Titulaires de subvention – Transformation 2020

Scientific disciplines are never transformed in a flash, but there are times when technological and conceptual advances poise a field for reinvention. Biodiversity science finds itself in this situation, and past investments have positioned Canada to lead a transformation with impacts that extend from this field of science through cognate disciplines to the very sustainability of our planetary ecosystem. This opportunity derives from a simple proposition—that the analysis of sequence diversity in targeted gene regions (DNA barcodes) enables a system allowing anyone to identify any species. Seven years of successful proof-of-principle studies spurred Canadian researchers to activate the International Barcode of Life Consortium in 2010. Within five years, its first research program had delivered barcodes for 500,000 species. Importantly, these records enabled the development of predictive analytics that effectively automated the recognition of new species. As such, DNA analysis gained the capacity to rapidly register millions of new species and to track biodiversity change, advances with profound societal implications.

Although the power of DNA barcoding was clear, its capacity to scale was constrained by cost. High-throughput sequencers (HTS) have now shattered this barrier, permitting the analysis of 50,000 specimens at a time. As a result, single specimens will soon be barcoded for $1 and HTS platforms already support a new analytical path, DNA metabarcoding, which allows the species composition of bulk environmental samples to be ascertained for pennies per specimen. As a consequence, biodiversity science now has the potential to quantify species diversity, to probe species interactions, and to track species distributions with unprecedented scale and resolution. Stimulated by this fact, iBOL launched a second research program, BIOSCAN, in mid-2019. This 7-year, $180M endeavour will develop the protocols, the research alliances, and the societal linkages needed to achieve three key scientific goals (inventory all species, document their interactions, establish a global bio-surveillance system) and to use this new knowledge in diverse socio-economic contexts.

While BIOSCAN's overarching goals are clear, there is much need for innovation to achieve them. Analytical costs must be reduced, data quality must be improved, and data validation must be automated. The resultant data streams must then be interpreted and contextualized to allow examination of policy and regulatory implications. Achieving these goals demands the convergence of experts from diverse fields, and BIOSCAN assembles them. To meet the need for specimens and samples, it includes specialists in freshwater, marine, and terrestrial ecosystems based in 30 nations. To optimize sequence acquisition and image analysis, it includes leaders in computer vision, database management, genomics, machine learning, metagenomics, and phylogenetics. Subsequent data interpretation and contextualization will be advanced by world leaders in biodiversity science, global change biology, conservation, ecological modelling, systematics, and taxonomy. Their work will enable predictions of biodiversity decline, enabling priority setting (areas, lineages). To maximize societal impacts, our team includes individuals and organizations with the capacity to develop and implement monitoring programs as well as economic, policy, and regulatory frameworks at national and international levels.

Global change is restructuring ecosystems on a planetary scale, creating an urgent need to track impacts on biodiversity. This is challenging because life is very diverse—the biosphere comprises more than 10 million multi-cellular species. Until now, this complexity meant that the activation of an Earth-observing system for biodiversity was inconceivable. However, the increased power of DNA sequencers and the recognition that species can be discriminated by short stretches of DNA have revealed a way forward. This approach will revolutionize our understanding of biodiversity by completing the inventory of species, by revealing their interactions, and by assessing their response to ecosystem modifications. This new information will position humanity to mitigate one of the great crises of our times—a looming mass extinction, the first in 65 million years. The need for action is acute given predictions that an eighth of all species will be extinct by 2100 unless practices and priorities shift.

The activation of a global bio-surveillance system will demand innovation, resources, and international cooperation. It is science on a scale that is novel for biodiversity and it cannot be pursued without deep involvement by experts in diverse fields. Until recently, biodiversity science was unprepared to lead a megaproject, but the community has now gained cohesion and ambition. As well, societal recognition of threats to biodiversity has been elevated by assessments from diverse intergovernmental organizations. Our project, BIOSCAN, capitalizes on this progress to propose actions that will transform biodiversity science so it can tackle the extinction crisis. To start, our project will strengthen and diversify collaborations. It will begin by intensifying alliances between biodiversity scientists and molecular geneticists to shrink costs for tracking biodiversity with DNA. New collaborations with data scientists and with specialists in Artificial Intelligence will aid the curation and interpretation of the immensely expanded data streams. The resultant information will be contextualized by global change biologists, and the results of their work will flow to organizations charged with biodiversity management at national and international levels. Because these new data will have broad knock-on consequences (economics, policy, regulatory), our team includes scholars in these domains.

BIOSCAN extends alliances and activities initiated by the International Barcode of Life Consortium, which is led by Canada. Since 2010, it has promoted the adoption of DNA-based approaches in biodiversity science, creating a workforce able to implement projects on a global scale. However, it has been a challenge to fully exploit this capacity because most biodiversity hotspots lie in nations where science funding is very limited. BIOSCAN will overcome this impediment by adopting a strategy that has worked well for astronomy and particle physics—build core infrastructure and share it. BIOSCAN researchers will benefit from access to the globally unique sequencing and informatics platforms developed at Canada's Centre for Biodiversity Genomics (CBG) and a facility modelled on it under construction at Naturalis (Netherlands). Access to this infrastructure will allow radical advances in biodiversity science, opening the opportunity for uptake by many national and international organizations with involvement in environmental sustainability.

The scope of the project is novel in its combined concern with the well-being of Indigenous Peoples and the conservation of biodiversity; it is also unique in its intention to build capacity within Indigenous communities to document and mobilize knowledge about biodiversity-well-being in ways that are recognized by regional-national-global institutions of biodiversity conservation. The research project was defined in collaboration with Indigenous organizations and partners in Canada and globally. We propose a place-based participatory approach that allows for capacity-building, evidence-based research, knowledge mobilization and action in key regions globally. Led by Indigenous scholars and an Indigenous Advisory Council, the research team will engage in collaborative community-based research within Canada and five other global hubs. Building from the successes of existing networks in Canada and elsewhere (e.g., Tracking Change), the project team will draw on expertise and tools from across the tri-councils to document and mobilize knowledge. The foundation of the research approach and anticipated outcome will be holistic and based on concepts from Indigenous knowledge that are inherently interdisciplinary. By year six, we will have addressed the following outcomes:

• WELL-BEING of INDIGENOUS COMMUNITIES: The well-being of Indigenous communities globally is recognized as an urgent concern by the United Nations and national governments, including Canada. Indigenous Peoples, particularly youth, are overrepresented in statistics on food insecurity, health service inequity and within the justice system. However, emphasis on Indigenous communities as vulnerable and "ill" can be used to perpetuate paternalistic policies/institutions and relations of dependency. Through the project, we particularly aim to elevate and nurture the voices of youth and communities with the hope of bolstering the work of Indigenous leaders in Canada and globally who are reframing colonial narratives about Indigenous Peoples and building capacity within communities to care for themselves and their own lands and resources.
• BIODIVERSITY CONSERVATION: The loss of biodiversity globally is a critical challenge for communities, who depend on the sustainability of ecosystems. It is predicted that numerous species are being lost annually with dire predictions for 2050. Curbing biodiversity losses and creating opportunities for biodiversity restoration, through this project is possible with the increased recognition of best/wise practices of Indigenous communities, based on the diverse multi-generational knowledge systems that exist in Canada and globally.
• GOVERNANCE: By mobilizing Indigenous knowledge and creating tools for communities to track and inform local-global decisions about the importance of biodiversity to their well-being, this project will address inequities in governance that exist in Canada and elsewhere. By doing so we address inequities in Indigenous engagement in natural resource governance locally and globally. We also serve all Canadians in responding to the calls to action of the Truth and Reconciliation Commission on Residential Schools and supporting Canada and other nations in efforts to respect and implement the principles of the United Nations Declaration on the Rights of Indigenous Peoples.
  
  Indigenous Peoples, including hunters, fishers, herders, and others, are stewards of over 25% of the world's surface area; approximately 80% of Earth's biodiversity is located within those areas. As global biodiversity is threatened, echoing impacts are anticipated for the well-being of Indigenous Peoples. Current approaches to biodiversity conservation are not sufficient to address the problem. Many tend to be colonial in origin, are based on narrow disciplinary perspectives and, as a result, have systemically marginalized Indigenous values and voices. Despite this history and associated socio-economic and political barriers, Indigenous communities in many regions of the globe are demonstrating significant leadership and spirit in their efforts to protect their heritage. This project answers the call of Indigenous leaders, Canada's Truth and Reconciliation Commission and recommendations of recent global assessments to rethink "conservation" and elevate these best/wise practices of Indigenous communities. Of particular concern are communities and ecosystems under stress where biodiversity has been lost, species are already at risk/endangered and where land-use conflicts and lack of government protections have created conditions of vulnerability. Through this Indigenous and community-led project, which includes an interdisciplinary team of scholars and resource peoples, we will mobilize Indigenous knowledge and create tools for communities to track and inform local-global decisions about the importance of biodiversity to their well-being.

OBJECTIVES:

• CAPACITY BUILDING: a) Build capacity within Indigenous and local communities to document, share and apply their own knowledge in ways that are culturally meaningful and socio-politically relevant to issues of biodiversity conservation within their territories; b) Nurture the development/rediscovery of Indigenous knowledge and management systems so as to ensure biodiversity conservation contributes to well-being.
• EVIDENCE-BASED RESEARCH: c) Build from the significant body of work related to common pool resources, community-based resource management and Indigenous-led conservation, to carry out evidence-based research aimed at determining "design principles" (best/wise practices) that detail, where and how, biodiversity conservation and well-being of Indigenous communities are interconnected; d) Explore how biodiversity is a protective factor and/or determinant of well-being and cultural security and continuity for Indigenous peoples and local communities.
• POLICY TRANSFORMATION: Local—e) Create tools and models of best/wise practices that can be used by other communities to assess, track and inform decision-making; f) Contribute to intergenerational knowledge sharing and educational outcomes within communities to improve well-being and cultural continuity. Regional-Global—Transform the processes and institutions that are engaged in national-global biodiversity conservation (i.e., Conventional Biological Diversity) such that Indigenous knowledge and the voices of Indigenous and local peoples are foregrounded in decision-making. This will be achieved in the short term by; g) Creating culturally appropriate indicators and models about the relationship between biodiversity-well-being; and h) Creating principles and platforms (i.e., ethical space) that generate social and institutional learning within NGOs, governments and the public.

Over the past few decades, it has become increasingly clear that combinatorial approaches—applying more than one treatment at a time—are needed to tackle the multifactorial problem of nerve fibre (axon) regrowth in the spinal cord. However, a minimally invasive biomaterial platform to host multiple treatments has not been invented. Standard approaches have been to construct a patterned scaffold outside of the body and then insert it, invasively, into the lesion, or more recently to inject gel or liquid materials that stiffen inside the lesion, but cannot be patterned with any precision.

Our approach brings together chemists, physicists, neuroscientists and engineers to develop a biomaterial platform that meets the requirements of the SCI field. Our platform will be injected through a fine needle into the spinal cord, filling and conforming to the complex shape of each unique lesion. The delivery mechanism—a machine vision-guided robotic procedure—will use novel multimodal imaging techniques to provide structural information about the lesion and avoid damaging remaining tissue structures. Once in the body, we will use various methods to align and pattern the biomaterials, producing ordered microchannels that guide the axons, as well as endogenous cells, to bridge the lesion site. The nature of the biomaterials and their in vivo arrangement will spatially organize hosted drugs into gradients, which will biochemically incentivize nerves to continue growing in a particular direction. Other drugs will simultaneously block inhibitory pathways such as scar formation and growth inhibitors acting on the growing axon tips (growth cones). Electrical stimulation protocols will be used to encourage growth and facilitate functional reconnection to spinal neuronal networks. We will also investigate a physical insertion of a preformed scaffold for the case of complete injuries—,with the addition of the combinations increasing the likelihood of success over previous attempts.

The goal of this project is to demonstrate effective and minimally invasive treatments for SCI in preclinical models that are truly representative of human injuries. Success will mean preparation for human trials—meeting the high threshold of evidence for an ethical trial. Along the way, our research will invent new methods for aligning and patterning biomaterials in vivo, and for controlled drug release. We will also develop and apply multimodal imaging techniques to characterize the lesions and evaluate the impact of our minimally invasive procedure on the cord. And, at a more fundamental level, our research will have impact in understanding the influence of injected material properties on cellular growth processes.

In advance of this project, we have garnered an understanding of the needs of stakeholders, including orthopaedic spine and neurosurgeons (technology adopters), and particularly those with spinal cord injuries. As part of this project, we will develop a collaborative roadmap for technology development and translation, taking into account the perspective of the SCI community, neuroethicists, health economists and other stakeholders, including policymakers and industry. These partners, and our diverse and interdisciplinary team, have the experience and expertise to creatively and flexibly address a huge challenge and unmet need: to mend the gap.

Our ultimate goal is to repair the injured spinal cord—with the aim of launching human trials after 6 years.

Globally, over 27 million people live with spinal cord injury (SCI) and there are 930,000 new cases each year. This is a diverse community, but disproportionately represented by those in developing countries, visible minorities in developed countries, First Nations peoples in Canada, and young people in general. The costs for a lifetime of care with SCI are astounding (est. CAD$3-6M per patient) compared to many serious health conditions, partly due to secondary complications like pressure ulcers.

SCI is a debilitating condition that involves paralysis and the loss of control over body functions, leading to cardiovascular complications, urinary tract infections, muscle spasms, osteoporosis, chronic pain, and respiratory problems. Severe psychological issues and lost life opportunities are also common. While the spinal column can be surgically stabilized and rehabilitation training yields improvement for incomplete injuries, there is no treatment for the injured cord itself. Restoration of motor control, bladder and bowel function, blood pressure regulation, perspiration and touch sensation all usually prove intractable. In Canada, life expectancy is reduced by 23 years for a young person with a high cervical injury, making SCI severely life threatening. Repairing the injured spinal cord and bringing back even partial function will have a major medical, societal and economic impact.

The challenge posed by SCI arises from the central nervous system's inability to naturally regenerate, combined with an inhospitable environment for cellular regrowth in the injury site (lesion). This means spinal neurons typically do not regrow. Some form sprouts, but these are unlikely to reconnect across a gap often more than 20 mm across—a gap that is further constrained by scar tissue and inhibitory biomolecules.

Many approaches have been taken to treat SCI. The injury-triggered immune response can be tempered by introducing anti-inflammatories to protect remaining neurons, but only one drug has been approved for humans and shows minimal effect sizes and possible side effects. The insertion of material scaffolds into the lesion has been explored to provide physical support for nerve growth across the gap. However, this approach is only suited to complete injuries and not the majority of incomplete injuries, as it requires cutting into the lesion scar and likely damaging remaining connected neurons, therefore losing the possibility of regaining some function over time. Injecting molecules and particles that reduce scar formation, neutralize inhibitory biomolecules and promote growth is being investigated. Stem cell transplants are being studied to replace lost cells and reconstitute neural relays across the gap. And electronic implants have been used to bypass the injured site, by reading signals on one side and passing them electronically to stimulators on the other side of the lesion.

However, in the end, there is little that is practically effective for patients beyond rehabilitation training paired with electrically stimulating the spinal cord to awaken leftover connections; an approach which has recently made headlines, although the benefits are still small. Despite decades of advances, those living with SCI have little prospect of recovering control over their hands, legs, bladders, bowels or sexual organs.

To build demand-side capacity, we propose a transdisciplinary, multi-sectoral social innovation laboratory named IDEA (Inclusive Design for Employment Access). The laboratory will design, pilot, evaluate and disseminate solutions for enhancing demand-side capacity to recruit, hire, onboard, retain and promote persons with disabilities (PWDs) in a range of employment opportunities. We will also develop and maintain an accessible online platform to facilitate access to existing evidence-informed tools, resources, employment supports, programs and services. A unique feature is the integration of natural, social and health sciences, including engineering, environmental design, and information technology.

Using experience-based co-design (EBCD), IDEA will provide a platform for researchers, industry champions, technical experts, designers, employment service providers, PWDs and labour/unions to collaborate on identifying priorities and building solutions to be piloted, evaluated and scaled up. EBCD is a systematic, evidence-informed approach to system change, based on participatory action research, narrative theory, and design thinking. Developed for quality improvement, it is used to create solutions through design thinking and rapid prototyping. Using EBCD, IDEA participants will identify challenges, set priorities, and rapidly transition to building solutions. The laboratory will address the pressing need for resources and tools to improve demand-side capacity, establish a best-practice methodology for co-designing solutions, and develop EBCD-based research capacity in work disability.

Our approach is evidence-informed, solution-driven co-design with consideration of priority needs. All participants will undergo EBCD training to ensure key principles are integrated, e.g., intersectionality, transdisciplinarity, equal standing of all partners, equity, diversity, and inclusion. Some participants are well versed in EBCD; others have years of experience undertaking transdisciplinary, applied research in the work disability arena. Many have partnered on groundbreaking projects; e.g., a tool for employers on recruitment and retention of persons with mental illness, a Work Disability Management System Standard developed through a multi-stakeholder consensus-based approach, and a Pan-Canadian Strategy for Disability and Work developed with and for civil society. EBCD provides a platform to leverage our collective expertise to transform the work disability arena and advance opportunities for PWDs.

Mixed teams of researchers and industry, service providers, community and labour collaborators will work together to identify challenges, then develop and evaluate prototype solutions targeting priority issues identified through environmental scans of needs/challenges, knowledge gaps, existing tools, and promising practices. Participants will work in four thematic hubs: 1) workplace systems and partnerships; 2) employment support systems; 3) transitions to work and career development; and 4) inclusive design. This robust and dynamic structure will revolutionize how research is conducted in the work disability arena and has the potential to create innovative solutions to some of the biggest barriers that continue to restrict opportunities for PWDs in the labour market. The direct market-output potential has been identified at $62.2B, with $47.3B in multiplier effects for calendar year 2017.

Despite efforts to improve employment outcomes of PWDs, their labour-force participation and employment rates remain substantially lower than persons without disabilities. Among those working, many remain stuck in entry-level, precarious employment, earning less money than their able-bodied counterparts (e.g., participation rates are 20% lower, and of those working, 26% work part-time compared to 2%, according to the 2017 Canadian Survey of Disability). This situation remains a significant social problem. In a study funded by Employment and Social Development Canada (ESDC), an effort to monetize the cost of exclusion to Canadian society across all social domains valued the loss at 17.6% of GDP ($337.7B) for calendar year 2017. Lower employment rates create higher dependency on social transfers. Caseloads on disability benefit systems are increasing and, once on benefits, many are unable to exit. These facts underscore the critical need for the labour market to become more accessible and inclusive, such that PWDs can participate at levels comparable to persons without disabilities.

Work has evolved as a result of new technologies and globalization, providing new opportunities for persons with different abilities and needs. New remote platforms can be leveraged by persons previously limited by barriers associated with transportation, communication, and work hours. Prior to the COVID-19 pandemic, projected labour shortages were a significant threat to the Canadian economy (e.g., in 2018 the Development Bank of Canada found that 39% of small and medium-sized businesses had difficulty finding new workers), and PWDs represented an untapped talent pool. The current downturn risks further marginalizing PWDs if not appropriately handled. Research in Canada and internationally has focused on interventions that prepare PWDs for employment. Less attention has been dedicated to building capacity for employers to hire, accommodate, retain, and promote PWDs.

Although there is broad support for inclusive workplaces, many employers remain apprehensive due to a lack of knowledge and skills. Some external supports exist for hiring and retaining PWDs, but they are piecemeal and inadequate. More contextualized, integrated, evidence-informed resources and tools are needed to expand labour-market opportunities. We call this demand-side capacity building, which includes improving access to supports by employers, increasing knowledge of best practices for disability management, providing more effective employment support services, supporting effective employer/union collaboration, and enhancing peer mentorship. This expansion is urgent. Failure to act now risks missing the opportunity created by recent developments (e.g., introduction of the Accessible Canada Act), and could have lasting negative economic, social and health implications for PWDs and society at large.

We plan to respond to this urgent need via a transdisciplinary, multi-sectoral social innovation laboratory. The potential gains are substantial: $62.2B (3.2% GDP) in direct output and productivity effects, $47.3B (2.5% GDP) in market multiplier effects, and $76.7 B (4.0% GDP) in spillover effects for 2017, based on an ESDC funded study. This project builds on our legacy of partnered research but represents a new framework for working together via robust, transdisciplinary teams who will engage in a solution-focused user-centred co-design process.

The following eight work packages have been devised for this proposal:

1. Assessment of the socio-economic and community development context for product innovation
   
   The goals of this subproject are to develop an understanding of the economic and cultural histories of coastal communities, especially in relation to fish waste.
2. Development of innovative processing approaches to extract value from marine feedstocks
   
   We propose to use shellfish by-products (snow crab, green crab, mussels, shrimp, etc.), finfish residues (guts, trimmings, bones, head, etc.), eel, sea cucumber, and seaweed as feedstock for value-added or secondary processed products.
3. To assess the quality and safety of marine and fishery raw materials and products: e.g., nutrient and functional assessment
   
   We propose to use both targeted and untargeted metabolomic approaches to assess the composition of the raw materials, feedstock or extracts obtained from section 2 to determine suitability for product development.
4. Development formulation and evaluation of novel functional foods, biomaterials, nano-fertilizers and aquaculture feed
   
   The goals will be to investigate the development, formulation and testing of functional foods, biomaterials and nano-biofertilizers from the extracts and waste/residues obtained from objective 1.
5. To establish the health benefits of isolates/extracts, functional foods and nurtaceuticals for marine products
   
   The goals of this section are to establish the health benefits of isolates/extracts and other bioactives for which nutrient quality assessment is established using animal models, clinical populations and cell disease models.
6. To advance sustainable coastal entrepreneurship and economic development opportunities
   
   Together, the integration team will undertake three major tasks: 1) organize a governance structure and ongoing engagement processes throughout the project to facilitate co-construction of knowledge; 2) bring together the insights and findings from the previous projects to assess their socio-economic potential and community interest and acceptance to provide a foundation for pilot commercialization; and 3) evaluate the process and incorporate capacity building throughout.
7. Knowledge mobilization and impact assessment
   
   WP7 will interconnect other work packages (WP1-6) in this proposal, following Memorial University's public engagement model which upholds that engagement is built on mutual contribution, is based on mutual respect, and ought to generate mutual benefit.
8. Informatics of marine biomass, rural or community assets and value-added products
   
   This work package will provide an overall data management plan for the entire project, as well as use multivariate analysis and date integration techniques to assess the value of marine waste and raw materials in the development of value-added marine based products. We will also use metabolomics to assess or validate use, efficacy, bio activities and health benefits of marine ingredients or products in different applications. Furthermore, this work package will provide a platform to help maintain data access and integrity. It will provide state-of-the-art informatics support for the entire team to better understand the relationships between the data collected across the various disciplines and how these can be integrated to facilitate better project success.

Through this application, we seek sustainable solutions to coastal ecosystem, economic, and social issues. We view economic innovation as integral to sustainability, and will seek to identify new products by repurposing marine waste with validated use or applications in agriculture, food, nutraceuticals, biomaterials, and health industries. An integral part of the research includes assessment of the socioeconomic implications and commercial value of any product and potential new revenue streams for firms. We propose an integrated approach to assess, repurpose, and develop novel or innovative products and processes from marine raw materials for the benefit of coastal communities.

A key outcome of this project will be the training of highly qualified personnel, including Indigenous students, postdoctoral fellows, and graduate and undergraduate students, who will gain new skills in the integration of coastal sustainability, entrepreneurialism, and ocean-based research. By integrating socio-economic and lab-based product research, we aim to enhance the capacity of coastal communities to launch and support small and medium-sized enterprises (SMEs). We recognize that Newfoundland and Labrador, and Atlantic Canada in general, have a distinct climate, and, as such, marine species have adopted unique biochemical composition to survive in the cold waters. As of yet untapped, this presents opportunities to develop novel products from marine species. Developing nutraceuticals and functional foods (i.e., omega3-enriched oils) from marine waste will also buttress current fisheries activity, and build upon ongoing economic and social connections between rural and Indigenous communities.

We will partner with coastal and Indigenous communities—including Qalipu Development Corporation (QDC) and their 67 primarily coastal and fisheries-dependent communities; and St. Anthony Basin Resources Inc. (SABRI), representing 13 Northern Peninsula communities—and industry partners to delineate integrated approaches to coastal resilience. We emphasize community engagement and the co-creation of knowledge between all partners, and aim to build new networks for product development. An integral part of the research includes assessment of the socioeconomic implications and commercial value of any product and potential new revenue streams for firms. Our approach recognizes that: social and cultural sustainability and healthy populations are integral to resilient rural regions; eco-innovation is key to the economic resilience of Atlantic Canada; and place-based identities and cultural traditions, along with participatory research design and community engagement, are essential to sustainability research. Our focus on marine waste is guided by a recognition that there is value in 30-70 wt% of the landed species that is made up of shells, guts, trimmings, bones, etc. We therefore propose an end-to-end approach to fishery residues to develop processes and products from finfish, crab, mussels, sea cucumber, seal, seaweed, eels, and shrimp by-products.

We have secured $774,000 in research funding as cash contributions from our research collaborators, including eight industry partners, to contribute to this proposal. This indicates that we have very strong industry support for the work we proposed in this application and that the outcome will be truly transformative and beneficial to their business, rural communities and the industry sector.

Our approach relies upon a recent Canadian discovery in which a common class of organic molecules was shown to form strong bonds to a multitude of types of metal, in a variety of sizes and shapes, from highly curved nanoparticles and nanoclusters to completely planar surfaces. In this proposal, we bring together an international team of researchers from various sectors to explore and develop this carbon-on-metal coating to solve issues related to corrosion and metal redistribution/decomposition on all length scales from nano to macro. Our team is composed of physicists, chemists, medical researchers, nanoscientists, theorists and experimentalists, with clinical and industrial collaborators. This diverse team is essential to develop practical coatings that will protect large-scale infrastructure projects, next-generation lightweight automobiles and airplanes, while also enabling new approaches to microelectronics manufacturing and nanomedical approaches to precision cancer treatment.

The coatings industry is already a billion-dollar industry due to the frequent need to protect metal infrastructure from constant attack by the environment. In addition to the constant battle against rust in typical automobiles, changes in fuel emission standards in the automotive industry are being met by the increasing use of lightweight alloys that are highly sensitive to corrosion. Similar issues in the aerospace industry are compounded by the need for robust exterior coatings with improved thermal barriers and decreased friction coefficients. Our work on the development of an entirely new approach to protective coatings will position Canada at the leading edge of the barrier coatings industry, which has an economic impact of $31B/yr in Canada, and currently employs 211,000 Canadians.

The drive towards smaller and smaller electronic devices has put significant pressure on the microelectronics industry to fabricate metallic interconnects with nanometer precision, and to prevent metal migration during use that would destroy these intricate patterns. Our team will develop novel bottom-up methods to prepare intricate metallic patterns needed for modern microchips. These innovations represent a growth area for Canada in an area that will only be increasing over the next decades.

On the nanoscale, our robust carbon-on-metal approach will bring the vision of directed chemotherapy, precision radiation therapy and improved imaging to reality. Since one in two Canadians will develop cancer in their lifetimes, improved chemotherapy treatments will impact the health and well-being of millions of Canadians.

In addition to these specific applications, the work will provide comprehensive new knowledge in areas of global importance and will improve Canada's position in important global high-tech sectors. By bringing together experts in corrosion, nanoscience, medicine, surface science, solid-state physics and synthetic chemistry, we will also train future scientists, engineers, medical researchers and clinicians. The integrated approach we have proposed, requiring every graduate student involved in the project to be co-supervised by researchers from disparate areas, will greatly improve the employability of trainees graduating from our program, and will facilitate bottom-up cross-disciplinary approaches to this problem of global importance.

From automobiles to bridges to airplanes to electrical wiring and cell phone circuitry, it is difficult to imagine modern life devoid of metals. Protecting these key structural or functional elements against degradation is a billion-dollar industry.

Remarkably, only a handful of elements (gold, silver, copper and platinum) can be found naturally in the metallic form in any substantial quantity. All other metals are present as oxidized form, and are only converted to their metallic states via high energy, expensive industrial processes. Once in the metallic form, reversion to oxide is an energetically favourable process, necessitating a variety of approaches to prevent oxidation, corrosion, and rusting. On the nano and micro length scales, the drive to low energy takes place by loss of engineered patterns and shapes.

Micrometer- or nanometer-thick copper lines form key interconnects in microchips, but are sensitive to metal migration, a process through which metals are redistributed in the device, leading to loss or degradation of function. Even manipulating the metals into the desired patterns occupies a considerable fraction of the time and expense in micro and nanofabrication industries. Gold nanoparticles and nanoclusters are also sensitive to reorganization of metal atoms, which ultimately leads these high-energy species to decompose to bulk gold. Since confinement in the nano state creates unique properties, loss of structure results in a complete loss of function. If the nanomaterials in question are of interest for their biological properties (for example, treatment of cancer), degradation of the nanoform can also cause accumulation in the renal system.

Current approaches to corrosion prevention include the use of paints and coatings, which are only physically adhered to the metal surface and suffer from frequent failure requiring costly reapplication in order to maintain a basic level of surface protection. On the micro scale, metal migration is driving the industry to examine entirely new types of metals, while challenges in the manufacture of smaller and smaller devices remain a problem with few viable solutions.

Metallic nanoparticles, which are at the forefront of advances in precision medicine, are protected from reorganization and loss of shape/size by the application of a coating of sulfur-containing molecules. These coatings are based on 1980s technology that is known to be sensitive to degradation thermally, oxidatively and in vivo, and is one of the most significant limitations in the clinical translation of metal nanoparticle-based medicine. The sensitivity of this coating to removal in vivo is additionally problematic since this coating technique is used not just to protect the nanoparticle, but also to attach biomolecules that enable the nanoparticle to find and kill cancerous tissues.

To address these issues, we will develop a fundamentally new approach for the protection of metal surfaces at all length scales. The approach relies on the formation of carbon-to-metal coatings with unprecedented strength and resistance to oxidation. The development of a novel, scale-independent method will provide a considerable boost to key Canadian manufacturing industries, such as automotive, shipping, aerospace, and construction. In addition, this unique technology will open up markets in green energy, microelectronics manufacturing and nanomedicine.

To address the mission to modify human organs via advanced donor organ interventions applied on Ex Vivo Organ Perfusion (EVOP) systems, the multidisciplinary team will pursue the following projects:

• Aim 1: Extended organ preservation (short term)—Current EVOP platforms enable organ preservation from four to 12 hours. However, the rehabilitation of organ injuries may require perfusion for several days. Thus, a team of surgeon-scientists and engineers will explore the development of sophisticated EVOP platforms (perfusate modification, homeostatic systems with integrated hemodialysis, temperature cycling). Impact: Enable days-long preservation and the full realization of advanced therapies in Aims 2 and 3.
• Aim 2: Improved organ tolerance (short to long term)—Prolonged donor organ acceptance in the transplant recipient will be a target for improvement via: the clearing of donor organ infections, using light-based therapies, chimeric antigen receptor (CAR) T-cells, fusion toxin proteins and monoclonal antibodies; creating universal blood type organs, using specific enzymes to convert whole units of A and B blood to universal type O in donor organs; and organ modification via pro-tolerogenic cell therapies (via delivery of regulatory cell types [T-regs, CAR-Tregs, mesenchymal stem cells] during EVOP to modify the immunological properties of the donor organ and achieve tolerance in the recipient. Impact: Increased availability of clinically acceptable donor organs for transplant, reduced post-transplant morbidity, rejection and need for anti-rejection medications, and enhanced fairness in organ allocation independent of patient blood group.
• Aim 3: Custom donor organs (long-term)—To meet the global demand for organ transplantation, we will use EVOP to create custom organs specifically designed for the recipient, bringing precision medicine to the patient bedside. Studies will include: organ regulation via CRISPR gene editing and gene activation to induce endogenous gene expression, a precision medicine approach to target the repair of specific lung injuries and improve immunomodulation; and organ generation, in which we will develop new methods for de novo regeneration of whole organs from acellular scaffolds, including controlled targeted de- and re-cellularization ex vivo. Impact: Long-term graft success and recipient survival, using manufactured organs with outcomes equivalent to traditional transplanted donor organs that will fulfill demand and eliminate wait lists.

Throughout each aim, we have integrated close consideration of the ethics and social framework regarding fair organ allocation. We will collaboratively develop new ethical and legal guidelines to ensure that the principles that govern equitable access and maximize net benefit to recipients are maintained, and engage with end users across Canada to examine the ethical implications of our project outcomes. Impact: Development of principle-based framework for adjusting organ allocation policies.

The path to a successful and transformative outcome will require leveraging our international network of global leaders across research disciplines, including transplantation, ex vivo perfusion, ethics, immunology, molecular biology, stem cell therapies and CRISPR technologies. Our multidisciplinary approach will ensure novel expertise at all stages of the project and help to address our unified goal: making transplantable organs available for every patient in need.

Canada is a global leader in organ transplantation, a life-saving intervention for patients with end-stage organ disease. Toronto's University Health Network (UHN) is at the forefront of this effort, with over 700 lives saved via organ transplantation in 2019, the highest in North America. However, there still remains a vastly insufficient supply of clinically acceptable donor organs to meet current and future transplant needs. Four thousand, five hundred Canadians, and more than 113,000 people in the US, are currently wait-listed for a transplant, resulting in more than 20 patients dying every day due to not receiving a life-saving organ transplant in time.

For over two decades, UHN has built a tightly knit clinical and research program focused on creating a new paradigm shift in how the world thinks about organ transplantation. Led by Nominated Principal Investigator Dr. Shaf Keshavjee (Director, Toronto Lung Transplant Program; Surgeon-in-Chief, Sprott Department of Surgery; and Director, Latner Thoracic Research Laboratories), UHN has introduced a number of research breakthroughs into the transplant clinic. These include the lung preservation solution that is currently the gold standard worldwide (Perfadexr), the world's first triple-organ (liver, lung and pancreas) transplant in 2015, and a successful Phase I clinical trial resulting in the first safe use of Hepatitis C-positive donor lungs for transplantation into HCV-negative recipients in 2018.

The most impactful innovation has been the team's development of the Toronto Ex Vivo Lung Perfusion (EVLP) system. EVLP uses specialized machines to maintain and treat donor lungs outside of the body just before transplant. By maintaining the organ at body temperature, clinicians can carefully assess its physiological function and determine its suitability for the transplant recipient. At UHN, EVLP application has fully doubled the number of transplants performed (over 200 per year), resulting in widespread adoption in transplant centres worldwide. UHN also leads the development of Ex Vivo Organ Perfusion (EVOP) systems for the liver, kidney, pancreas and heart.

The multi-organ transplant team at UHN will now address a new mission: to optimize donor organs using the developed EVOP platforms—a world-leading approach that will truly revolutionize the organ transplant field. UHN will drive novel national and international collaborations across a number of key disciplines whose own breakthrough applications will be integrated towards improving transplant outcomes across all organs.

The team's multidisciplinary approach will help to address the following project goals:

• Development of safe, days-long organ maintenance and preservation via EVOP
• EVOP-based strategies to promote donor organ tolerance, including clearing infections, creating universal blood type organs, and improved long-term acceptance by the recipient immune system
• Custom donor organs via CRISPR gene editing and organ generation
• Ethical and social strategies to address fair organ access by all communities

The team is deeply experienced in translating research outcomes to the bedside. The ultimate goal is to eliminate the transplant wait list and ensure the availability of organs for all in need, providing durable organs that will outlive the recipient into which they are placed—a true transformation in the field of transplant medicine.