Retina organoids mimic the structure and function of the human retina to serve as a platform to study underlying causes of retinal diseases, test new drug therapies, and provide a source of cells for transplantation. Credit: David Gamm, M.D., Ph.D., University of Wisconsin-Madison
by Vicky Marsh Durban, PhD, Director of Custom Organoid Services, Molecular Devices
Over the past decade, organoids have become one of the most important scientific advances in biopharma. From their first development in academic labs, they are transitioning to industrial settings where they are harnessed for studying human diseases, tailoring personalized therapies, and reshaping clinical trials. Their use spans a range of applications, including drug screening and intricate disease modeling. As this technology continues to evolve, these 3D systems are increasingly positioned to expedite drug development from laboratory discovery to patient treatment.
Expanding the boundaries of organoid applications
Upon their initial discovery over a decade ago, it was expected organoids would be used primarily as “grow-your-own-organs” in the fields of regenerative medicine and tissue engineering. The development of organs-on-a-dish started in 2009 when Sato et al. successfully modeled intestinal tissue using adult stem cells1. Intestinal tissue was targeted initially due to the ease of sourcing biopsies, the robust proliferation of intestinal stem cells, and the simplicity of the intestinal epithelium structure compared to other organs. Over the next four years, academic research expanded the organoid portfolio, developing renal organoids in 20102, cerebral organoids in 20133, liver and pancreatic organoids in 20134,5, lung organoids in 20146, and mammary gland organoids in 20157. While organoids are able to mimic specific tissue characteristics, they have never reached the full functionality of human organs. Instead, they have experienced a paradigm shift that has expanded their utility far beyond their original scope within regenerative medicine.
In recent years, the application of these 3D cellular structures has shifted from “organ-on-a-dish” to “disease-on-a-dish” models. Organoids are used as disease models to establish systems for drug screening, genotype-phenotype correlation tests, biobanking, tailored treatments, and cell therapies. Early research used organoids to model genetic diseases such as cystic fibrosis, by recapitulating the CFTR mutation8. Since then, their applications have broadened to include cancer, Alzheimer's, Crohn's disease, microcephaly, and infectious diseases9,10. For instance, neural progenitor cells infected with the Zika virus were used to develop brain organoids and study strain pathogenicity and genomes11. More recently, respiratory and intestinal organoids have been utilized to evaluate the impact of SARS-CoV-2 infection12. Over the past decade, the applications of organoids have evolved from mimicking tissue characteristics to serving as versatile models for studying diseases. In recent years, they have emerged as valuable tools for advancing both drug development and pharmaceutical research.
Shifting drug development with organoids
In biomedical research and pharmaceutical development, organoids are used to study complex cellular processes, like stem cell dynamics and cell-to-cell interactions, that cannot be observed using traditional 2D cell structures. They also address ethical concerns tied to in vivo testing, presenting a more accessible, cost-effective, and accurate alternative to animal models. The recent FDA Modernization Act 2.0 recognized organoids as New Alternative Methods (NAMs) in drug development, thereby setting the stage for their usage—either alone or in conjunction with animal studies—in preclinical validation, including drug testing, high-throughput drug screening, or disease modeling13. The legislation has allowed organoids to become the next game-changers for the pharmaceutical industry, offering a “fail fast and fail cheap” strategy in drug development. By enabling large-scale screening of potential modalities early in the drug development pipeline, non-viable candidates can be promptly eliminated, saving both time and resources. Moreover, organoids grown from patients’ cells have the unique advantage of modeling specific diseases, understanding patient-specific drug responses and thereby facilitating personalized medical treatments.
Overcoming technological limitations
With an expected growth rate of 22% between 2023 and 2030 and a market size anticipated to reach over $6.5 billion by 203014, industry is increasingly recognizing the value of organoids. However, organoid systems still face several inherent and technological challenges that limit their ability to accelerate drug development. For example, organoids lack specific cell types found in whole organs, such as immunological, neuronal, or endothelial cells. This restricts their use in more comprehensive studies like immuno-oncology treatments.
A major technological challenge lies in standardization. Due to the novelty of organoids as a screening tool, there is a lack of uniform protocols and culture techniques across different studies and laboratories. Moreover, most organoid cultures are still grown manually, relying on the individual skills of researchers, which adds variability. Finally, expertise is required not only to maintain these 3D systems in culture but also to collect, analyze, and interpret the complex data they generate. One approach to overcoming these challenges involves using patent-pending bioprocess technology from Molecular Devices. Our customized organoid expansion services provide a more standardized and reproducible method for researchers who choose not to handle this step in-house.
Another limitation hindering the broad application of organoids in the fast-paced pharmaceutical industry is that the expansion process is labor-intensive and time-consuming, taking months for manual expansion. Organoid expansion services can help overcome this barrier, enabling high-throughput methods that produce between 4 to 6 million adult stem cell-derived organoids in a single batch. This represents a 10-fold increase compared to conventional manual methods. And because they’re supplied in a ready-to-use format, researchers can decide as late as Friday to conduct an experiment the following Monday without the need for months of planning to cultivate an adequate number of organoids. These services, available at Molecular Devices, can enable quicker, more efficient screenings of multiple potential therapies while ensuring the organoids used are reliable, reproducible, and of high quality. Addressing these challenges of organoid development through providing hardware solutions and expansion services can enable broader acceptance of organoid-based findings in drug development, streamlining the screening of therapeutic modalities.
Unlocking the future of organoid research
The field of organoid research is advancing at a rapid pace, promising an exciting future. The next technological advancements are expected to integrate automation into research workflows, improving the robustness and reproducibility of organoids and further optimizing drug development and screening processes15. Additionally, advanced analytical tools, like high-resolution live imaging and mass spectrometry imaging, will enable real-time tracking of cellular and molecular processes with 3D organoid systems16. Such capabilities will ensure rigorous quality controls, consistently producing high-quality organoid cultures for research.
Greater control over organoid culture will lead to more standardized protocols, tailored to the development of distinct tissues. This will pave the way for broader applicability of 3D organoid systems, such as toxicity studies. Moreover, solving the challenges of scalability, reproducibility, and standardization in these 3D systems will increase confidence in the technology within pharma and biotech. We foresee increased accessibility to organoids through strengthened academia-industry partnerships and specialized organoid banks.
Diversity in clinical trials
Better availability of tissues will allow organoid starting cultures to be sourced from a wider range of donors, enhancing diversity in preclinical research and ensuring the safety and effectiveness of tested therapies for all. The FDA has already placed a strong emphasis on ethnic and racial diversity in clinical trials in their draft guidelines released in 202217. With the advancements in organoid research, this commitment to diversity can be upheld in both clinical and pre-clinical settings.
Conclusion
As the pharmaceutical and biotechnological landscapes continue to evolve, cutting-edge tools and methodologies to streamline drug development are crucial. Organoid cultures bridge the gap between lab-scale experiments and industry-scale applications, offering a more precise, ethical, and patient-centric approach to drug discovery and development.
About the author
Vicky Marsh Durban, PhD, is Director of Custom Organoid Services at Molecular Devices, where she helps researchers access large batches of standardized, assay-ready organoids, provided at scale using a patent-pending bioprocess technology. Vicky's journey started with a Ph.D. from Cardiff University in 2008, focusing on cancer genetics. Her path led her to University of California, San Francisco (UCSF), where she held a post-doctoral research scholarship investigating targeted therapeutic approaches in malignant melanomas. She returned to Cardiff in 2014 for a Research Fellowship at the European Cancer Stem Cell Research Institute. In 2016, she embraced her first commercial role at ReNeuron, excelling as Principal Investigator. Her rise continued at Cellesce, from Lead Scientist to COO and CEO by 2021. The acquisition of Cellesce by Molecular Devices in 2022 celebrated Vicky's leadership.
References:
1. Sato T, Vries RG, Snippert HJ, van de Wetering M, Barker N, Stange DE, et al. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature [Internet]. 2009 May 29;459(7244):262–5. Available from: https://www.nature.com/articles/nature0793
2. Unbekandt M, Davies JA. Dissociation of embryonic kidneys followed by reaggregation allows the formation of renal tissues. Kidney Int [Internet]. 2010 Mar;77(5):407–16. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0085253815542737
3. Lancaster MA, Renner M, Martin C-A, Wenzel D, Bicknell LS, Hurles ME, et al. Cerebral organoids model human brain development and microcephaly. Nature [Internet]. 2013 Sep 19;501(7467):373–9. Available from: https://www.nature.com/articles/nature12517
4. Lee J-H, Bhang DH, Beede A, Huang TL, Stripp BR, Bloch KD, et al. Lung Stem Cell Differentiation in Mice Directed by Endothelial Cells via a BMP4-NFATc1-Thrombospondin-1 Axis. Cell [Internet]. 2014 Jan;156(3):440–55. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0092867414000099
5. Huch M, Dorrell C, Boj SF, van Es JH, Li VSW, van de Wetering M, et al. In vitro expansion of single Lgr5+ liver stem cells induced by Wnt-driven regeneration. Nature [Internet]. 2013 Feb 14;494(7436):247–50. Available from: https://www.nature.com/articles/nature11826
6. Greggio C, De Franceschi F, Figueiredo-Larsen M, Gobaa S, Ranga A, Semb H, et al. Artificial three-dimensional niches deconstruct pancreas development in vitro. Development [Internet]. 2013 Nov 1;140(21):4452–62. Available from: https://journals.biologists.com/dev/article/140/21/4452/76732/Artificial-three-dimensional-niches-deconstruct
7. Nguyen-Ngoc K-V, Shamir ER, Huebner RJ, Beck JN, Cheung KJ, Ewald AJ. 3D Culture Assays of Murine Mammary Branching Morphogenesis and Epithelial Invasion. In 2015. p. 135–62. Available from: https://link.springer.com/10.1007/978-1-4939-1164-6_10
8. Dutta D, Heo I, Clevers H. Disease Modeling in Stem Cell-Derived 3D Organoid Systems. Trends Mol Med [Internet]. 2017 May;23(5):393–410. Available from: http://dx.doi.org/10.1016/j.molmed.2017.02.007
9. Lancaster MA, Huch M. Disease modelling in human organoids. Dis Model Mech [Internet]. 2019 Jul 1;12(7). Available from: https://journals.biologists.com/dmm/article/12/7/dmm039347/3370/Disease-modelling-in-human-organoids
10. Heydari Z, Moeinvaziri F, Agarwal T, Pooyan P, Shpichka A, Maiti TK, et al. Organoids: a novel modality in disease modeling. Bio-Design Manuf [Internet]. 2021 Dec 9;4(4):689–716. Available from: https://doi.org/10.1007/s42242-021-00150-7
11. Han Y, Yang L, Lacko LA, Chen S. Human organoid models to study SARS-CoV-2 infection. Nat Methods [Internet]. 2022 Apr 8;19(4):418–28. Available from: https://www.nature.com/articles/s41592-022-01453-y
12. Chia SPS, Kong SLY, Pang JKS, Soh B-S. 3D Human Organoids: The Next “Viral” Model for the Molecular Basis of Infectious Diseases. Biomedicines [Internet]. 2022 Jun 28;10(7):1541. Available from: https://www.mdpi.com/2227-9059/10/7/1541
13. Co JY, Klein JA, Kang S, Homan KA. Toward Inclusivity in Preclinical Drug Development: A Proposition to Start with Intestinal Organoids. Adv Biol [Internet]. 2023 Mar 18;2200333:2200333. Available from: 10.1002/adbi.202200333
14. Organoids Market Size, Share, Trends, Growth, Opportunities & Forecast [Internet]. Verified Market Research. 2023 [cited 2023 Aug 21]. Available from: https://www.verifiedmarketresearch.com/product/organoids-market/
15. Louey A, Hernández D, Pébay A, Daniszewski M. Automation of Organoid Cultures: Current Protocols and Applications. SLAS Discov [Internet]. 2021 Oct;26(9):1138–47. Available from: https://doi.org/10.1177/24725552211024547
16. Beghin A, Grenci G, Sahni G, Guo S, Rajendiran H, Delaire T, et al. Automated high-speed 3D imaging of organoid cultures with multi-scale phenotypic quantification. Nat Methods [Internet]. 2022 Jul 13;19(7):881–92. Available from: https://www.nature.com/articles/s41592-022-01508-0
17. FDA Takes Important Steps to Increase Racial and Ethnic Diversity in Clinical Trials [Internet]. FDA. 2022. Available from: https://www.fda.gov/news-events/press-announcements/fda-takes-important-steps-increase-racial-and-ethnic-diversity-clinical-trials