Imagine the possibility of crafting complex assemblies of cells that resemble human tissues. The reality of this technology is now here with organoids as innovative 3D models that are established based on stem cells. In the past, research on disease models and drug discovery were observed in mice and other animal models. However, with organoids, we can now conduct research on models that resemble human organs, including the brain, kidney, lung, and intestines. This becomes particularly significant to study complex human diseases, like neuropsychiatric diseases, that are unique to humans.1
Figure 1: Brain organoid culture 1
Specifically, organoids can be used to test drug efficacy. For example, intestinal organoids have been developed, which contain diverse intestinal cells like intestinal stem cells, enterocytes, goblet cells, enteroendocrine cells, fibroblasts and smooth muscle cells.2 The intestinal organoids also express drug transporters, efflux transport activity, and activation of P450, the drug-metabolizing enzyme.2 From this, intestinal organoids facilitate the testing of drug efficacy. In fact, metastatic gastrointestinal cancer organoids have been used to evaluate the response to cancer treatment among patients.2 Vlachogiannis et al. demonstrated a high sensitivity and specificity of the organoids accurately representing the treatment responses of GI cancer.3
Figure 2: Development of organoid models 2
Furthermore, organoids can be used as therapeutic tools. Scientists from the Harvard Stem Cell Institute have made groundbreaking advances in transforming cells to serve as treatment for diseases. One example is Dr. David Breault and Dr. Qiao Zhou’s work on transforming intestinal cells into insulin producing beta cells for diabetes treatment. This transformation is feasible as the cells are derived from the same region in the organoids and have many similar characteristics. Dr. Breault and Zhou also tested the modified insulin-producing cells into a diabetic mouse, which revealed efficacy in regulating blood sugar levels. From this, Dr. Breault believes that organoids derived from patient induced pluripotent stem cells can be transformed into new insulin-producing beta-like cells. This would enhance the treatment of diabetes with organoid cells directly tailored to individual patients.1
In fact, this idea of personalized medicine is already being studied with organoids. Cultures of patient-derived organoids (PDOs) can resemble both the phenotype and genetics of the patient’s tumor epithelium.4 Every patient has their own genetic differences and potentially rare mutations, which presents a limitation for group clinical trials and drug efficacy testing.4 In fact, a study that used organoids for predicting chemotherapeutic outcomes in colon cancer showed an accurate prediction of treatment response in over 80% of patients undergoing irinotecan-based therapies.5 Therefore, by combining molecular and therapeutic profiling of PDOs, researchers can help predict treatment response on an individual basis and craft personalized cancer treatment.4
Although this innovation is evolving rapidly, there are still limitations to the current organoid technology. For example, organoids are limited to only the epithelial layer, as it lacks the full tissue microenvironment from the immune and nervous system.2 Furthermore, organoids rely on the extracellular matrix of Matrigel. Given that Matrigel is produced from mouse tumor lines, this raises concern for their suitability to humans.2 Matrigel can also impact drug penetration and can hinder the use of organoids in drug development. Lastly, the culture medium used in developing the organoids contain growth factors and molecular inhibitors, which can affect drug responses in organoids.2
Despite the current limitations, the advancing organoid technology poses significant potential in replicating organ development and understanding human diseases. It also stands as a great platform to predict therapy responses, advance drug development, and facilitate personalized medicine. Undoubtedly, future scientific efforts will further enhance this innovative tool for broader clinical applications.
References
Barbuzano J. Organoids: A new window into disease, development and discovery. Harvard.edu. Published November 7, 2017. https://hsci.harvard.edu/organoids
Xu H, Jiao Y, Qin S, Zhao W, Chu Q, Wu K. Organoid technology in disease modelling, drug development, personalized treatment and regeneration medicine. Experimental Hematology & Oncology. 2018;7. doi:https://doi.org/10.1186/s40164-018-0122-9
Vlachogiannis G, Hedayat S, Vatsiou A, et al. Patient-derived organoids model treatment response of metastatic gastrointestinal cancers. Science. 2018;359(6378):920-926. doi:https://doi.org/10.1126/science.aao2774
Li Y, Tang P, Cai S, Peng J, Hua G. Organoid based personalized medicine: from bench to bedside. Cell Regeneration. 2020;9(1). doi:https://doi.org/10.1186/s13619-020-00059-z
Ooft SN, Weeber F, Dijkstra KK, et al. Patient-derived organoids can predict response to chemotherapy in metastatic colorectal cancer patients. Science Translational Medicine. 2019;11(513):eaay2574. doi:https://doi.org/10.1126/scitranslmed.aay2574