Turning Skin Cells into Brain Cells for Research

Imagine watching a human brain grow and develop in real-time. This may sound like science fiction, however, new advances have made this possible. In recent years, researchers have discovered that accessible cell types, such as skin cells, may be transformed into brain cells and even small pieces of brain-like tissue (Sloan et al. 2018). This has revolutionized how researchers can approach questions about human brain development and the role of human genetics in neurological disorders. 

There are many challenges to researching the living human brain at the molecular level. Imaging studies may be performed to examine brain function and activity. However, to examine the brain at the molecular level, researchers typically rely on invasive techniques to collect human brain tissue. This tissue must be extracted during invasive brain surgery or post-mortem. Therefore, researchers have typically relied on model organisms such as mice, fruit flies, and zebrafish to answer their questions about neural development and neurological disorders. While model organisms are advantageous for certain research questions, human brain models allow for new molecular insights that are relevant for individuals with neurological disease.

To create brain cells, the researcher uses a sample of human donor cells that are relatively easy to access, such as blood cells, skin cells, or muscle cells. The people donating these cells know that their cells are going toward research and provide consent to provide samples. Once in the lab, specific gene changes are induced to “reprogram” these cells. This reprogramming causes the cells to revert to an embryonic-like state. After reprogramming, the cells are pluripotent, meaning they can be manipulated into becoming any cell type in the human body (e.g., heart cells, lung cells, pancreas cells, etc.).

In order to transform these cells into brain cells, specific biochemical factors are added to mimic what the cells would experience during fetal development. As a result, multiple types of brain cells can be created depending on the specific biochemical factors added and the duration and concentration of the biochemical factors used. This process can make different types of brain cells, such as neurons, astrocytes, and neural precursor cells. Additionally, the cells can be clumped together during the process, resulting in a 3D spherical mass of brain cells called neural organoids. This sphere of cells develops a network of different brain cells resulting in a patient-derived model of the human brain.

These 3D human brain models give researchers a chance to examine human brain development up close. Peering inside the spherical mass of brain cells, the researcher can observe the electrically active cells and watch as the network of cells communicate with each other as they would in the human brain. This can give researchers insight into how cell-to-cell communication can be altered in neurological disorders. Additionally, these 3D human brain models can survive for months or even years. This allows researchers to examine later points of human development, which is currently not possible with other brain models and techniques. This exciting advancement allows researchers to uncover differences in how the human brain develops, to further examine the role of genetics in human brain development and may help to identify new patient-relevant therapeutics for neurological disorders.

This type of innovative research is happening right here at the University of Manitoba. One such researcher is ENRRICH member Dr. Galen Wright. The Wright Lab at the PrairieNeuro Research Centre uses 3D human brain models to examine a rare neurodevelopmental disorder called Rett syndrome. As a graduate student in the Wright lab, I create Rett syndrome 3D brain models to examine how altering certain genes impacts brain development in Rett syndrome. We hope that by understanding the role of genetics in Rett syndrome, new therapeutics options may be identified.

I chose to pursue my doctoral studies at the Wright lab as I fascinated by this innovative technique. I was excited to hear of the opportunity to work with personalized human brain cells as I felt it aligned well with my research interests. My main research interest is understanding how genetics and environment influence treatment options for specific individuals. Many individuals may have the same neurological disorder but may respond differently to various treatment options. The use of personalized human models allows researchers to better understand and identify these differences, therefore creating more effective treatment options for more individuals. While I began my research working with 2D human brain cells, I found my research questions may be better addressed with a 3D model. As a result of this curiosity, I was fortunate to be chosen for the 2023 Brain Organogenesis Program at Stanford University. This program taught me how to create these 3D brain models and how I may use them to answer my research questions. I hope to share this knowledge with other researchers in Manitoba to make this technique more accessible to the community.

The Wright lab is currently collaborating with other University of Manitoba researchers to expand the use of this technique in Manitoba. Thanks to the generosity of the Children’s Hospital Research Institute of Manitoba, the Wright lab is creating a local platform to use 3D human brain models to investigate neurodevelopmental disorders. It is our hope that these models and this exciting technology will become widely used methods for brain research to support a better understanding of neurodevelopment, brain health and disease, and the development of future therapeutics.

• References

  Sloan SA, Andersen J, Pașca AM, Birey F, Pașca SP. Generation and assembly of human brain region-specific three-dimensional cultures. Nat Protoc. 2018 Sep;13(9):2062-2085. doi: 10.1038/s41596-018-0032-7. PMID: 30202107; PMCID: PMC6597009.

Published Jan 2, 2025

About the Author

Alana Slike is a PhD student in Dr. Galen Wright's lab at the Kleysen Institute for Advanced Medicine. Alana completed her undergraduate studies at the University of Winnipeg with a B.Sc. Hons. in Neuroscience. She is currently pursuing a MSc at the University of Manitoba in the Department of Pharmacology and Therapeutics. For her MSc project, she is investigating FAN1, a gene implicated in DNA damage repair, as a genetic modifier in the neurodevelopmental disorder Rett syndrome.