Australasian researchers, including those from Australia and New Zealand, have a rich history of medical innovation which has helped shape the world as we know it today. Between the textbook discoveries of penicillin by Sir Howard Florey, T-cell immunity by Professor Peter Doherty (together with Rolf Zinkernagel) and telomere functionality by Professor Elizabeth Blackburn, Australasian scientists have cemented their place as global leaders in health and medical research. Importantly, research aimed at understanding cell survival and cell death has long been integral to many of Australasia’s most notable scientific breakthroughs. This Editorial, composed by members of the Australasian Cell Death Society (ACDS) committee, aims to celebrate the long and storied history of cell death research within Australia and New Zealand.

It was Australian pathologist John Kerr who first coined the term “apoptosis” (Greek for “falling off,” in reference to the falling leaves from trees in autumn) to describe the unusual phenomenon of ordered cell death during acute liver injury in rats.1, 2 In a series of electron microscopy images, Kerr laid out the unique morphological features of apoptosis that are still referenced half a century later. These described an ordered process of cellular dismantlement that begins with nuclear and cytoplasmic condensation, and ends with the engulfment of apoptotic bodies by surrounding cells (Figure 1a).2 While first considered a somewhat esoteric field of study, today the search term “apoptosis” generates nearly half a million hits in PubMed, an impressive accolade owing to its vital role in organism development, homeostasis and immune function, as well as its important influence in human disease.3 Since John Kerr’s landmark publication, the cell death field has expanded to now recognize at least twelve distinct forms of programmed cell death, including both intrinsic and extrinsic apoptosis, necroptosis, pyroptosis, ferroptosis, NETosis and autophagy-dependent cell death, to name a few.4 To this day, Australasian researchers continue to make pivotal discoveries that define the complex biochemical processes of programmed cell death.

Examples of cell death studied in Australasia. (a) TEM of UV-irradiated apoptotic A431 cells (provided by Satoko Arakawa, Tokyo Medical and Dental University). (b) Lattice light sheet image of necroptotic HT29 cells following TSI treatment (yellow: Annexin V; magenta: mTagRFP–membrane fusion protein; cyan: TO-PRO-3; provided by Andre Samson, WEHI). (c) Confocal microscopy image of pyroptotic macrophages after LPS/nigericin treatment (gray: DAPI; yellow: ASC; red: alpha-tubulin; cyan: vimentin; provided by Caroline Holley, University of Queensland). (d) TEM of UV-irradiated Bax/Bak DKO MEFs undergoing autophagy-dependent cell death (provided by Satoko Arakawa). ASC, Apoptosis-associated speck-like protein containing a CARD; DAPI, 4′,6-diamidino-2-phenylindole; DKO, double-knockout; LPS, lipopolysaccharide; MEF, murine embryonic fibroblast; TEM, transmission electron microscopy; TSI, TNF, Smac mimetic and IDN-6556; UV, ultraviolet; WEHI, the Walter and Eliza Hall Institute of Medical Research.

Since the late 1980s, researchers at the Walter and Eliza Hall Institute of Medical Research (WEHI) in Melbourne have investigated the proteins that regulate intrinsic apoptosis. Beginning with the breakthrough discovery of B-cell lymphoma (BCL)-2 as a novel oncogene promoting survival of B-cell leukemia,5 WEHI researchers have continued to perform fundamental research aimed at understanding the molecular mechanisms of apoptosis. This includes studies on the prodeath apoptotic effectors, BAX and BAK,6-8 including key structural biology insights,9-12 identification of the oncogenic transcription factor MYC,13 therapeutic targeting of BCL-2 proteins in cancer14-16 and the discovery of the BH3-only protein BIM,17-20 including identifying its essential role in deleting self-antigen reactive lymphocytes.21 Notably, deletion of self-antigen reactive lymphocytes is the cornerstone of the clonal selection theory that earned Australian Sir MacFarlane Burnet the Nobel Prize in Medicine and Physiology in 1960. This extensive portfolio has paved the way for subsequent research that further delineates the mechanisms and downstream functions of intrinsic apoptosis, such as the release of cytochrome-c22 and mitochondrial DNA,23 the formation of apoptotic bodies24 and crosstalk that enables proinflammatory cytokine release.25

In parallel to this significant body of work detailing the regulation of intrinsic apoptosis, Australasian researchers have also made an impressive contribution to our understanding of extrinsic death receptor signaling. After the international discovery of the death-inducing ligands, Fas ligand (FASL) and tumor necrosis factor (TNF), Australasian findings indicated that two distinct apoptotic pathways existed, as Fas-induced death was found to be independent of BCL-2.26 Since this discovery, Australasian research has continued to expand our knowledge of extrinsic apoptosis. Key studies include those on TNF receptor signaling,27, 28 TNF receptor-associated protein with a death domain (TRADD),29 Mind Bomb-2 (MIB2),30 and inhibitor of apoptosis proteins,31-33 including the crucial discovery of the inhibitor of apoptosis protein antagonist Smac/DIABLO.34 Australasian researchers have also detailed the intersecting apoptotic pathways during T- and natural killer-cell killing,35, 36 and discovered the novel apoptotic effector protein, caspase-2,37 among many other ground-breaking publications on extrinsic cell death.38-42

In addition to apoptosis, Australasian researchers have also pioneered our understanding of alternative cell death modalities. In Adelaide, fundamental research investigating cell death mechanisms in Drosophila43-46 uncovered a unique caspase-independent pathway known as autophagy-dependent cell death (Figure 1d).47, 48 At WEHI, the pseudokinase mixed-lineage kinase domain-like (MLKL) was shown to form pores in the plasma membrane and cause another caspase-independent form of cell death called necroptosis (Figure 1b).49, 50 Recent studies have now detailed important structural and functional insights into the regulation of MLKL activity and processes that drive cell death.51, 52 Australasian research has also focused on other key necroptotic regulators, including receptor-interacting protein kinase 1 and 3 (RIPK1 and RIPK3), and highlighted their critical roles in inflammation and human disease.53-55 In addition, Australasian researchers working internationally have uncovered extensive plasticity and crosstalk between apoptotic and lytic modes of cell death such as necroptosis.54, 56-59

At the University of Queensland, Australasian researchers have made seminal contributions to the field of inflammasomes and pyroptotic cell death (Figure 1c). These include detailing how the pyroptotic effector caspase-1 is regulated,60 inflammasome-mediated crosstalk between pyroptosis and apoptosis,61 and the discovery of inflammasome-driven NETosis.62 Crucially, many studies have now highlighted the critical role of inflammasome signaling and pyroptosis in disease.63-66 Broadening the implications of dysregulated cell death in disease, work performed in Melbourne has also revealed the novel connection between extrinsic apoptotic and necroptotic cell death and inflammasome signaling.42, 67

These discoveries have revolutionized our understanding of basic cell biology, revealing the complex interlocking mechanisms controlling cell survival and death. In addition to maintaining homeostasis, cell death is also implicated in a wide number of conditions, including cancer, autoimmune, neurodegenerative, inflammatory and infectious diseases.68-70 Given this close association between cell death and disease, Australasian cell death research has also had an immense impact on human health. The most notable example showcasing the translation from basic cell death research to the clinic is the development of Venetoclax. Building on their foundational studies from the 1980s,5, 71, 72 researchers at WEHI, in collaboration with industry partners AbbVie and Genentech (Roche), designed and developed the first “BH3 mimetic” to target the prosurvival protein BCL-2.14 Also known by the moniker ABT-199, the drug Venetoclax is now approved for the treatment of chronic lymphocytic leukemia and acute myeloid leukemia73-75 in the European Union, the United States and Australia. Furthermore, teams at WEHI, The Alfred Hospital and the Australian Centre for Blood Diseases were involved in the identification of the anti-apoptotic BCL-2 family member, MCL-1, as an attractive target for cancer therapy.76 As such, the French pharmaceutical company Servier has developed the first specific MCL-1 inhibitor that is in clinical trials for acute myeloid leukemia and other blood cell–derived malignancies in Melbourne and many other parts of the world.15 These are just some of the many Australasian success stories where basic research has led to drug development and improvement of patient outcomes on a global scale. With the abundance of Australasian cell death groups currently investigating models of disease and therapeutic development,77-81 we can expect to see many more pioneering Australasian studies being translated into the clinic.

The ACDS was established in 2021 to harness the long history of Australasian cell death research illustrated in this Editorial, and to support the next generation of upcoming scientists. The overriding goal of the ACDS is to create a supportive cell death community where national and international collaboration can flourish. By facilitating connectivity and communication between early, mid- and senior career researchers, the ACDS aims to build upon the Australasian reputation as global leaders in cell death research. The ACDS recognizes the barriers that upcoming scientists face, such as scarce and highly competitive funding, and strives to support the professional development of its junior members through Career Development Awards, networking and seminar opportunities as well as exposure through the easily accessible Cell Death Researcher Database. The ACDS was the vision of postdoctoral scientist Dr Georgia Atkin-Smith (ACDS President) and is led by a committee of enthusiastic PhD students and postdocs from across Australasia. The society pays tribute to the Pioneers of Australasian cell death research, Professor Andreas Strasser, Professor Sharad Kumar, Professor Suzanne Cory, Associate Professor Ruth Kluck, Professor Jerry Adams, Professor Peter Colman, Professor David Vaux and Dr Kim Newton, who have been appointed as Honorary Members to provide strategic oversight. Many of Australasia’s most notable cell death findings were made possible through strong collaborations with international researchers. As such, the ACDS is honored to welcome Professor Shigekazu Nagata to its Pioneer Board, as the society strives to further strengthen its ties between Australasia and Japan. In addition to its Pioneers, the ACDS showcases inspirational leaders in the cell death field as Luminaries, who hail from the WEHI, Peter MacCallum Cancer Centre, Monash University, the Hudson Institute of Medical Research, La Trobe University, the Olivia Newton John Cancer Research Institute, The University of Adelaide, The University of Queensland, The University of Otago (Te Whare Wānanga o Ōtākou) and Genentech.

Given the long and distinguished history of cell death research in Australasia, the ACDS is excited to celebrate its 1-year anniversary by endorsing a Virtual Australasian Cell Death Issue of Immunology & Cell Biology (ICB) that includes works by Pioneers, Luminaries and emerging leaders in the field.

ACKNOWLEDGMENTS

We thank the following for providing the microscopy data presented in Figure 1: (a, d) Satako Arakawa (Tokyo Medical and Dental University), (b) Andre Samson, Niall Geoghegan and Ying Zhang (WEHI) and (c) Caroline Holley (University of Queensland). We also thank Andreas Strasser for his constructive oversight to this Editorial and the ACDS Sponsors (WEHI, Abacus DX, Promega and Thermo Fisher Scientific) for their financial support.

CONFLICT OF INTEREST

The authors declare no conflicts of interest.