MQ-funded researcher Dr Sergiu Pasca has created 3D brain circuits ‘in a dish’ for the first time with the hope that it will tell us more about the causes of schizophrenia. But how did he do this? And what does it mean for understanding mental illness? PhD student Sam Crossman explains.
When an architect is designing a new building, it is often the earliest stages that prove to be the most critical. If the plans aren’t sufficiently detailed and the foundations aren’t laid in the correct place, the final structure that is made will never be fully functional. The same principle holds true for the brain as it grows and develops in the mother’s womb. When errors occur in these crucial early stages of development, the brain is unable to reach its full capacity and this can cause problems later in life.
This situation poses a tricky problem for mental health researchers. We know that many mental illnesses have their roots in the developing foetus but ethically it isn’t possible to look at human tissues at these stages. Other methods, like looking at the brain posthumously and studying animal models provides some fascinating insight but leaves gaps in our knowledge when we try to apply our findings back to humans.
In recent years, researchers have sought to fill these gaps by growing human tissues in a lab. Whilst these tissues, known as organoids, might sound like the stuff of science fiction, they actually sit at the forefront of modern research and are allowing scientists to gain insight into the earliest stages of human development in unprecedented detail. That’s why when MQ-funded researcher Dr Sergiu Pasca was able to create the most elaborate model of lab-grown human brain tissue – in a paper that was recently published in leading journal Nature - it offered a breakthrough for understanding the brain and also, how mental illness might develop.
The starting material used when engineering an organoid is a stem cell and it is important to know a little about stem cells and how they function if you are to understand Sergiu’s study. Stem cells are unusual cells that are unique in their ability to divide and give rise to any tissue in the body. Think of stem cells as fresh-faced students starting their first year of school. At this age you could go on to be a mathematician, a beautician, a lawyer or a chef – the possibilities are endless. Compare this to a 55-year-old accountant, who will find it much harder to change his mind and forge a successful career in another profession. The stem cell is like the young student that can go on to do whatever it likes, whereas most of our cells have committed to a speciality and are no longer able to change their mind so easily. A single stem cell can be convinced to develop into all different types of cells, from flat skin cells to doughnut-shaped blood cells – and, importantly for Sergiu, brain cells. (figure 1).
To make their organoids Dr Pasca’s team took stem cells and fed them a rich broth to provide them with the nutrients required for growth. By tweaking their recipe they were able to generate organoids that resembled two different brain regions - one that sits towards the centre of the brain and one that occupies the outer surface. It is known that cells from the inner regions invade and infiltrate the outer regions during development and this process is essential for healthy brain function. Using their organoid model, the researchers were able to record this ‘migration’ process for the first time in living human tissues – watching the cells communicate and fuse together. (figure. 2).
The videos that were made revealed an unexpected finding. As the cells migrated from one region to the other, they didn’t crawl along as one might expect but instead hopped and jumped throughout the tissue. Moreover, when researchers investigated organoids derived from people living with the rare genetic disorder Timothy syndrome, which is strongly linked with autism and epilepsy, they saw that this process was disrupted and the migration occurred much less efficiently. The abnormal behaviour of these organoids suggests a potential explanation for some of the symptoms associated with the condition.
This study beautifully demonstrates two of the concepts that make organoid research so exciting. Even though lab-grown systems remain a long way from reproducing the complexity of a fully-functioning human brain, they do provide a fascinating picture of the early stages of development that are simply inaccessible when using traditional techniques.
This enhanced understanding means we can delve into the intrisicies of how the brain develops. Sergiu’s next steps are to take the stem cells from people living with mental illnesses, offering a unique opportunity to see how mental illnesses could first occur – and providing the important first step for creating better treatments.
Last updated: 28 May 2017