By Sophie Reay
Organoids are miniature, three-dimensional (3D) tissue cultures that mimic the structure and function of specific organs. They are generated from the in vitro culture of stem cells, which have the ability to self-organise and self-renew1. In 2009, a landmark study conducted by the Clever group demonstrated that adult intestinal stem cells could form multi-cellular 3D structures in vitro2, sparking a rise in organoid research. To date, a wide range of organoids have been developed including brain3, lung4 and liver5, with many more models emerging. Organoid technology serves as a critical bridge between in vitro 2D cell culture and in vivo animal models, with the potential to redefine drug development and personalised medicine.
Organoid technology shows potential for a wide range of biomedical applications including drug development, personalised medicine, disease modelling and regenerative medicine6. Although cell culture provides a simple, reliable and cost-effective platform for testing investigational medicinal products, 2D cultures fail to accurately simulate the complex cellular microenvironment, lacking complex cell-cell and cell-extracellular matrix interactions which are critical in driving cellular differentiation and proliferation7. Organoids are more physiological relevant models, enhancing the accuracy of in vitro drug screening and toxicology studies, therefore de-risking drug development by eliminating ineffective or unsafe candidates early in the process. Moreover, animal-based data does not always correlate well with humans, with a staggering 90% of drugs that appear safe and effective in animals failing to receive Food and Drug Administration approval in humans8. The development time of a typical innovative drug ranges from 10-15 years, with an average cost of $2 billion to translate it to market9. Organoids offer a cheaper and time-efficient alternative to animal models, streamlining the drug development process and advancing innovation.
Interestingly, patient-derived organoids (PDOs) can be synthesised from patient-derived stem cells, paving the way for precision medicine. Drug screening can be conducted on PDOs to predict which drugs are most likely to be effective for individual patients. A significant advantage of organoids is their ability to model diseases. The first human pathology to be modelled in organoids was cystic fibrosis, a disease caused by mutations in CFTR gene10. Deckers et al generated cystic fibrosis-patient-derived intestinal organoids that could recapitulate the disease in vitro. They developed a swelling assay that provided a facile way to identify CFTR modulators11. Organoids can also model acquired diseases and are particularly prevalent in the oncology therapeutic area. Tumour-derived organoids can replicate the phenotypic and genomic characteristics of primary tumours, including histological complexity and genetic heterogeneity12. For example, Sacha and colleagues generated over 100 breast cancer organoids and showed that DNA copy number variations and sequence changes in the organoids were consistent with the original tumour tissue13. PDOs have been generated from a range of human cancers, with PDO biobanks becoming established globally. Unlike traditional biobanks, where tissue samples are finite and typically limited to a single study, PDO ‘living’ biobanks are renewable, enabling unlimited expansion and experimentation to advance preclinical testing14. PDOs have been pivotal in modelling the stages of carcinogenesis in various types of tumours including colon cancer15 and breast cancer16. This allows better understanding of the molecular mechanisms that underpin tumour initiation, therefore aiding identification of novel diagnostic biomarkers for cancers17. PDOs also show promise as valuable platforms to identify predictive response to cancer treatment. For example, Vlachogiannis and colleagues developed PDOs derived from 110 metastatic tumour samples and found that they had an 88% positive predictive value, meaning 88% of drugs that were efficacious in organoids were also efficacious in primary tumours18. Organoids also have the potential to overcome the major limitations of organ transplant including donor organ shortage as well as organ rejection and associated adverse effects induced by immunosuppressive drugs. Substantial progress has been made in the transplantation of human organoids, with intestinal organoids being particularly well-studied6. In 2022, researchers from Tokyo Medical and Dental University conducted the world’s first autologous organoid transplant using intestinal organoid cultured from healthy intestinal mucosal stem cells of an ulcerative colitis patient19.
Despite their potential in biomedical research, organoids face several challenges. A major limitation is their lack of immune cell diversity and vasculature. Recent advancements in microfluidic technology have led to the development of organoids-on-chips, which are devices that recapitulate the biochemical, mechanical, structural, and functional features of the human cellular microenvironment, thereby producing more complex and physiologically relevant models. A further development is the integration of multiple organoids within a single microfluidic device, forming interconnected multi-organoid systems that offer powerful tools for disease modelling and personalised medicine20. Currently, organoid models lack standardisation due to variability in cell sources, culture conditions, and matrix compositions across laboratories. To address this issue, research communities are working toward consensus standards, including naming cell sources, culture techniques and validation methods21. While organoids generally raise less ethical concerns compared to animal models, organoids models such as brain and embryoid remain highly controversial. As organoid research continues to expand exponentially, further optimisation and overcoming current limitations is crucial to unlocking their full potential in transforming drug development and personalised medicine.
As organoid technology continues to transform biomedical research and clinical innovation, collaboration among researchers, clinicians, and industry will be crucial. If you're exploring organoid-based models or looking to partner on advancing precision medicine, get in touch to see how we can help accelerate your next breakthrough.
References
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