ORGANOIDS: MINI ORGANS IN A DISH Organoids are cells grown from human or mouse organ tissues to create simplified, three-dimensional mini organs that possess some of the same structures and functions as their real counterparts. The Scientist Magazine named organoids one of the biggest scientific advances of 2013, and since then the field has snowballed rapidly. Organoids help researchers understand tissue development and study disease directly by using a patient’s own tissues, which allows for the possibility of personalized medicine.
Q: TELL US ABOUT YOUR WORK WITH ORGANOIDS.
Dr. Jeff Wrana, CIBC Breast Cancer Research Scientist and the Mary Janigan Research Chair in Molecular Cancer Therapeutics at the LTRI, aims to expose the communication networks that control how these complex structures form and how disturbances cause disease. He creates organoids to understand the progression of cancer and how to regenerate tissue.
Q: WHICH BIG QUESTIONS ARE YOU USING ORGANOIDS TO EXPLORE?
I M A G E C R E D I T: D R . M A S A H I R O N A R I M AT S U
An intestinal organoid from the lab of Dr. Jeff Wrana. Dr. Wrana’s team uses organoids like these to study how organs regenerate after injury and how colorectal cancer initiates and grows. 32
Dr. Wrana: With sequencing of the human genome, you basically went from a sailing ship trying to find new land to a satellite that showed you the entire Earth. And then the challenge became, OK, what do all the genes do and how do they all interact with each other and make a human, which led to the discovery of stem cells. And what goes wrong with cells globally and not just on a single-gene level when people get a disease? We started to study how proteins, which are the functional product of our genome, communicate between cells and instruct them on how to become a liver cell or a kidney cell. This work provided a toolkit that has driven an explosive area of biomedical research, where we can take stem cells and get them to make different kinds of organoids.
Dr. Wrana: One is how cancer initiates. The second is, how do tissues regenerate? The intestine has a tremendous turnover capacity: We turn over our intestinal lining every two to three weeks. The kidney has a limited regenerative capacity. So we’re interested in trying to compare and contrast those two tissues. We’re applying some remarkable new technologies that allow us to profile, basically, all individual cells in a tissue, and this gives us remarkable insight into how organs respond to injury. And because the organoid is in a dish, it’s much easier to do those experiments than if you were trying to do it in the context of a whole animal, like a mouse. And what we discovered, actually, is taking some cells out of a tissue and then making them grow for a couple of weeks in a dish — that’s basically regeneration. Also, you can grow an organoid in a dish and knock out a gene in the dish and see
what happens in terms of tumour initiation and regenerative capacity. What are the signals that are controlling these processes, and how can we exploit them to identify potential targets for new therapies? In our recent work, we discovered a new cell type that arises when we damage the intestine, and it seems to be critical to repair damaged intestine. Now we’re really interested in whether this cell type is also present in tissues with limited regenerative capacity, like the kidney, and whether we might be able to activate it to improve repair. Q: HOW MIGHT ORGANOIDS ONE DAY IMPROVE PATIENT CARE?
Dr. Wrana: One example of what we’re working on is glioblastoma, the devastating tumour that Gord Downie, lead singer of The Tragically Hip, recently died from. So now we’re taking human cerebral organoids — mini brains — and growing glioblastomas in them so we can understand how the glioblastoma and the normal human brain tissue are interacting with each other. This could be a really important model to screen for new therapeutics. Q: ARE THERE ETHICAL CONCERNS AROUND THE USE OF ORGANOIDS?
Dr. Wrana: With cerebral organoids, there is considerable discussion with respect to ethics. At what point does brain tissue become truly human brain-like? At what point is there consciousness, or pain? But it’s important to remember that at this point in the technology, these are really tiny pieces of tissue in a dish — they’re only a millimetre in diameter and have nowhere near the complexity of even a mouse brain, let alone a human brain. Q: WHAT’S MOST EXCITING FOR YOU ABOUT THIS RESEARCH?
Dr. Wrana: The discovery of a new cell type critical for regeneration. I gave you the analogy of going up into a satellite. Now it’s like being above the solar system, looking at this exquisite global view of tissues but also seeing it at the single-cell level. It’s blowing my mind.
