Brain organoid: definition, how they are made and what they are used for

A brain organoid is a three-dimensional piece of neural tissue grown from human pluripotent stem cells that self-organizes into structures resembling parts of the developing brain. Usually a few millimeters across, brain organoids contain neurons and glial cells, produce electrical activity, and are used to study development, disease and biological computing.

Key takeaways

• Brain organoids are grown from embryonic stem cells or induced pluripotent stem cells (iPSCs).
• Lancaster et al. described cerebral organoids in Nature (2013) and used them to model microcephaly.
• Organoids resemble early fetal brain tissue, not an adult brain, and they lack blood vessels and sensory input.
• Their electrical activity can be recorded on a microelectrode array, which makes them the main substrate for organoid intelligence.
• Key limitations are size, variability between batches, cell stress, and incomplete maturation.

What is a brain organoid? #

An organoid is a small 3D tissue that forms when stem cells are given the right signals and allowed to organize themselves. Organoids have been grown for the gut, kidney, liver and other organs. A brain organoid is the neural version: stem cells become neural progenitors, which divide and give rise to neurons and supporting cells arranged in layered zones similar to those of the embryonic cortex.

Several names are in use. “Cerebral organoid” usually refers to the broadly patterned tissue from the Lancaster protocol. “Cortical organoid” or “cortical spheroid” refers to tissue directed toward the cerebral cortex, as in the 3D cultures described by Pasca et al. in Nature Methods (2015). “Mini-brain” appears in the press but overstates what organoids are.

How are brain organoids made? #

The process differs between labs, but the main stages are similar. Our guide how brain organoids are grown covers them step by step.

1. Start with pluripotent stem cells. Human embryonic stem cells or iPSCs, reprogrammed from adult cells such as skin or blood, are expanded in culture.
2. Form aggregates. Cells are clustered into small 3D balls called embryoid bodies or spheroids.
3. Induce neural fate. Growth factors and small molecules push the cells toward neural tissue. Eiraku et al. showed in Cell Stem Cell (2008) that stem cells can self-organize into polarized cortical tissue under such conditions.
4. Provide a scaffold and movement. Many protocols embed aggregates in a gel matrix and move them to spinning or shaking culture to improve nutrient exchange.
5. Mature over months. Neurons form connections, astrocytes appear, and network activity develops.

Guided vs unguided protocols #

Unguided protocols, like the original cerebral organoid method, let tissue develop multiple brain-region identities with minimal patterning. Guided protocols add specific signals to produce a chosen region, which tends to improve consistency. Region-specific organoids can be fused into assembloids to study how brain regions connect.

Brain organoid vs other neural models #

Organoids fill a gap: they are living, human and three-dimensional, though far simpler than a real brain.

Do brain organoids have electrical activity? #

Yes. Neurons in organoids fire action potentials and form synapses, and their networks develop coordinated network bursts. Trujillo et al. reported in Cell Stem Cell (2019) that cortical organoids recorded over months developed increasingly complex oscillatory activity, which they compared with features of preterm infant EEG. Recording this activity is the domain of electrophysiology, usually on standard or high-density microelectrode arrays.

How are brain organoids used in research? #

Brain organoids first drew wide attention as disease models. Lancaster et al. (2013) grew cerebral organoids from the cells of a patient with microcephaly, a condition in which the brain is abnormally small, and reported that the patient-derived organoids were smaller and showed premature neural differentiation compared with controls. That study showed organoids could reveal human-specific aspects of development that mouse models had missed.

Since then, uses have broadened:

• Developmental biology, to study how cortical layers and cell types emerge.
• Disease modeling, using cells from donors with genetic conditions.
• Drug and toxicity testing, in human tissue rather than animal tissue.
• Sensory circuits. Quadrato et al. reported in Nature (2017) that some long-cultured organoids developed photosensitive cells and that their neural activity could respond to light.
• Biocomputing, discussed below.

Why do brain organoids matter for biocomputing? #

Organoid intelligence relies on brain organoids as its hardware. Compared with flat cultures, organoids hold many more cells, more cell types and more complex 3D connectivity, which researchers hope will support richer computation. Cai et al. used a brain organoid as the core of a reservoir computing system in Nature Electronics (2023), and closed-loop learning experiments in neural cultures, such as DishBrain, motivate similar work in organoids. See what is organoid intelligence for the wider context.

What are the limitations of brain organoids? #

• Size and necrosis. Without blood vessels, oxygen must diffuse inward, so organoid cores can become stressed or die. Mansour et al. (2018) showed that organoids transplanted into mouse brains became vascularized, and organoid vascularization in vitro remains an active goal.
• Variability. Organoids can differ between batches and cell lines. Velasco et al. reported in Nature (2019) that a guided dorsal forebrain protocol produced organoids with reproducible cell diversity, showing the problem can be reduced.
• Cell stress. Bhaduri et al. reported in Nature (2020) that cortical organoids show elevated cell stress that impairs how neurons acquire their specific subtype identities, compared with the developing human cortex.
• Immaturity. Organoids resemble fetal tissue and lack the inputs that shape a mature brain.
• Interface. Flat electrodes reach only the surface of a 3D tissue.

What are the ethical questions around brain organoids? #

Brain organoids raise questions about donor consent for the cells used, about the ownership and sharing of data, and, as organoids become more complex, about whether any morally relevant capacities could emerge. The Baltimore declaration (Hartung et al., 2023) recommended that ethics be built into organoid intelligence research. Read more in the ethics of organoid intelligence and on our ethics page.

Brain organoids are the living layer of the stack we are building software for at Organoid Programming.

Frequently asked questions

Are brain organoids actual brains?

No. Brain organoids are millimeter-scale tissues that resemble parts of the developing human brain, often the cortex, at an early fetal stage. They lack blood vessels, sensory input, a body, and the large-scale wiring of a real brain. The popular term ‘mini-brain’ is misleading; researchers prefer ‘brain organoid’, ‘cerebral organoid’ or ‘neural organoid’.

How long does it take to grow a brain organoid?

Neural tissue begins forming within the first weeks of a protocol, but organoids keep maturing for months. Electrical network activity typically becomes more complex over time; Trujillo et al. (2019) tracked cortical organoids for many months and reported increasingly structured oscillatory activity. Exact timelines depend on the protocol and the research question.

How big is a brain organoid?

Most brain organoids grow to a few millimeters in diameter. Growth is limited because they have no blood supply, so oxygen and nutrients must diffuse in from the surrounding medium. Cells deep inside large organoids can become stressed or die, which is why researchers are developing vascularization and microfluidic culture methods.

Can brain organoids feel pain or think?

There is no evidence that current brain organoids feel pain or have thoughts. They lack pain receptors, sensory organs and the brain-wide circuits associated with awareness. Because organoids are becoming more complex, ethicists recommend ongoing review of how they are made and used, and the Baltimore declaration (2023) called for ethics to be embedded in organoid intelligence research.

What are brain organoids used for?

Brain organoids are used to study human brain development, to model neurological and neurodevelopmental disorders with patient-derived cells, to test drugs and toxic compounds, and, more recently, as substrates for biocomputing research known as organoid intelligence. Their value comes from being human tissue with some three-dimensional structure, which animal models and flat cultures cannot fully provide.

Sources

1. Lancaster et al. (2013). Cerebral organoids model human brain development and microcephaly. Nature.
2. Eiraku et al. (2008). Self-organized formation of polarized cortical tissues from ESCs and its active manipulation by extrinsic signals. Cell Stem Cell.
3. Pasca et al. (2015). Functional cortical neurons and astrocytes from human pluripotent stem cells in 3D culture. Nature Methods.
4. Trujillo et al. (2019). Complex oscillatory waves emerging from cortical organoids model early human brain network development. Cell Stem Cell.
5. Velasco et al. (2019). Individual brain organoids reproducibly form cell diversity of the human cerebral cortex. Nature.
6. Bhaduri et al. (2020). Cell stress in cortical organoids impairs molecular subtype specification. Nature.
7. Mansour et al. (2018). An in vivo model of functional and vascularized human brain organoids. Nature Biotechnology.
8. Quadrato et al. (2017). Cell diversity and network dynamics in photosensitive human brain organoids. Nature.
9. Hartung et al. (2023). The Baltimore declaration toward the exploration of organoid intelligence. Frontiers in Science.