Honours, Masters and PhD Project Book

Advance your career Advance medical research Our mission Mastery of disease through discovery Our vision To be an innovative medical research institute that engages and enriches society and improves health outcomes through discovery, translation and education. Research themes ● , and Immunity ● Research and Treatments ● Health Development and Ageing ● New Medicines and Advanced Technologies ● Computational Biology Our goals To make discoveries that shape contemporary scientific thinking, increase understanding and improve prevention, diagnosis and treatment of , immune disorders and infectious diseases.

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We offer undergraduate (Honours) and graduate coursework (Masters) and graduate research education (PhD) as the Department of Medical Biology in the Faculty of Medicine, Dentistry and Health Sciences of the University of . The Institute can host students enrolled in a Masters by coursework degree for a research project, from other Departments.

Research projects: 2021 intake We offer a number of student research project places (Honours, Masters and PhD) each year covering a broad range of medical research fields and disease areas.

Medical Biology PhD Program We offer graduate research training as the Department of Medical Biology of the . At any one time, more than 140 PhD students are enrolled.

Honours program Honours is a fourth-year program which gives you the opportunity to draw together your previous science, biomedical or health science studies and focus your knowledge, skills and intellect on an exciting piece of original research.

Masters by Coursework We offer research training for the Master of Biomedical Science (Medical Biology); and Master of Science students in bioinformatics, mathematics, statistics and computational biology.

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Project type indicated by: Hon Honours M Masters PhD PhD Contents by research theme and division of primary supervisor Infection, Inflammation and Immunity Immunology division T lymphocytes: how memories are made 6 A new regulator of ‘stemness’ to create dendritic cell factories for immunotherapy 6 Developing a new drug that targets plasmacytoid dendritic cells for the treatment of lupus 7 Using cutting-edge single cell tools to understand the origins of cancer 7 TICKER: A cell history recorder for longitudinal patient monitoring 8 The molecular controls on dendritic cell development 8 Targeting the epigenome to rewire pro-allergic T cells 9 When healthy cells turn bad: how immune responses can transition to 9 Understanding the neuroimmune regulation of innate immunity 10 Infectious Diseases and Immune Defence division Development of a novel particle-based vaccine 10 Dissecting host cell invasion by the diarrhoeal pathogen Cryptosporidium 11 Interaction with Toxoplasma parasites and the brain 11 Essential role of glycobiology in malaria parasites 12 Human lung protective immunity to tuberculosis 12 Epigenetic biomarkers of tuberculosis infection 13 Structure and biology of proteins essential for Toxoplasma parasite invasion 13 Inflammation division Control of cytokine signaling by SOCS1 14 Minimising rheumatic adverse events of checkpoint inhibitor cancer therapy 14

Healthy Development and Ageing Population Health and Immunity division Naturally acquired immune response to malaria parasites 15 Understanding malaria infection dynamics 15 Modelling spatial and demographic heterogeneity of malaria transmission risk 16 Ubiquitin Signalling division Understanding the proteins that regulate programmed cell death at the molecular level 16

New Medicines and Advanced Technologies ACRF Chemical Biology division Development and mechanism of action of novel antimalarials 17 Targeting host pathways to develop new broad-spectrum antiviral drugs 17 Targeting post-translational modifications to disrupting the function of secreted proteins 18 Defining the protein modifications associated with respiratory disease 18 Structural Biology division Structural basis of β-catenin-independent Wnt signalling 19 Understanding the proteins that regulate programmed cell death at the molecular level 19

4 2021 RESEARCH PROJECTS Computational Biology Bioformatics division Microbiome strain-level analysis using long read sequencing 20 Predicting the effect of non-coding structural variants in cancer 20 Advanced methods for genomic rearrangement detection 21

Cancer Research and Treatments ACRF Cancer Biology and Stem Cells division Targeting the immune microenvironment to treat KRAS-mutant adenocarcinoma 22 Identifying novel treatment options for ovarian carcinosarcoma 22 Blood Cells and Blood Cancer division Understanding the genetics of neutrophil maturation 23 Evolution of haematopoiesis in vertebrates 23 Investigating the role of mutant p53 in cancer 24 Delineating the pathways driving cancer development and therapy resistance 24 Personalised Oncology division Interactions between tumour cells and their microenvironment in non-small cell lung cancer 25

Application checklists 26

WALTER AND ELIZA HALL INSTITUTE 5 Infection, Inflammation and Immunity Immunology division T lymphocytes: how memories are made Details of project Our lab is developing a new theory of cell fate regulation based on competition within individual cells for different outcomes such as death, division and differentiation. Experimental work to inform this new theory requires measurement of immune cell fates in single cells using flow cytometry or single cell imaging. We have recently discovered a simple numerical and timing rule for how naive CD8 T cells integrate signals determining the number of times they divide before returning to the resting state (Marchingo et al; Science. 2014, 346:1123 and Heinzel et al. Nat. Immunol. 2017;18:96)) We now want to investigate how these rules affect the differentiation into effector or memory cells and whether similar rules govern the expansion of memory cells upon reactivation. We aim to test this in in-vitro systems and translate these findings to in-vivo pathogen models. Hon

PhD Professor Phil Hodgkin Dr Susanne Heinzel Immunology division Immunology division [email protected] [email protected]

A new regulator of ‘stemness’ to create dendritic cell factories for immunotherapy Details of project Dendritic cells (DCs) are being harnessed for cancer immunotherapy considering their potent ability to activate T cells. However, they cannot be generated in large numbers.We have identified a novel molecule that negatively regulates stemness activity in DC progenitors in culture such that when the gene is deleted, DCs grow indefinitely – an unprecedented observation that may extend to other cell types too. The student will use a suite of tools to understand how this protein regulates stemness, what its transcription factor and histone deacetylase binding partners are, and whether it could be harnessed to generate clinical scale DCs for immunotherapy. Techniques will include cell culture, flow cytometry, CRISPR, molecular techniques such as ChIP-Seq, proteomics, using bespoke PROTAC tools and in vivo cancer immunotherapy. Hon

PhD Dr Shalin Naik Immunology division [email protected]

6 2021 RESEARCH PROJECTS Return to contents Infection, Inflammation and Immunity Immunology division Developing a new drug that targets plasmacytoid dendritic cells for the treatment of lupus Details of project This project would suit someone with an interest in medicinal chemistry and immunology. Plasmacytoid dendritic cells (pDCs) have been implicated in the systemic lupus erthymatosus (SLE), known simply as lupus. We have identified a novel small molecule in a drug screen that blocks their development from bone marrow progenitors. If one could block pDC development in patients, one may be able to reduce the symptoms or disease progression. This project will aim to identify the molecular target of this drug in pDC progenitors, and test drug candidates in models of pDC development. This project will be at the frontier between chemistry and biology and suit a student willing to undertake a highly multidisciplinary project, and learn a lot of techniques from chemistry, proteomics, molecular and cell biology. A successful project may result in new treatments, and a deeper understanding of immune cell development. Hon

PhD Dr Shalin Naik Professor Guillaume Lessene Immunology division ACRF Chemical Biology division [email protected] [email protected]

Using cutting-edge single cell tools to understand the origins of cancer Details of project Cancer derives from a single cell. However, for many cancers, the precise cell of origin is unknown. We have a suite of cutting-edge single cell technologies that can help answer this question. Using cellular barcoding that either delivers or create DNA barcodes inside cells, this project will identify the clonal origins of from haematopoietic (blood) stem and progenitor cells. In particular, the student will use a novel LoxCode technology that creates DNA barcodes inside cells within a live organism (unpublished, but similar to PolyLox system). The student will examine how different cancer mutations affect the expansion of single cells in the prelude to becoming cancerous. They will also use novel approaches using virus-delivered barcoding (see Naik, Nature, 2013) that we have developed to understand what a single cell would normally make, and how that would change with a cancer-causing gene. This will suit technology-minded students who can think deeply about single cell biology, and will involve many techniques including cell culture, in vivo experiments, single cell RNA-sequencing, molecular biology and computational analysis. Hon

PhD Dr Shalin Naik Dr Ashley Ng Associate Professor Marco Herold Immunology division Blood Cells and Blood Cancer Blood Cells and Blood Cancer [email protected] division division [email protected] [email protected]

Return to contents WALTER AND ELIZA HALL INSTITUTE 7 Infection, Inflammation and Immunity Immunology division TICKER: A cell history recorder for longitudinal patient monitoring Details of project Cells are exquisite sensing ‘machines’ that continuously monitor their environment for signals. These signals dictate cell differentiation, division or biological function. Unfortunately, there is no ‘recording’ left behind to correlate a cell’s past with its current state. Recent engineering technologies have enabled cells to record biological processes into their DNA, so called ‘cell recorders’. However, they currently can’t record signal strength, duration and order simultaneously. In this project, a ‘cell history recorder’ is developed that overcomes these limitations using insertion of DNA barcodes (produced in response to cellular events) into a defined locus. Termed Triggered Induction of Cassettes that Knock-in and Elongate for later Readout or TICKER, creates a DNA ‘TICKER-tape’ that can be read out via sequencing. TICKER is anticipated to become a powerful synthetic biology tool for patient monitoring, disease prediction, and basic science. This project suits someone with interests in synthetic biology, molecular biology and DNA sequencing. Hon

PhD Dr Shalin Naik Dr Tom Weber Immunology division Immunology division [email protected] [email protected]

The molecular controls on dendritic cell development Details of project Dendritic cells (DCs) are professional antigen-presenting cells, located throughout the body. They form the first line of defence against pathogens. To provide this protection DCs have evolved into specialised subsets that perform unique functions. Given their ability to initiate an adaptive response they hold great therapeutic potential, and therefore constitute an essential target in efforts to generate therapeutic immunity against cancer. Our research aims to understand the molecular mechanisms underpinning DC diversity as these studies will pave the way to uncover novel approaches to alter DC fate to tailor DC-based therapeutic approaches. Combining cellular, molecular biology, and high throughput technologies the candidate will investigate the role of novel transcription factors in governing DC fate. Hon

PhD Professor Stephen Nutt Dr Michael Chopin Immunology division Immunology division [email protected] [email protected]

8 2021 RESEARCH PROJECTS Return to contents Infection, Inflammation and Immunity Immunology division Targeting the epigenome to rewire pro-allergic T cells Details of project Cells in allergic diseases such as asthma show changes in gene transcription owing to epigenetic alterations. However, targeting the epigenome for the treatment of these diseases is a nascent field. The overarching goal of this project is to develop novel therapeutic approaches to rewire the T cells which drive allergic disease. The particular approach will be tailored to the interests of the successful applicant but could involve 1) CRISPR screening to identify novel epigenetic regulators; 2) analysis of the three-dimensional chromatin interactome to identify novel non-coding targets; 3) drug discovery approaches to develop novel inhibitors of targets previously identified in our lab (Allan, Nature 2012 487(7406):249-53; Keenan, JCI Insight 2019 4(10)e127745). Skills that will be acquired include flow cytometry, genomics, CRISPR editing, disease models. Hon

PhD Dr Rhys Allan Dr Christine Keenan Immunology division Immunology division [email protected] [email protected]

When healthy cells turn bad: how immune responses can transition to lymphoma Details of project The immune response is a controlled proliferation burst of pathogen specific T and B cells. This clonal expansion is tightly controlled with too little or too much proliferation causing diseases such as , immunodeficiency or even lymphoma. We have recently established a novel culture system where we can follow the transformation of healthy naive B cells into lymphoma-like cells that grow unrestrained in vitro and in vivo. In this project we will use this system to investigate the cellular and molecular mechanisms that control the expansion and contraction of the healthy immune response and that are deregulated in progressive steps to lead to continuous growth and survival. Further reading: Horton et al, JI 2018 201:1097 Heinzel, et al Nat Immunol.2017;18:96 Marchingo et al Science. 2014;28;346:1123

PhD Professor Phil Hodgkin Dr Susanne Heinzel Immunology division Immunology division [email protected] [email protected]

Return to contents WALTER AND ELIZA HALL INSTITUTE 9 Infection, Inflammation and Immunity Immunology division Understanding the neuroimmune regulation of innate immunity Details of project The discovery of innate lymphoid cells (ILCs) has forced immunologists to rethink how the immune system provides tissue protection. Our pioneering work revealed that ILCs not only react to pathogens but also actively regulate the function of the organs in which they reside. In the gut, ILCs interact with neurons to sense food intake which promotes protective immunity against invasive micro- organisms, while at the same time fostering nutrient uptake (Seillet, Nature Immunology, 21(2), 168). This project aims to identify new neuronal regulators of ILCs and the environmental factors influencing these neuroimmune communications. This research will involve cutting-edge approaches in cellular culture, flow cytometry, 3D imaging and single cell RNA sequencing.

PhD Dr Cyril Seillet Professor Stephen Nutt Immunology division Immunology division [email protected] [email protected]

Infection, Inflammation and Immunity Infectious Diseases and Immune Defence division Development of a novel particle-based malaria vaccine Details of project We are working towards the development of a combination malaria vaccine that targets multiple life cycle stages in the parasite’s development in humans and mosquitoes. In this project we will work with novel particle-based and nanopatch vaccine delivery platforms This project will have three potential components: 1. Immunoprofiling and functional analysis of animal serum for anti-parasite activity 2. Immunoscreening of human plasma samples from malaria-endemic regions for responsiveness to vaccine antigens 3. Generation and characterisation of human monoclonal antibodies to key vaccine target antigens Hon

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PhD Dr Julie Healer Dr Stephen Scally Professor Alan Cowman Infectious Diseases and Immune Infectious Disease and Immune Infectious Diseases and Immune Defence division Defence division Defence division [email protected] [email protected] [email protected]

10 2021 RESEARCH PROJECTS Return to contents Infection, Inflammation and Immunity Infectious Diseases and Immune Defence division Dissecting host cell invasion by the diarrhoeal pathogen Cryptosporidium Details of project Cryptosporidium is a single celled eukaryotic parasite that resides in the cells of the small intestine and is the second leading cause of severe childhood diarrhea and crippling levels of morbidity and mortality in developing nations. Indeed, cryptosporidiosis is now considered one of the biggest killers of children <5 in Africa and SE Asia and has no effective treatments. Poor immunity against Cryptosporidium and recurrent mean that cryptosporidiosis is a key contributor to the vicious cycle of poverty and infection, which keeps developing nations from prospering. It is our goal to understand how Cryptosporidium recognises and invades host cells, which is absolutely required for parasite survival. Whilst we understand in some detail how related Toxoplasma and malaria parasites invade their cognate cells nothing is understood about this process in Cryptosporidium nor if this process can be blocked to develop the first vaccine or drugs to clear infection. It is only now the field has the experimental tools to dissect invasion in Cryptosporidium whilst WEHI has also novel capabilities to understand this process. This project will utilise molecular genetics to epitope tag and make knockouts of candidate parasite adhesins and dissect their role in invasion. New experimental techniques will also be used to determine the function of key proteins on the surface of Cryptosporidium and how they interact with host cells. Furthermore, this project will determine whether invasion can be targeted by antibodies to prevent infection, thus paving the way to developing the first vaccine against this insidious and deadly parasite. Hon

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PhD Associate Professor Chris Tonkin Infectious Diseases and Immune Defence division [email protected]

Interaction with Toxoplasma parasites and the brain Details of project Manipulation of host cells by intracellular pathogens is critical for their survival. Here pathogens inject their own proteins (called effectors) into the host cell and interfere with cell death and immune pathways to ensure their survival in the face of these human defence mechanisms. Pathogen effectors and mechanisms used to export these proteins into the host cell are thus critical for disease, whilst also representing a fascinating glimpse into how two organisms interact. We are interested in identifying mechanisms of neuron manipulation by the brain-dwelling parasite Toxoplasma – the causative agent of blindness, congenital birth defects and disease in immunocompromised. Further, Toxoplasma has been linked to neuropsychiatric diseases suggesting that Toxoplasma may manipulate infected neurons to elicit behavioral changes. This project will use powerful molecular genetics available in Toxoplasma in combination with an infection model where cells report infection by expressing GFP. This project aims to identify effectors and characterise their role during infection and behavioral changes. Hon

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PhD Associate Professor Chris Tonkin Infectious Diseases and Immune Defence division [email protected]

Return to contents WALTER AND ELIZA HALL INSTITUTE 11 Infection, Inflammation and Immunity Infectious Diseases and Immune Defence division Essential role of glycobiology in malaria parasites Details of project Malaria causes approximately 600,000 deaths annually and remains an enormous global health problem. One reason for this is that there is no highly effective vaccine. The only licensed malaria vaccine RTS,S (Mosquirix) offers poor efficacy that wanes over time. Part of the problem may be that the recombinant malaria antigen in RTS,S is not glycosylated like the endogenous malaria protein. Glycosylation is important for vaccine development because carbohydrates decorate the surface of nearly all microbes and carbohydrate antigens activate immune cells and are recognised by antibodies. It has long been believed that malaria parasites do not glycosylate proteins. On the contrary, these parasites do glycosylate proteins and we have shown this is involved in infecting the mosquito and human host. This is significant because several malaria vaccines in development are aimed at preventing infection by using antigens that are glycosylated by malaria parasites but not in the vaccine. This project focuses on understanding the role of glycosylation in malaria parasite infection of mosquitoes and the liver, before a malaria infection can take hold. It will also determine the function of uncharacterised glycosylated proteins as potential vaccine candidates. The project will use state-of-the-art conditional genetic systems to identify essential components of the glycosylation machinery and substrates in Plasmodium falciparum transmission. The project will involve working in an insectary with mosquitoes, producing all lifecycle stages and studying infection biology in multiple hosts. The student will learn a multidisciplinary skill set including parasitology, molecular genetics, cell culture, preclinical infection models, microscopy, proteomics and biochemical techniques.

PhD Associate Professor Justin Associate Professor Ethan Boddey Goddard-Borger Infectious Diseases and Immune ACRF Chemical Biology division Defence division [email protected] [email protected]

Human lung protective immunity to tuberculosis Details of project The majority of people who get infected with the tuberculosis (TB) bacteria do not get sick. Given there are billions of latently infected individuals globally, the only way to eradicate TB is by stopping people developing disease when infected. The fundamental step required for TB eradication is to truly understand human protective immunity to TB. Without this we cannot develop better diagnostics for those at risk of progressing to TB nor rapidly develop vaccines, as preclinical studies require an immunological correlate of protection to gauge potential efficacy of future candidates. This project will utilise a systems biology approach applying RNAseq, tissue proteomics, cellular phenotyping and microbiome analysis to human lung samples isolated from individuals with differing TB risk to identify mechanisms of human TB protective immunity.

PhD Dr Anna Coussens Dr Dylan Sheerin Infectious Diseases and Immune Infectious Disease and Immune Defence division Defence division [email protected] [email protected]

12 2021 RESEARCH PROJECTS Return to contents Infection, Inflammation and Immunity Infectious Diseases and Immune Defence division Epigenetic biomarkers of tuberculosis infection Details of project Despite 10 million cases of tuberculosis (TB) everyone year, we currently have no diagnostic test of current infection. We also can’t predict who, of the estimated quarter of the global population who has been exposed to Mycobacterium tuberculosis (Mtb), will develop TB disease at some stage in their life. Using samples collected from a longitudinal cohort of TB household contacts, who are followed for 2-3 years to identify those who develop TB, we are developing a blood signature of TB risk. This project will use nanopore long-read sequencing to investigate DNA epigenetic markers of TB infection and disease risk and use CRISPR/Cas9 targeting to develop and a multiplex DNA biomarker assay. In vitro Mtb infection assays will be used to understand the impact of identified epigenetic markers on the human innate cell response to Mtb infection.

PhD Dr Anna Coussens Dr Dylan Sheerin Infectious Diseases and Immune Infectious Disease and Immune Defence division Defence division [email protected] [email protected]

Structure and biology of proteins essential for Toxoplasma parasite invasion Details of project How pathogens enter host cells is a fascinating biological problem – an understanding of which can yield insight into the design of vaccines and new drugs. At the molecular interface this involves interactions between pathogen proteins and cognate receptors of the host cell. We are interested in understanding this molecular interaction in apicomplexan parasites that cause malaria and toxoplasmosis. This project will utilise the experimental tractability of Toxoplasma and structural biology techniques to understand the AMA1-RON complex. Students will make transgenic parasite incorporating tags that can be used to purify the complex and perform CryoEM to solve the structure of this complex. This exciting project will elucidate atomic detail of how apicomplexan parasites invade host cells which will provide insights to design strategies to block invasion.

PhD Dr Wilson Wong Associate Professor Chris Tonkin Infectious Diseases and Immune Infectious Diseases and Immune Defence division Defence division [email protected] [email protected]

Return to contents WALTER AND ELIZA HALL INSTITUTE 13 Infection, Inflammation and Immunity Inflammation division Control of cytokine signaling by SOCS1 Details of project Cytokine signaling is the linchpin of cell-to-cell communication, controlling inflammation, and cell division and differentiation. SOCS (Suppressor Of Cytokine Signaling) proteins are vital negative regulators that dampen the signaling pathways, and offer an intriguing handle to control cytokine signaling in human disease. SOCS proteins are expressed in response to cytokine signaling, bind to activated cytokine receptors, and trigger degradation of the receptor complex as well as directly blocking kinase activity. We have recently developed new tools which will allow you to study SOCS1 in its native environment. You will be researching the biology of SOCS1 in primary macrophages using microscopy and proteomics, as well as exploring the inhibition of SOCS1 to improve cancer treatment. Hon

PhD Associate Professor Sandra Dr Colin Hockings Dr Karen Doggett Nicholson Inflammation division Inflammation division Inflammation division [email protected] [email protected] [email protected]

Minimising rheumatic adverse events of checkpoint inhibitor cancer therapy Details of project Autoimmune diseases occur when the body’s immune system is chronically overactive and attacks healthy cells. We are researching the immunological basis of autoimmune disorders and extend such knowledge towards novel therapeutic applications. Immune checkpoint inhibitors (ICIs) have revolutionised cancer therapy by boosting patient’s own immune responses against tumours. However, many cancer patients can develop treatment-related autoimmune side-effects, including inflammatory arthritis. The aim of this project is to identify new anti-rheumatic strategies that can mitigate ICI-induced autoimmune adverse events without compromising the anti-tumour effects of ICIs. Student will perform proof-of-principle (genetic and pharmacologic) experiments using a preclinical model of ICI-induced arthritis.

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PhD Dr Cynthia Louis Professor Ian Wicks Inflammation division Inflammation/Clinical Translation [email protected] division [email protected]

14 2021 RESEARCH PROJECTS Return to contents Healthy Development and Ageing Population Health and Immunity division Naturally acquired immune response to malaria parasites Details of project Malaria is an infectious disease caused by Plasmodium parasites. We aim to understand naturally acquired immune responses in humans generated against Plasmodium, and to utilise these findings for development of novel tools for malaria elimination. An example of this is the development of serological markers of recent exposure to the species P. vivax (Longley, Nature Medicine 2020 26:741–749. We have a number of projects that could be undertaken, including understanding the development of immune memory and antibody longevity, application of serological exposure markers, and sero-epidemiological studies assessing associations of antibody responses with protection from clinical disease. These projects will use a variety of immunological techniques, epidemiology, computational data analysis, and will involve work with international collaborators. Hon

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PhD Dr Rhea Longley Professor Ivo Mueller Population Health and Immunity Population Health and Immunity division division [email protected] [email protected]

Understanding malaria infection dynamics Details of project Malaria is an infectious disease caused by Plasmodium parasites. Renewed intensification of global malaria control interventions over the past decade has had significant success. However, as we try to eliminate malaria infections become harder to detect yet contribute to ongoing transmission. We aim to better understand infection burden in areas approaching elimination. Using samples collected from large-scale epidemiological field studies in Asia-Pacific, this project will apply novel genotyping and molecular diagnostic techniques to identify and track malaria infections over space and time and within individuals. Genetic data will be related to epidemiological data helping us understand spatiotemporal infection dynamics and risk factors. This project will develop your skills in genetic and next-generation sequencing techniques, epidemiology, computational data analysis, and will involve work with international collaborators. Hon

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PhD Dr Shazia Ruybal Associate Professor Leanne Professor Ivo Mueller Population Health and Immunity Robinson Population Health and Immunity division Population Health and Immunity division [email protected] division [email protected] [email protected]

Return to contents WALTER AND ELIZA HALL INSTITUTE 15 Healthy Development and Ageing Population Health and Immunity division Modelling spatial and demographic heterogeneity of malaria transmission risk Details of project After 15 years of decreases in overall burden, malaria transmission has now become highly heterogeneous in space (with areas of high transmission surrounded by vast areas of little or no transmission) and/or restricted to specific high-risk groups such migrants, forest workers or miners. If elimination is to be achieved, it will essential to be able to accurately identify and map such high-risk areas / populations and understand the key processes driving this heterogeneity. As part of this PhD you will apply advanced statistical methods to extensive longitudinal and cross-sectional dataset (incl. epidemiological, genetic and immunological variables) from Papua New Guinea, Cambodia, Thailand and Brazil investigate key factors that contribute to these differences and develop novel metrics to quantify heterogeneity. Integrating this knowledge into mathematical malaria transmission models (White et al 2018), you will explore how current and novel intervention can be used to target transmission ‘hotspots’. Requires strong numerical abilities.

PhD Professor Ivo Mueller Population Health and Immunity division [email protected]

Healthy Development and Ageing Ubiquitin Signalling division Understanding the proteins that regulate programmed cell death at the molecular level Details of project Mitophagy - a cellular process that leads to the destruction of damaged mitochondria by autophagy - is regulated by phosphorylated ubiquitin, and uncharacterised Lys6-linked ubiquitin chains. These specialised ubiquitin signals are generated by the ubiquitin kinase PINK1 and the ubiquitin E3 ligase Parkin. Importantly, mutations of Parkin or PINK1 lead to inherited forms of early-onset Parkinson’s disease. In the past five years, we have provided a detailed molecular description of the ubiquitin signals generated by the PINK1 and Parkin enzymes involved in mitophagy (Gladkova et al, Nature 2018, 559(7714)410; Schubert et al, Nature 2017, 553(7683)51). We are now keen to target the system with small molecules, which may be useful to treat neurodegenerative diseases such as Parkinson’s disease. This project will involve multiple molecular and cell biology techniques including protein chemistry, structural biology, tissue culture.

PhD Professor David Komander Associate Professor Grant Ubiquitin Signalling division Dewson [email protected] Ubiquitin Signalling division [email protected]

16 2021 RESEARCH PROJECTS Return to contents New Medicines and Advanced Technologies ACRF Chemical Biology division Development and mechanism of action of novel antimalarials Details of project Malaria is a devastating disease that causes 450,000 deaths annually. No new class of antimalarial drug has entered the market in the last 15 years resulting in the emergence of resistance against all clinically used drug classes. Therefore, there is an urgent need to develop new antimalarial clinical candidate drugs. This project will utilise medicinal chemistry to optimise the antimalarial activity of recently identified classes of drug-like small molecules to achieve efficacy in laboratory models of malaria. The project also aims to employ complementary cutting-edge genetic and chemical biology techniques to discover the mechanism by which the novel antimalarials under development kill the malaria parasite. The overall goal is to develop lead candidates for pre-clinical development with industry partners. Hon

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PhD Dr Brad Sleebs ACRF Chemical Biology division [email protected]

Targeting host pathways to develop new broad-spectrum antiviral drugs Details of project The ongoing COVID-19 pandemic highlights how important it is to develop new broad-spectrum antiviral drugs. This goal can be realised by targeting common host biochemical pathways that are required by viruses for replication. I recently published a review outlining how this approach could be used to repurpose existing drugs for the treatment of COVID-19 (Williams & Goddard-Borger, Biochemical Society Transactions, 2020, doi:10.1042/BST20200505). This chemistry project will focus on the development of new small molecules that have been optimised to shutdown host cell pathways that are required for the folding and trafficking of essential virus glycoproteins. These compounds will be evaluated against a number of viruses, including SARS-CoV-2, in the institute’s high-containment facility. This is an excellent opportunity for those interested in medicinal chemistry.

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PhD Associate Professor Ethan Professor Marc Pellegrini Goddard-Borger Infectious Disease and Immune ACRF Chemical Biology division Defence division [email protected] [email protected]

Return to contents WALTER AND ELIZA HALL INSTITUTE 17 New Medicines and Advanced Technologies ACRF Chemical Biology division Targeting post-translational modifications to disrupting the function of secreted proteins Details of project Modern drug discovery efforts are enabled by new therapeutic modalities that target proteins for destruction rather than simply inhibiting them (e.g. PROTACs). Building on this concept, we are developing molecules that block a range of post-translational modification processes in the cell to disrupt a protein’s function by driving its mislocalisation and destabilisation. This approach is particularly promising for drug targets that transit through the secretory pathway. The project will involve the chemical synthesis of new molecular probes, which will be guided by structural biology, and the evaluation of these compounds against their targets and closely related enzymes. These probes will also be evaluated against a range of tumour cell lines at the Institute. This is an excellent opportunity for those interested in chemical biology.

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PhD Associate Professor Ethan Goddard-Borger ACRF Chemical Biology division [email protected]

Defining the protein modifications associated with respiratory disease Details of project The composition of pulmonary mucus, which is secreted to protect the airways, changes with the onset of respiratory diseases like asthma, COPD and IPF. These changes are relatively well-understood at the protein level but it is less clear how the post-translational modifications of these proteins changes with the onset of disease. We and others have shown that these post-translational modifications, particularly O-glycosylation, plays a defining role in the function of these mucosal proteins (Goddard-Borger, Nature Communications, 2020, doi:10.1038/s41467-020-16223-7). This highlights the importance of investigating how mucosal protein modifications differ in respiratory diseases. This project will focus on the development of tools and methods to characterise the post-translational modifications of mucosal proteins. It is an excellent opportunity for those interested in protein science and/or proteomics.

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PhD Associate Professor Ethan Associate Professor Goddard-Borger Rhys Allan ACRF Chemical Biology division Immunology division [email protected] [email protected]

18 2021 RESEARCH PROJECTS Return to contents New Medicines and Advanced Technologies Structural Biology division Structural basis of β-catenin- independent Wnt signalling Details of project Wnt ligands are a family of secreted glycoproteins that regulate many processes of cell proliferation, polarity, differentiation, and migration. Wnt signalling is absolutely crucial for embryonic development and in adults its dysregulation underlies the progression of many cancers. Wnt signalling is mediated by Wnt proteins that activate Frizzled receptors (FZD). Different combinations of Wnts/FZD/co-receptors can elicit different signalling outcomes through the engagement of different cellular partners. This project will specifically focus on understanding the structural basis of how Wnt binding to FZD leads to G protein coupling. We will use a wide range of molecular biology and biochemical techniques to create a stable complex suitable for structure determination using cryo-electron microscopy. Once successful, the student will learn sample preparation, imaging, data processing, and structure analysis. Hon

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PhD Dr Alisa Glukhova Structural Biology division [email protected]

Understanding the proteins that regulate programmed cell death at the molecular level Details of project Apoptosis is the principle pathway that targets cells for programmed death and is required for removal of faulty cells, for example due to viral infection or cancer. Defective cell death can contribute to disease in a variety of settings including cancers, heart attack, stroke or degenerative disease (Moldoveanu and Czabotar, Cold Spring Harbour Perpec Biol 2020 vol 12). We are interested in understanding how the pro-apoptotic protein Bax, a member of the BCL-2 family, promotes apoptosis. To understand this we will characterise 3 D structures of Bax using X-ray crystallography and CryoEM. In addition we will characterise binding of ligands to Bax using a combination of structural and biophysical techniques. The project will suit students interested in protein crystallography, structural biology, drug discovery and protein-ligand interactions. Hon

PhD Associate Professor Peter Czabotar Structural Biology division [email protected]

Return to contents WALTER AND ELIZA HALL INSTITUTE 19 Computational Biology Bioformatics division Microbiome strain-level analysis using long read sequencing Details of project Technologies and analysis tools are being developed to enable understanding of communities of microbes - microbiomes. A key aspect is knowing, at the finest genomic level (strain level), what microbes are present, their relative abundance, and details of specific genes present. This project concerns using sequence data from the latest long read technologies to identify important genetic features of strains in a microbiome. Project: 1. Assess the feasibility of building more accurate genomic sequences for those strains present in a microbiome sample. 2. Investigate methods to genetically characterise bacterial strains in a microbiome sample using only long reads, long combined with short reads, and possible improvement to recently published methods. The Speed Lab has expertise in long read sequencing analysis and its application to microbiomics. Hon

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Dr Chris Woodruff Professor Bioinformatics division Bioinformatics division [email protected] [email protected]

Predicting the effect of non-coding structural variants in cancer Details of project This is an exciting new opportunity that has emerged recently. Currently, non-coding structural variation is ignored in clinical sequencing and in cohort studies. There are hardly any tools to annotate or predict the effect of such mutations. This project will involve the exploratory analysis of several cohorts with matched whole genome and transcriptome sequencing: 1. Rare cancer cohort 2. ICGC Pan-Prostate Cancer Genome project (>1200 patients with WGS and ~700 with RNAseq) 3. TCGA 4. Potentially other big somatic and germline datasets The aim is to identify recurrent SVs that may impact gene expression (e.g. https://www.biorxiv.org/ content/10.1101/2019.12.18.881086v1.full) and to develop machine learning approaches to predict the effect of non- coding SV mutations for use in cases lacking RNAseq data. Many rare cancers have low tumour mutation burden with few (often one or no) known drivers. The role of SVs in these cancers could be highly important.

PhD Professor Tony Papenfuss Dr Justin Bedo Bioinformatics division Bioinformatics division [email protected] [email protected]

20 2021 RESEARCH PROJECTS Return to contents Computational Biology Bioformatics division Advanced methods for genomic rearrangement detection Details of project Cancer, along with other genetic diseases, can be caused by genomic rearrangements or structural variants (SVs). This project will build on previous state-of-the-art bioinformatics methods developed in the lab to detect such mutations (Cameron et al, Genome Research 2017, 27:2050; Cameron et al, bioRxiv 2020.02.27.967240). You will contribute to a suite of methods to identify chromosomal rearrangements and to make sense of cancer genome sequencing data. This project could cover: 1) Integrating linked read, long read data, and optical mapping data into a caller 2) Single nucleotide resolution copy number detection 3) Germline event classification 4) Detecting structural variants from genome graphs This project would suit a student with a background in computer science, mathematics or statistics. You will have the opportunity to be involved in major national and international cancer genomics projects.

PhD Professor Tony Papenfuss Dr Daniel Cameron Bioinformatics division Bioinformatics division [email protected] [email protected]

Return to contents WALTER AND ELIZA HALL INSTITUTE 21 Cancer Research and Treatments ACRF Cancer Biology and Stem Cells division Targeting the immune microenvironment to treat KRAS-mutant adenocarcinoma Details of project Lung cancer is the leading cause of cancer-related death worldwide. Lung adenocarcinoma is the most common subtype of lung cancer with 35 per cent of cancers associated with oncogenic driver mutations in KRAS (TCGA, Nature 2014 511(7511):320). We have recently identified that pro-tumourigenic macrophages infiltrate KRAS-mutant lung adenocarcinoma, and their depletion can restrict tumour development (Best, Nature Communications 2019 10(1):4190). This project will explore therapeutic modalities that can inhibit macrophage development and infiltration in KRAS-mutant lung adenocarcinoma to further the clinical translation of our findings. This project will involve the use of a wide variety of experimental techniques, including pre-clinical models of lung cancer, tissue/tumour pathology, microscopy and flow cytometry. Hon

Dr Sarah Best Dr Kate Sutherland ACRF Cancer Biology and Stem ACRF Cancer Biology and Stem Cells division Cells division [email protected] [email protected]

Identifying novel treatment options for ovarian carcinosarcoma Details of project Ovarian carcinosarcoma (OCS) and high grade serous endometrial cancer (HGSEC) are rare and very aggressive gynaecological cancers. Due to their rarity, there are few evidence-based treatment options for these cancers because supportive data is simply not available. Standard treatment comprises surgery with platinum/taxane-based chemotherapy. Both OCS and HGSEC have poor responses to chemotherapy compared to other more common gynaecological cancer subtypes. This project will involve the analysis of patient samples using a variety of techniques including genomics, 3D organoid culture, live cell imaging, immune profiling, drug library screening, and CRISPR screening. The aim is to identify pathways that mediate response to conventional chemotherapeutics and that show potential for targeting with novel agents, to inform clinical trial design in these under-studied cancers. Hon

PhD Professor Clare Scott Dr Holly Barker Dr Kristy Shield-Artin ACRF Cancer Biology and Stem ACRF Cancer Biology and Stem ACRF Cancer Biology and Stem Cells division Cells division Cells division [email protected] [email protected] [email protected]

22 2021 RESEARCH PROJECTS Return to contents Cancer Research and Treatments Blood Cells and Blood Cancer division Understanding the genetics of neutrophil maturation Details of project Neutrophils are early responders to inflammation. They contain antimicrobial granules which they release to combat infection. They are also characterised by a polymorphic nucleus which becomes multilobed in mature neutrophils. We have been conducting an image based CRISPR screen to identify genes that are involved in two key components of neutrophil maturation – granule production and the increasing complexity of nuclear morphology. In this project, you will characterise hits we have identified from this screen in detail. Firstly, you will use CRISPR and other molecular biology techniques confirm whether the genes have a role in neutrophil maturation. Confirmed hits will be further characterised with microscopy to study morphological defects and in vitro assays to characterise functional defects. Hon

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PhD Dr Carolyn de Graaf Professor Blood Cells and Blood Cancer Blood Cells and Blood Cancer division division [email protected] [email protected]

Evolution of haematopoiesis in vertebrates Details of project The major hematopoietic lineages have existed since early in vertebrate evolution, covering the key functions of oxygen transport, clotting and defense against infection, yet the details of how these functions are performed are unique to mammals. Using single cell transcriptomes, we have profiled the gene expression from mammals to early vertebrates. You will use this data to search for genes which are associated with mammalian specific processes such as polyploidy in megakaryocytes. These genes will be screened for function with an imaging based CRISPR screen, before follow up in vitro studies to confirm their role. This project will involve both wet and dry lab techniques. Hon

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PhD Dr Carolyn de Graaf Professor Doug Hilton Blood Cells and Blood Cancer Blood Cells and Blood Cancer division division [email protected] [email protected]

Return to contents WALTER AND ELIZA HALL INSTITUTE 23 Cancer Research and Treatments Blood Cells and Blood Cancers division Investigating the role of mutant p53 in cancer Details of project Mutations in the tumour suppressor p53 are frequently detected in human cancers of diverse origin. These mutations impair the response of malignant cells to anti-cancer agents that cause DNA damage and patients with tumours carrying defects in p53 often have a poorer prognosis. Our research aims to understand how p53 mutations contribute to the initiation and sustained growth of and other types of cancer, and their response to cancer therapy. This work builds on previous work using innovative mouse models, cell biology techniques and bio-informatic analysis published in Aubrey et al, Genes and Dev 2018. The student will gain experience in working with sophisticated pre-clinical models of cancer and will learn a wide range of techniques including FACS, CRISPR/Cas9 genome editing, RNA-Seq analysis.

PhD Dr Gemma Kelly Professor Andreas Strasser Blood Cells and Blood Cancer Blood Cells and Blood Cancer division division [email protected] [email protected]

Delineating the pathways driving cancer development and therapy resistance Details of project Cancer is a complex disease caused by the aberrant expression of diverse gene products. Large sequencing studies have shed some light onto the nature of these cancer specific aberrations, but many of the critical tumour driving pathways and mutations that cause therapy resistance have not been discovered yet. To explore this, we have developed novel pre-clinical models, which will be combined with cutting edge CRISPR technology to unravel critical cancer driving and therapy resistance genes. The PhD candidate will learn diverse CRISPR techniques (knockout, activation, base editing) to manipulate single genes and will use them as a screening tool in vitro and in vivo. These skills will be complemented with standard laboratory techniques (molecular cloning, western blotting, tissue culture, flow cytometry) and new nucleotide sequencing methods. Additionally, the candidate will have the possibility to acquire basic and advanced bioinfomatic analysis tools offered by the Institutes Bioinformatics division. The PhD candidate will learn diverse CRISPR techniques (knockout, activation, base editing, prime editing) to manipulate single genes and will use them as a screening tools in vitro and in vivo. These skills will be complemented with standard laboratory techniques (molecular cloning, western blotting, tissue culture, flow cytometry) and new nucleotide sequencing methods. Additionally, the candidate will have the possibility to acquire basic and advanced bioinfomatic analysis tools offered by the Institute’s Bioinformatics division.

PhD Associate Professor Marco Herold Blood Cells and Blood Cancer division [email protected]

24 2021 RESEARCH PROJECTS Return to contents Cancer Research and Treatments Personalised Oncology division Interactions between tumour cells and their microenvironment in non-small cell lung cancer Details of project Lung cancer is the leading cause of cancer death worldwide, with a five-year survival rate of less than 15 per cent. In recent years, check point immunotherapies have made remarkable breakthrough in restoring anti-tumour immunity, and have brought clinical benefits to many cancers. Unfortunately, about 80 per cent of non-small cell lung cancer (NSCLC) patients do not respond to this therapy. Mechanisms of resistance to immunotherapy include tumour intrinsic and extrinsic factors mediated by the tumour microenvironment. This project aims to characterise the interactions between immune cells and tumour cells in NSCLC to understand resistance mechanisms and propose new targets for the development of therapy. The project will combine single cell profiling and in situ imaging analysis with genetic studies in preclinical models of NSCLC and in clinical samples. Hon

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PhD Associate Professor Marie-Liesse Asselin-Labat Personalised Oncology division [email protected]

Return to contents WALTER AND ELIZA HALL INSTITUTE 25 Application checklists

Honours and Masters 1. Review this project booklet or visit wehi.edu.au/studentprojects for the list of Honours and Masters projects. 2. Contact potential supervisors and explore suitability for project, they will request your CV, academic transcripts and meet online for an interview. 3. Application Part A: email the following to the Scientific Education Office [email protected]: ■ a cover letter outlining your interest in Honours or Master of Biomedical Science; ■ curriculum vitae; and ■ academic transcript. 4. Honours application Part B: Lodge an online application to the University of Melbourne for admission to Honours, with Department of Medical Biology via http://mdhs-study.unimelb.edu. au/degrees/honours/apply-now by Saturday 31 October 2020. ■ Select your supervisor’s project in SONIA. Change of preference can be made up to Friday 13 November 2020. ■ Honours offer dates: ■ Round 1 offers will be sent via email by the University of Melbourne by late December 2020. Students must promptly accept by the offer lapse date noted in their University offer letter. ■ 2nd round offers commence in January 2021. Please contact the Scientific Education Office to discuss [email protected]. 4. Masters application Part B: Lodge an online application to the University of Melbourne for admission to Master of Biomedical Science, with the Department of Medical Biology via https://study.unimelb.edu.au/find/courses/graduate/master-of-biomedical-science/how-to- apply/ by 30 November 2020.

PhD 1. Review this project booklet or visit wehi.edu.au/studentprojects for the list of prospective PhD projects.

2. Contact potential supervisors, explore suitability for projects, and agree on a potential research project with your prospective supervisor.

3. Notify the Scientific Education Office of your intention to submit an application

4. Complete the University of Melbourne Graduate Research online application for PhD candidature admission, this application also puts you into consideration for a University scholarship. ■ PhD candidature can be applied at any time of the year, however there are strict University scholarship application deadlines. The major round closes 31 October 2020. ■ The final deadline for second semester commencement is end of May 2021. ■ In some exceptional circumstances, host laboratories may agree to award interim funding until an external scholarship is attained. 5. University of Melbourne PhD Scholarship offers will be announced from mid-December 2020. Please contact the Scientific Education Office if you receive the University scholarship or any other external scholarship. Student’s then need to confirm official start date with their supervisor.

Key contacts Walter and Eliza Hall Institute Scientific Education Office [email protected]

Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne Honours [email protected] Master of Biomedical Science [email protected] PhD [email protected]

26 2021 RESEARCH PROJECTS Return to contents View projects online

wehi.edu.au/studentprojects wehi.edu.au/education

Walter and Eliza Hall Institute of Medical Research 1G Royal Parade Parkville 3052 Australia +61 3 9345 2555 www.wehi.edu.au

WEHIresearch WEHI_research WEHImovies WEHI_research Walter and Eliza Hall Institute

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