St. Michael’s Hospital is now home to the first fully automated high-throughput zebrafish screening facility in Canada and one of the most advanced screening facilities in the world.
The facility is headed by Dr. Xiao-Yan Wen, a global leader in zebrafish research and usage who was recruited to St. Michael’s in 2009 to lead the zebrafish functional genomics initiative.
Dr. Wen received $2 million infrastructure funding from the Canada Foundation for Innovation to build the Zebrafish Centre for Advanced Drug Discovery.
Zebrafish, small, striped, guppy-like fish, were originally found in slow streams and rice paddies in East India and parts of Southeast Asia. They have recently become a popular organism for biomedical research – especially cardiovascular development and disease, Canada’s top public health threat.
Zebrafish are vertebrates, meaning they more closely resemble humans than some other popular research animals such as fruit flies and nematodes. They breed rapidly and prolifically and their hearts start beating at about 24 hours after fertilization. Because they are transparent and the eggs develop outside the mother’s body, researchers can watch the effect of drugs in real time.
Screening by hand is labour intensive. The new automated facility will allow researchers to use live zebrafish embryos to screen millions of compounds annually.
“This lab will enhance our ability to identify novel mechanisms and therapies that will improve health, to attract leading scientists, to train highly qualified personnel and to stimulate technology transfer and commercial application,” says Dr. Arthur Slutsky, vice-president of research at St. Michael’s.
Working with Dr. Subodh Verma, a cardiac surgeon; Dr. Thomas Parker, a cardiologist; and Dr. Philip Marsden, a nephrologists and vascular biologist, Dr. Wen’s lab has been screening chemical compounds targeting angiogenesis and studying their molecular mechanisms. They have already identified one drug, rosuvastatin—a cholesterol-lowering statin sold as Crestor by AstraZeneca—that suppressed the growth of transplanted human prostate cancer cells in mice.
Other projects in the centre include method development and screening of compounds targeting inflammation, nicotine addiction, diabetes, sepsis, hypoxia, hypertrophic cardiomyopathy and a number of neural degenerative diseases. Dr. Wen is building many local, national and international collaborations and partnerships to find a cure to battle these diseases.
“The zebrafish laboratory makes us an important centre for defining new treatments for a range of important medical diseases including heart and vascular disease, infection and critical illness,” says Dr. Ori Rotstein, surgeon-in-chief at St. Michael’s and associate director of the Basic Science Research Program at the hospital’s Li Ka Shing Knowledge Institute.
“While the jump from fish to man seems like a big one, research using zebrafish provides the critical first step in defining new and effective therapies for patients suffering from these and others diseases.”
The zebrafish screening process starts with an iSPAWN device that can generate thousands of embryos a day, which are then loaded onto a high throughput screening platform. The embryos, injected with a fluorescent, are then sorted automatically onto 96-well plates by a large particle sorter. A liquid handling system automatically injects the drug being screened and a high throughput compatible scanning confocal imaging system captures images to assess the drug efficacy. Three robots and other application procession devices are fully integrated into the enclosed platform, which is controlled by computer systems to deliver fully automated screens.