Award Recipients: 2022 Transformation

Despite medical advances in prevention, screening, early detection and treatment, cancer remains the leading cause of death in Canada with nearly 1 in 2 Canadians expected to be diagnosed with cancer during their lifetime and 1 in 4 will die from the disease. While survival rates continue to climb for cancers diagnosed in early stages, mortality rates for metastasized disease remain dismal. Nuclear medicine has the potential to transform clinical medicine to address the urgent need for targeted and effective treatments for metastatic cancer. This powerful approach allows non-invasive imaging and treatment of the disease at the molecular and cellular level; this is accomplished by injecting patients with very small amounts of radioactive isotopes attached to designer molecules (i.e.; biomolecule) that can selectively deliver the radioactive warhead to a diseased cell or region in the body. This technique results in low radiation doses for imaging and minimal harm to surrounding healthy tissue for therapy – the holy grail in cancer treatment. A prime example is the radioactive isotope actinium-225 (Ac-225), which ejects four alpha particles during its decay. When incorporated into a radiopharmaceutical that targets the cancer, Ac-225 can kill cancer cells with limited harm to nearby healthy tissue. It therefore has the potential to revolutionize cancer treatments. Like a sniper, the isotope can eliminate its target by delivering an intense but highly localized blast of energy. The energy of each alpha particle is deposited in a very short distance (<10 cell diameters) and is so powerful it can break bonds in DNA, effectively incapacitating the cancer cell’s ability to repair or multiply, killing tumours; this mechanism can destroy some of the most stubborn cancers. This remarkable potential was recently demonstrated in a German study, where an Ac-225 drug targeting prostate cancer induced complete remission in patients with end-stage metastatic disease who had exhausted all other treatment options. The imminent need to develop novel and effective therapies for late-stage and hard to treat cancers is undeniable, and radiotherapeutic drugs hold the potential to revolutionize cancer treatment. However, the widespread use and routine clinical application of targeted radionuclide therapies (TRTs) to treat cancer has been obstructed by world-wide radioisotope supply issues and shortage, and consequently a lack of development towards integrating these novel isotopes into radioligand therapies to cure metastatic cancers. In particular, the world-wide supply of actinium-225 is equivalent to a few grains of sand and enough to treat no more than 2000 patients a year, making it inaccessible to most researchers and clinicians. In addition, there exists a toolbox of other radioisotopes with promising combinations of radiological half-life and chemical properties that make them ideal for incorporation into TRTs for treating cancers, if only there would exist a proven path towards clinical translation. The proposed research will bring together a world-leading international team of researchers to establish a reliable and adequate supply of rare isotopes such as actinium-225 and use them to develop effective and safe radiopharmaceuticals that will bring new therapies to the clinic, ultimately transforming cancer therapy in Canada and around the world. The goal of this proposal is to take advantage of the therapeutic potential of rare isotopes as constituents in radiopharmaceuticals, ultimately to revolutionise cancer therapy. Our approach involves five aspects: (1) Isotope production: We will produce cutting-edge clinically relevant radio-therapeutic and complementary radio-diagnostic isotopes that meet clinical standards and in adequate quantities to supply the world. We will produce actinium-225 to meet the imminent demand of this popular radioisotope. Furthermore, we will establish supply chains for a library of clinically promising candidates of therapeutic and diagnostic isotopes; for example, lead and terbium both have therapeutic and diagnostic isotopes that we will develop. We will develop targets and establish processing and purification of each radionuclide to ensure that they are of high quality for radiopharmaceutical development. (2) Radiopharmaceutical chemistry: We will optimize the radiolabeling chemistry needed to attach each rare isotope to a disease targeting molecule. This will involve developing tailored bifunctional chelating ligands (BFC) for each radioisotope. A BFC is a molecular agent used to tether the nuclide to the biomolecule and ensures safe delivery of the radioactive warhead to the disease site. (3) Disease target development: We will pursue extensive optimization of biomolecules designed to target several specific cancer types. Our initial focus will entail clinical translation of one vector that has proven potential (i.e., prostate specific membrane antigen [PSMA] analogues for prostate cancer). Other vectors targeting melanoma, pancreatic, breast, and blood cancers will be studied extensively. Preclinical studies of each radiopharmaceutical will be assessed to select the best candidates to move to clinical trials.(4) Clinical translation: We will bring novel radiopharmaceuticals to the clinic. This will entail dosimetry, toxicology studies, and good-manufacturing procedure (GMP)-grade pharmaceutical production. Regulatory compliance and Phase I/II clinical trials will be conducted. Radiopharmaceuticals are administered in micro-doses (nano-mole to pico-mole quantities) and are often classified as being “sub-pharmacological”; as a result, they have relaxed testing guidelines (e.g. fewer animal and toxicology studies required), which allows radiopharmaceuticals to accelerate through the drug pipeline and reach clinical trials at a much faster pace compared to traditional pharmaceuticals. (5) Health economics: Finally, we will address social acceptability and health economics aspects of implementing these new drugs into the clinic, to ensure wide acceptance and use of our powerful new tools in cancer therapy.Our stellar international team integrates expertise in nuclear physics, nuclear engineering, chemistry, biology, radiology, oncology, clinical medicine, and health economics toward guaranteed success of this interdisciplinary and transformative research. We will establish the infrastructure and network needed to provide the urgent and unmet need for targeted radionuclide therapies to Canada. Our access to TRIUMF – Canada’s particle accelerator centre, and our team’s diverse expertise make us uniquely qualified to bring novel radioligand therapies to mainstream clinical medicine that will have significant impact on the quality of life and life expectancy of patients with metastatic cancers, many of which are currently untreatable.

Cardiovascular disease is the leading cause of death worldwide, accounting for nearly one-third of all global deaths. In Canada, the most rapidly rising form of cardiovascular disease is heart failure, a disorder in which the heart cannot pump blood to the body at a rate commensurate with its needs. Each year approximately 70,000 Canadians suffer a heart attack (also known as a myocardial infarction—MI), accounting for the majority of the approximately 50,000 new cases of heart failure diagnosed annually. The adult human heart has very limited regenerative capacity, so muscle lost to MI or other injury is replaced by non-contractile scar tissue, often initiating progressive heart failure. Existing therapies for heart failure are largely aimed at easing symptoms or slowing disease progression rather than restoring lost contractile function, and the median survival for heart failure patients remains only 2.1 years. This situation and the very limited supply of donor hearts for transplantation has led to a worldwide quest to promote heart regeneration. The transplantation of some adult stem cells appears to mediate small improvements in contractile function, but there is consensus that these cells do not yield significant numbers of new cardiomyocytes (CMs) and instead work through indirect mechanisms, such as immunomodulatory or pro-angiogenic signaling. However, CM deficiency underlies most causes of heart failure.Our New Frontiers program proposes to develop and translate ground-breaking regenerative therapies for intractable forms of heart failure based on human pluripotent stem cell (hPSC)-derived CMs and cardiac tissues. Past efforts to regenerate the heart have been hindered by grand challenges related to the immature phenotype of hPSC-CMs, cell manufacturing, and poor survival, integration, and function of the implanted cells. To overcome these barriers, our multi-institutional, international team with expertise across six diverse disciplines has co-designed three translational research aims:Aim 1. Create hPSC-derived cardiac microtissues (cMTs) for regenerating infarcted hearts. Key deliverables: optimized methods for large-scale manufacturing of all relevant cardiac cell types and cMTs; the first protocol for the differentiation of specialized Purkinje fibers (PFs) from hPSCs; pivotal preclinical safety and efficacy data with an injectable cell product for post-MI heart failure; and an early health technology assessment (HTA). Aim 2. Create augmented human ventricular myocardium – “better than nature”. Key deliverables: the first proof-of-concept for “next generation” cardiac cell therapies engineered to have enhanced functional properties; an HTA for these technologies; and a new framework of ethical and social principles to guide this new paradigm in regenerative medicine. Aim 3. Develop the first biological biventricular pump (bio-biVP) using hPSCs. Key deliverables: a prototype neonatal-scale 3D bioprinted human heart construct (in normal and, ultimately, augmented versions incorporating outputs from Aim 2); a complete data set describing bio-biVP functionality in vitro and in vivo; an HTA; and early planning of clinical trial design and bioethics. Aim 1. Create hPSC-derived cardiac microtissues (cMTs) for regenerating infarcted hearts. In Y1-2, we will generate mature left and right ventricular CMs at scale, establish a protocol for guided differentiation of specialized cardiac Purkinje fibers from hPSCs, and engineer hPSC-derived microvessels. In Y2-3, we will determine the optimal combination of the various cardiac cell types for infarct regeneration and generate injectable hPSC-derived cardiac microtissues (hPSC-cMTs) for preclinical testing. Finally, to ensure innovation viability, we will conduct a heath technology assessment (HTA) for the regenerative therapies developed in Aims 1-3. Impact: This work will develop and validate a truly regenerative therapy based on hPSC-cMTs for patients with post-MI heart failure, which would be a landmark achievement for the field. These foundational studies will also unlock the possibility of even greater advances via the creation of enhanced cardiac tissues (Aim 2) and ultimately whole replacement organs (Aim 3). Aim 2. Create augmented human ventricular myocardium – “better than nature”. We will integrate synthetic biology, gene editing, and regenerative medicine to create hPSC-derived cMTs engineered with enhancements such as arrhythmia resistance, ischemia tolerance, enhanced contractility, increased longevity and/or pathogen resistance. To ensure that the enhanced cardiac cell therapies that we will develop are safe, efficacious and ethical, we will establish a new framework of governing ethical and social principles (Y2-3) and use mathematical modeling to make predictions about the effects of specific augmentations (Y2-5). After creating and validating augmented hPSC-cMTs in vitro (Y2-4), we will advance the most promising cell products to preclinical testing (Y3-6). Impact: Technologies developed in this aim will substantially improve the safety and efficacy of hPSC-based cardiac cell therapy. Proof-of-concept for replacing damaged myocardium with tissue potentially better than what was lost would be a revolutionary advance in the field and a major step toward our envisioned “heart of the future”. Aim 3. Develop the first biological biventricular pump (bio-biVP) using hPSCs. In work combining stem cell biology, cell manufacturing, mathematical modeling, and tissue engineering, we will use 3D bioprinting to create the world’s first bio-biVP heart construct comprised of the authentic human cell types (Y3-5). Our human bio-biVP will be comprehensively phenotyped and ultimately tested in preclinical transplantation experiments (Y5-6). Impact: The successful creation and validation of a bio-biVP would represent a ‘tour de force’ for tissue engineering and a tremendous advance toward the long-term goal of providing an alternative to organ transplantation for heart failure patients. Our bio-biVP technology would also have immediate application as a near-physiological human heart model suitable for investigating cardiac development, modeling of complex cardiac diseases, and drug discovery.The proposed NFRF program will result in revolutionary new therapeutic options for heart failure and a paradigm shift in clinical care. Our interdisciplinary program will provide unique career development opportunities for ECRs and trainees. In the long term, our efforts to apply the tissue engineering and synthetic biology toolkits to hPSCs will inspire an entirely new form of regenerative medicine applicable to diseases even beyond the heart.

The challenge: how to effectively integrate and adapt existing advanced computational methods, such as artificial intelligence (AI), into Indigenous Knowledge systems; how to develop new computational practices from within Indigenous contexts to support the flourishing of Indigenous communities; and how to use the knowledge we generate to help guide the development of AI, generally and globally, towards a more humane future—a future of abundance. AI technology has enormous potential for helping us better understand and interact with our world. The Canadian government, for instance, has identified AI as a national research priority, calling it "likely transformative" on the scale of the internet and industrial revolution. However, we are discovering serious flaws in current approaches to designing, developing, and deploying AI systems. They incorporate deep structural blindnesses that render them incompetent, if not outright dangerous, when confronted with the complexity and variety of human social systems. These blindnesses threaten the scientific validity, engineering competence, and social beneficence of the entire field. Attempts to confront these biases are often undertaken in the context of ‘AI ethics’. We argue, however, that the root problem lies deeper. We maintain that the flaws ingrained in the current trajectory of AI development are the result of certain Western rationalist epistemologies which embed a series of assumptions about how to create computational systems. These include: the user is an individual; the individual prioritizes her personal well-being; text and context can be separated; and the only useful knowledge is that produced through rational instrumentality. This makes AI system scientists and engineers blind to vital aspects of human existence—such as trust, care, and community—that are fundamental to how intelligence actually operates. The refusal to engage, explore, and operationalize knowledge frameworks that centralize these aspects is a tremendous scientific failing. It creates huge gaps between the diverse forms of human and non-human intelligence and what the AI industrial-academic complex is building to replicate it. Such narrow ways of knowing and viewing ‘intelligence’ are not a sufficient foundation on which to adequately, robustly, and humanely conceptualize AI. This research program will allow us to think more expansively about these AI systems, to expand the operational definition of intelligence used when building them to include a more extensive spectrum of behaviour that humans and non-humans use to make sense of the world. This will require exploring epistemologies different from the normative Western approaches favoured by current AI research. We will draw upon Indigenous epistemologies to develop our imaginations, frameworks, and languages used to transform our understanding of what it means to be intelligent, and, more importantly, what it means to be human. In doing so, we will establish new methods for creating advanced computational technologies like AI that will refashion these tools from their current role in systemizing and entrenching colonial practices of exclusion, extraction, and eradication into engines for increasing our care of one another and our world. Our methodological approach is grounded in Indigenous epistemologies that contain robust conceptual frameworks for understanding how technology can be developed in ways that integrate it into existing lifeways, support the flourishing of future generations, and are optimized for abundance rather than scarcity. We will ask the following questions: 1. How can we integrate and adapt existing advanced computational methods into Indigenous Knowledge systems? 2. How can we develop new computational practices from within Indigenous contexts to support the flourishing of Indigenous communities? 3. How can we use the knowledge we generate to help guide the development of AI, generally and globally, towards a more humane future? To answer these questions, we will: 1. Collaborate with Indigenous communities to imagine AI systems designed from Indigenous epistemologies and with Indigenous protocols; 2. Partner with creators of AI systems to devise new approaches to designing them; 3. Develop engineering and design capacity within and across Indigenous communities, thus affording Indigenous people greater sovereignty with regards to AI specifically and scientific and engineering innovation generally; 4. Map out an ethical and robust development path for Indigenous communities to create and use such systems.Anticipated changes or impacts Indigenous Knowledges develop from living in long-standing relationships with place, relationships characterized by close observation, relationship protocols, and reciprocity that have produced well-tested practices for supporting a thriving community. Integrating these systems and practices with the Western knowledge systems that inform current computational technologies is fraught with epistemic danger, but also promises to fundamentally transform how we develop such technologies. Core questions about what counts as knowledge, how we understand it, and how we act on it become acute when such different frameworks for engaging the world come into relationship with one another. What a person operating within an Indigenous Knowledge framework considers worth knowing about a domain diverges significantly from what a non-Indigenous scientist considers necessary. Accordingly, the research program’s most significant impact will be to centre Indigenous Knowledges and priorities in the development of these new technologies. We anticipate the following specific outcomes: (a) Indigenous-grounded imaginaries of the future of A.I. systems; (b) Indigenous-centered A.I. design guidelines, customized for specific communities; (c) A.I. systems designed and implemented using those guidelines; (d) increased capacity within the Indigenous community to design and build such systems; (e) a critical path that shows how such systems can go from concept to use; and (f) the formation of an international network of Indigenous (or Indigenous-engaged) media, arts, culture, and technology research labs capable of conducting research into advanced computational media. The primary impact will be to benefit Indigenous communities in North America, the Pacific, and elsewhere in exerting sovereignty over their computational landscape, while also benefiting society in general by better equipping all of us to adapt to both the challenges and benefits of AI.

Neurodegenerative diseases are devastating to affected individuals and their caregivers. Yet despite the growing prevalence of these conditions, accompanied by an economic burden that is expected to reach $6 trillion in the US and Europe alone by 2030, the number of therapies in the pipeline for these disorders is meagre. Other than the controversial recent approval of aducanumab by the FDA, no successful disease-modifying treatments have been produced in the last three decades. At a cost of ~$50 million to bring a single compound to clinical trial and ~$1 billion to then progress to a regulatory marketing submission, drug development is expensive. Given that clinical trials on promising compounds fail to reach final approval more than 90% of the time, drug discovery in this space is a high-risk endeavour. Consequently, many pharmaceutical companies have divested themselves of their neuroscience divisions to focus on more readily treatable (i.e. profitable) conditions. Why are there so many drug discovery failures in the neurosciences? The vast number of cell types in the brain and the complex interactions between them, further modulated by sex or hormones, makes it challenging to understand disease mechanisms, to identify promising molecular targets and to screen therapeutic candidates. Much of this early discovery work occurs in cells and tissues outside living organisms, after which decisions to take drugs forward into clinical trials are informed by preclinical work in whole animal models. Many of these models lack predictive validity despite having a modest or high degree of face validity (i.e. recreating disease endophenotypes or being mechanistically related to the in vitro work). Furthermore, preclinically-derived biomarkers such as beta-amyloid plaques in Alzheimer’s are often used as treatment-related endpoints rather than functionally relevant outcomes such as cognitive impairment that are the foremost concern for patients. This disparity underlies the controversy with aducanumab. Finally, while free and open sharing of methodological approaches and data from preclinical and clinical studies could speed up the drug development cycle, there are only embryonic business, legal and ethical frameworks to implement open science approaches. The challenge here extends both to entrenched business models based on proprietary barriers, and to the quality and reproducibility of basic and translational studies within and between labs. Our goal is to overcome these challenges by building an innovative open science platform for neuroscience drug discovery to translate findings around basic disease mechanisms into approved drugs in a manner that optimizes success for a candidate therapy, while eliminating those likely to fail at the earliest possible point in the process. Our platform will de-risk the drug development pipeline by evaluating candidate hits across a broad range of levels of analysis—all the way from cells to patients—to bridge the "valley of death" between basic scientific research and translation to novel therapeutics. Information derived from mechanistic assays in brain organoids will be transferred to specific, cutting-edge model systems, starting with mice and then moving to marmosets as appropriate, informed by an understanding of sex differences. Critically, human-relevant cognitive assessment and brain imaging methods will bridge from mice to marmosets to humans much more effectively than standard approaches. Our multitiered drug evaluation approach integrates neuroscience leaders across Canada, as well as their international partners, to develop a globally unique one-stop shop for selecting first-in-human candidate therapies. It begins with evaluating promising hits from our partners in brain-mimicking cell culture systems using patient-derived induced pluripotent stem cell (iPSC) brain organoids, which capture the diversity of cell types found in the human brain. Those showing mechanistic promise are then evaluated on human disease-relevant molecular and circuit level mechanisms and human disease-relevant cognitive outcomes in new mouse models. The most promising candidates will progress to marmoset models, which present genome, brain circuitry and inflammatory responses that are closer to humans. Both the mouse and the marmoset models will be assessed using advanced computational approaches applied to molecular and whole brain imaging techniques. This will be combined with cognitive testing and neuroimaging that is identical to that used in human patient populations, ensuring that hits have high relevance to human functional outcomes related to cognitive impact. Only treatments that pass each of these stages will be candidates for first-in-human trials, the rest will be triaged. This approach holds great promise both for improving our understanding of the underlying biology in animal models (including sex and hormones) on drug discovery and for developing more mechanism-driven therapeutics in a cost-effective way. It is facilitated by recent advances in biomaterials and genetic manipulation, which have made engineered brain organoid systems possible, as well as revolutionary neurotechnology, which allow observation and manipulation of the brain in animal models with unprecedented precision. Micro- and mesoscopic imaging methods will further validate observations of molecular, morphological and circuit level function to be carried across model systems and species, increasing their translational validity. Finally, our approach leverages an innovative and widely adopted automated, robust high-throughput touchscreen-based cognitive testing platform we developed that enables testing mice (and extensible to marmosets) on disease-relevant, high-level cognitive tasks that are similar or identical to those used to assess humans. All of this work will be done within the context of developing open science business models, including data, knowledge, materials and tool sharing, industry partnerships based on novel IP assets, together facilitating reproducible and rigorous results and access. We will demonstrate this powerful approach in neurodegenerative disorders characterized by the aggregation of misfolded alpha-synuclein, which includes Parkinson’s disease and Dementia with Lewy Body Disease, and also present in a large number of people affected by Alzheimer’s disease. As we have buy-in from academic and biotech-based researchers, as well as several consortia with some existing therapeutic candidates for synucleinopathies, we envision being able to select novel disease-modifying therapeutics for first-in-human testing within 6 years.Developing such a unique, socially engaged neurotherapeutic evaluation platform in Canada would have enormous impact as an invaluable catalyst for re-invigorating neuroscience drug discovery worldwide and for accelerating urgently needed first-in-human trials of therapeutics for neurodegenerative disease.

The incidence of neurological disorders is reaching epidemic proportions with ~103 million individuals projected to be afflicted globally by 2030, posing a major challenge for 21st century healthcare. Included are a diverse set of neurodegenerative (e.g., Alzheimer’s disease, stroke) and neurodevelopmental (e.g., epilepsies) disorders that manifest with distinct neurological symptoms due to the loss or dysfunction of specific neuronal pools. The associated cognitive, sensory and motor deficits are largely irreversible due to the rarity of naturally occurring neuronal replacement and repair. The lack of a brain regenerative response, combined with a paucity of neurotherapeutics, has led researchers to explore various neuronal replacement strategies. Exogenous cell transplants or the stimulation of endogenous neural stem cells have yet to reliably promote sufficient neuronal integration for long-term functional recovery. Therefore, current drug and rehabilitation therapies can only alleviate and not cure adverse symptoms of neurological disease. The resultant increase in morbidity and mortality is devastating to individuals and their loved ones and has a heavy socioeconomic toll. The estimated global cost of treating individuals with neurodegenerative disorders is immense. Alzheimer’s disease and stroke together cost over one trillion USD globally in 2020 and are projected to surpass eight trillion USD by 2050 as the world population ages. The annual cost to Canadians is ~$4 billion, including associated healthcare costs, lost wages and productivity. While the financial burden of treating childhood epilepsies is lower (~$2 million annually in Canada), these disorders can attack the very young and persist as untreatable disorders throughout life. There is a clear unmet need for new therapeutics. An endogenous repair strategy to replace lost/dysfunctional neurons would be ideal, as it would avoid cell transplant issues, such as tumorigenicity, immune rejection, supply constraints and ethical concerns. Here, we will use an interdisciplinary approach to exploit the potential of direct neuronal reprogramming for endogenous brain repair. Our approach is compelling given that glial activation is used for brain repair in regenerative species, like fish, so we are reactivating a latent repair pathway that has been lost over evolutionary time. The approach relies on lineage-specifying transcription factors to convert brain astrocytes that become activated after injury and in disease, into subtype-specific induced neurons. This approach may benefit brain health by transforming astrocytes, which can contribute to disease pathology, into specific types of neurons that are lost or dysfunctional. Strong pre-clinical data from our team members supports the idea that in vivo neuronal reprogramming drives functional nervous system recovery in three neurological disease models. Our short-term objectives are to solve three unmet needs: 1) To optimize subtype-specific neuronal reprogramming strategies. 2) To develop novel gene delivery strategies to brain astrocytes. 3) To develop clinically-relevant, assessment measures. Our long-term objectives are to create an integrated, interdisciplinary team that will work towards improving patient care by developing neuronal reprogramming as a customizable strategy for the treatment of neurological disorders. An added benefit, we anticipate the creation of patents, licensing agreements and spin-off companies. There are no cures for neurological disorders associated with neuronal dysfunction or loss, and symptomatic therapies have limited efficacy across disease course. Direct neuronal reprogramming has the potential to become an endogenous repair strategy that can transform clinical practice. It involves the lineage conversion of resident brain cells, namely astrocytes, to a neuronal fate by expressing neurogenic transcription factors. Our interdisciplinary teams of experts will work together to overcome three main barriers to translating neuronal reprogramming into clinical practice. Pillar 1. Optimizing neuronal reprogramming strategies to make clinically relevant cell types. Each brain region contains unique types of neurons and circuits that can be negatively impacted by each neurological disorder. However, current neuronal lineage conversion strategies often do not consider the neuronal subtype produced. Our goal is to customize neuronal reprogramming strategies to efficiently convert brain astrocytes to specific neuronal subtypes depleted by different disease processes. We will use computational modeling to guide the identification of hub transcription factors that specify neuronal fates, and test their efficacy as neuronal reprogramming factors, alone or in combination. We will remove obstacles to neuronal reprogramming that make the process inefficient, including epigenetic and post-transcriptional barriers. Reprogramming strategies will be developed in readily accessible rodent cells and models, and then translated to human astrocytes as a next step towards the clinic. This pillar will develop optimal transcription factor(s) and genetic and/or epigenetic modulatory approaches that will increase the specificity and efficiency of neuronal conversion. Pillar 2. Implementing ‘clinic-ready’ in vivo gene delivery strategies to the brain. Currently, most gene delivery strategies to the brain rely on adeno-associated-viruses (AAVs). However, there are no astrocyte specific viral capsids or promoter elements that can ensure that reprogramming transcription factors are only expressed in astrocytes, our target cell for lineage conversion. To circumvent these issues, we pivot to novel, promoter-less RNA technologies, coupled with smart targeting of nanoparticles and extracellular vesicles to astrocytes as delivery vehicles. Finally, to meet the challenge of delivery across the blood-brain-barrier, we will develop focused ultrasound and bacteriophage as membrane permeabilizing or bypassing technologies, respectively. This pillar will develop novel gene delivery strategies to specifically target astrocytes and add focused ultrasound to direct RNA cargo to specific brain regions impacted by disease. Pillar 3. Defining clinically relevant outcome measures of neuronal reprogramming. To assess the effects of neuronal reprogramming in rodent models, we employ lineage tracing, ablation assays, behavioral assays and measures of neural circuit activity. To prepare for the next challenge of assessing neuronal reprogramming in patients, we will first use rodents to evaluate the capacity of the latest magnetic resonance imaging technologies in detecting the impact of neuronal reprogramming in live animals. We will establish a cross-cutting platform to promote patient engagement and to establish clinical advisory panels from the outset to accelerate the speed of clinical translation, increase transparency and enhance relevance of our research.

Canada has vast renewable energy capacity yet remains deeply reliant on fossil fuels. The key barrier to the expansion of renewable sources is a lack of seasonal storage: our renewable energy supply is 6-months out of sync with demand. Storing the excess summer-generated renewable energy for use in winter is a grand challenge, which can only be addressed with grid-scale conversion of renewable electricity into storable fuels. The urgency of global stressors and local needs preclude the conventional approach of technology-first followed by piecemeal adoption, assessment of implications in hindsight, and decades of iteration. Northern challenge and goal: The Yukon has an isolated electrical grid, powered by renewable energy (hydropower) with fossil fuel backup, which serves small, geographically dispersed communities with no opportunity for electric power import or export. Seasonal water level requirements and availability lead to wasted energy in the summer and insufficient capacity in the winter when energy demand is highest. Technical challenges specific to this application include the development of reliable, integrated systems that are responsive to renewable supply, are flexible with respect to CO2 source (point source or air capture), and can produce drop-in ready fuels. Our socio-economic analysis will include the impact of expanding renewable energy production capacity in the region, a topic that is hotly contested—energy and capacity expansion in the Yukon requires the consideration of ecology, modern treaty agreements and First Nations governance authority, and a multiplicity of stakeholder concerns. The goal for the northern application is to develop a renewable energy seasonal storage solution built upon an informed social framework, clear assessment of community, energy and environmental costs and benefits, and a robust, integrated technological system that merges with existing community infrastructure and needs—a social, economic and technological pathway to deploy seasonal energy storage on the Yukon Energy grid, displacing 50% of fossil fuel–based electricity generation. Southern challenge and goal: While distributed integrated systems are the northern model, centralized scaled systems are the norm in the south. From a social perspective the externalities of centralized energy operations in all forms also scale with implications for communities, energy and climate. Our focus will be Southern Ontario, but expect findings to be broadly applicable across grid-connected southern Canadian jurisdictions and internationally. A key challenge is to develop a robust assessment of the costs and benefits of increased renewable energy storage to shape policy and to inform technological development. Another challenge is defining a workable innovation pathway, from lab to pilot to commercial adoption and scaling—a business strategy to enter the high-volume, low-margin marketplace dominated by the world’s largest energy and chemical incumbents. A core technological challenge is increasing the efficiency with which we convert electrical energy into chemical forms and maximizing the value of those streams while minimizing waste. The goal for the southern application is to develop a made-in-Canada renewable energy storage solution to be scaled globally—enabled by unprecedented foresight and clarity with respect to the community, energy and environmental costs and benefits of such a transformation. This project builds upon an NFRF-T 2020 proposal that was in the final selection stage, although it was not among those selected for funding by the jury. This new proposal addresses all feedback from the multidisciplinary/multisectoral review panel and jury stages. Changes include the addition of international collaborators, further integration of industry, and refined community-centered goals in the south. To mitigate climate change and address social inequality, energy systems need to be re-envisioned. Transformations in the energy sector are often driven by technological innovation, yet technological fixes often have negative spillover effects. The CANSTOREnergy team is proposing an energy storage transformation that is informed by an examination of unintended consequences and a diverse set of community perspectives at the outset. Our approach disrupts the usual pattern of developing new technologies, putting them into practice, and only then realizing their consequences. With attention to the environmental and social trade-offs that accompany energy production, CANSTOREnergy will integrate policy, community engagement, and ownership models to steer technological development. CANSTOREnergy applies this hybrid-holistic approach with three interdisciplinary sub-teams:DIRECT: To inform research approaches, this sub-team will integrate a diverse set of community needs and perspectives on energy futures. The Direct sub-team will focus on two Canadian regions with differing seasonal challenges, population densities, grid integration/isolation, and political organization: the Yukon (north) and southern Ontario (south). DISCOVER: Hydroelectricity and solar energy peak in spring and summer, while fuel demand spikes in fall and winter. To enable the storage of electrical energy on seasonal timescales, the Discover sub-team will advance the science and technology of conversion of renewable electricity into renewable carbon-based fuels. Canada enjoys a global competitive advantage in this area of research, and the team will build on these strengths to ready the technology for the challenging demands of ultimate application in northern and southern contexts. DEVELOP: The Develop sub-team will apply the Direct sub-team’s insight and the Discover sub-team’s technological advances to develop targeted renewable energy storage transformations. This sub-team will assess policy contexts, value streams, public and private interests, and existing energy utility structures to develop viable solutions for seasonal renewable energy storage. The Develop sub-team’s expertise will be further applied to measure the performance and impacts of all project elements against key performance metrics and goals. CANSTOREnergy impacts. The ultra high-reward outcome for the north is a carbon net-zero means of seasonal storage for renewable energy that merges with existing community infrastructure. In the south we are motivated by the opportunity to reduce fossil fuels use, to consider the diverse needs and goals of both urban and rural communities and for Canada to lead in a transformation of the energy system with economic benefits nationally and climate benefits globally—a made-in-Canada renewable energy storage solution that considers local concerns and displaces fossil fuel use. CANSTOREnergy is shaped and supported by foresight and clarity on the community, energy and carbon costs and benefits of such a significant shift.