Congratulations to our members who were successful Marsden Grant recipients in the latest funding round.
Associate Professor Louise Bicknell, Biochemistry
ORC3: A novel disease gene with a moonlighting role in brain development
Biological complexity in higher organisms has been achieved in part by proteins taking on new moonlighting roles. While mutations in other ORC subunits cause a global reduction in growth, the team has discovered mutations in ORC3 in patients with a severe neurological disorder. They hypothesise that this clinical and genetic data has uncovered a moonlighting role for ORC3 in the brain, and they will explore this novel function using both in vitro and in vivo approaches. This project has the potential to define a novel disease gene and discover a novel moonlighting function for ORC3 in brain development.
Associate Professor Liz Ledgerwood, Biochemistry
Probing functional protein oligomerisation in the crowded cellular environment
A fundamental and widespread driver of protein functional diversity is oligomerisation. Within the crowded cellular environment, changes in oligomeric state will impact how proteins move, where they are localised, and what they interact with. However, most work on protein oligomerisation has used purified proteins, and we have little understanding of how these behaviours relate to function in living cells. By combining the use of live cell fluorescence fluctuation microscopy and oligomeric state-specific protein labelling the researchers will learn how oligomeric state controls function in the context of peroxiredoxins. Peroxiredoxins are proteins that are central to redox metabolism in all aerobic life forms, and switch between dimeric and ring-type decameric structures. As a prototypical example of the relationship between function and structural dynamics, this work will not only provide new insights into peroxiredoxin biology, but will also shed light more generally on whether oligomeric transitions identified in vitro predict in vivo behaviour of proteins.
Dr Nic Rawlence, Zoology
Unlocking the past: a novel approach to quantifying biodiversity loss in the fossil record
Accurately distinguishing between living and extinct species in the fossil record relies on the assumption that living species have changed little in the recent past. Preliminary data suggest this key assumption may often be violated, which could lead to overestimates of biodiversity loss and faunal turnover in the geological record across the tree of life. However, these two competing interpretations, and their relative frequency, cannot be distinguished based upon fossil data alone. Dr Rawlence and his teame will resolve this universal challenge by applying a novel geometric morphometric and genetic approach to contemporary and Holocene reptile specimens from New Zealand and New Caledonia.
Dr Simon Jackson, Microbiology and Immunology
Understanding bacteriophage-pathogen specificity to support phage therapy
The use of bacterial viruses (phages) is an emerging approach to treat antimicrobial-resistant bacterial infections, termed phage therapy. A major challenge for phage therapy is that closely related bacteria can differ vastly in their phage susceptibility profiles – highlighted by several recent clinical applications of phages that required screening thousands of phage candidates. Our research aims to understand the genetic basis for phage-bacteria specificity, focusing on immune systems that bacteria use to protect themselves from phages infections. Using new high-throughput genetic screens, Dr Jackson’s team will uncover how phages have evolved anti-immune proteins to evade or inactivate bacterial immunity. We will then discover which bacterial immune systems have evolved to counteract phage anti-immune proteins. Knowledge gained in this research will directly support future genomics-based approaches to developing phage-based therapies for bacterial infections.
And also, to our members who were awarded Fast Start Grants:
Dr Megan Leask, Physiology
Omics led discovery and in vivo screening of Māori and Pacific immune variation
The human immune system is incredibly diverse and subject to recent population-specific adaptation, yet what we have learnt so far about genetic regulation of immune biology has been restricted to European based datasets. Expanding genetic analyses to Māori and Pacific peoples presents a significant opportunity to: 1. understand novel immune mechanisms in these populations, and 2. address a critical issue in genetics research – inequity of participation of minority populations. Leveraging substantial ‘omics data from Māori and Pacific peoples and a world-first quantitative in vivo enhancer assay, Dr Leask will screen and functionally test a panel of population-specific genetic variants for immune activity. The outcomes of this project will provide mechanistic proof that associated Māori and Pacific variants, genes and metabolites are causal in inflammatory conditions, revealing biology that can immediately proceed to drug development.
The information gained here in this research will also be incorporated into the Genomics Aotearoa projects Rakeiora and Variome, critical to the implementation of genomic based medicine into the healthcare system of Aotearoa. This research will contribute to capacity building in Māori and Pacific genetics and is the step change required for equitable access to precision medicine in Aotearoa.
Dr Leah Smith, Microbiology and Immunology
The influence of bacterial dormancy – Uncovering factors that affect phage-biofilm interactions
Viruses that infect bacteria (phages) represent a potential strategy towards combating antibiotic-resistant infections. However, a greater understanding of fundamental phage-bacterial interactions is needed to inform on applied therapies. In both nature and clinical settings, bacteria predominantly exist as biofilm aggregations where cell metabolism ranges from active to dormant. Most phage characterization has been performed using metabolically active bacteria, ignoring the complexity of the biofilm state. Dr Smith will use directed evolution and sequencing to identify phage factors that facilitate dormant cell infection and assess phage-biofilm interactions using single-cell analyses. This research will guide selection of phage characteristics to improve therapeutic outcomes.
Dr Ludovic Dutoit, Zoology
Harnessing the power of hybrids to resolve the role of gene expression in evolution
Understanding the way organisms adapt to change is a fundamental goal of biology. Genetic changes happen at two levels: in the underlying DNA code of proteins or in the DNA code that regulates how much of a given protein is produced. Knowledge of this regulation process is limited. Dr Dutoit’s team will use hybrids of two species of New Zealand short-horned grasshopper and game-changing genomic approaches to disentangle the relative role of the different regulatory elements. Their study is well-placed to revolutionise the understanding of gene-expression evolution, improving the way we understand biological adaptation in our changing world.
Recently published work by GO members Brodie Foster, Graham McCulloch, Yasmin Foster, Gracie Kroos, Tania King and Jonathan Waters shows that a NZ insect has developed a unique ‘cheating’ strategy to avoid being eaten by mimicking a highly toxic species.
Read more on the Otago Bulletin or see publication details below:
ebony underpins Batesian mimicry in melanic stoneflies
Brodie J. Foster, Graham A. McCulloch, Yasmin Foster, Gracie C. Kroos, Tania M. King, Jonathan M. Waters
Genetics Otago co-director Associate Professor Logan Walker has led an international study, which also includes Genetics Otago member Dr George Wiggins, to improve RNA diagnostics for laboratories worldwide.
You can read more about this breakthrough on the Otago Bulletin.
Logan C. Walker, Miguel de la Hoya, George A.R. Wiggins, Amanda Lindy, Lisa M. Vincent, Michael T Parsons, Dafodil M Canson, Dana Bis-Brewer, Ashley Cass, Alexander Tchourbanov, Heather Zimmermann, Alicia B Byrne, Tina Pesaran, Rachid Karam, Steven Harrison, and Amanda B Spurdle
The American Journal of Human Genetics, Vol. 110, No. 7, pp.1046-1067, July 06, 2023
Genetics Otago members Dr Ludovic Dutoit and Dr Nic Rawlence have been featured across several media platforms recently for their paper on the evolutionary origins of the pygmy whale Caperea marginata.
Read more about their work in the Otago Bulletin.
Convergent evolution of skim feeding in baleen whales
Ludovic Dutoit, Kieren J. Mitchell, Nicolas Dussex, Catherine M. Kemper, Petter Larsson, Love Dalén, Nicolas J. Rawlence, Felix G. Marx
Marine Mammal Science
Congratulations to our members who were successful in their HRC Grant applications this year. The five successful members received a total of almost $6 million. You can read the details of their projects below.
Professor Julia Horsfield
Fighting leukaemia colonisation of the haematopoietic niche
Acute myeloid leukaemia (AML) has a low survival rate of 22 per cent in New Zealand. Treatment options for AML are limited and new strategies are needed to combat this disease. Understanding the function of AML-associated gene mutations is required to develop new therapies. Mutations in genes of the cohesin complex are present in ~12-20% of AML. Leukaemia stem cells can survive and evade treatment through interaction with the surrounding microenvironment known as the ‘niche’. We found that cohesin mutation enhances adhesive characteristics of leukaemia cells. We propose that these characteristics could promote increased interaction and colonisation of the leukemic cells into the niche. Zebrafish are an excellent model to study leukaemia development in vivo. This project will utilise cohesin mutant zebrafish models to examine the interaction and invasion potential of cohesin mutant cells within the niche, and determine whether niche interactions can be targeted for therapeutics.
Dr Euan Rodger
Identifying epigenetic markers for early detection of colorectal cancer
Colorectal cancer (CRC) death rates are particularly high in Aotearoa New Zealand and are increasing in younger people (age <50 years) and Māori, who are more likely to present with advanced stages of disease. Prognosis and survival of CRC patients rely heavily on the stage at diagnosis. Therefore, there is an urgent need for accessible and easily clinically-deployable biomarkers that enable early diagnosis and improve CRC outcome. Recent work demonstrates that DNA methylation patterns could be used as a powerful tool for highly specific and highly sensitive early tumour detection. We aim to use unbiased whole genome-scale analysis to identify DNA methylation markers in the blood that can be used for minimally invasive early detection of CRC patients. In the future, our work will contribute further to enhanced surveillance for relapse and treatment response to improve CRC outcomes in New Zealand.
Dr Rachel Purcell
Targeting the tumour microenvironment to improve outcomes in rectal cancer
The incidence of rectal cancer is increasing in NZ, particularly in younger people (< 50 years). Radiotherapy is often used to treat rectal cancer but patients have varying response, and currently, there are no predictive biomarkers of response available. Our recent work has identified an immune signature in rectal tumours that is predictive of response to radiotherapy, and, based on this, we will validate a biomarker test in an international cohort to predict response to radiotherapy and better direct treatment for rectal cancer patients. In addition, we found that the immune signature is linked to a specific tumour microbiome. We will use state-of the art techniques to determine the tumour immune-cell microenvironment that co-operates with radiotherapy and explore the potential of microbiome-based interventions to improve response to radiotherapy. This work will lead to the development of novel tests and microbiome-based treatments for rectal cancer, and ultimately improve outcomes for cancer.
Dr Htin Aung
Understanding inequitable tuberculosis transmission in Aotearoa
In Aotearoa New Zealand tuberculosis (TB) disproportionally affects Māori and Pasifika particularly children under five and 5-14 years, suggesting ongoing transmission is occurring in these communities. Adding to this problem, there are variants of TB-causing Mycobacterium tuberculosis bacteria which predominate in these communities. Our research project will investigate TB transmission in Māori and Pasifika communities, by combining the expertise of bacterial genetics, epidemiology, and social science research teams. This will involve working alongside communities and combining expertise from public hospitals, New Zealand universities and Te Whatu Ora in a collaborative approach. Utilising this culturally-responsive, transdisciplinary approach, our research project also aims to serve as a blueprint to tackle other infectious diseases in New Zealand and promote better health outcomes for New Zealanders.
Professor Merilyn Hibma
A molecular triage test to reduce colposcopy referrals after HPV testing
In 2023, the primary test for cervical screening will change to human papillomavirus (HPV) testing. HPV testing can be carried out on a self-collected swab, improving accessibility of screening for Māori and other women. However, a follow-up invasive triage test may be required. Additionally, many women referred to colposcopy following an HPV+ test do not have disease and would be better managed with monitoring. The purpose of this research is to develop a triage test for HPV+ women using the cells from a self-collected vaginal swab that will distinguish high-grade disease requiring treatment from low-grade disease that can be monitored. RNA sequencing will be used to identify disease-associated changes in gene expression and an assay will be developed and evaluated for its diagnostic effectiveness in a cross-section of HPV+ women. If successful, this test will have a significant impact on women’s health and on health delivery nationally and globally.
Genetics Otago members Associate Professor Aniruddha Chatterjee, Dr Rachel Purcell and Dr Euan Rodger have pinpointed a key feature that leads to the aggressive spread of colon cancer. Colorectal (bowel) cancer is Aotearoa’s second highest cause of cancer death.
Read more on the Otago Bulletin Board
Euan J. Rodger, Gregory Gimenez, Priyadarshana Ajithkumar, Peter A. Stockwell, Suzan Almomani, Sarah A. Bowden, Anna L. Leichter, Antonio Ahn, Sharon Pattison, John L. McCall, Sebastian Schmeier, Frank A. Frizelle, Michael R. Eccles, Rachel V. Purcell, Aniruddha Chatterjee,
An epigenetic signature of advanced colorectal cancer metastasis,
Volume 26, Issue 6,
Two GO members Associate Professor Christopher Brown (Department of Biochemistry) and Associate Professor Aniruddha Chatterjee (Department of Pathology) have been named as the only Otago University academics to receive Health Research Council Explorer Grants.
Associate Professor Christopher Brown
Department of Biochemistry
There is an urgent need for replacements for antibiotics. During evolution bacterial viruses have evolved to manipulate or destroy specific human pathogens. There are huge and rapidly increasing numbers of sequences from bacterial viruses in the public domain, but this wealth of data has not been able to be fully utilised. We believe that it has now become possible to mine this data for new antibiotics. In preliminary studies we have identified thousands of potential anti-bacterials – the difficulty is choosing the best ones. To select these we propose to develop novel computer methods to predict their hosts, biophysical, functional, and expression properties. If successful, this research will provide proof of principle by discovering and testing pre-clinically new anti-bacterials. It will open up a novel and flexible computational approach to transform antibiotic discovery.
Associate Professor Aniruddha Chatterjee
Department of Pathology
Although about 90% of cancer deaths are caused by metastasis, the underlying molecular events that drive it are poorly understood. This limited understanding hinders the development of effective cancer treatments. Initially thought to be driven by genetic mutations, our work indicates that epigenetic changes such as DNA methylation may be responsible for driving metastasis. Until recently it has not been possible to directly demonstrate that specific methylation changes alter metastatic potential. However, the development of precision editing tools now provides an opportunity to specifically edit epigenetic states target genes and to exclusively investigate the effect of these changes on cancer cell function. Our proposed research will further develop CRISPR/Cas technology to enable high-throughput interrogation of epigenetic drivers of metastasis. We aim to demonstrate that epigenetic mechanisms drive metastasis. This will open new avenues for understanding metastasis biology, lead to better outcome prediction, and identify new therapeutic targets to treat metastatic cancers.
The full Otago University recipient list for HRC grants can be read here.
Genetics Otago member Hamish Spencer is Sesquicentennial Distinguished Professor in the Department of Zoology at the University of Otago who writes a column for the ODT ‘Biological Taonga’. Read his latest article here.
Professor Jon Waters (Genetics Otago member, Department of Zoology) shares research authored by fellow GO members Dr Felix Vaux (Department of Zoology) and Associate Professor Ceridwen Fraser (Department of Marine Science) and other colleagues describing how kelp genomics can aid in revealing the impacts of ancient earthquakes.
Read more in the Otago Media Release.
Integrating kelp genomic analyses and geological data to reveal ancient earthquake impacts
Felix Vaux, Ceridwen I. Fraser, Dave Craw, Stephen Read and Jonathan M. Waters
Journal of the Royal Society Interface