Scientists are turning to small lab-grown cell clusters to probe basic questions, model diseases and test drugs
It may sound like science fiction, but researchers are growing organ-like objects in the lab. Called organoids, these three-dimensional clusters of cells are often just a few millimetres in size – but they mimic some of the structure and function of the human body at the cellular level and resemble aspects of real organs.
“Some people refer to them as mini brains, but that’s not really appropriate,” said Jeffrey Wrana, a professor of molecular genetics of the University of Toronto who works with cerebral organoids. “They’re really just modelling very specific aspects of neural functions. They’re not functioning in any kind of meaningful way.”
The same is true of organoids of the liver, kidney, intestines and blood vessels – they aren’t nearly as large or multifunctional as organs in the human body. But they’re useful for investigating basic questions, modelling diseases and testing drugs. In time, organoids could be used as part of personalized medicine and even for cellular-level transplants. They could also eventually reduce the reliance on animal testing in medical research.
“Organoids have revolutionized what we can hope to do in our research,” said Andrew Stadnyk, a professor in the department of microbiology and immunology at Dalhousie University, who uses them in his work on the digestive system. And as University of British Columbia professor Josef Penninger, who works with vascular organoids, put it: “The field is exploding.”
The science behind organoids developed over several decades, thanks to discoveries that showed stem cells in vitro can self organize and differentiate themselves into cell types that do various tasks. About a decade ago, organoids became a viable research model. Scientists built the first cerebral organoid in 2013. Dr. Wrana has been working with organoids for five years now, and in that time he said he has seen researchers grow increasingly complex systems for a range of organ types.
Dr. Penninger and SBME researchers Dr. Nozomu Yachie, and Dr. Nika Shakiba have been funded as Allen Distinguished Investigators to lead a project that traces the “family trees” of individual stem cells as they grow and divide into organoids—lab-grown mini-organs.
Now they’re becoming big business. The worldwide organoid market was worth US$689 million in 2019, and is estimated to grow to over US$3 billion by 2027, according to venture capital and private equity firm Insight Partners. University researchers such as Dr. Penninger are securing patents and creating spin-off companies.
Tracking disease development
In the case of Dr. Stadnyk, he used to look at cancer cells (a common practice for in vitro research) to study the digestive tract. “These cells are not normal, so there’s limits to extrapolating information,” he said. In animal models, there’s too much “noise” to isolate basic cellular functions. But organoids recently enabled him and a master’s student to confirm that epithelial cells make the molecule interleukin 10, which is relevant for understanding inflammatory bowel disease. “It’s a super simple question,” admitted Dr. Stadynk. “But it’s been hotly debated.”
In brain organoids, researchers are able to track disease development. At the University of Calgary, professor of medical genetics Deborah Kurrasch is studying how parts of “normal” brains develop compared to those that will go on to suffer from epilepsy. Meanwhile at U of T, Dr. Wrana’s lab looks at how genetics influence aspects of early brain development that could relate to autism spectrum disorder. And at UBC, Dr. Penninger observes vascular organoids to understand blood vessel malformations, including those that happen in diabetes, and to see how they respond to medications.
Dr. Wrana said 90 per cent of drug candidates fail, but disease modelling via organoids could improve that rate. “If you could increase the efficiency of the drug discovery process it would have a huge impact on society,” he said.
The promise of personalized medicine
Future work could see advances in personalized medicine. For example, researchers could grow organoids using cells from a particular patient who is not responding to treatment, then test which drugs work. Dr. Penninger has already transplanted vascular organoids into mice, where they adapted and became functional. In time, researchers might grow parts of organs to perform cellular-level transplants in people.
This could lead to ethical concerns, but it’s unlikely researchers could ever grow a full organ for transplant. “They’re not perfect. And we don’t entirely understand how far from perfect they are,” said Dr. Stadnyk. One challenge is how to keep these cell cultures alive long-term. Currently, they cluster up and the inner cells then die off, which may impact their research value. “How does that influence signalling and connectivity?” pondered Dr. Kurrasch. Labs are fine-tuning the model and sharing tips – Dr. Kurrasch has heard of one researcher who physically trims her organoids, which allows the inner cells access to nutrients.
Dr. Wrana said researchers are perfecting the model as their work progresses, but that’s never the main focus. “You can get funding to ask questions, and then you develop the model as part of that. You can’t just work on organoids full-time.”
Another problem is organoids that have been grown in a lab for months resemble fetal or child-aged organs. “If you think you’re going to take an organoid to study Alzheimer’s, and it only gets to the maturity of maybe a two-year-old child, that’s a very different brain than a 70-year-old brain,” said Dr. Kurrasch.
As well, the reagents that are used to start an organoid are pricey. Companies now make kits so the process goes more quickly and is more reliable, but they cost even more. Dr. Kurrasch calls the model “ridiculously expensive.” She said her lab was spending $1,200 a month on reagents at one point. But Dr. Wrana predicts that in time, widespread use and greater competition will help drive prices down.
For now, animal research may remain a cheaper option for labs that are already set up for that. Animal research rose by 11 per cent in 2020, according to the Canadian Council on Animal Care. While some researchers hope that organoids could help reduce that trend one day, it may not be as simple as choosing one or the other. “For most complex diseases, we need animal testing,” said Dr. Penninger. “This is not about displacement of animal models but about using the best model possible, in many cases, together.”
This article by Diane Peters originally appeared on the University Affairs website.
Nico Werschler, a PhD candidate in the Penninger lab served as a source for the story.