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How Stem Cells Are Shaping Drug Discovery

Rectangle Image

How Stem Cells Are Shaping Drug Discovery

Stem cell biology is a rapidly advancing field of research, that has contributed to a substantially diverse array of scientific disciplines, ranging from developmental biology through to regenerative medicine. In recent years, one of the most promising applications for stem cell biology has been in drug discovery. Stem cells are increasingly being used in new and innovative ways to improve the drug discovery process – spanning academia, biotech start-ups and large pharmaceutical companies.

In this list we’ll take a look at how stem cells are being used in the drug discovery process – from disease modeling, to target identification, through to compound screening, and toxicity testing. We will also discuss pivotal stem cell technologies and how these are shaping the pharmaceutical industry. 

Disease modeling

Drug discovery relies on having accurate models of human disease. Historically, disease modeling has been restricted to animal models, simple single cell organisms such as yeast, and immortalized human cancer cell lines. While contributing substantially to our understanding of various diseases, animal models do not fully approximate human physiology, and studies cannot be sufficiently scaled up for large-scale comprehensive phenotypic assays. Immortalized cell lines on the other hand can be scaled up, but are sometimes unreliable models of human disease due to substantial karyotypic abnormalities. HeLa cells for example have been reported to contain up to 80 chromosomes.1 Furthermore, certain cell types such as terminally differentiated neuronal subtypes are difficult to obtain from immortalized cell lines.

Ground-breaking work by Shinya Yamanaka in 2006 helped circumvent these issues, by showing that genetic reprogramming could turn terminally differentiated adult cells back into an embryonic like state. These resulting stem cells, termed induced pluripotent stem cells (iPSCs) share many characteristics of embryonic stem cells (ESCs), including pluripotency.4

2-D in vitro disease models can only go so far in recapitulating human diseases, since cells in the human body do not exist in isolation. Furthermore, maturation of iPSCs into functionally mature adult cell types has often proved challenging in a 2D tissue culture environment.

Compound screening

Translating complex stem cell derived in vitro models into large scale, reproducible phenotypic assays that allow the screening of thousands of compounds, is a vital yet challenging step in stem cell-based drug discovery. 

Target identification

Target identification is the process of identifying a molecular target that has the potential to be modulated by a therapeutic agent. Identifying novel drug targets using stem cells can come via several different routes. Stem cell-based models of disease offer many academic groups a faster, cheaper and often more accurate way to investigate novel disease mechanisms, resulting in a greater understanding of the molecular basis of disease.

Building on this, a number of large-scale academic collaborations have been set up to amass a wealth of biomedical data from iPSCs. A key example of this is the Human Induced Pluripotent Stem Cell Initiative, where genomic, transcriptomic, proteomic and phenotypic data was collated from thousands of healthy and disease associated iPSC lines. This open source platform aims to provide researchers with a global resource that can be used to identify novel disease specific molecular targets.27

Finally, as mentioned, stem cell-derived phenotypic screens offer a holistic and empirical method for identifying novel compounds that revert disease associated phenotypes. Using downstream deconvolution strategies, it is then possible to identify novel molecular targets for these diseases. This approach is particularly useful when trying to identify novel targets for diseases where the mechanistic landscape is not completely understood.

Toxicity screening

While stem cell-based models are incredibly useful in early stage disease specific phenotypic screens, stem cells can also be an incredibly useful tool for identifying off-target adverse effects of drugs already in development. Identifying such effects early on in the drug development pipeline can be much more cost-effective than identifying these effects later in animal studies – or in some cases during clinical studies.

Indeed, there are now several stem cell-derived toxicity screens that have been shown to work, by identifying adverse side-effects of already available drugs. These include cardiac toxicity screens,28 and liver toxicity screens.29 It is hoped that screening for toxicity early on in the drug development process will make it easier to re-design compounds to reduce their toxicity.


Stem cells are fast becoming an invaluable tool in the drug discovery process. Stem cells offer the remarkable capacity to generate an unlimited source of disease relevant cell types from which to identify novel molecular targets, perform large-scale phenotypic screens and also identify off-target toxicities.


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Martins, J. M. F. et al. (2020). Self-Organizing 3D Human Trunk Neuromuscular Organoids. Cell Stem Cell. doi:10.1016/j.stem.2019.12.007.

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Campisi, M. et al. (2018). 3D self-organized microvascular model of the human blood-brain barrier with endothelial cells, pericytes and astrocytes. Biomaterials. doi:10.1016/j.biomaterials.2018.07.014.

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Yang, Y. M. et al. (2013). A Small Molecule Screen in Stem-Cell-Derived Motor Neurons Identifies a Kinase Inhibitor as a Candidate Therapeutic for ALS. Cell Stem Cell. doi:10.1016/j.stem.2013.04.003.

Ho, S. M. et al. (2016). Rapid Ngn2-induction of excitatory neurons from hiPSC-derived neural progenitor cells. Methods. doi:10.1016/j.ymeth.2015.11.019.

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Stacey, P. et al. (2018). Plate-Based Phenotypic Screening for Pain Using Human iPSC-Derived Sensory Neurons. Slas Discovery. doi:10.1177/2472555218764678.

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Choudhury, Y. et al. (2017). Patient-specific hepatocyte-like cells derived from induced pluripotent stem cells model pazopanib-mediated hepatotoxicity. Scientific Reports. doi:10.1038/srep41238.