“Human Organoids: Tools for Understanding Biology and Treating Diseases” (2020), by Frans Schutgens and Hans Clevers

In 2020, Frans Schutgens and Hans Clevers published “Human Organoids: Tools for Understanding Biology and Treating Diseases,” hereafter “Human Organoids,” in the journal Annual Review of Pathology: Mechanisms of Disease. Organoids are miniature, three-dimensional structures that closely mimic the structure and function of a specific organ. Scientists make organoids in the lab using stem cells, which are a type of cell that has the ability to replicate themselves or to develop into various cell types in the body. “Human Organoids” is a review article that describes the use of human organoids as tools for understanding development, the biological processes that occur in the body, and the treatment of diseases and disorders. “Human Organoids” provided researchers with an in-depth resource on the use of organoids for disease modeling, finding new treatments for various forms of cancer, and treating genetic conditions.

1. Background and Context
2. Article Summary
3. Impact

Background and Context

At the time of the article’s publication, both Schutgens and Clevers were affiliated with the Hubrecht Institute, at the Royal Netherlands Academy of Arts and Sciences in Utrecht, The Netherlands. The Hubrecht Institute is a research institute that centers on developmental biology and stem cell research. Clevers led the Clevers Group, which as of 2025 is called the Organoid Group and aims to study tissue development and cancer progression using organoids. Schutgens was Clevers’s doctoral student, and the two researchers collaborated on various research projects that primarily encompassed the use of organoids. Additionally, Schutgens was also affiliated with the Department of Pathology at the Amsterdam University Medical Centers in Amsterdam, The Netherlands.

Organoids are a type of three-dimensional, or 3D, cell culture technology that enables scientists to study human development, diseases, and tissue regeneration in new ways. Organoids allow cells to interact in a complex, three-dimensional environment that closely mimics their natural conditions within the body. In contrast, researchers grow two-dimensional, or 2D, cell cultures on flat surfaces, which fail to capture the intricate cellular dynamics of living organisms. Researchers can derive organoids from the cells of healthy or diseased tissues.

The specific cells that researchers create organoids from are stem cells. More specifically, they use pluripotent stem cells, or PSCs, and adult stem cells, or ASCs. PSCs can differentiate into almost any cell type and include embryonic stem cells, or ESCs, and induced pluripotent stem cells, or iPSCs. ASCs are stem cells that can differentiate into the cell types of the tissue or organ in which they are found. They can help maintain and repair the tissue from which they originate. Researchers primarily use organoids made from ASCs to model or study tissue repair and regeneration. The ASCs can come from diverse organs and tissues such as the brain, bone marrow, and skin. Those organoids can help shed light on the regenerative capabilities of different tissues. In contrast, scientists use PSCs and iPSCs to make organoids to study various aspects of organ research. Those PSC organoids are useful for research into embryonic development, congenital diseases, and organ physiology.

Article Description

The authors split the article into six sections. In the first section titled "Introduction," Schutgens and Clevers explore the transition from traditional 2D cell cultures to more realistic and versatile 3D organoid models in biomedical research, and how organoids come to be. In section two, "Organoids as Experimental Tools," the authors explore how organoid technology is reshaping researchers' understanding of tissue physiology by enabling the study of previously unculturable cell types that couldn't be grown before, facilitating complex multicellular models, and keeping the cells' genetic information stable over time. In the next section, "Organoid Biobanking: As a Lab Tool and For Treating Patients," they outline the development and impact of organoid biobanks, repositories that store diverse organoid collections, and how they are providing tailored models for understanding and treating various conditions. In section four, "Organoids: Toward Treating Patients," the authors explain the use of CRISPR-Cas9 to correct genetic defects in organoids, the challenges of applying that technique in patient treatment, and its promising implications for metabolic diseases, alongside the potential of organoid transplantation in treating various conditions. In the next section, "Limitations," Clevers and his co-author discuss the challenges of using organoids in research and clinical applications, including the reliance on animal-based materials, the complexity of organoid cultures, and the potential solutions that researchers are studying. In the last section, "Perspectives," the article summarizes the potential of organoids and the promise of organoid technology in future medical research and therapy development.

In the "Introduction," Schutgens and Clevers discuss the shift from traditional 2D cell cultures to the use of organoids, the benefits it provides, and how organoids come to be. The authors start off by explaining the initial cell culture technologies that researchers have used, including 2D cell culture lines and patient-derived xenografts, which, according to Hans and Cleavers, have too many limitations. One example the authors provide is 2D cell culture lines, which require culturing cancerous cells, and if used as a model, they cannot mimic the actual environment inside the body accurately. Instead, there are complex interactions happening between the cancerous cells and the other cell types found in the body. In contrast, the authors explain how organoids have fewer disadvantages than previous technologies and offer a more accurate representation of human tissues by forming complex structures similar to actual organs. The authors then go into depth on how to create organoids, which include an extracellular matrix, which is a set of molecules that act as a scaffolding for growing cells, and a special mixture that allows the cells to proliferate and differentiate into other cells.

In the same section, “Human Organoids” explains which form of stem cell is better for different forms of research, such as developmental or disease research. PSC organoids can show how organs form and change during development. They can take a few months to grow and can be useful for studying diseases, development, and infections. On the other hand, authors explain, ASC-derived organoids mimic how adult tissues repair themselves. They are less complex than PSC-derived ones, quicker to create, and useful for studying both normal and diseased tissues, which is helpful for personalized medicine. Personalized medicine is a way to improve health care by using detailed biological information about a person, such as their genes, proteins, and other biological markers, to customize their healthcare. That method aims to provide the right treatment at the right time by focusing on what makes each patient unique, ensuring that medical care is more effective and precisely targeted to individual needs.

In “Organoids as Experimental Tools,” there is a subsection titled “Tissue Physiology” where the authors explain how organoid technology has allowed researchers to study cell and tissue development that was previously impossible. One of the examples the author provides is the culture of hepatocytes, or liver cells, which was previously impossible. The authors relay that researchers were able to observe hepatocyte organoids that were able to expand over multiple passages while retaining their essential liver functions, such as producing liver-specific enzymes and forming bile duct structures. The authors also include that through organoids, researchers are able to examine the complex physiological processes that contribute to development. The authors end the section by emphasizing the organoid’s ability to be genetically stable, so researchers can study the mutations of single stem cells.

In the next subsection titled "Disease Models," Schutgens and Clevers explain the advantage of using organoids to study the disease progression of various viruses, bacteria, and parasites. The authors relay that organoids allow researchers to model many diseases that researchers could previously not study in vitro, outside of the body. One example the authors provide is the parasite Cryptosporidium, which can affect immunocompromised people, or those who have a weak or impaired immune system. It can result in respiratory symptoms and severe diarrhea. Schutgens and Clevers explain that the parasite has a complex life cycle, with different forms of reproduction, which researchers were only able to study through different organoids. In the same subsection, under the title "Genetic Disease," the authors explain that scientists can grow organoids from the cells of patients with genetic diseases, and that those organoids present with the same condition, which researchers can observe. That means the organoids can get sick in the same way as the patients' organs, helping scientists study the diseases better. The researchers provide various examples, one being Alagille syndrome, a genetic disorder that primarily impacts the liver's bile ducts, which are structures that help drain the bile. As the authors explain, organoids from a patient with that condition fail to develop proper bile duct cells, mirroring the disease's hallmark bile flow obstruction.

Continuing into the subsection, under "Cancer," the authors discuss how organoids are instrumental in preserving the genetic diversity of tumors, thus enriching the studies on tumor heterogeneity and drug resistance. Tumor heterogeneity refers to the presence of diverse cell types within a single tumor, differences between the same type of tumors in different patients, or differences between the primary tumors and the secondary tumor, which is the tumor that spreads from the original one. Schutgens and Clevers explain that researchers can make tumor organoids or genetically alter epithelial cells, which results in tumors due to mutations. That results in the tumors having different characteristics and behaviors, making cancer treatment more challenging. Researchers using organoids have identified resistant cells within tumors even before treatment, highlighting the urgent need for more effective therapies. Moreover, the authors explain, organoids can help to understand metastatic disease. Metastatic disease is cancer that spreads from its original site to other parts of the body. Researchers transplant engineered or patient-derived organoids into mice to observe cancer spread and to gain a better understanding of metastasis. "Human Organoids" argues that those experiments are leading to new approaches for targeting cancer stem cells, despite the continuous challenge posed by the adaptability of cancer cells.

In "Organoid Biobanking: As a Lab Tool and For Treating Patients," the authors exhibit the dual utility of organoid biobanks in medical research and patient treatment. Biobanks typically contain a large repository of biological samples, and organoid biobanks house many kinds of organoids, which are mostly derived from tumors. Schutgens and Clevers go on to describe the many forms of organoid biobanks that researchers have created, as well as their benefits. The authors relay that through the use of biobanks, researchers have observed the common genetic differences and similarities between different forms of the same cancer type with organoid biobanks. They also relay that although the genetic and biological compositions are mostly similar between the organoid and the original tissue, there are still some differences in the gene expression. Furthermore, the authors note that researchers can develop organoid technology by extracting tumor cells from the samples, which is less invasive than organ biopsies. Organ biopsies are medical procedures where doctors remove a small piece of tissue from an organ to examine it for disease. “Human Organoids” reports that analyzing how organoids react to treatments can predict the effectiveness of those treatments in actual patients. The ability to predict results can help doctors make better-informed treatment decisions, improving patient outcomes and moving away from the less effective trial-and-error approach often used in cancer treatment. However, the authors caution that organoids may not fully replicate organ complexity because they lack components like immune and blood cells, which might influence treatment responses.

In the same section, the authors consider the ethical implications of the organoid biobank, particularly around informed consent, ownership, and intellectual property. They emphasize the need for a broad consent model, which allows donors to give permission for researchers to use their samples in a wide range of future studies, considering the personal nature of organoid sources and the potential clinical applications for donors. They explain that the debate extends to the fair distribution of financial gains from organoid-based discoveries, the difference in use of animal models, the use of tissues from fetuses, and the cultivation of human brain tissues, which touches on the issue of consciousness. The authors recommend including regulations on the distribution of any financial gains from intellectual property. That is due to the number of people involved in the process, including the donors and those working at the research institute. They also advise researchers to inform donors about how they will create and regulate the biobank, the parties involved with it, any other findings the researchers find, and how donors can leave the project at any time.

In section four, “Organoids Toward Treating Patients,” the authors review other ways to treat patients with conditions such as genetic disorders using genetically modified organoids and organoid transplants for organ damage. They created organoids from the intestines of two patients with cystic fibrosis and used the technology of gene editing with CRISPR-Cas9 to correct a mutation that causes it. Cystic fibrosis, or CF, is a genetic disorder that leads to thick, sticky mucus in different organs such as the lungs and the pancreas. That results in blockages in the organs and, consequently, organ damage. After that correction, the organoids showed signs of typical function, indicating that the repair was successful. While promising, translating that technique to direct patient treatment is complex due to CF’s widespread nature in the body and the amount of cellular correction required. However, the authors declare that the same strategy shows greater promise for metabolic diseases, where minor enhancements in enzyme levels could significantly impact health. The authors also explain that research indicates the potential of organoids in therapeutic transplantation. For example, researchers treating mice with an inflamed colon using colon organoids demonstrated beneficial outcomes such as weight stabilization.

In the same section, Schutgens and Clevers explain that tumor-derived organoids have proven valuable in uncovering the mechanisms through which cancers evade the immune system. Research on colorectal cancer organoids reveals that blocking specific chemical messengers can shrink tumors and prevent metastasis. Moreover, they relay that, as of publication, a new technique exists where researchers can cultivate organoids that preserve the immune cells surrounding the tumors. As a result, it offers a more accurate replication of the tumor microenvironment that allows researchers to explore and create more personalized immunotherapies. One such personalized immunotherapy, the authors note, is adoptive cell therapy, which is where researchers transplant cells that help increase the immune response. The article also explains that in the Netherlands, scientists used organoids to personalize CF treatments through a test that measures organoid response to specific substances. As Schutgens and Clevers explain, different mutations cause CF, and there are nearly 2,000 known mutations. The problem is that not all treatments work the same for everyone, even if they have the same mutations. Additionally, some mutations are so rare that it's hard to test drugs on them in big studies. The authors explain that researchers have created a biobank of intestinal organoids to examine and solve the problem by allowing them to predict treatment outcomes for patients with rare CF mutations. That led to the adoption of the test to determine eligibility for receiving a drug called ORKAMBI based on how their organoids respond, ultimately improving patient health.

In the next section, “Limitations,” Clevers discusses that using organoids has some challenges, including the material required to grow organoids, its cost, and finding a way to create all aspects of the organ. First, organoids need to grow in animal-based matrix extract, which is a special jelly-like substance that can be unpredictable and difficult to replicate and might cause problems if transplanted in humans. Researchers are trying to find better ways to grow organoids, like using collagen or a safer gel made from synthetic materials, but it’s still a work in progress as of 2025. The authors also mention another issue, which is that growing organoids is more expensive than traditional flat cell cultures because they need special nutrients and the animal-based matrix extract, which can be costly. Furthermore, Clevers explains that organoids mostly just show the surface layer of organs and don’t include other important parts like blood vessels, immune cells, or nerves. That is true for cancer organoids, too, except for one type of kidney cancer organoid that can grow those extra components briefly.

In the last section, “Perspectives,” the authors summarize the role of organoids in disease modeling, personalized drug screening, treating genetic conditions, and cancer research. They argue that airway organoids offer a novel approach for studying infections, and their utility extends to genetic disorders. Despite those advances, optimizing cancer organoid culture conditions remains a challenge. The authors discuss that while using organoids for therapy through transplantation is still far away, successes like the personalized medicine approach for CF show that researchers are heading in the right direction. “Human Organoids” explains that the establishment of large-scale biobanks will be helpful for drug development, allowing for the screening of many compounds for specific diseases or vice versa. That is especially significant for rare genetic diseases where traditional clinical trials are not practical due to low patient numbers, offering new avenues for therapy development through organoid technology.

Impact

As of 2025, according to Google Scholar, “Human Organoids” has been cited 488 times. Many researchers cite Schutgens and Clevers’s work as a reference for their own organoid research. For example, a research article written by Anna Winkler and colleagues, researchers from Milan, Italy, explores the use of organoids to test the effect of microplastics on human airways. The researchers refer to “Human Organoids” to provide an explanation for why they decided to work with organoids. There are also many researchers exploring the potential of organoid research and refer to “Human Organoids” to explain the benefits it has in comparison to other technologies. With Schutgens and Clevers’s background in organoid research, “Human Organoids” has had a role in shaping current research and methodologies in organoid science. The article served as a key resource for researchers exploring organoid applications in disease modeling and therapy development. The significance lies in its contribution to a deeper understanding of organoids as versatile tools in biomedical research, influencing advancements in personalized medicine and regenerative therapies.

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