Mini-organs with big potential

The clumps of cells are modest in size, ranging from just a few millimetres to a couple of centimetres – yet their impact on medical research could be huge. Known as organoids, they are the focus of much of the research carried out by Barbara Treutlein, Professor of Quantitative Developmental Biology at ETH. These organ-like systems are made up of different cell types arranged in complex tissue structures, essentially making them the 3D extension of 2D cell cultures. All the specimens in Treutlein’s lab are grown from human tissue. “Organoids help us tackle questions in various fields of medicine,” says Treutlein.

One of these questions concerns the possible causes of autism spectrum disorders. Analysis of patient data has already identified a link between certain genes and autism. To find out how exactly these genes influence brain development, researchers grew a brain organoid by turning stem cells into neurons. They then switched off certain genes in the organoid using the “genetic scissors” of the CRISPR-Cas method. This experiment was performed by colleagues from the Austrian Academy of Sciences and picked up by Treutlein’s research group, which deployed the cutting-edge bioinformatics tools required to analyse the vast quantities of data obtained from single-cell analysis. “We eventually succeeded in pinpointing the effects of inactivating those genes. We are interested in whether there are mechanisms that affect all genes, and whether some mechanisms are specific to certain genes,” Treutlein says. “By taking this approach, we can try to gain a better understanding of a disease.” In this case, the researchers discovered which gene networks in which type of brain cell are responsible for the development of autism.

As well as studying abnormalities in brain development, Treutlein’s laboratory is also working on the Human Cell Atlas, a project that aims to draw up a map of every cell type in the human body, from development to adulthood. Researchers around the globe are putting immense effort into creating this reference atlas.

The main contribution from Treutlein’s research group is data obtained from characterising the cells of the nervous system. In their experiments, the team analyse more than 20,000 genes per cell, repeating this process for thousands of cells. This generates vast quantities of data, which the scientists interpret with the help of machine learning. “The algorithms spot patterns within this huge volume of data,” says Treutlein. This information is then added to the reference atlas, which researchers worldwide can use for experiments.

Cells form patients

Some of the organoids in Treutlein’s lab are derived from embryonic stem cells (ESCs), which international organisations have been preserving as stem-cell lines for decades. Because ESCs emerge very early on in the development of the embryo, they can be used to produce any type of cell – given the right environment – and thus any type of organoid.

The research group also generates its own stem cells from adult tissue. Known as induced stem cells, these are produced from body cells such as skin cells or white blood cells. By introducing the right factors into these body cells, they can be turned back into stem cells, which can then be used to grow a new organoid. “We can isolate cells from patients, transform them into stem cells and then generate an organoid,” says Treutlein. “What makes this approach so exciting is that we’re essentially mimicking organ development on the level of the individual patient.” Using this method, researchers can model how a disease develops in a Petri dish and try to understand the mechanisms involved.

Periventricular heterotopia is one such disorder that is currently being studied by a doctoral student in Treutlein’s research group. This is a condition in which the neurons fail to migrate properly during the initial development of the cerebrum. Epilepsy can be one of its manifestations. Scientists know that 21 genes are affected. When they switch off these genes in the brain organoid, this creates an imbalance in the different cell types. For now, these are still just the preliminary findings from initial experiments. “But if we can improve our understanding of the mechanisms involved, that could lay the foundations for new therapies,” says Treutlein.

More than one cell type

Treutlein’s research group has analysed the individual cells of the tumouroids. Unlike analysis under the microscope, which merely permits a generalised pronouncement as to whether the tumour tissue is dying or not, Treutlein’s single-cell technology yields much more precise conclusions. “Organoids are complex structures,” she says. “That’s why it’s important to analyse them in detail.” By analysing genes and proteins at the single-cell level, scientists can determine how efficiently a cancer therapy works on a tumouroid.

“This project highlights why our partnership with the IHB at Roche is so beneficial,” says Treutlein. This sentiment is echoed by Matthias Lütolf, head of the IHB and Professor of Bioengineering at EPFL: “ETH Zurich is one of the world’s leading universities, which makes them the perfect partner for the IHB. They have outstanding doctoral students and researchers – and that’s a big reason why our joint research activities are doing so well.” Treutlein believes this success primarily comes down to the difference in focus between academia and the pharma industry: “As a university, it’s easier for us to take on longer-term projects, which are, of course, more risky. At the same time, we benefit from the private sector's practical focus, which is required to advance real-world applications.”

ETH Zurich and Roche have also launched a joint programme for doctoral students, and Treutlein’s laboratory will soon be welcoming a doctoral student from the IHB. Both she and Lütolf see major benefits in the decision to locate ETH Zurich’s Department of Biosystems Science and Engineering in Basel. “Our joint students need easy access to both partners’ labs and the ability to move quickly from one institute to the next,” he explains. “It’s this kind of personal contact that I believe is the key to successful research.”