Author: Brina Stančič
In my previous blog post, I have written about the importance of communication in the brain and the attempts of the neuroscientific community to restore it when damaged. While saving lives is of uttermost importance, designing therapies without knowing the brain is like building a house without foundation.
So, do we have the foundation? Do we really understand the human brain in all its complexity?
A mouse is a mouse and a human is a human
The answer is: not enough. The human brain is very complex and very mysterious. Compared to many other mammals, it is largely expanded and extensively folded. This uniqueness suggests humans as the only accurate model for the job. But just thinking about invasively studying a human embryo inside the womb seems a monstrous idea. Due to the ethical concerns, non-invasive techniques are widely used to visualize the developing fetal brain. Nevertheless, they do not allow a resolution that would help us understand it.
Since studying the living human brain is impossible, brains of laboratory animals have been studied instead. It is not surprising that most of our knowledge about the human brain comes from another species: the mouse. Despite the similarities in the structure of human and mouse brains, these two species followed different evolutionary paths, adapting the brains for their respective lifestyles. This reflects in large differences in the brain development (Figure 1), which explains why animal models can only partially recapitulate human biology and cognitive function. Also, some of the most prominent neuropsychiatric or neurodevelopmental diseases are uniquely human and cannot be replicated in animals. And even if we achieve to mimic them, cures in animal models don’t always translate into cures for humans. While they have helped us to understand the fundamental mechanisms, animal models have left us with many unanswered questions. A model with inherent human peculiarities is therefore needed.
Figure 1. So similar, yet so different. Compared to the brain cortex of the mouse, the human cortex is over 1,000 times larger by area and number of neurons. Importantly, its surface is largely folded, while the surface of the mouse brain is smooth.
Isolated human neurons that grow in two dimensions (2D) on flat dishes represent an alternative that takes into account the human factor (Figure 2). But as with movies, videogames and life in general, cellular world also exists in three dimensions (3D). Neurons in the brain have a specific microenvironment, as they are surrounded by other cells and extracellular matrix, a 3D network of macromolecules and minerals. In order to study the human brain, this environment has to be as accurately replicated as possible. And this can only be achieved by adding the third dimension.
How can we do that?
Figure 2. 2D vs 3D. 3D cell culture environment allows cell-cell and cell-extracellular matrix interactions, enabling proper structural architecture and function of normal tissues.
Mini organs: science fiction or reality?
As described in previous blog posts, stem cells can divide indefinitely and produce different cell types. By creating the right environment, they can follow their own genetic instructions to self-organize, forming tiny 3D tissue structures that resemble cell types, structure and function of miniature organs. These simplified organ tissues are called organoids. Depending on the stem cell type and the environment, they can form organoids that resemble the brain, kidney, lung, intestine, stomach, and liver.
By exposing stem cells to a specific mix of nutrients and giving them support of a protein gel, called Matrigel, brain organoids were generated for the first time in 2008. They look like a pea-sized piece of white tissue that you can visualize with the naked eye (Figure 3). They are kept floating in a reddish liquid that contains all the nutrients, which allows them to survive for weeks, months and even years. They can grow to about 4 millimeters, which is the size of an embryonic human brain at roughly nine weeks. While simple on the outside, on the inside they contain thousands of cells of multiple brain cell types that interact with each other in complex ways. Excitingly, they also exhibit functional neurons capable of electrical excitation, as well as coordinated waves of electrical activity. Popularly known as mini brains, they faithfully replicate several aspects of human brain development and the anatomic structure of the fetal human brain. Excitingly, the internal clock of their maturation in a laboratory environment is strikingly similar to the timeline of human brain development.
Is it all as perfect as it sounds?
Of course not. Even though they are known as mini brains, they only consist of 2.5 million neurons, compared to 86 billion neurons in the human brain. They lack non-neural cell types, such as immune cells; blood supply, which is needed to keep them nourished and healthy; as well as sensory input, input from other parts of the brain and other body tissues. Despite these limitations, they offer an obvious advantage over the existing models and methods for studying the human brain.
Figure 3. Simple, yet complex. Human brain organoids are tiny, off-white globules that resemble misshapen marbles just milimeters in diameter. On the inside, they consist of rapidly dividing proliferative zones (red) and their final result, neurons (green).
Mini brains for maxi discoveries
Brain organoids give unprecedented insights into the development of the human brain, which is impossible to study as a human embryo develops. Importantly, they offer a way to understand uniquely human conditions, which cannot be recapitulated in mouse models. So far, human neurological and neurodevelopmental disorders, such as epilepsy, schizophrenia, autism spectrum disorders and microcephaly caused by the Zika virus have already been modeled in brain organoids. Not only do they open a window for improved understanding of these detrimental diseases, they also give us the opportunity to see how drugs interact with these mini organs. As such, they represent an excellent tool that can revolutionize the field of drug discovery and open new approaches to personalized medicine.
Brain organoids represent the foundation we have been looking for. And it is only a matter of time before we will be able to build houses as well.
References
Chiaradia, I., Lancaster, M.A. Brain organoids for the study of human neurobiology at the interface of in vitro and in vivo. Nat Neurosci 23, 1496–1508 (2020). https://doi.org/10.1038/s41593-020-00730-3
Qian X, Song H, Ming GL. Brain organoids: advances, applications and challenges. Development. 2019;146(8):dev166074. Published 2019 Apr 16. doi:10.1242/dev.166074
Photo credits
https://sciwri.club/archives/4291
Rakic, P. Evolution of the neocortex: a perspective from developmental biology. Nat Rev Neurosci 10, 724–735 (2009). https://doi.org/10.1038/nrn2719
Chiaradia, I., Lancaster, M.A. Brain organoids for the study of human neurobiology at the interface of in vitro and in vivo. Nat Neurosci 23, 1496–1508 (2020). https://doi.org/10.1038/s41593-020-00730-3
https://www.eurekalert.org/multimedia/644257
https://www.spectrumnews.org/news/toolbox/new-method-probes-genes-function-in-brain-organoids/