In his research, neurobiologist Nael Nadif Kasri turns skin cells or blood cells into brain cells. It's an astonishing ‘magic trick’ that is based in part on research by Shinya Yamanaka, for which he was awarded the Nobel Prize in 2012. Kasri puts the cultured brain cells in small containers, where they make contact with each other. This creates a network of interconnected brain cells that emit electrical signals just like the brain cells in our own heads. This makes it possible to create a personalised brain network – a mini-brain in a container – based on some skin cells or blood cells.
Brain with a basic rhythm
Kasri discovered that after some time these cultured brain cells start to emit signals in a certain pattern. A kind of basic electrical rhythm is created, which Kasri can listen to with a chip on the bottom of the culture containers. In their research that was published recently in Stem Cell Reports, Kasri and colleagues showed that this basic rhythm is the same for everyone with healthy brain cells
“Regardless of whether the cells come from men, women, teenagers or elderly people, the same basic pattern is always created,” says Kasri. “That means that we have a very robust and reliable system that we can use to study brain activity in vitro.”
Deviating patterns
The researchers not only studied mini-brains from healthy people, for that matter. The basic rhythm of people with neurological problems or developmental disorders can also be identified. The cultured brain cells of people with a brain disorder also show a basic rhythm, but this rhythm deviates from the ‘normal’ basic rhythm.
Depending on the neurological problem, other basic rhythms arise in the mini-brains. For example, people with MELAS (Mitochondrial Encephalomyopathy, Lactate Acidosis and Stroke) show the same abnormal pattern, which is characteristic for this condition. And people with Koolen-de Vries syndrome have a slightly different characteristic pattern. The electrical pattern of the cultured brain cells therefore says something about the biological processes that take place in people's actual brain cells.
Faltering synapses
The advantage of such personalised mini-brains is that it makes it much easier to study these biological processes. In collaboration with the company Khondrion, Kasri has done this for people with one of the most common mitochondrial diseases – MELAS – in which the synapses do not work as well as in healthy individuals. Mitochondria are the ‘power plants’ in the cell; if they don't work correctly, a body has less energy to perform activities. Synapses are the contact points between nerve cells; if the synapses falter, then communication between the nerve cells in the brain also falters.
Method to test drugs
Kasri: “Khondrion is investigating the drug sonlicromanol as a possible treatment for MELAS. We added this drug to three cultured mini-brains from three different patients. In another article in Stem Cell Reports we wrote that in two out of three mini-brains 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 rhythm. In this way, it may be possible to determine which people can benefit from treatment. Often, only part of the patients responds well to a drug. If you can determine who they are in advance, that is extremely valuable.”
Solving puzzles
The mini-brains are also very suitable for improving our understanding of the underlying disease mechanisms. After all, the networks formed by cultured brain cells consist of the same hereditary material (DNA) as that in the skin or blood cells of the patient they were taken from.
It is known that people who suffer from Koolen-de Vries syndrome, named after two researchers at Radboud university medical center, lack the KANSL1 gene or have mutations in that gene. But it is still unknown how this genetic variant leads to mild to moderate intellectual disabilities and other symptoms of the syndrome. That puzzle has now been solved by research that Kasri published in the journal Autophagy with colleagues Katrin Linda, David Koolen, Bert de Vries and others.
Gone is gone
The researchers showed that the KANSL1 gene plays an important role in autophagy. That is the process in which a cell breaks down proteins and uses the remaining fragments to make new proteins. If KANSL1 is missing or does not work correctly, then these proteins are not recycled and reused effectively. This creates more and more waste that accumulates in the brain cells, which causes them to function poorly or die. This is problematic because people do not create any new nerve cells during their lifetimes. When these cells are gone, they are not replaced.
Research into potential treatment
“Much of the damage to the brain cells in people with Koolen-de Vries syndrome is caused by oxidants,” says Kasri. “We can greatly reduce that damage in our mini-brains with antioxidants. This is an important starting point for further research and could potentially become a treatment in the long term.
In addition, we think that autophagy may play a role in other developmental disorders and intellectual disabilities. There are several other genes that, together with KANSL1, are responsible for that recycling process in brain cells. If these genes don't work correctly, they might cause similar problems.
Biological twins?
The recently published articles illustrate the interesting perspectives of mini-brains for new and innovative brain research. In a sense, mini-brains and other 2D and 3D cultured biological models are a sort of biological twins, comparable to the digital twins in the computer world. These are virtual copies (digital twin) or computer models that act as counterparts to physical objects or processes.
By operating and modifying such digital twins, new insights can quickly arise that can be tested in ‘real life’. Perhaps mini-organs, organs-on-chips and organoids can be developed into biologically useful copies that will help to enhance individualised medicine. The potential of this new approach is underlined by the recent decision of ZonMw to allocate 4 million euros to the BRAINMODEL project, of which Nael Nadif Kasri is co-initiator.
A TV news segment, available on the NOS website, reported on this study. Read here how a cultured mini-brain revealed disruptions in neurological communication.
Image: Pixabay