Tiny models for big questions: Growing mini brains to understand schizophrenia

For decades, scientists have studied human cells in 2 dimensions – cells were grown as a single flat layer on a clear plastic surface, which allowed for easy observation by microscopy. However, cells in the human body are organized in 3 dimensions (3D), and the 3D connections between cells have a huge influence on cell behaviour and the development of organs with specific functions. Knowing the importance of these 3D connections, scientists have developed new 3D human cell culture models – mini organ-like clumps of cells known as organoids. Organoids are 3D tissue structures grown in labs from stem cells – unspecialized cells that become specialized to make up all the parts of your body. The stem cells are grown under specific conditions that cause them to organize and develop into tiny models of a human organ, like a liver, skin, or mini brain (cool, right? Check out this TED-Ed video for a quick 101 https://www.youtube.com/watch?v=s_LxZx42sIk).

The human brain is notoriously difficult to study, so researchers have had to rely on methods like animal models and brain imaging. However, many questions remain unanswerable with current techniques – especially those that are uniquely human, like disorders of the brain and mind. Scientists are now using organoids to study aspects of the human brain and its diseases that were never before possible. In a recently published study, researchers investigated schizophrenia, a severe and often disabling mental illness where people experience delusions, hallucinations or disorganized speech and may appear to lose touch with reality. This complex psychiatric disorder is thought to begin early in human development, based on the malformations observed in brains of schizophrenia patients – these malformations likely arise during the development of brain structure in utero (i.e. when a baby is growing in the womb).

In this study, the researchers grew organoids using stem cells from schizophrenia patients and control people (no schizophrenia diagnosis). The general development of the control and schizophrenia organoids appeared similar, but there were big differences upon closer inspection. There were distinct layers in the control organoids that were absent in the schizophrenia organoids (Fig 1), and moreover, the maturation of neurons in the cortex was impaired and the formation of the cortex was blocked in the schizophrenia organoids. The cortex is the outermost layer of the brain, responsible for performing all those cognitive functions that make us human (e.g. consciousness, memory, language).

To gain more insight, the researchers then studied a protein (a worker in the cell) that has a key role in orchestrating development of the body and brain. The amount of this protein present in the cortex was drastically reduced in the schizophrenia organoids compared to the control organoids. They then found that if they treated growing control organoids with a drug that blocked this protein from performing its job, the control organoids developed similar abnormal characteristics to those seen in the schizophrenia organoids.

This study provides evidence for in utero programming of schizophrenia and identifies one particular protein as a likely key player in its origins in early development. A problem with this key protein may explain the malformations seen in brains of schizophrenia patients, and has implications for potential preventative measures in the future (of course, after much more research). This is a significant contribution to work on schizophrenia, and is also a fantastic illustration of the exciting possibilities organoids hold for science.


Figure 1: Control and schizophrenia mini brains at 2 weeks of development. Images show cross-sections of the organoids, and each dot/squiggle is a cell. Distinct layers can be seen in the control organoid, but they appear disorganized in the schizophrenia organoid. Red = young dividing neural cells (i.e. developing brain cells), green = mature neurons (i.e. functional brain cells), blue highlights other cells present. CZ = cortical zone or cortex. Mature neurons form the cortex (outermost layer of the brain) of the control organoid, but the same area of the schizophrenia organoid lacks mature neurons. (VZ = ventricular zone, IZ = intermediate zone)

Summary written by: Camille Cassel de Camps

To read the full article, please click the following link:

Cerebral organoids reveal early cortical maldevelopment in schizophrenia—computational anatomy and genomics, role of FGFR1

E. K. Stachowiak, C. A. Benson, S. T. Narla, A. Dimitri, L. E. Bayona Chuye, S. Dhiman, K. Harikrishnan, S. Elahi, D. Freedman, K. J. Brennand, P. Sarder,  M. K. Stachowiak

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