Prof James Vince, Lab Head | WEHI Researcher Profile

Q: Using lipid nanoparticles to deliver mRNAs that regulate cell death

Too much cell death has been implicated in many diseases, from autoinflammatory conditions, to infections and cancer. It is now recognised that there is often redundancy and cross-talk in the cell death machinery and, from a therapeutic perspective, several cell death pathways may need to be targeted at the same time. We are developing multi-functional mRNAs that will inhibit several cell death and inflammatory pathways, and intend to deliver these using lipid nanoparticles to treat relevant conditions.

Q: Cell death and inflammation in liver cancer

Hepatocellular carcinoma (HCC) represents 85% of liver cancers, is the sixth most common cancer and, globally, is the fourth leading cause of cancer deaths. This project makes use of our cell death and inflammation deficient animals to study the molecular players that promote or inhibit HCC, using a HCC model driven by genetic mutations that cause liver cancer in humans.

Q: Post-translational regulation of inflammasome function

Cytosolic inflammasome protein complexes drive cell death and inflammation, and while they are key for innate immunity against pathogen infections, their excess activation causes a variety of autoinflammatory conditions. We recently defined a key post-translational modification of the inflammasome-associated cytokine IL-1beta (Nature Communications 2021). This project uses a CRISPR screen to identify the enzymes responsible for IL-1beta modification and will examine their function in inflamamsome-driven disease models. This project may uncover new targets for manipulating inflammasome activity for therapeutic benefit.

Q: Signalling pathways in cytokine shock syndromes

Cytokine shock syndromes are frequently lethal conditions often triggered by infectious pathogens in genetically susceptible people (e.g. sepsis, hemophagocytic lymphohistiocytosis, macrophage activation syndrome). We have developed models of cytokine shock syndromes to identify the critical cell death and inflammatory pathways involved, and are using biochemical experiments and genetic manipulation (e.g. cell type-specific targeting) in order to define new therapeutic targets. Potential targets will be tested using new nanobody approaches and, in collaboration with industry, small molecule inhibitors.

Q: Cell death in inflammatory bowel disease

Host and microbial molecules both contribute to inflammatory bowel disease (IBD). This project examines how the combined actions of inflammatory cytokines and pathogen ligands can combine to cause pathological cell death in IBD using human intestinal organoid models. Using a variety of genetic (CRISPR/Cas9) and pharmacological approaches we are mapping the relevant cell death pathways identified via biochemical and genome-wide transcriptional profiling, and are translating these in vivo using relevant animal models.

About

I run a laboratory at the Walter and Eliza Hall Institute (WEHI) in Melbourne, Australia, and am the Science Director of Mermaid Bio, a new biotech startup with its headquarters in Munich.

Our research focuses on the receptors and molecular signalling networks that cause cell death and inflammation. A particular interest is understanding how the potent pro-inflammatory protein, interleukin-1 (IL-1), is activated and promotes pathology in inflammatory diseases. Understanding how IL-1 activity is controlled will allow the targeted design of next-generation anti-inflammatory therapeutics.

Our recent research revealed molecular links between apoptotic and necroptotic cell death and inflammatory cytokine production, including inflammasome activity. We are continuing to decipher exactly how cell death and inflammation are inextricably linked at the molecular level, with our studies implicating specific cell death modalities and inflammasome signalling in diseases such as gout, cytokine shock syndromes, cancer and infections such as SARS-Cov-2 and Legionnaires’ disease.

Our ultimate goal is to use genetics, biochemistry, and disease modelling to understand how cell death and inflammation are controlled, and how they influence each other, as a basis for new treatments. To progress this goal and develop therapies against disease-causing proteins WEHI has teamed up with Mermaid Bio. Together, we are developing new “intrabody” therapies – where lipid nanoparticles, such as those used in the COVID-19 vaccines, are being harnessed to delivery mRNAs encoding for therapeutic nanobodies, a type of antibody that can be generated to target any intracellular protein of interest, and which has several advantages when compared to small molecule compounds.

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Selected publications from Prof James Vince

Saller BS, Wöhrle S, Fischer L, Dufossez C, Ingerl IL, Kessler S, Mateo-Tortola M, Gorka O, Lange F, Cheng Y, Neuwirt E, Marada A, Koentges C, Urban C, Aktories P, Reuther P, Giese S, Kirschnek S, Mayer C, Pilic J, Falquez-Medina H, Oelgeklaus A, Deepagan VG, Shojaee F, Zimmermann JA, Weber D, Tai Y-H, Crois A, Ciminski K, Peyronnet R, Brandenburg KS, Wu G, Baumeister R, Heimbucher T, Rizzi M, Riedel D, Helmstädter M, Buescher J, Neumann K, Misgeld T, Kerschensteiner M, Walentek P, Kreutz C, Maurer U, Rambold AS, Vince JE, Edlich F, Malli R, Häcker G, Kierdorf K, Meisinger C, Köttgen A, Jakobs S, Weber ANR, Schwemmle M, Groß CJ, Groß O. Acute suppression of mitochondrial ATP production prevents apoptosis and provides an essential signal for NLRP3 inflammasome activation. Immunity. 2025;58(1):10.1016/j.immuni.2024.10.012

Tye H, Conos SA, Djajawi TM, Gottschalk TA, Abdoulkader N, Kong IY, Kammoun HL, Narayana VK, Kratina T, Speir M, Emery J, Simpson DS, Hall C, Vince AJ, Russo S, Crawley R, Rashidi M, Hildebrand JM, Murphy JM, Whitehead L, De Souza DP, Masters SL, Samson AL, Lalaoui N, Hawkins ED, Murphy AJ, Vince JE, Lawlor KE. Divergent roles of RIPK3 and MLKL in high-fat diet–induced obesity and MAFLD in mice. Life Science Alliance. 2025;8(1):10.26508/lsa.202302446

Anderton H, Bandala-Sanchez E, Simpson DS, Rickard JA, Ng AP, Di Rago L, Hall C, Vince JE, Silke J, Liccardi G, Feltham R. Correction to: RIPK1 prevents TRADD-driven, but TNFR1 independent, apoptosis during development. Cell Death & Differentiation. 2024;31(12):10.1038/s41418-024-01401-7

Lee C, Park M, Wijesinghe WCB, Na S, Lee CG, Hwang E, Yoon G, Lee JK, Roh D-H, Kwon YH, Yang J, Hughes SA, Vince JE, Seo JK, Min D, Kwon T-H. Oxidative photocatalysis on membranes triggers non-canonical pyroptosis. Nature Communications. 2024;15(1):10.1038/s41467-024-47634-5

Tran HT, Kratina T, Coutansais A, Michalek D, Hogan BM, Lawlor KE, Vince JE, Silke J, Lalaoui N. RIPK3 cleavage is dispensable for necroptosis inhibition but restricts NLRP3 inflammasome activation. Cell Death & Differentiation. 2024;31(5):10.1038/s41418-024-01281-x

Lawlor KE, Murphy JM, Vince JE. Gasdermin and MLKL necrotic cell death effectors: Signaling and diseases. Immunity. 2024;57(3):10.1016/j.immuni.2024.02.011

Vince JE. IFNγ: Priming for death. Journal of Cell Biology. 2024;223(3):10.1083/jcb.202401127

Guzman LGM, Hyland CD, Bidgood GM, Leong E, Shen Z, Goh W, Rautela J, Vince JE, Nicholson SE, Huntington ND. CD45 limits early Natural Killer cell development. Immunology and Cell Biology. 2024;102(1):10.1111/imcb.12701

Simpson DS, Anderton H, Yousef J, Vaibhav V, Cobbold SA, Bandala-Sanchez E, Kueh AJ, Dagley LF, Herold MJ, Silke J, Vince JE, Feltham R. Mind bomb 2 limits inflammatory dermatitis in Sharpin mutant mice independently of cell death. PNAS Nexus. 2023;3(1):10.1093/pnasnexus/pgad438

Speir M, Tye H, Gottschalk TA, Simpson DS, Djajawi TM, Deo P, Ambrose RL, Conos SA, Emery J, Abraham G, Pascoe A, Hughes SA, Weir A, Hawkins ED, Kong I, Herold MJ, Pearson JS, Lalaoui N, Naderer T, Vince JE, Lawlor KE. A1 is induced by pathogen ligands to limit myeloid cell death and NLRP3 inflammasome activation. EMBO Reports. 2023;24(11):10.15252/embr.202356865

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Lab research projects

Using lipid nanoparticles to deliver mRNAs that regulate cell death

Cell death and inflammation in liver cancer

Post-translational regulation of inflammasome function

Signalling pathways in cytokine shock syndromes

Cell death in inflammatory bowel disease

Prof James Vince

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