cell biology approaches to study how the heart adapts to extreme environments (like high altitude) to learn what genes control stress responses in cells.
- Study the biology of how venoms of marine and terrestrial species impact heart function using cells, whole organ models, and animal models.
Contact me for a discussion about current opportunities and specific projects available.
Supervision history
Current supervision
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Doctor Philosophy
Using genomic data and epigenetic annotations to identify genetic causes of cell differentiation
Principal Advisor
Other advisors: Dr Jian Zeng, Dr Amy Hanna
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Doctor Philosophy
Using signatures of cell identity to improve cell type prediction in single cell analysis pipelines
Principal Advisor
Other advisors: Dr Quan Nguyen, Dr Woo Jun Shim
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Doctor Philosophy
Understanding genetic adaptation of the heart to extreme environments
Principal Advisor
Other advisors: Dr Sonia Shah
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Doctor Philosophy
Multilineage differentiation from pluripotency reveals genetic regulators of cardiovascular physiology
Principal Advisor
Other advisors: Dr Quan Nguyen
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Doctor Philosophy
The long-term cardiovascular complications of COVID-19
Associate Advisor
Other advisors: Dr Helen Mayfield, Professor Colleen Lau, Dr Linda Gallo, Associate Professor Kirsty Short
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Doctor Philosophy
Identifying the structure, function, and mechanism of action of cardiotoxic components in the venoms of box (Chironex fleckeri) and Irukandji (Carukia barnesi) jellyfish
Associate Advisor
Other advisors: Dr Andrew Walker, Professor Glenn King
Completed supervision
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2024
Doctor Philosophy
Genetic regulation of Wnt-dependent mesendoderm differentiation from pluripotency
Principal Advisor
Other advisors: Dr Christian Nefzger
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2022
Doctor Philosophy
Understanding Cell Identity Through the Lens of Genome-Wide Epigenetic Repression
Principal Advisor
Other advisors: Professor Mikael Boden
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2020
Doctor Philosophy
Genetic regulation of cardiac differentiation at single-cell resolution
Principal Advisor
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2024
Doctor Philosophy
Cyclic peptides as therapeutics for ischemic heart disease and heart failure
Associate Advisor
Other advisors: Professor Glenn King
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2023
Doctor Philosophy
Cell death, inflammation, and macrophages in cardiac ischemia and metabolic disease
Associate Advisor
Other advisors: Professor Jennifer Stow
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2021
Doctor Philosophy
Identifying Genetic Regulators of Cell Fate Through Computational Analysis of Epigenetic Repression
Associate Advisor
Other advisors: Professor Mikael Boden
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Media
Enquiries
Contact Associate Professor Nathan Palpant directly for media enquiries about:
- bioengineering
- cardiovascular disease
- cardiovascular system
- differentiation
- genome engineering
- genomics
- heart development
- heart disease
- heart regeneration
- human pluripotent stem cells
- stem cells
- vascular development
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