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Genome-based community modeling reveals essential metabolite exchanges in anaerobic microbial communities

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Overview

The vast majority of microbes in the environment live in close association with one another in mixed communities. These communities maintain high levels of complex interactions exchanging nutrients, vitamins and other chemicals. The microbes in these mixed communities therefore function very differently from microbes isolated in pure cultures in the laboratory, producing phenotypes unable to be replicated in one individual cell type. Thus, complex microbial communities and their interactions must be studied as a whole to fully understand their properties and dynamic relationships.

Through Ontario Genomics’ SPARK program, Elizabeth Edwards and Radhakrishnan Mahadevan at the University of Toronto are developing computational models using microbial genomes and metagenomes to identify metabolic gaps pointing to nutrients or vitamins (metabolites) that are exchanged between members of a microbial community. The team will then further validate these predictions experimentally using an anaerobic subsurface mixed microbial community that contains microbes used for bioremediation of toxic chlorinated solvents such as chloroform.

The knowledge gained from this project will serve to not only boost the efficiency of dechlorination in groundwater remediation, but will also resolve metabolic gaps in genome-scale models at the microbial community level. This will pave the way for other applications to uncover metabolic interactions in complex microbial communities such as in the human gut and in deep marine sediments, which are intractable using pure culture studies.

Discovery of the microbiome of corn silks: The entry point for fungal pathogens including Fusarium

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Overview

In corn, the hollow tubes through which sperm from the pollen travel are called silks, visible as the threads that arise from the tips of corn cobs. Some of the most serious fungal pathogens affecting Ontario corn enter the grain through these hollow channels of the silks, leading to hundreds of millions of dollars in cumulative crop losses in Ontario and Canada, as well as the accumulation of toxins in the grain, affecting the health of both humans and livestock.
Like humans, plants are inhabited and coated by a huge diversity of naturally occurring probiotic microbes. Manish N. Raizada’s lab at the University of Guelph have proposed that the cells of immobile plants have evolved to maintain specific mobile probiotic microbes that act in a manner analogous to human immunity cells: to seek and destroy invading pathogens.

With help from the Ontario Genomics SPARK program, the Raizada team aims to discover probiotic microbes inhabiting the hollow channels of Ontario corn silks. This project has huge implications for the more than 21,000 Ontario corn farmers in addition to the province’s livestock industry, grain processors, and consumers. This research will SPARK follow-up studies on pollen tube microbiomes to identify genetic markers that promote the colonization of silk-associated probiotics for use in breeding programs. The identification of probiotics which can be applied to silks in order to combat the crop diseases afflicting grain farmers will decrease the requirement for and reliance on pesticides and therefore result in more sustainable and effective industry practices.

CRISPR/Cas9 conjugative plasmids for microbiome control

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Overview

Composing the vast majority of the known species and biomass on the planet, microorganisms are fundamental players in human health, environmental processes, agriculture and food production. Their diverse range of essential functions across industry and nature render them essential in humanity’s efforts to optimize bio-industrial applications, prevent and treat diseases, and remediate environmental disturbances.

However, in the quest to understand and control microorganisms to overcome humanity’s challenges, the field of microbiology and microbial ecology faces a crucial obstacle: the necessary tools to selectively control the composition and abundance of microbes do not yet exist.

With the aid of Ontario Genomics’ SPARK program, Drs. David Edgell and Gregory Gloor of the University of Western Ontario are working to develop and test a CRISPR/Cas9 conjugative plasmid system to enable precise user-defined manipulation of the composition of a microbial community. Coupling the power and ease-of-use of CRISPR-based technologies with a self-transmissible plasmid, this novel microbial control system aims to enable the selective elimination of individual bacteria from a mixed population of bacteria. If successful, the plasmid-based CRISPR microbial control system has broad-ranging applications in basic biomedical research, industrial food-related process, and human health.

The Mammalian Membrane Two-Hybrid (MaMTH) assay: Advanced proteomics technology for biomedical research

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Overview

Integral membrane proteins have roles in many human diseases, but are notoriously difficult to study due to their unique biochemical features. Dr. Igor Stagljar and his team at the University of Toronto recently developed a powerful new technology, the Mammalian Membrane Two-Hybrid (MaMTH) assay, which can map protein-to-protein interactions (PPIs) of integral membrane proteins directly in the natural context of the cell. They now propose to further develop MaMTH technology by converting it into a platform that can map these PPIs on an extremely large scale. This work will allow researchers to develop better-targeted therapies for human disease more rapidly. The technology will be the foundation for an Ontario-based company called Protein Network Sciences that will offer easy access to this novel disruptive MaMTH technology, advancing biomedical research and therapeutic discovery while benefiting Canadian social and economic infrastructure.

Synthetic inhibitors of ubiquitin-binding cancer targets

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Overview

Our cells remove damaged or nonfunctional proteins through a small protein called ubiquitin, which attaches to target proteins and signals their destruction. In many diseases, ubiquitin does not work as it should. Dr. Sachdev Sidhu of the University of Toronto is using an innovative high-throughput molecular genetics engineering platform, which is unique in the world and has attracted intense interest from industry and academia, to enable the rapid and cost-effective development of highly specific and potent ubiquitin-like molecules. These molecules attach to key, cancer-associated enzymes of the ubiquitin system, to block or enhance their function. The project will enable the discovery of new drug targets, speed up drug development and generate effective anti-cancer drugs with fewer side effects, all of which should be of great socio-economic benefit to Canadians.

SANGRE-seq (systematic analysis of blood gene regulation by sequencing): Bringing RNA-seq to clinical diagnostics

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Overview

Diagnostic tests based on blood samples are mainstays of the healthcare system. Adding RNA sequencing (RNA-seq) can extract more information from blood samples, including a snapshot of all the genes active in a patient’s blood cells. Such a snapshot can tell us about the current condition of the patient’s immune system, whether there are cancer cells in the blood and/or whether blood cells are fighting an infection. Drs. Michael Wilson and Adam Shlien of The Hospital for Sick Children are developing an RNA-based clinical test called SANGRE (systematic analysis of blood gene regulation in blood) that will provide unprecedented power to use RNA expression as a routine and affordable test that can better diagnose disease, disrupting clinical practice and improving the health of Canadians.

Development of a digital microfluidic platform to identify and target single cells from a heterogeneous cell population for lyses in an ultra-low volume

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Overview

Genetic abnormalities are a leading cause of death among Canadian newborns and infants. Less invasive, less expensive prenatal diagnostic techniques that are able to provide relevant information at earlier stages of pregnancy are needed. Scientists and physicians at Toronto’s Mount Sinai Hospital have developed a method to collect and isolate fetal cells non-invasively, using a technique similar to a PAP smear. Now Dr. Aaron Wheeler’s research group at the University of Toronto is developing techniques to isolate and analyze these cells for prenatal diagnosis of genetic abnormalities. If successful, these techniques could transform the way prenatal diagnosis is delivered, resulting in higher coverage of the population, reduced patient anxiety, increased medical options for at-risk pregnancies and significant reductions in healthcare costs.

Functional genomics in human cells for drivers of lethal metastatic human cancers

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Overview

Often in cancer it’s the spread of the cancer to other areas of the body, a process called metastasis, that kills. This is particularly the case with two highly lethal types of cancer, medulloblastoma (MB), the most common malignant brain tumour in children, and pancreatic adenocarcinoma, the fourth leading cause of cancer deaths in Canadians. Recent results from the lab of Dr. Michael Taylor of The Hospital for Sick Children have shown that the biology of the metastases is extremely different from the primary tumour, making it unlikely that treatments developed to treat the primary tumour will work on the metastases. Dr. Taylor has teamed with Dr. Rama Khokha (Princess Margaret Cancer Centre) to develop and deploy unique tools to discover the drivers of metastasis, helping to improve survival rates of Canadians with these deadly human cancers.

Solid-state nanopore-based quantification of low-abundance biomarkers

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Overview

Many illnesses, such as cancer or cardiovascular disease, leave physical evidence in our bodies, called biomarkers. Spotting these biomarkers early would make it possible to begin treatment with personalized, targeted therapy, or even prevent disease entirely. Solid-state nanopore-based devices can do this, but are too expensive for widespread use. Dr. Tabard-Cossa’s laboratory has pioneered a technique to fabricate nanopore devices more rapidly and at substantially lower cost than present-day technology. They are integrating the devices into a disposable cartridge within compact platforms offering comprehensive sample-in, answer-out capability. The lab is positioned to develop a point-of-care prototype that can be used in the lab and the clinic, resulting in significant economic and health benefits for Canada.

Development of SIMPL, a novel protein-protein interaction assay based on split intein for biomedical research

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Overview

Proteins control every function of every cell in our body. Proteins, however, never act alone; rather, they interact with many other proteins in what are called protein-protein interactions (PPIs). Gain or loss of PPIs can be the driving force behind disease development. Dr. Igor Stagljar of the University of Toronto is leading a team to develop and implement a novel disruptive genomics technology that can detect and monitor PPIs in human cells. This technology can be used to identify novel proteins as components of many essential cellular processes, leading to greater understanding of the role of specific proteins in our cells. Furthermore, the technology also has the potential to identify drugs that disrupt a defined set of PPIs when the PPIs cause disease.