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Monomeric genome-editing nuclease (2012)

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Overview

The ability to alter the genetic material of mammalian cells in a precise and time-effective manner will enhance our ability to understand the molecular basis of disease and facilitate treatment options. Altering the genetic makeup relies on the development of biochemical reagents that interact with DNA in a site-specific manner, with minimal interactions at unwanted sites. Developing these reagents is not trivial given the size of the human genome. The biochemical reagents in question are “molecular scissors”, site-specific DNA endonucleases that make a break in DNA at defined sites. The lab under Dr. David Edgell and Dr. Gregory Gloor at The University of Western Ontario has recently developed a new type of molecular scissor based on the nuclease (or cutting domain) from the phage T4 protein I-TevI that is fused to the TAL effector targeting domain which encodes DNA sequence specificity. The Tev-TAL fusions promise to be more specific and smaller than existing reagents. To realize the potential of the Tev-TAL nucleases, the DNA recognition “code” of the Tev-TAL scissors must be fully understood. That is, we must know what DNA sequences we can and cannot target with the Tev-TAL scissors. Knowing this code will allow us to design Tev-TAL scissors that will facilitate both basic and applied research. For instance, it will allow researchers to use Tev-TALs to knockout candidate genes in mouse models of human diseases, accelerating our basic understanding of complex human diseases.

Enhanced metabolite profiling for newborn screening (2012)

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Overview

Newborn screening (NBS) programs represents one of the few proven strategies to prevent infant mortality and long-term disabilities associated with rare yet treatable genetic diseases. Early detection allows for prompt therapeutic intervention that improves clinical outcomes for infants. The recent advent of tandem mass spectrometry (MS/MS) has revolutionized NBS by enabling rapid metabolite profiling of dried blood spot samples collected via a heel prick of every newborn in Ontario. Despite the remarkable success of MS/MS technology, sample pretreatment currently limits the range of metabolites and classes of genetic diseases that can be reliably screened. This project, under Drs. Philip Britz-McKibbin (McMaster University) and Osama Aldirbashi (Newborn Screening Ontario, Children’s Hospital of Eastern Ontario), will develop a novel chemical reagent that permits efficient labeling of clinically relevant metabolites under mild/ambient conditions while potentially boosting sensitivity over two orders of magnitude. This is crucial for expanding NBS to encompass trace levels of metabolites that are difficult to analyze by MS/MS yet serve as primary biomarkers of various genetic disorders. To translate these findings into a marketable product for the clinical laboratory, the metabolomics team at McMaster University will optimize a chemical reagent kit which will be evaluated and validated at Newborn Screening Ontario in the Children’s Hospital of Eastern Ontario. This project will not only enhance the analytical performance of metabolite profiling by MS/MS for additional genetic diseases at minimal incremental costs, but also improve the efficacy of NBS programs by replacing classical biochemical assays that are prone to false-positives.

Creating a non-invasive Norway Maple (2014)

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Overview

Led by Travis Banks and Darby McGrath of Vineland Research and Innovation Centre, this project will initiate work to develop a Norway maple tree that is no longer invasive, in an effort to keep our cities green. Pests and disease are destroying city trees and there are no alternatives suitable to survive the extreme conditions of Ontario urban environments. Having fallen out of favour because of invasiveness, Norway maple was used extensively as an urban tree, which thrives in polluted and compact soils, withstands hot summers and cold winters, and suffers few diseases. SPARK funding will enable DNA sequencing of the Norway maple genome and update methods to identify new Norway maple plants that are unable to create fertile seeds.

Genomic ancestry in a non-model wildlife species at risk, the Eastern Wolf (2014)

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Overview

Led by Brent Patterson and Linda Rutledge, Trent University and the Ontario Ministry of Natural Resources & Forestry (OMNRF), this project aims to improve wolf conservation in Ontario. The research team will be collaborating with scientists at Princeton University to validate and optimize a rapid and efficient genetic mapping approach on the Eastern Wolf, which has the potential to make genomics more accessible to labs with limited resources and provide researchers with an effective, low-cost methodology for genomic analysis of fish and wildlife populations.

Methane to bioplastics: Bacterial strains for production of high value bioplastics on methane feedstock (2014)

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Overview

Led by Trevor Charles, University of Waterloo, this project will focus on using bacterial genomics and synthetic biology approaches to create bioplastics. The use of plastics is widespread in society. However, the detrimental environmental consequences of plastic pollution have raised the need for alternatives. This work, using waste methane as feedstock, could lead to the production of valuable renewable materials from a potent greenhouse gas that is a key waste product of landfills and wastewater treatment systems.

Developing biosensors to promote healthy plant growth (2015)

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Overview

Plant hormones determine plant growth, and breeding programs designed around hormone action have profoundly affected crop yields.
Strigolactones (SL) are plant hormones that stimulate the growth of symbiotic mycorrhizal fungi, that help promote plant growth and development. However, SL also trigger germination of parasitic plant seeds that can compete with key crop plants, especially in the developing world. To better understand how these hormones interact with their receptors in plants, Dr. Peter McCourt (University of Toronto) and his team will use synthetic biology to develop a biosensor for SL activity. With SPARK and additional support from The DOE-Joint Genomics Institute, the team will synthesize over 250 SL receptor variants that will be screened for activity within the plants. This information will be used to develop a toolbox for being able to promote healthy growing agriculturally important plants, instead of the noxious plants that compete with them.

Developing diverse chemical libraries (2015)

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Overview

Synthetic chemical libraries are a common source of drug discovery molecules. The challenge is that these libraries adhere to synthetic structures and biological activities. By contrast, naturally occurring chemicals have a vast diversity of structure but their industrial or medical uses are limited due to the complexity and inaccessibility of these natural products.

Can we then take these synthesized chemical libraries and expose them to a plethora of plant enzymes that could increase the diversity of these compounds exponentially, and find new functions?

Drs. Eiji Nambara, Peter McCourt (University of Toronto) and Dario Bonetta (University of Ontario Institute and Technology), aim to just that. The team is using plant genomics resources to create libraries of various chemical compounds for industrial uses. In an effort to produce the advantages of these two systems, this project aims to set up an enhanced system to evaluate metabolic conversion of diverse chemical library by plant xenobiotic enzymes, which will be useful sources to identify chemicals with new functions.

Micro laser beams used to develop new methods of genomics analysis (2015)

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Overview

Not all cells in our bodies are created equal. Scientists around the world are working hard to understand the differences. The work has been difficult because even seemingly uniform tissues like skin can consist of a diverse population of cells, usually in many different states. The differences between cells are important because, for example, they can lead cells to respond in surprisingly different ways to the same drug treatments. Progress has been slowed by the lack of good tools for accurately tagging individual cells in intact tissues for careful study including genomics. Researchers in Ontario are developing innovative technologies to address that need.
Drs. Matthew Bjerknes and Hazel Cheng (University of Toronto) aim to develop new methods for measuring the genomic status of single cells in intact tissues. Collaborating with scientists at the University of Georgia, the research team will validate and optimize efficient methods using micro laser beams to attach unique barcodes to cells. This will make single cell genomics more accessible to labs with limited resources and provide researchers with an effective, low-cost, and easy to use methodology for tagging individual cells in intact tissues for genomic analysis.

Antenna-in-a-cell: A tool for forest insect pest research and management (2015)

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Overview

Insects damage important crops and forests and some insect species are responsible for the transmission of diseases. If we better understand which compounds mediate the attraction of these insects, we could better control the damage. SPARK funding for this project will help Drs. Daniel Doucet and Jeremy Allison (Great Lakes Forestry Centre) develop the antenna-in-a-cell platform that aims to find physiologically-active odorants, and how they interact the insects’ odorant receptors (OR). This research holds promise for the development of odorant molecules as operational insect lures.
The project focused on the validation of the approach on two invasive insects of critical concern in forestry: the Emerald Ash Borer and the Brown Spruce Longhorned Beetle. Results have allowed the identification of key ORs in both species and their potential roles in volatile odor detection. The results will allow narrowing down the search for optimal odor blends to use against these two insect species.

The impact of antibiotics on gastrointestinal dysbiosis and bloodstream infections in the neonatal intensive care unit

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Overview

The human microbiome is the collection of the trillions of naturally occurring microbes that exist on and within the human body. Established during a critical period of development in the first two years of life, the healthy microbiome performs many functions essential to the maintenance of human health.

The structure and composition of the microbiome is susceptible to the influence of environmental and chemical factors, which can cause changes that have the potential to be harmful in both the short and long term. Antibiotic treatments, for example, have produced significant microbiome disruptions in adults that have been associated with subsequent infections. In an era where antibiotic use and antibiotic resistance has become a global priority, better understanding of the impact of these drugs is essential to improving healthcare outcomes. Of particular importance is the impact of antibiotic use on the microbiome of infants. In the Neonatal Intensive Care Unit (NICU), antibiotics are among the most heavily used medications. However, inadequate research and data limits the ability to discern the impact of antibiotic use on the microbiome of this vulnerable population during a critical period of development.

Michelle Science at SickKids in collaboration with Bryan Coburn from the University Health Network are utilizing Ontario Genomics’ SPARK program to address this critical knowledge gap. They will examine how antibiotic treatment affects the microbiome in neonates and establish whether these changes are associated with short-term consequences. The results of this study will provide important information that will guide decision-making and prescribing practices for infants and neonates in health care facilities, with the ultimate goal of improving patient outcomes.