Modeling the Brain in a Dish: What Stem Cells Can Teach Us About Brain Development and Disorders

Image of human stem-cell derived excitatory neurons courtesy of Xiaoting Zhou.

The human brain is one of the most complex organs in the body, made of billions of cells that form trillions of connections with one another – all wired together in a way that allow us to think, feel, walk, talk, and even to read the words on this page[1]. It’s easy to forget that the whole human brain forms from a handful of cells early in development. These starting cells, known as stem cells, are able to make any other kind of cell in the human body.

So, how does the entire human brain form from a couple stem cells? And what happens if something in that process goes wrong? Researchers studying the human brain are restricted in the tissue samples available to them – people can’t donate their brain cells the same way they can donate blood. To overcome this limitation, brain cells can now be generated from stem cells in a laboratory setting, allowing scientists to get a close-up look at human brain development in a dish.

Image of a 1-month-old brain organoid courtesy of Linda Boshans Lee.

A Nobel Prize-winning discovery in 2012 enabled researchers to turn any ‘mature’ human cell type, such as skin or blood cells, back into a stem cell-state, known as induced-pluripotent stem cells (iPSCs)[2]. Since then, researchers have identified key factors that can turn stem cells into a variety of brain cell types, including different kinds of neurons,[3,4] and support cells in the brain, such as astrocytes[5] and microglia[6]  in as little as three weeks. These stem cells can also be turned into ‘mini-brains’ known as organoids that contain many different cell types and develop over the course of several months[7].

Human stem cell models of the brain allow researchers to better understand the cellular processes involved in normal development, as well as the mechanisms that go wrong in neurodevelopmental, psychiatric, or neurodegenerative disorders such as autism, schizophrenia, or Alzheimer’s Disease. Mutations in hundreds of different genes are involved in these conditions, and each one can be introduced into stem cell models to see how they affect brain cell function[8]. For example, a recent study mutated three genes thought to contribute to Autism in human stem cells, and then formed brain organoids and saw abnormal development of specific kinds of neurons[9].

Another way researchers have used stem cell models to study brain disorders is to compare neurons in a dish generated from people with or without a specific disorder. For example, stem cell-based neurons from a group of people with schizophrenia had trouble forming proper connections[10], and neurons in a dish from a group of people with bipolar disorder were sending messages to each other more often than normal11. Some of the differences in patient neurons were helped by treating the cells with medications commonly given to individuals with schizophrenia or bipolar disorder[10,11]. In general, human stem cell models will allow researchers to better understand the processes that go wrong in human disorders such as autism, schizophrenia, and bipolar disorder, enabling the design of better treatments for the people living with these conditions.

1. von Bartheld, C. S., Bahney, J. & Herculano-Houzel, S. The search for true numbers of neurons and glial cells in the human brain: A review of 150 years of cell counting: Quantifying neurons and glia in human brain. J. Comp. Neurol. 524, 3865–3895 (2016).

2. Takahashi, K. et al. Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors. Cell 131, 861–872 (2007).

3. Zhang, Y. et al. Rapid Single-Step Induction of Functional Neurons from Human Pluripotent Stem Cells. Neuron 78, 785–798 (2013).

4. Yang, N. et al. Generation of pure GABAergic neurons by transcription factor programming. Nat Methods 14, 621–628 (2017).

5. Tcw, J. et al. An Efficient Platform for Astrocyte Differentiation from Human Induced Pluripotent Stem Cells. Stem Cell Reports 9, 600–614 (2017).

6. Speicher, A. M., Wiendl, H., Meuth, S. G. & Pawlowski, M. Generating microglia from human pluripotent stem cells: novel in vitro models for the study of neurodegeneration. Mol Neurodegeneration 14, 46 (2019).

7. Benito-Kwiecinski, S. & Lancaster, M. A. Brain Organoids: Human Neurodevelopment in a Dish. Cold Spring Harb Perspect Biol 12, a035709 (2020).

8. Hoffman, G. E., Schrode, N., Flaherty, E. & Brennand, K. J. New considerations for hiPSC-based models of neuropsychiatric disorders. Mol Psychiatry 24, 49–66 (2019).

9. Paulsen, B. et al. Autism genes converge on asynchronous development of shared neuron classes. Nature 602, 268–273 (2022).

10. Brennand, K. J. et al. Modelling schizophrenia using human induced pluripotent stem cells. Nature 473, 221–225 (2011).

11. The Pharmacogenomics of Bipolar Disorder Study et al. Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder. Nature 527, 95–99 (2015).