10 September

Thesis defense Joep Beumer – Constructing roadmaps towards functional cell types using organoids

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Joep Beumer, from the group of Hans Clevers, successfully defended his thesis “Constructing roadmaps towards functional cell types using organoids – Shaping and changing the functions of the intestine” on the 10th of September. During his PhD, Beumer studied the fundamental principles that determine how different cell types in the intestine are made, particularly those that produce different types of hormones. And then, when the SARS-CoV-2 coronavirus hit the world, he used his model system to gain more insight into the infection of our cells by the virus. 

Our intestines are not only the place where our food is digested, but they also get confronted with countless of micro-organisms every day and are the largest hormone producing organ in our body. These hormones are produced by so-called enteroendocrine cells and can induce hunger or satiety, coordinate movement of intestinal muscles and affect insulin levels.

The gut hormone challenge

Enteroendocrine cells only comprise about 1% of the lining of the gut. To complicate this further, more than 20 different hormones are produced by at least 5 subtypes of these enteroendocrine cells of which some even more rare than others. This would mean you would have to look at more than 1000 cells to find an enteroendocrine cell that makes a specific hormone. Therefore, it is very difficult to study how these cells exactly respond to the food in our gut.

A mini-intestine, or organoid, with dramatically increased numbers of enteroendocrine, or hormone-producing, cells. Different hormones are shown in red, purple and green. The nuclei of all cells are blue/green. Credit: Joep Beumer, copyright Hubrecht Institute
Mini-intestines

During his PhD, Beumer set out to study these hormone producing cells, and other cells, in the intestine, for which he used organoids, or mini-organs, of the intestine. These tiny organs, only around 1mm in size, can grow in the lab from the stem cells that reside in the intestine. During his PhD, he was able to label different hormones with different fluorescent colors and strongly increase the number of hormone producing cells in such organoids. Beumer: “Marking all major gut hormones with colors allows us to selectively collect any subset of enteroendocrine cells and study even the rarest enteroendocrine cell types.”

Using these approaches, Beumer identified new receptors that the cells use to sense food and release their hormones. In addition, he found potential hormones that have never been identified in the gut before. With these newly developed tools and data, researchers can do large-scale screens to study which molecules in our food are sensed by which types of enteroendocrine cells, how the enteroendocrine cells actually sense these molecules, and which hormones are produced in response.

Coronavirus

When the coronavirus hit the Netherlands earlier this year, Beumer was ready for his defense: his thesis was printed, the date was set. And then the country went into lockdown. His thesis defense was postponed. But instead of waiting out the lockdown, Beumer and his colleagues saw an opportunity to use their model system, the mini-intestines, to study the coronavirus, because previous studies had shown that some of patients also have gastrointestinal problems and that the virus can also be detected in their stool.

Intestinal organoids, the right one infected with coronavirus SARS-CoV-2. The coronavirus is colored white, the organoids themselves are colored blue and green. Credit: Joep Beumer, copyright Hubrecht Institute
Infecting mini-intestines

Together with virus experts in Rotterdam they successfully infected the mini-intestines with the SARS-CoV-2 virus in the lab, and provided evidence that the virus can infect the intestinal cells and multiply there. Beumer: “We were excited when we first looked at the infected mini-intestines – together with my boss, Hans, at the microscope, that doesn’t happen very often. When we saw the large amount of virus in the mini-intestines, and that this amount increased over time, we knew: this is important, we have to share this knowledge as soon as possible.” The new model system allows researchers to study the interaction between human cells and the virus in great detail and in a controlled setting. Currently, they are working on infecting mini-lungs or lungs organoids in the lab to study the interaction between human lung cells and this respiratory virus. 

When asked about this sudden swift to studying covid-19 with his intestinal organoids, Beumer explains his motivation: “Even if you can only contribute in a small way to better understanding the corona-virus, I think it is your responsibility to do so.” 

 

 

Joep Beumer did his PhD research in the group of Hans Clevers, where he will continue to finish up some projects. After that he hopes to explore the opportunity for a new company based on part of their work, that could focus on potential drugs combatting metabolic diseases.