Potential mini brains for innovative brain research

For his research, neurobiologist Nael Nadif Kasri grows brain cells from skin cells. A technique that its inventor, the Japanese Yamanaka, received a Nobel Prize in 2012. The cultured brain cells are placed together by Kasri in trays. There the cells make contact with each other. Then a network of interconnected brain cells is created that emit electrical signals, similar to the way ‘real’ brain cells do in our heads. With this technology it is possible to make a personal ‘brain network’ of each individual.

Recently publications becomes the potential of the mini-brains for new and innovative brain research. The mini-brains and other 2D and 3D cultured biological models are in a sense a kind of biological twins. These can be used for easy calculation and tinkering, so that new insights can quickly arise that can be tested in ‘real life’. The potential of this new technology was recently further underlined when ZonMw awarded 4 million euros to the project BRAINMODEL, of which Nael Nadif Kasri is a co-initiator.

Signal pattern mini brains

Ultimately, the cultured brain cells give off a certain pattern. This creates a kind of basic electrical rhythm. That rhythm can be ‘eavesdropped’ by Kasri using a chip on the bottom of the breeding tray. In healthy people, the rhythm is the same for everyone, Kasri’s research showed. “Whether cells come from men, women, teenagers, the elderly; the same basic pattern always arises. This means that we have a very robust system with which we can reliably study people’s brain activity in culture trays,” says the neurobiologist.

The same new method for brain research can also be applied to people with a neurological abnormality. The cultured brain cells of those people also show a basic rhythm. That deviates from the normal basic rhythm. Depending on the neurological problem, other basic rhythms arise in the ‘mini brains’. It can be concluded from this that the type of abnormality can say something about the biological processes that take place in human brain cells.

For example, researchers can use the cultured brain cells to conduct more targeted brain research. The brain cells of people with MELAS (Mitochondrial Encephalomyopathy, Lactate Acidosis and Stroke) show the same abnormal basic rhythm, while people with Koolen-de Vries syndrome show a slightly different characteristic pattern.

Innovation for brain research

Brain research becomes a lot easier with the help of the mini brains. Together with Khondrion, Kasri conducted research in people with MELAS, a common mitochondrial disease in which the synapses also work less well. “Khondrion is investigating sonicromanol as a possible drug against MELAS. We added this drug to three cultured mini brains from three different patients. In another article in Stem Cell Reports we write that in two out of three we saw an improvement in communication in the brain network. The underlying molecular processes also improved and the deviant basic rhythm shifted to the ‘normal’ healthy form. In this way it may be possible to determine which people benefit from a medicine. Often only a part of the patients manages well on a drug. If you can determine who they are in advance, that is extremely valuable,” says Kasri.

In addition, the mini-brains are also suitable for gaining a better understanding of underlying disease mechanisms. This is because the networks formed by brain cells in the trays consist of the same genetic material (DNA) as the skin or blood cells of the individual patient.

It is known that the cause of people with Koolen-de Vries syndrome, named after two researchers at Radboudumc, is the lack of the KANSL1 gene or mutations in that gene. However, it was not known how this genetic variant leads to, among other things, mild to moderate intellectual disabilities. New brain research, using the mini-brains, has now solved this riddle. Which research was performed by Kasri, together with Katrin Linda, David Koolen and Bert de Vries.

They showed that the KANSL1 gene plays an important role in autophagy. That is the process by which a cell breaks down proteins and uses the remaining fragments to make new proteins. In the absence or malfunctioning of the KANSL1 gene, too few are reused. The waste from the proteins then accumulates in the brain cells, which then work less well or even die. “A lot of damage to brain cells in people with Koolen-de Vries syndrome is caused by oxidants. In our mini-brains we can greatly reduce that damage with antioxidants. This is an important starting point for further research and possibly a potential treatment in the long term. In addition, we think that autophagy may play a role in more developmental disorders and intellectual disabilities. There are a few other genes that, together with KANSL1, are responsible for that recycling process in brain cells. If they don’t work properly, they might cause similar problems,” explains Kasri.