Organoids – An Alternative to Lab Rats?

By Ian Cheng 鄭朗健

The Problems of Using Lab Rats

People often jokingly say "you are a lab rat" when one is being experimented on something new. For decades, early stages of clinical trials use rodents like rats and mice before testing on human subjects. However, there are still two major issues around the use of animal models. First, the ethical dilemma: Does the benefit of drug testing outweigh the cost of animal suffering? Can we minimize the use of vertebrates in research? Second, the scientific dilemma: Can rats sufficiently represent human? Scientists have used rats and mice for modeling complex mammalian physiology and pathology. This is based on the notion that the making of the human body is instructed by a network of conserved proteins that are mostly found in rats and mice. Nevertheless, it remains challenging to accurately predict drug efficacy in animal models [1].

What if we can grow models of human organs, using real human cells instead?

Organoids in a Nutshell

Enter organoids, self-assembling, 3D miniature cell clusters that mimic aspects of the real organ. The word “organoid” has two parts: “Organ” refers to a collection of cells and tissues that work together to perform specific functions, while the suffix “-oid” means the resemblance of a specified object – in this case an organ.

So … is an organoid just an organ, with the same geometry but just smaller? Not exactly. Organs, as you may know, have a characteristic shape and internal structures. For example, the small intestine is a tubular structure. However, an organoid of a small intestine does not look like winding tubes under a microscope. In fact, the small intestine organoid, which is the first organoid to be developed, appeared as spherical hollow sacs, with small bud-like protrusions on their surface. These buds mimic intestinal crypts, pockets that house stem cells in real intestines, though the overall structure bears no resemblance to the winding tube shape [2].

The Story of the First Organoid

It is well known that the absorptive and secretory cells on the surface of our intestine are periodically replaced by new cells that are derived from stem cells. However, the exact identity of the stem cells remained elusive until 2007, when Hans Clevers' group made a pivotal advance [3]. They identified Lgr5, a marker unique to stem cells residing in crypts of small intestine. With these cells now identifiable and purifiable, it begs the question: Could they be grown outside the body? Toshiro Sato joined the lab as a postdoctoral fellow to answer precisely this question [2].

In the beginning of the study, Clevers and his team encountered a major problem – Intestinal stem cells would die when separated from the other cells in the intestine. Sato tried thousands of combinations of growth factors to arrive at the conditions suitable for "eternal growth." They used a cocktail of three growth factors: R-spondin, epidermal growth factor, and noggin [4]. Instead of working on a 2D surface, they used a soft, porous material called Matrigel, which provides the stem cells with a 3D space to grow, just like inside of the body [5].

The results were shocking.

"[Toshiro] realized what he had created was not just a lump of stem cells. It was a structure that recapitulates the normal structure of a gut and contains all the cell types of the epithelium, and even the cell types would be in the right location," Dr. Clevers recalled [2].

The stem cells did not simply multiply; they differentiated into multiple cell types and self-organized into unique spheroid structures.

Sato and Clevers were not the first to use the term "organoid." It had been applied without consistent definitions to various 3D cultures since mid-1960s. But their 2009 breakthrough launched a field explosion: Stomach, colon, liver, and pancreas organoids were created using the same principles – planting stem cells on a 3D culture supplemented with growth factors between 2010 and 2013 [5, 6]. This rapid expansion created a need for clarity. In 2014, Lancaster and Knoblich formally defined an organoid as "a collection of organ-specific cell types that develops from stem cells or organ progenitors and self-organizes through cell sorting and spatially restricted lineage commitment" – a definition that captured what Sato, Clevers and their colleagues had accidentally discovered five years earlier [5].

Why Do We Need Organoids?

In 2013, the Clevers and Watanabe labs published another pivotal research paper. They showed that intestine organoids transplanted to an injured area of the mice intestine could function normally [7]. The transplanted organoids integrated so well that they were indistinguishable from the host tissue when examined under the microscope [2].

The discovery opened a window for scientists to ponder the possibility of organoids in regenerative medicine. Patient-derived organoids enable autologous transplantation – transplanting one’s own tissues back to the body to replace the function of failing organs – solving the host-versus-graft problem in transplantation (the patient’s immune system attacks the transplanted organ from donor). In 2024, a group of researchers transplanted patient-derived organoids of pancreas (islets) into a patient with type I diabetes. Seventy-five days after the transplantation, the patient achieved insulin independence [8], in a disease which is otherwise lifelong, highlighting the potential of organoids in autologous transplantation. The success in this single patient warrants further clinical studies.

Beyond regenerative medicines, researchers use animal models traditionally as an analogy to humans, and it has indeed provided us with ample insights about treating diseases. Yet there are features specific to humans that we cannot model with animal models like rats and mice [9].

Organoids derived from humans can act as a window to these features. A prime example is using organoids to understand the human brain – arguably the most complex object in the universe. Brain organoids are a simplified version of the brain, making the task of understanding the organ more manageable [10]. For example, some researchers harness brain organoids to trace how brain cells develop and migrate in the fetus, while others connect a few brain organoids to investigate how pain signals travel from our skin to our brain [10].

More importantly, to be able to model a disease in rodents, scientists need to know the cause of it, and that takes about a year [9]. Patient-derived organoids can speed up the process significantly, allowing scientists to move faster when developing a model. In brain organoid research, scientists have already used brain organoids derived from patients to model Alzheimer's disease and Parkison’s disease [6].

Perhaps a more exciting is the application of organoids in drug screening. For a long time, poor assessment of drug toxicity in the preclinical stage has been a major cause behind the failure of many drug developments [6]. This is particularly true for cancer therapies, which may have severe, sometimes lethal side effects. To this end, drug efficacy and toxicity can be better studied by comparing the response of organoids that are derived from normal and cancer cells from the same patients [6].

The End of Lab Rats?

So where does this leave us? Are organoids the end of "you're a lab rat?" Not yet. Model organisms still have unique value in the scientific community. With a large body of work and laboratory techniques already established, animal models allow a low-cost way for fundamental research [9]. While the potential for organoids in precision and regenerative medicine is widely recognized, the field of organoids is still in its infancy, with major technical bottlenecks ahead and limited clinical outcomes. However, regulatory progress has been made with the passing of the “FDA (Food and Drug Administration) Modernization Act 2.0” in the United States. It authorizes the use of “new approach methodologies,” including organoids and AI-based computational models, as alternatives to the compulsory animal testing to support an investigational new drug application [11, 12]. This enables new drugs to be tested in a more effective and human-relevant way [12]. In April 2025, the FDA further announced a roadmap to phase out animal studies in the next three to five years [11]. The end of lab rats – in clinical trials – might not be that far away, after all.

References

[1] Perrin, Steve. “Preclinical research: Make mouse studies work.” Nature, vol. 507, no. 7493, 2014, pp. 423–425. https://doi.org/10.1038/507423a.

[2] Clevers, Hans. “Hans Clevers (Hubrecht I., UU) 1: Discovery and Characterization of Adult Stem Cells in the Gut.” Youtube, uploaded by Science Communication Lab, 19 February 2020, https://www.youtube.com/watch?v=HgVivkoA7UA.

[3] Barker, Nick, et al. “Identification of stem cells in small intestine and colon by marker gene Lgr5.” Nature, vol. 449, no. 7165, 2007, pp. 1003–1007. https://doi.org/10.1038/nature06196.

[4] Paré, Jean-François, and James L. Sherley. “Biological Principles for Ex Vivo Adult Stem Cell Expansion.” Current Topics in Developmental Biology, vol. 73, 2006, pp. 141–171. https://doi.org/10.1016/S0070-2153(05)73005-2.

[5] Simian, Marina, and Mina. J. Bissell. “ Organoids: A historical perspective of thinking in three dimensions.” Journal of Cell Biology, vol. 216, no. 1, 2017, pp. 31–40. https://doi.org/10.1083/jcb.201610056.

[6] Corrò, Claudia, et al. “A brief history of organoids.” American Journal of Physiology: Cell Physiology, vol. 319, no. 1, 2020, pp. C151–C165. https://doi.org/10.1152/ajpcell.00120.2020.

[7] Yui, Shiro, et al. “Functional engraftment of colon epithelium expanded in vitro from a single adult Lgr5⁺ stem cell.” Nature Medicine, vol. 18, no. 4, 2012, pp. 618–623. https://doi.org/10.1038/nm.2695.

[8] Wang, Shusen, et al. “Transplantation of chemically induced pluripotent stem-cell-derived islets under abdominal anterior rectus sheath in a type 1 diabetes patient.” Cell, vol. 187, no. 22, 2024, pp. 6152–6164.e18. https://doi.org/10.1016/j.cell.2024.09.004.

[9] Kim, Jihoon, et al. “Human organoids: model systems for human biology and medicine.” Nature Reviews Molecular Cell Biology, vol. 21, no. 10, 2020, pp. 571–584. https://doi.org/10.1038/s41580-020-0259-3.

[10] Zimmer, Carl. “What We Can Learn From Brain Organoids.” The New York Times, 8 Nov. 2025, https://www.nytimes.com/2025/11/06/science/brain-organoids-neurons.html.

[11] “S.5002 – 117th Congress (2021-2022): FDA Modernization Act 2.0.” Congress.gov, 2022, https://www.congress.gov/bill/117th-congress/senate-bill/5002.

[12] “FDA Announces Plan to Phase Out Animal Testing Requirement for Monoclonal Antibodies and Other Drugs.” U.S. Food and Drug Administration, 10 Apr. 2025, https://www.fda.gov/news-events/press-announcements/fda-announces-plan-phase-out-animal-testing-requirement-monoclonal-antibodies-and-other-drugs.