Target Health Blog

Brain Waves Detected in Mini-Brains Grown in a Dish

September 23, 2019


This flow chart outlines the basic steps to create a cerebral organoid. The process takes a span of months and the size of the organoid is limited by the availability of nutrients. Graphic credit: by keval_tilva - Own work, CC BY-SA 3.0,

The human brain is an extremely complex system of heterogeneous tissues and consists of an extremely diverse array of neurons. This complexity has made studying the brain and understanding how it works a difficult task in neuroscience, especially when it comes to neurodegenerative diseases.

A cerebral organoid, or brain organoid, describes artificially grown, in vitro, miniature organs resembling the 1) ___. Cerebral organoids are created by culturing human pluripotent stem cells in a three-dimensional rotational bioreactor and develop over a course of months. The purpose of creating an in vitro neurological model is to study these diseases in a more simple and variable space; free of in vivo limitations, especially when working with humans. The varying physiology between human and other mammalian models limits the scope of study in neurological disorders. Cerebral organoids are synthesized tissues that contain several types of nerve 2) ___ and have anatomical features that resemble mammalian brains. Cerebral organoids are most similar to layers of neurons called the cortex and choroid plexus. In some cases, structures similar to the retina, meninges and hippocampus can form.

Stem cells have the potential to grow into many different types of tissues and their fate is dependent on many factors. To make an organoid, an embryoid (tissue that has some embryonic features) grown from natural stem cells is used. Embryos have three layers: 3) ___, mesoderm and ectoderm. Each turns into various body parts. The nervous system grows from the ectoderm (which also contributes dental enamel and the epidermis). 4) ___ cells were placed into gel droplets and floated in a nutrient broth in a rotating bioreactor, which supported cell growth without forming by the container. After ten days the organoid developed neurons. After 30 days it displayed regions similar to parts of brains. Lacking a blood supply, cerebral organoids reach about 4 mm across and can last a year or more. The general procedure can be broken down into 5 steps. First human pluripotent stem cells are cultured. They are then allowed to cultivate into an embryoid body. Next the cell culture is induced to form a neuroectoderm. The neuroectoderm is then grown in a matrigel droplet. The matrigel provides nutrients and the neuroectoderm starts to proliferate and grow. However, the lack of vasculature limits the size the organoid can grow. This has been the major limitation in organoid development, however new methods using a spinning bioreactor have allowed an increase in the availability of nutrients to cells inside the organoid. This last step has been the key breakthrough in organoid development. Spinning 5) ___ have been used increasingly in cell culture and tissue growth applications. The reactor is able to deliver faster cell doubling times, increased cell expansion and increased extra-cellular matrix components when compared to statically cultured cells. 

Scientists have now created miniature brains from stem cells that developed functional neural networks. Despite being a million times smaller than human brains, these lab-grown brains are the first observed to produce brain waves that resemble those of preterm babies. The study, published August 29, 2019, in the journal Cell Stem Cell, could help scientists better understand 6) ___ brain development.

The level of neural activity that researchers are able to create is unprecedented in vitro. This research being conducted at the University of California, San Diego is one step closer to a model that can actually generate these early stages of a sophisticated neural network. The pea-sized brains, called cerebral organoids, are derived from human pluripotent 7) ___ cells. By putting them in culture that mimics the environment of brain development, the stem cells differentiate into different types of brain cells and self-organize into a 3D structure resembling the developing human brain. Scientists have successfully grown organoids with cellular structures similar to those of human brains. However, none of the previous models developed human-like functional neural networks. Networks appear when neurons are mature and become interconnected, and they are essential for most brain activities.

Brain organoids are used for several things, including understand normal human neurodevelopment, disease modeling, brain evolution, drug screening, and even to inform artificial 8) ___. The California research team designed a better procedure to grow stem cells, including optimizing the culture medium formula. These adjustments allowed their organoids to become more mature than previous models. The team grew hundreds of organoids for 10 months and used multi-electrode arrays to monitor their neural activities. The team began to detect bursts of brain waves from organoids at about two months. The signals were sparse and had the same frequency, a pattern seen in very immature human brains. As the organoids continued to grow, they produced brain waves at different frequencies, and the signals appeared more regularly. This suggests the organoids have further developed their neural networks. This is a result of having more functional synapses, and more connections between the neurons. The interactions between neurons contribute to signals at various frequencies.

To compare the brain wave patterns of organoids with those of human brains early in development, the team trained a machine learning algorithm with brain waves recorded from 39 premature babies between six and nine-and-a-half months old. The algorithm was able to predict how many weeks the organoids have developed in culture, which suggests these organoids and human brain share a similar growth trajectory. It's not likely these organoids have mental activities, such as consciousness. The organoid is still a very rudimentary model - with no other brain parts and structures. These brain waves might not have anything to do with activities in real brains. In the future, further research may develop something that is close to the signals in human brains that control behaviors, thoughts, or memory. There is no evidence right now of those attributes.

Looking forward, the team aims to further improve the organoids and use them to understand 9) ___ associated with neural network malfunctioning, such as autism, epilepsy, and schizophrenia. This cutting edge research can help people with neurological conditions by giving them better treatments and better quality of 10) ___. But it's up to us, humans, to decide where the limit is. It might be that the technology is not ready yet, or we don't know how to control the technology. This is the same kind of discussion around CRISPR in babies, and that's why we have ethics committees to represent all parts of society.

Sources:; Authors: Cleber A. Trujillo, Richard Gao, Priscilla D. Negraes, Jing Gu, Justin Buchanan, Sebastian Preissl, Allen Wang, Wei Wu, Gabriel G. Haddad, Isaac A. Chaim, Alain Domissy, Matthieu Vandenberghe, Anna Devor, Gene W. Yeo, Bradley Voytek, Alysson R. Muotri. Complex Oscillatory Waves Emerging from Cortical Organoids Model Early Human Brain Network Development. Cell Stem Cell, 2019; DOI: 10.1016/j.stem.2019.08.002; University of California at San Diego; Wikipedia

ANSWERS: 1) brain; 2) cells; 3) endoderm; 4) Ectodermal; 5) bioreactor; 6) human; 7) stem; 8) intelligence; 9) diseases; 10) life

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