Organoids: the new technique for creating a brain

Doctor of Biomedicine Pablo Barrecheguren explains the role of organoids as one of the major techniques in biomedical research.

One of the greatest obstacles facing neuroscience is the difficulty of obtaining in vivo information from a human brain.

There are certainly techniques, such as functional magnetic resonance imaging or intracranial electrode implantation, that allow us to obtain information about brain activity…, but the real challenge is at the molecular level: being able to analyze cellular development and interconnection as it occurs, since until right now the possibilities have mostly been limited to post mortem studies or cell cultures whose results often cannot be extrapolated to the behavior of a human brain as a whole. To address this problem, one of the best options is brain organoids.

Brain organoids

What organoids are

Organoids are self-assembled cellular aggregates formed from stem cells, and their main characteristic is that to some extent they reproduce the architecture and cellular composition of the organ they are intended to model.

Initially one of the research fields was the creation of organoids that reproduced intestinal epithelia, but currently the technique has expanded to other organs, with brain organoids being one of the most interesting areas.

Methods of producing organoids

There are two main ways to produce them:

1. Unguided techniques: start from human pluripotent stem cells that are cultured in vitro limiting as much as possible the use of external biochemical signals that direct growth. This leads to great variability that in some cases results in the formation of organoids with a cellular composition quite similar to that of a developing human brain.
2. Guided techniques: start from the same basis but involve greater intervention in the development of the organoid through the use of biomolecules. This results in the production of much more specific organoids, which have cellular compositions that mimic those of particular parts of a developing human brain.

In general, these organoids manage to reproduce, to a certain extent, the cellular and structural composition of a human brain. Additionally, gene expression analysis data of these organoids as a whole partially match those of a developing human brain.

Limitations of these models

However, it should be remembered that these models still have several very important limitations, for example:

• Organoids are of a very small size. They are approximately 4 mm in size while the human cerebral cortex alone is around 15 cm in diameter. From this situation arise many structural differences that separate an organoid from a human brain.
• They do not develop any vasculature. Brain organoids do not have blood vessels per se, and even when cultured together with epithelial cells it has not been possible to create functional capillaries within the tissue. The lack of blood vessels is already a major structural difference in itself, but it also creates an additional problem: the organoid can only acquire nutrients through its outer surface, which causes, once it reaches a certain growth point, the cells in the deepest parts of the organoid to develop necrosis due to lack of nourishment.
• The cells of the organoid reproduce the cellular state of a developing brain, so the information they can give us about an adult or even elderly brain is limited.

Important technique in biomedical research

However, despite all these limitations, organoids are emerging as one of the major techniques in biomedical research for three reasons.

• First, it should be noted that they are made from pluripotent stem cells, and that currently this cell type can be obtained directly or from adult cells that are then reprogrammed in the laboratory (for example using a sample of blood cells, which are subsequently reprogrammed to become what are known as induced pluripotent stem cells). This has made it possible to create organoids that reproduce congenital malformations such as microcephaly, or organoids are even used together with viral cultures to investigate the neuronal effects of the Zika virus.
• Second, these models serve to study brain development, and there are clinical conditions such as schizophrenia or autism spectrum disorders that are already being studied.
• And third, brain organoids from other animals can be created, which facilitates carrying out evolutionary studies comparing different species.

Currently brain organoids are very valuable research tools and studies that combine them with other techniques have great potential.

However, when reading published papers on this area one must never forget that they are an experimental model and, no matter how much they are called “miniature brains”, they also have many essential differences from an adult human brain.

Bibliography

• Elizabeth Di Lullo and Arnold R. Kriegstein. The use of brain organoids to investigate neural development and disease. Nat Rev Neurosci. 2017 October; 18(10): 573–584
• Harpreet Setia, Alysson R. Muotri. Brain organoids as a model system for human neurodevelopment and disease. Seminars in Cell and Developmental Biology (2019)
• Xuyu Qian, Hongjun Song and Guo-li Ming. Brain organoids: advances, applications and challenges. Development (2019) 146, dev166074

“This article has been translated. Link to the original article in Spanish:”
Organoides: la nueva técnica para fabricar un cerebro