Search Rutherford Discovery Fellowship awards 2010–2017

Public Summary: From apparently simple beginnings, some forms of life have evolved enormous complexity. Yet, understanding how complexity has evolved is not trivial. Complexity per se is not selectively advantageous. Consequently, rather than being a direct product of natural selection, the complexity of molecular systems and processes is generally viewed as an evolutionary by-product. What is it a by-product of is less clear however. A number of models by which systems may evolve to greater complexity have been proposed, including the process of gene duplication and subsequent functional divergence of the copies. However, few of these models have been directly tested. I aim to test four specific hypotheses relating to biological complexity, all of which examine so-called constructive neutral evolutionary mechanisms through which complexity may emerge: 1) that in populations where genetic drift will be a significant evolutionary process, non-adaptive mechanisms of complex gene expression, such as editing, may emerge, 2) that some horizontally mobile elements may result in increased complexity of a system without directly benefitting the recipient, 3) that retrotransposition (a copy-paste gene proliferation process) of small RNAs in eukaryote genomes creates greater complexity through emergence of mosaic expression patterns, despite there being no net increase in biological function, 4) that large multisubunit protein complexes are refractory to chimaerism following endosymbiosis. I will test these hypotheses using standard experimental or comparative genomics methods.

Public Summary: As humans spread out around the globe they initiated significant environmental changes. I will study the evolutionary processes associated with two such impacts: domestication and extinction. New Zealand provides an unparalleled opportunity to investigate both phenomena because of the recency (c. 800 years ago) of its settlement by humans.
Domestication involves a gradual continuum progressing from wild to fully domesticated variants as humans select individuals with desirable traits from natural populations. Many modern crops, on which humanity now depends, have been found to have low genetic diversity. The point along the domestication continuum at which this reduction in genetic diversity is most pronounced is a long-standing question of crop anthropology, relevant to modern crop management. However, most crops around the world are thousands of years old, with aspects of their initial domestication indeterminable.
My focus is four endemic New Zealand plant species that Maori brought into cultivation and translocated around New Zealand within the last 800 years. Building on my existing results, high throughput DNA sequencing will be used to improve the resolution of genetic relationships within each species and determine the number of times and location(s) where each species was brought into cultivation and the way in which domestication has reduced genetic diversity in the cultivated populations. The genetic data from multiple species, combined with traditional oral histories, will also reflect and illuminate pre-European Maori settlement routes and mobility.
The second focus of my research is examining the spatial patterns of species declines, which is necessary to develop effective conservation strategies and prevent further population loss. There has been considerable debate over whether declining species contract to populations in the centre of their historical geographic ranges or to the edge, as well as the role of altitude in declines. Another controversy concerns the distribution of genetic diversity across species’ ranges: the long-held perception that peripheral populations have lower genetic diversity and are more genetically divergent than those in the centre has been challenged recently.
Many of New Zealand’s birds and reptiles now occupy a small portion of their pre-human ranges; for example, kiwi and kakapo. The survival of populations of these species in different locations, despite their similar former distributions, indicates differing responses to the extrinsic factor(s) causing their declines. My novel approach using New Zealand’s exceptional subfossil record, which is young enough to yield ancient DNA, is the first to use a temporal framework to accurately reconstruct the pre-decline distributions, genetic structuring and diversity levels of multiple relictual species. This data will resolve long-standing debates about the relative influences of range position (centre vs. edge), altitude and pre-decline levels of genetic diversity on population survival. It will also enable determination of the part of a species’ range that is most resistant to extinction, a subject that has been debated for many years but still remains controversial and topical. With continuing human impacts worldwide, such as habitat fragmentation, exotic species introductions and climate change, this information is critical for prioritisation of conservation efforts and the effective positioning of nature reserves.

Public Summary: Disruption of normal communication between brain areas is a feature of a number of common brain disorders. In stroke, death of cells in the cortex results in disruption in communication between the halves of the brain, and an imbalance in activity. The consequence is that the unaffected half tends to inhibit the affected side, making the generation of movements on that side even more difficult. In epilepsy, the normal balance between excitation and inhibition is perturbed, leading to overactive brain areas and seizure generation. In the proposed research I will use two complementary approaches to alter inhibition and try to restore balance and improve function in these brain disorders. First, using electrical stimulation modelled on natural brain rhythms, I will attempt to restore balance between halves of the cortex in a model of stroke and determine whether reducing inhibition accelerates functional improvement. Second, using new technology in development at Otago, I will set up a system whereby an imbalance between excitatory and inhibitory circuits is detected and a treatment is administered to the offending brain area to reset the balance and prevent the progression of the seizure. These ideas will be advanced during the Fellowship towards clinical trial in humans.

Public Summary: Chronic kidney disease is common, affecting about 500,000 New Zealanders. Chronic kidney disease is important because it increases our chances of heart disease and death and may lead to needing treatment with dialysis or a kidney transplant. Dialysis therapy is a heavy and costly burden for patients and their families and the health system. However, finding reliable evidence to improve patient outcomes is hindered by the lack of rigorous summaries of evidence for many clinical questions that patients, doctors and policy-makers need answers to. The first focus for this research will be to understand whether using surrogate markers of health, common to research in this field, is useful when deciding whether treatments work. The second research focus explores important potential causes of poor quality of life for people with chronic kidney disease which can be tested in future trials to improve patient health and wellbeing. The third research focus will be to provide a comprehensive framework of understanding about existing treatments known to protect kidney function, so that clinicians, patients and funders can know which, of many, treatments is best with the fewest side-effects. Finally, the research will focus on how patients and healthcare providers experience chronic kidney disease care in Canterbury so that they can work together to find new and sustainable ways to improve healthcare for their own region. The research programme as a whole aims to provide rigorous overviews of existing research and participant-led enquiry to provide better and more useable information for clinicians, consumers and policy-makers in the field of chronic kidney disease.

Public Summary: The Polynesians travelled the Pacific to reach New Zealand around 800 years ago, bringing a distinct worldview, expanding knowledge of Pacific flora and fauna, and introducing new species to the highly endemic biota in both New Zealand and the island environments encountered en-route. Despite the well documented ecological impacts of this migration, key socio-ecological links of Pacific peoples with the environment remain largely unrecognised in conservation biology. Pacific cultures have highly developed oral traditions that reveal connections between people, practices and ecology. In Maori culture, whakatauki (ancestral sayings) are an enduring record of ecological understandings based on tribal memory. Whakatauki can inform contemporary scientific approaches by adding ecological knowledge and cultural context to modern conservation methods. I will build strong and powerful new bridges between traditional Maori ecological knowledge and empirical data through an integration of (1) a 'top-down' Pacific-wide perspective informing the embedded knowledge of local whakatauki, and (2) a 'bottom-up' exemplar case study. The Pacific-wide perspective will be obtained by contrasting whakatauki that arise after arrival in New Zealand with those of source Polynesian and en-route populations, to identify both commonalities and New Zealand-specific knowledge. I will focus initially on native species interactions and connections in the new New Zealand temperate ecosystems. I will unpack the science embedded within the matauranga (traditional knowledge) and explore linked biological and cultural contexts and their likely origin. I will consider the usefulness of concepts such as 'cultural keystone' species that are weighted differently in indigenous and western cultures, before focussing on transported species in the whakatauki. Introduced species have accompanied humans globally and are culturally important in many indigenous cultures, including across the Pacific where they are integral to cultural narratives, yet they are often regarded as pests in conservation biology. This conflict between cultural incorporation and pest status will form the basis of the bottom-up integrated exemplar case study; the application of kaitiakitanga principles to management of introduced species in native ecosystems remains un-researched, yet has far-reaching implications. One such species is the Pacific rat (kiore), that provided Maori with a lifeline ensuring survival, and maintained ancestral links to the wider Pacific. Kiore remain a culturally valued species that has controversially survived eradication, and is harvested by iwi. I will assess kiore resource use, past and present, to address cultural and ecological risks and benefits in managing its harvest; test how kiore-prey interactions strengthen or de-couple with changes that affect resource acquisition; and analyse some of the challenges for kaitiakitanga. The integration of 'top-down' and 'bottom-up' approaches to elucidating Maori ecological knowledge will provide powerful insights into human interactions with flora and fauna, and the human adaptability that underlies resource use of unfamiliar and introduced species. This fundamental advance, recognising reciprocal interactions between humans and nature, accounting for cultural values, and including local and global dynamics, will provide new perspectives on adaptability and extinction risk within New Zealand, and globally, and a solid foundation from which to examine management of native and introduced taonga species with significant applied benefits for iwi and conservation biologists.

Public Summary: An enormous amount of everyday products are reliant on synthetic chemistry for their production, including pharmaceuticals, agrochemicals, polymers, functional materials and dyes to name but a few. When constructing any of the above, chemists rely on functional group transformations to make new bonds during the synthesis process, a traditional practice that lacks atom, step and redox efficiency. The shortcomings associated with these existing methods have resulted in a demand for new initiatives that deliver more economical and environmentally friendly ways to make chemical bonds. Currently ignored when it comes to chemical synthesis, carbon-hydrogen (C-H) bonds are among the least reactive in organic chemistry. However, C-H bonds are highly abundant within organic molecules and thus constitute readily available handles upon which to conduct topologically obvious synthetic transformations. If these C-H bonds could be reacted in selective fashion, our reliance on inefficient functional group transformations would substantially diminish. In what constitutes a paradigm shift from traditional methods, this research will show that these readily available C-H bonds can be selectively manipulated (in a process called C-H functionalization) during the efficient chemical synthesis of several compounds relevant to the everyday products outlined above. The research will deliver valuable alternatives to the synthetic repertoire and will redefine how C-H bonds are perceived, moving them away from being classed as inert bystanders to being viewed as useful synthetic handles that can be manipulated selectively and efficiently.

Public Summary: The causes of genetic disorders range from mutation(s) in a single gene, where the mutation has a strong impact, through to complex disorders, which are caused by many mutations in different genes with a weak individual impact of each mutation. Identifying the genetic causes of monogenic disorders has become tractable through the advent of next-generation sequencing technology (exome sequencing) and consequently the genes underlying hundreds of different monogenic disorders have been identified through this approach. Conversely, identifying the many genetic variants which collectively make up the heritable component of complex disorders and consequently understanding their functional detriment, continues to be challenging. Here, I propose an alternative route for investigating the genetic complexity of many diseases: characterise modifiers of single gene disorders as a starting point. Specifically, variability among different individuals in single gene disorders could be a consequence of additional genetic variants in each patient genome influencing the patient’s clinical features. These variants may only have a phenotypic effect when inherited together with other particular variants; such a genetic scenario could underlie instances of more complicated heritability and therefore this approach may provide insight into the genetics of complex disorders. A tremendous amount of genomic data is generated from exome sequencing in searching for often a single mutation causing the genetic disorder; however this data can be further analyzed in more detail to provide additional insight into how the final phenotype is shaped in each patient. As an initial focus, I will study a rare genetic condition of extreme growth failure, microcephalic primordial dwarfism (MPD). Using exome data, I propose to investigate possible instances of additional genetic variants impacting on the patient phenotype in MPD patients. Using a bioinformatics approach, I will prioritize variants of interest based on their functional consequence, the relevance of the gene within which they lie, or whether additional published genetic mapping data highlighting variants (eg. GWAS studies or eQTL hits) suggest functional relevance. The specific variants of significant genes will be introduced in the genomes of human cell lines and model organisms using genome editing technology and then assessed for their impact on growth to determine which variants may act as modifiers in MPD patients. Understanding how a genetic condition, whether complex or monogenic, is shaped in each patient by multiple genetic factors will be critical for moves towards personalized medicine (using an individual’s genetic information to inform on healthcare). From a scientific perspective, it presents an additional opportunity to use human genetics to delineate cellular pathways and networks.

Public Summary: Cancer is a leading cause of morbidity and mortality worldwide. Metastasis (i.e., spread of primary cancers to distant organs) is responsible for ~90% of cancer-related deaths. Remarkable progress has been made in the last decade to document genetic events that cause primary cancers. However, a big unsolved question is how a primary cancer cell becomes metastatic and what are the molecular events that underpin this process. Extensive sequencing efforts indicate that gene mutations may not be a causal factor underpinning the primary to metastatic transition. On the other hand, epigenetic alterations (modifications in DNA structure that can alter gene expression without changing the actual genetic sequence) are dynamic in nature and therefore are likely to play an important role in deciphering the metastatic phenotypes. This area of research is only now starting to become appreciated. I propose to identify causal epigenetic factors in the metastasis process and to elucidate the molecular mechanisms by which these epigenetic changes decipher metastatic properties to cancer cells. I plan to build my research programme around two complimentary themes. First, I want to perform integrative epigenomic (DNA methylation), transcriptomic and genomic profiling of metastatic tumours, circulating tumour cells (CTCs) and pre-metastatic tumours from the same individuals to identify epigenetic-drivers of metastasis. To test the generalisability and validity of these epigenetic factors, I will perform large-scale computational analysis using publicly available cancer patient data (THEME 1). For the second theme, I aim to provide evidence for causality of the identified epigenetic-drivers in dictating metastatic cell function. I will employ a newly available epigenome editing tool to specifically engineer methylation levels at the epigenetic-driver loci and using cellular assays, I will investigate whether this exclusive epigenome editing results in altered cellular properties (THEME 2). I aim to focus on melanoma and colorectal cancer for the proposed work as New Zealand has one of the highest death rates for these two cancer types. However, I envisage applying these approaches to prostate, lung and breast cancers in the future. The proposed work aims to identify molecular factors and mechanisms responsible for metastasis and therefore will address one of several outstanding questions in cancer biology. This research will enable establishment of several new methods and expand the capability of genomic science in NZ. There is substantial interest in developing methylation-based biomarkers (as these are DNA based, they are stable and easily measurable). Further, unlike genetic changes, epigenetic changes are reversible and the growing efforts to develop combinatorial therapies (e.g. immunotherapy with epigenetic therapies) are already showing promising results. Improved understanding of functional epigenetic changes from this proposed project would significantly contribute to develop early cancer detection strategies and new epigenetic therapies to enhance patient outcomes.

Public Summary: The field of legal theory (jurisprudence) is in the midst of a revival of attention to the analysis and justification of law beyond the paradigm of ‘State law.’ No longer content with analysing or evaluating law in the state context, or arguing for the conditions under which state law is justified in imposing obligations on its subjects, the turn towards what I call ‘pluralist jurisprudence’ addresses those questions with answers attuned to both state and non-state legal systems. In particular, this emerging field argues that theories of law cannot justifiably be limited to exploring the obvious or paradigmatic instances of State law. Instead, they must be attuned to phenomena of international law, transnational law, regional law, indigenous law, customary law, religious law and other distinct legal phenomena, and be able to explain and evaluate their interactions with each other and with State law. My proposed project seeks to build a fully-worked out pluralist theory of law, a ‘jurisprudence without borders.’which focuses squarely on the possibility that a theory of law neither needs nor should have borders around the phenomena that it explains. I will argue that such a theory must be able to explain the normativity of law (the conditions under which law is binding), law’s institutionalization (the forms, institutions, and systems thorough which law operates upon subjects), law’s coercive character (the extent to which it can justifiably coerce subjects), and importantly, its role in the pursuit of a just political structure. These are among the core questions addressed by philosophers of law, but they have yet to be approached systematically, in an integrated fashion, with an eye to the problems posed by legal pluralism. The challenge here is not simply to identify the impact of legal pluralism upon the core questions in philosophy of law, rather it is to address these questions systematically and comprehensively, in a way that deals adequately with challenges from theories outside of the core canon of the subject.The challenge, to which this project is a response, is to integrate the different elements of a substantive theory of law (law’s authority, institutionality, coerciveness and justice) with concern for meta-questions surrounding the very viability of a comprehensive pluralist theory of law and the appropriate methodologies for its production. While the project speaks to an international audience of legal theorists, it has both local resonance and potential practical implications for legal/constitutional debates, the design of legal/political institutions,and substantive law reform. In particular, the New Zealand context features local legal pluralism, both in the form of tikanga Maori’s interaction with state law, and deep interactions between New Zealand’s legal system and the international and transnational legal orders. Both of these features will be explored in aspects of the extended project being proposed, and will be published in forms that make them accessible for public as well as academic engagement.

Public Summary: Iwi identity can be a powerful and enduring aspect of self in te ao Maori. Every Maori tribe has its own distinct whakapapa, history, aspirations, and reputation. For example, Ngapuhi are seen as an iwi who are fierce, entrepreneurial, uncompromising, risk-taking, and innovative, while Te Arawa are known as cultural ambassadors, orators, performers and strict adherents to tikanga (protocol). Consequently, pan-Maori research and development approaches are insufficient when it comes to implementing targeted approaches to accelerate Maori innovation, science and knowledge creation. In this project, I will examine the distinctive attributes of Aotearoa’s five largest iwi, and their historical and contemporary icons, to discover what this tells us about enduring identity traits, iwi aspirations, and the tribal educational research programmes that support Maori student success. I will use innovative and co-constructed research approaches to obtain unique access to iwi stories that advance our understandings of the potential of iwi knowledge (matauranga-a-iwi), both in its traditional applications and epistemology, and in its contemporary expression, to positively impact the educational aspirations of Maori students. An important educational question perennially facing educators is: ‘How can we foster cultural pride and academic aspiration among Maori students?’ This project will address this knowledge gap using a culturally informed combination of iwi-determined research methods to examine Maori perceptions of success from a variety of iwi viewpoints. This project will: 1. Consider iwi-specific research priorities, protocols, processes, and rules of engagement. 2. Examine the distinctive attributes of Aotearoa’s five largest iwi, and their historical and contemporary icons, to discover what this tells us about enduring identity traits 3. Examine how perspectives of success are informed by iwi-specific whakapapa, history, aspirations, and goals 4. Generate new narratives that contest notions of ‘pan-Maori’ identity, and instead produce iwi-specific knowledge and scholarly resources that can be used in educational settings to enhance positive self-concept and cultural pride in students of Maori heritage 5. Generate new and innovative research methodology models that are transferable and beneficial to other Indigenous contexts including Australia, Canada and Hawaii. By exploring what constitutes success and aspiration from an iwi perspective, this study will shift the emphasis from a deficit view of Maori potential to an affirmative view. The project will explore the ways schools and universities can make iwi knowledge a priority in the teaching of all New Zealand students, but especially Maori students, regarding diverse Indigenous knowledge systems. There is minimal research about iwi-specific attitudes, knowledge, and values regarding indigenous innovation and success. By representing iwi as powerful agents of their own destiny, this project will revitalize the traditional Indigenous knowledge bases and world views for the benefit of Maori students and Indigenous students globally. This study will establish the conditions in which Indigenous peoples can lead, transform and implement Indigenous knowledge production and innovation.