Universiteit Utrecht
Coupling organoids to study systemic effects of kidney disease and treatment
Bas van Balkom is a cell biologist in the Department of Nephrology and Hypertension of the UMC Utrecht. The lab is housed in the Regenerative Medicine Center Utrecht, where he aims to develop regenerative therapies for kidney diseases. As such diseases affect the entire body, animal research seems inevitable. But Bas is combining multiple organs on a chip, so that systemic effects of disease and potential therapies can be studied in vitro.

“It is estimated that around 10% of the human population has some form of kidney disease, and many people don't even realize that they have a kidney disease. Of course, early discovery of the disease will provide a higher chance at recovery. In later stages, we can only slow down the progression of the disease and ultimately provide kidney replacement therapy through dialysis or kidney transplantation. Finding a therapy that would really cure kidney disease patients, thus a regenerative therapy, would dramatically improve the quality of life for these patients, not only through the effects on the kidney directly, but also because kidney disease is also a risk factor for other diseases.”

What are you trying to find out?
As introduced, kidney diseases have systemic effects, but, besides that, also treatments affect more organs than only the kidney. These are two important arguments to study the interaction between different organs in health, disease, and, upon treatment, in a systemic manner. This complexity appears best mimicked using animal models. Increasing eviden
ce, however, indicates that many human physiological processes are not adequately represented in animal models, and it is difficult to dissect specific processes or mechanisms using animals. Using a Multi-Organ-on-a-Chip (MOC) approach, valuable information about disease mechanisms, organ-organ-interactions and potential therapeutics in a human background can be obtained in vitro. Our first aim is to establish MOC systems combining the kidney with other organs, such as the heart, liver, pancreas and fat, all based on human cells and organoids, and verify that normal physiological processes can be mimicked in these models. From there, we will mimic disease conditions and apply potential treatments in using this system.

Do you use animals in your experiments and how do you feel about that?
The kidneys are complex organs and play an important role in the homeostasis of the body’s physiology. Therefore our department has several animal models available, although I do not apply these in my own research at this time. In the past I have performed animal experiments, but I never liked to see the harm done to these little creatures. This motivated me to move towards alternatives for animal experiments.

Are you making progress?
I am very pleased that there are more and more initiatives to stimulate the reduction of the use of animal experiments. With the help of the Utrecht 3R Stimulus fund, the Dutch Society for the Replacement of Animal Testing (Proefdiervrij), Health Holland and the Dutch Kidney Foundation, I am now able to really move forward on this path. Together with Viv
ian Nguyen, who works in our lab as a PhD student, we have already accomplished MOC models combining the kidney with the heart and the liver. We now aim to expand these combinations and develop injury and disease models. It is exciting to combine developments currently ongoing in the Regenerative Medicine Center Utrecht, such as 3D patches of iPSc-derived cardiomyocytes and liver organoids (in collaboration with Experimental cardiology of the UMC Utrecht and the Liver group of the Faculty of Veterinary Medicine, respectively) with our expertise on kidney physiology and organoid culture. With the help of the company that provides the hardware for the MOC system, TissUse GmbH, we are confident that we can contribute to the Reduction, Replacement, and Refinement of animal experiments.

Will MOC systems be complex enough to really replace animals?
 That is a very good point, and to be honest I must say “probably not”. Combining different organs, or rather organ representatives, is a huge challenge to begin with, and it seems a miracle how organisms manage to do this. We aim to add complexity to our system step-by-step, but realize that there are limitations, and that there are organs, systems, or patient characteristics that are almost, if not at all, impossible to implement in MOC models. Think for instance of the immune system or the nervous system: the integration of such components goes far beyond our capabilities, so far. But, on the other hand, the absence of such factors, and thus the relatively low complexity of MOC systems, does allow us to study specific interactions between different organs, without ‘interference’ by other factors.
What is your dream?
My dream, or ambition, is to be able to provide valuable contributions to the lives of people with a kidney disease and to colleague scientists. For kidney patients, I dream that at one time in the future we can really invert the progression of chronic kidney disease. In our department, we are working hard on making the lives of these patients better through several approaches, including research on regenerative therapies, but also improved dialysis methods and higher success of kidney transplantations. For researchers, and of course for all the laboratory animals, my dream is that novel technologies, including the MOC systems, will lead to true replacement alternatives for animal models. I believe that ultimately, by combining data from in vitro (MOC) experiments with the huge amount of digital information available from in vitro, animal and human research will lead to integrated in vitro/in silico approaches which allow for the implementation of systems and factors that are (now) too complex to mimic in the lab. The funding from the Utrecht 3Rs Fund enabled me to initiate the realization of this dream, and has already lead to advances in the lab and additional funding for the development of human measurement models.