Turning Skin Into Brain

Image Citation: [1]

Written by Thanmay Kumar ‘27

Edited by Thomas Wang ‘26

Could your skin hold the secret to repairing our brain? Earlier this year, scientists at the Massachusetts Institute for Technology may have answered this question in a groundbreaking study where they converted skin cells directly into neurons [2, 3].

One of the reasons that this breakthrough is so important is that neurons are one of the few cells in our body that don’t divide often. Entering cell division would be harmful for the complex structure and connectivity of a mature neuron, so the body prioritizes the functional stability of its neural network over the ability to regenerate [4]. As a result, injuries to the spinal cord and brain, unlike a cut to the skin, are unlikely to heal on their own. However, a promising new field of science, neuroregenerative medicine, focuses on repairing this injured tissue and restoring damaged neurons.

The modern era of regenerative medicine began with the discovery of stem cells in the 1960s. Stem cells are cells that have yet to differentiate into specialized types of cells throughout the body. Substantial developments by the early 2000s allowed researchers to create artificially induced pluripotent stem cells (iPSCs). Essentially, they could reprogram adult somatic cells into a pluripotent state, meaning that they had the ability to differentiate into any specialized cell type that emerges from the embryo [5]. The iPSCs can give rise to the cardiac myocytes that form the heart, photoreceptors in the retina, and beta cells in the pancreas but cannot transform into extra-embryonic tissues such as placental cells.

These iPSCs could be used for personalized regenerative medicine as patient-specific tissues can be regrown that share the same exact genetic makeup as the patient’s own cells. Immune system rejection after transplantation can be avoided while also modeling exact disease mechanisms or drug efficacy in a copy of the patient’s own cells [6]. Researchers and clinicians began using the iPSCs to grow synthetic tissues and even entire organs in the lab to help replace those lost to disease, trauma, or congenital defects.

However, regenerative medicine methodologies for growing synthetic tissues are not without their limitations. A major problem with the traditional iPSC route was its reliance on an inefficient multi-step process. For instance, when studying techniques to regrow nervous tissues, skin cells were first reprogrammed into iPSC cells and then re-differentiated to form neurons. Not only was this process lengthy and time-consuming, it also introduced variability and risk as cells could get stuck in intermediate stages, producing low yields of the final specialized cell.

Problems can arise when neurons do not fully revert into iPSCs as partial reprogramming can lead to abnormal gene expression and residual epigenetic marks can remain from the original cell specialization. Additionally, germ cell tumors can form if the iPSCs themselves did not properly differentiate into their specialized cell type. These limitations made it difficult for researchers to produce large, reliable batches of tissue for research or clinical use with efficiency hovering around 0.1% to 1% [7]. 

Recent progress by MIT engineers has cut out the middleman entirely and dramatically changed efficiency. Instead of enduring a multi-step process with the iPSC intermediate stage, researchers converted skin cells directly to neurons by introducing a handful of key genes. They attached three transcription factors, proteins that tell the cell which genes to express, into a single modified viral carrier. At the same time, also injected two genes to control cell growth into the cells. These neuronal lineage-specific transcription factors both suppressed the fibroblast identity while also activating neuron-specific genes [2, 8]. Unlike iPSC formation, where cell identity is erased globally, the transcription factors open up chromatin for genes encoding neuron-specific machinery while also silencing fibroblast-specific genes. Neural growth factors, neurotrophic factors, and the right culture environment also aid in this process and help the cell develop axons, dendrites, and synapses [9]. Through bypassing the iPSCs, the researchers generated an incredible result: 1100% yield with a single skin cell producing eleven mature neurons while still faster than the traditional route.

Though the neurons looked the part, the researchers had to ensure that they could act the part too. They implanted the newly-grown neurons into the striatum of mouse brains. After two weeks they found the neurons forming new connections and generating electric impulses, just like normal neurons do [8]. These were both impressive indications that the engineered cells likely could engage in normal neuron function.

This revolutionary breakthrough has broad implications for both clinicians and researchers and holds the ability to accelerate the future of personalized medicine. For patients with ALS or spinal cord injuries, clinicians could potentially use a small sample of skin and convert them into healthy motor neurons before reintroducing them into the body. In the laboratory, scientists could create patient-specific models to study the mechanism and progression of diseases or test drug safety and efficacy. Many safety and ethical concerns of the traditional process, such as the potential for tumor formation, can be avoided entirely while also enhancing yields and shortening production timelines. A patient’s own cells can be used to generate healthy neurons and tissue, nearly eliminating the possibility for immune rejection of new cells, tissues, and organs. In the long term, this approach could democratize access to advanced therapies and help bring regenerative medicine one step closer to the clinic. As it turns out, the key to repairing our brain may lie in the palm of our hand.

References

1. A Multitude of Possibilities | HHMI’s Beautiful Biology [Internet]. Available from: https://www.hhmi.org/beautifulbiology/media-detail/multitude-possibilities

2. Wang NB, Lende-Dorn BA, Beitz AM, Han P, Adewumi HO, O’Shea TM, et al. Proliferation history and transcription factor levels drive direct conversion to motor neurons. cels [Internet]. 2025 Apr 16; 16(4). Available from: https://www.cell.com/cell-systems/abstract/S2405-4712(25)00038-9

3. Trafton A. MIT News | Massachusetts Institute of Technology. 2025. MIT engineers turn skin cells directly into neurons for cell therapy. Available from: https://news.mit.edu/2025/mit-engineers-turn-skin-cells-into-neurons-for-cell-therapy-0313

4. Aranda-Anzaldo A, Dent MAR. Why Cortical Neurons Cannot Divide, and Why Do They Usually Die in the Attempt? Journal of Neuroscience Research. 2017;95(4):921–9.

5. Cerneckis J, Cai H, Shi Y. Induced pluripotent stem cells (iPSCs): molecular mechanisms of induction and applications. Sig Transduct Target Ther. 2024 Apr 26;9(1):1–26.

6. Mohite P, Puri A, Dave R, Budar A, Munde S, Ghosh SB, et al. Unlocking the therapeutic potential: odyssey of induced pluripotent stem cells in precision cell therapies. Int J Surg. 2024 Jul 4;110(10):6432–55.

7. Saha K, Jaenisch R. Technical challenges in using human induced pluripotent stem cells to model disease. Cell Stem Cell. 2009 Dec 4;5(6):584–95.

8. Wang NB, Adewumi HO, Lende-Dorn BA, Beitz AM, O’Shea TM, Galloway KE. Compact transcription factor cassettes generate functional, engraftable motor neurons by direct conversion. cels [Internet]. 2025 Apr 16;16(4). Available from: https://www.cell.com/cell-systems/abstract/S2405-4712(25)00039-0

9. Vierbuchen T, Ostermeier A, Pang ZP, Kokubu Y, Südhof TC, Wernig M. Direct conversion of fibroblasts to functional neurons by defined factors. Nature. 2010 Feb;463(7284):1035–41.