An Organ Without a Body: How 3D Organoids Benefit Research

Imagine being able to study a fully functioning organ without the complexities of a cell or animal model or the need for clinical trial approval. Today’s technology allows scientists to grow organoids, a cluster of cells that can function like a complete organ, in the lab.

What is an organoid?

The growth process begins with pluripotent or adult stem cells that undergo a controlled differentiation process, including the biochemical factors and a 3D scaffold, with adherent conditions that encourage them to organize into an organ-like system.¹ The capacity to renew and differentiate themselves makes stem cells uniquely poised to form these organized structures. An organoid is technically defined as a “self-organized 3D system” that mimics key complex features of the desired organ. Many tissues have been successfully transformed into organoids, including the brain, lung, intestine, and thyroid. 

While the cells themselves and their arrangement are similar to the biological organ, there are differences between the model and the reality. Because the organoid is an isolated system, it lacks features that link the different systems of a body together in a natural biological setting such as immunological and vascular components. This makes organoids useful for studying phenomena isolated to an organ, but the implications of the work are limited to the specific organoid tissue. 

The tricky part of generating organoids is that providing the proper scaffold and conditions for growth is only half of the battle. The cultures and cell types that are generated do possess some randomness, so the resultant organoid must be monitored on a genetic and phenotypic level to ensure the correct organoid has been generated. The research team must also be careful not to damage the organoid when manipulating or moving it, as they are delicate. 

Organoids: The mock living system 

The mock-living system of organoids presents a unique opportunity to visualize the functioning of an organ independently of an organism. Mouse and human organoids have been used to study how systems such as the airway, kidney, and liver function in the presence of specific conditions.² Organoids are hugely versatile and allow for genetic manipulation not possible in animal models. They do not possess species-specific problems like many models from humble fruit flies to lab mice.³ 

Organoids can also be used to better represent interactions between cells or in the extracellular matrix (which fills the spaces between cells, acting as a binding agent and providing some structural integrity). These phenomena are extremely difficult to study using cell line and animal models. In a cell model, interactions between cells is altered because the cell line is not a complete biological system, but a limited model of it. In animals, visualizing the extracellular matrix and cell crosstalk can be challenging because of limited available technology and the need to keep the animal alive during examination. When studying regenerative medicine, this interspace between cells is essential because the crosstalk between cells is what guides their growth, formation, and overall functionality. Organoids might be the bridge connecting initial research in a cell line to clinical trials, providing much more insight and depth of information than is possible with a cell line alone without the challenges associated with animal test subjects. 

3D biological systems like organoids are rapidly changing the way doctors and researchers alike approach treatment options for various medical conditions. In oncology, patient-derived xenografts have been the gold standard.⁴ These consist of tumor tissue taken from the patient that is then grafted onto immunocompromised mice. This solves the problems of patient-specific drug response and genetic diversity, but the process is expensive and can take an extended period of time. Organoids are developed from patient-derived cells attained through a biopsy, a less expensive and time-consuming process than patient-derived tissue grafted onto immunocompromised mice and left to mature. However, organoids may still take 4-6 weeks to develop.

Another recent application of personalized medical treatment using organoids lies in the gut. Digestive conditions such as inflammatory bowel diseases can be difficult to treat because they differ vastly from one person to another. However, organoids generated from biopsied tissue from the individual can aid the search for improved treatment and care.⁵ 

Organoids present an exciting opportunity to explore a living system and its reaction to a specific treatment or situation. This “mock” living system can be harnessed to study a range of conditions not previously possible without a high risk of death without treatment including (but not limited to) terminal conditions like advanced cancer, severe viral infections like Ebola, and organ failure. 

Organoids as a 3D model

3D modeling has taken the research world by storm. What makes organoids a superior model for disease progression compared to other options? As detailed by the Harvard Stem Cell Institute, some conditions are uniquely human, which means that using model animals or cell lines is insufficient to monitor progression and determine whether treatments are successful because these models do not accurately represent how the organ or organism as a whole would behave in such a situation.⁶ Thus, enter the organoid. 

The year 2021 brought the ability to bioprint organoids by using macro-scale tissue generation and genetic engineering to stimulate maturation and vascularization.⁷ This was a leap forward that allowed deep, accurate study of organ systems using organoids. Using these new techniques, it is finally possible to study gene function and cell development, interactions between pathogens and their hosts and other processes. These new models also allowed for the study of the microbiome of body systems, shedding light on dysregulatory conditions, such as allergies and inflammatory bowel disease, that were previously difficult to study.

There are many diseases whose developmental steps, including signaling pathways and morphogenesis, remain largely unknown. Type 1 diabetes is one of these such cases. For those living with type 1 diabetes, their immune system targets islet cells, which are responsible for making insulin. Researchers hope that by using islet organoids, new information may show how type 1 diabetes forms and develop improved therapeutics for the condition. Another rising application of organoids is the study of oncological therapeutics. Using organoids, scientists can generate 3D tumor models that can be used to test and evaluate immunotherapies. In addition to this, progression of carcinogenesis has also been successfully replicated in organoids, lending new information about progression of cancer formation. 

The way forward 

The range of conditions that can be improved, studied, and applied to organoid use is wide. Organoids can solve the problem of individual conditions and reactions to treatment, and they are a substantial improvement over the limited applications of cell lines and animal models. As the cost and infrastructure required to use 3D biological models such as organoids becomes more accessible, we can expect to see organoids continue to improve the research possibilities of modern medicine. 

References

1. Yin, X. et al. 2016. “Engineering stem cell organoids.” Cell Stem Cell 18, 25-38. DOI: 10.1016/j.stem.2015.12.005.  
2. Dekkers, JF. et al. 2019. “High-resolution 3D imaging of fixed and cleared organoids.” Nature Protocols 14, 1756-1771. DOI: https://doi.org/10.1038/s41596-019-0160-8 
3. Kim, J, Koo, BK, & Knoblich, JA. 2020. “Human organoids: Model systems for human biology and medicine.” Nature Reviews 21, 571-584. DOI: https://doi.org/10.1038/s41580-020-0259-3.  
4. Bose, S., Clevers, H., Shen, X. 2021. “Promises and challenges of organoid-guided precision medicine.” HHS Public Access 2, 1011-1026. DOI: https://doi.org/10.1016%2Fj.medj.2021.08.005. 
5. Wang, Q. et al. 2022. “Applications of human organoids in the personalized treatment for digestive diseases.” Signal Transduction and Targeted Therapy 336. DOI: https://doi.org/10.1038/s41392-022-01194-6 https://www.nature.com/articles/s41392-022-01194-6. 
6. Barbuzano, J. 2017. “Organoids: A new window into disease, development, and discovery.” Harvard Stem Cell Institute. https://hsci.harvard.edu/organoids. 
7. Zarkesh, I. et al. 2022. “Synthetic developmental biology: Engineering approaches to guide multicellular organization.” Stem Cell Reports 17, 715-733. DOI: 10.1016/j.stemcr.2022.02.004.