Combination ribonucleic acid nanotechnologies to simultaneously study the multitude of mechanistic pathways found in complex diseases

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Chronic diseases are complex and difficult to study. A single biological aberration can cascade into additional problems, leaving cells and tissues vulnerable to more damage. Currently, when trying to study the cause of chronic diseases, researchers make use of small molecules that can block or activate certain mechanistic processes inside cells that we believe cause disease. Some processes contain multiple steps, and some of these steps are shared with other processes, which creates an extensive network. This overlap makes it difficult to exclusively target one process without accidentally activating another one. Moreover, given the incredible diversity of malfunctioning processes in chronic diseases, many targets of interest lack a corresponding small molecule that can provide control. Because of this lack of targeted control, there is a knowledge gap in our understanding of which malfunctioning cellular processes contribute to chronic disease. To bridge this gap and reveal hidden insights into the mechanics of diseases, new engineering tools capable of controlling elusive processes are desperately needed. Furthermore, many diseases arise from the failure of multiple processes. Thus, these tools must also have the ability to control many processes at once to perform meaningful studies. Our long-term vision is to discover what combination of malfunctioning processes lead to chronic diseases. We will leverage our interdisciplinary position in the University of Toronto's Centre for Machine Learning in Medicine, Institute of Biomedical Engineering and Department of Immunology to achieve this vision. To begin these studies, we require new engineering tools that allow us to precisely manipulate any process inside a cell to mimic the progression of disease. Thus, as our starting point, this Discovery Grant program will create a new nanotechnology that, when administered to cells, can adjust any process for research purposes. We then observe the outcome of these changes to understand how these processes influence the initiation and progression of disease. This nanotechnology is in the form of small particles that enter cells and deliver nucleic acids. Nucleic acids are instruction sets that cells can read and follow. After the nanotechnology delivers the nucleic acids, the cells will follow the instructions, which tell them how to change their internal processes to mimic a disease. We will screen many different nucleic acids to discover which instruction lead to disease. In this way, we will deduce the step-by-step sequences that lead to different diseases. This research will advance our fundamental understanding of why diseases occur and how they progress. In terms of benefits to Canadians, this program creates highly qualified personnel with skills in chemistry (organic synthesis of nanotechnology), cell biology (large-scale screens), analytical methods (cell observation and data collection), and machine learning (advanced disease modelling).