Organoids, miniature organ models grown from stem cells, replicate the complexity of actual organs on a scale of about one millimeter. They exhibit similar morphology and functions but lack crucial elements like vasculature and immune response. In contrast, organs-on-chips, while providing dynamic microenvironments, typically use less sophisticated biological models. By combining these technologies, we can leverage the biological accuracy of organoids with the dynamic capabilities of organs-on-chips. This synergy aims to replicate in vivo physiology, enabling a more accurate study of disease characteristics and drug responses.
The project’s centerpiece is to engineer heart organoids-on-chips, with functional vascular and immune components, to investigate hypertrophic cardiomyopathy (HCM). We will evaluate the efficacy of drugs in mitigating hypertrophic responses. In addition, the study will include perfusion of immune cells to analyze the role of inflammation in HCM progression, investigating immune cell recruitment.
This initiative coincides with the U.S. FDA’s pivot from mandatory animal testing for new drugs, marking a significant shift towards more relevant human-based models in drug development.
Failure to control bleeding, such as during trauma and childbirth, accounts for more than half of all operating room deaths. Platelets are blood cells that stick to sites of active bleeding and release proteins to initiate blood clotting. The gold standard therapy for treating severe bleeds is transfusing the patient with more platelets. However, in some cases, transfused platelets can have impaired clotting, thus increasing mortality. A strategy to improve platelet function is to load platelets with more clot-initiating proteins. We have previously shown that platelets can be engineered to express new proteins using mRNA-lipid nanoparticles (mRNA-LNP). This project will expand on these findings and use mRNA-LNP to deliver the genetic blueprint for clot-initiating proteins into platelets to enable the production of clotting factors that will prime the platelets for improved clotting. The research will be in active collaboration with academic and industrial partners to facilitate the development of a clinical product from any generated intellectual property. Enhancing the natural properties of platelets will improve options for bleeding control, with the potential to reduce the incidence of hemorrhage-related deaths in Canada.
Each cell has the same genetic information, our DNA. Yet, our body consists of many different cell types (eg. muscle cells, brain cells, etc). To become a specific cell type, our cells have the ability to turn genes in our DNA on or off. This selective control of genes is achieved via “epigenetics”, which means on top (epi-) of our genes (genetics). Epigenetics involves chemical changes to proteins that organize our DNA, which are called histones. Changes to histones are made by epigenetic enzymes. When epigenetic enzymes are defective the wrong changes are made to histones. In turn, the wrong genes are turned on or off, leading to disease. An example of such a disease is Sotos Syndrome, a neurodevelopmental disorder caused by a defect in the epigenetic enzyme NSD1. Exactly how defective NSD1 leads to misguided control of genes is unknown. To examine this, I will use gene editing and delete NSD1 in neuronal precursor cells. Next, I will study the effect of defective NSD1 on histone changes and identify which genes are wrongfully turned on or off in these cells. The results from this study will show how defective NSD1 leads to misguided gene control and can help identify new options for the treatment of Sotos Syndrome.
Drugs used in cancer treatment, unfortunately, also can harm healthy cells. We’re working on a better way to deliver these drugs directly to cancer cells, minimizing damage to healthy tissues. Imagine tiny particles, like microscopic delivery trucks, that carry cancer drugs. These particles are made from fats and can hold both a cancer-fighting drug, doxorubicin, and special iron particles. What’s unique about these tiny trucks is that they release their drug only when hit by a certain type of radio wave. This means we can target the drug right at the cancer cells, releasing it quickly and precisely. Our first goal is to make these special particles. Then, we’ll test if we can use radio waves to release the drug quickly in lab experiments. Lastly, we hope to show that this method works well in treating cancer in animal studies. Previously, our team has successfully translated scientific research into practical therapies, and we believe this might be yet another example of our achievement in advancing the efficacy of cancer therapy and safety.
Regenerative medicine such as stem cell based therapy holds great promise towards addressing many diseases that afflict millions of Canadians, including many forms of cancer, muscular and neurological degenerative disorders, diabetes, and arthritis. However, this promise has yet to be fully realized. Despite the many advances in stem cell biology, little is known on the mechanisms governing stem cell identity and on how this identity can be effectively changed and applied towards its target function. The lack of understanding in basic stem cell biology not only has hindered the proper application of stem cell therapy, but has also led to the proliferation of unproven and potentially unsafe applications in many private Canadian clinics.
My research aims to bridge this gap by studying how embryonic stem cells are able to self-maintain indefinitely, while retaining the ability to differentiate into any cell type of the body. Using cutting edge technologies such as gene editing, genomics, and single molecule imaging, our group plans to dissect the molecular underpinnings that make stem cells such versatile therapeutic agents.
