Modelling the human kidney with organoids
The kidney is a tremendously complex tissue with nearly a million structures called nephrons that filter waste products from the blood. Making miniature replicas of them in the lab – ones that can help answer important questions about kidney disease and treatments – is incredibly difficult. Nine years ago, Dr. Melissa Little, CEO of the Novo Nordisk Foundation Center for Stem Cell Medicine, and her colleagues published their research on developing the first kidney organoid. The protocol has since gone on to drive kidney organoid research around the globe.
On September 30, Little will give a MDC Lecture highlighting the groundwork that made kidney organoids possible. She will also discuss how the highly multicellular organoids have advanced and how they are helping researchers develop treatments for kidney disease. The following interview provides a peek at the topics she will discuss.
How long did it take to develop the first kidney organoid?
The road to the first organoid was 25 years of basic research into how the kidney forms using animal models. Without understanding how the organ forms normally, there’s no way you can identify whether you’ve succeeded in getting a stem cell to do the right thing.
What went through your mind when you succeeded?
When we actually saw in the dish that we could make something that looked like it was forming nephrons, it was quite exciting. It really was one of those big steps. We thought, ‘Oh, wow, that’s actually pretty cool.’
What has been the journey since that research was published in 2015?
We’ve spent almost a decade trying to fully understand what we have grown in a dish and how mature it is. We have also been discovering what we can do with an organoid and how we can make an organoid better. For example, we have done a lot of work to improve the architecture and maturation of the tissue components, including proximal tubes and the glomerulus.
Will it one day be possible to grow transplantable organs?
When I first started, I didn’t think this was feasible and was a bit dismissive about it. Today, I still think it will be extremely difficult. But what was perhaps once not even conceivable is now conceivable. Tissue engineering, I think, is about to drive some really big changes in the organoid field.
What challenges must be overcome before we get there?
We’ve got to make the protocols to generate organoids more accurate, more reproducible, more on target. We’ve got to scale them without losing function. We’ve got to ensure that whatever we transplant has some capacity to survive, mature and function long-term.
What questions are you excited about answering?
I’m excited about all of it. I want to know if we can find drugs to treat some of these genetic diseases that kids die from because there really are no alternatives other than dialysis or transplant. I want to understand how cells organize themselves using these models. The more we understand, the more we may be able to harness that knowledge.
What has delighted and frustrated you along the way?
Large numbers of people use our protocol, so it must work and that’s very pleasing. But it is distressing when we see some poor-quality research using these organoids – part of the problem is that people assume organoids are a perfect model of the human kidney and don’t understand the deficits.
What attracted you to become involved with reREW, an international collaboration between University of Copenhagen, Leiden University Medical Center and Murdoch Children’s Research Institute to advance translational stem cell research?
Products can come from high-quality fundamental research, but frequently they don’t because of institutional barriers in academia. Taking a risk and thinking, ‘ooh, could I make a product out of this?’ is non-intuitive if you want to retain employment in academia. With reNEW, we’re trying to create an opportunity for a bunch of really good stem cell biologists to take the risk and pivot towards translation. It’s a fascinating experiment to see how changing the paradigm of the research environment can impact outcome – one I am very excited about.
Interview: Laura Petersen
Dr. Melissa Little is CEO of the Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Chief Scientist at the Murdoch Children’s Research Institute and leader of the Kidney Regeneration Laboratory, Melbourne. Her MDC Lecture “Generating human kidney tissue using pluripotent stem cells” will be held on September 30 from 11 a.m. to 12 p.m. in MDC.C AXON 1. Register here.
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