Imagine growing a small, live version of a human organ in a dish— one that assembles itself, forms layers, and even carries out some of the same functions as its adult counterpart. This is the potential of organoids: three-dimensional, multicellular organ-like structures made from stem cells that self-assemble and replicate the architecture, cellular complexity, and sometimes the function of actual organs, all in the lab.
How are these systems so revolutionary? For many decades, scientists have used flat, two-dimensional cell cultures—easy, but far from the complexity of natural tissues. Animal models, though more realistic, have their own disadvantages: ethics, species differences, and expense. Organoids and similar stem cell-derived models fill this gap, presenting a physiologically relevant, human-specific, and ethically versatile tool for research and for medicine1.
But organoids are only one of an expanding array of sophisticated 3D culture systems. Spheroids, assembloids, and tissue-engineered tissues all take advantage of the stem cell’s dramatic capacity for self-organization and development2, 3. Though “organoid” describes a precise, organ-like structure, the general category is full of innovative models, every step drawing us closer to mirroring the complexity of living systems.
At the core of all these systems lies a simple but deep principle: stem cells, when provided with appropriate cues, can initiate their own developmental programs and self-organize into elaborate, tissue-like structures. It is this self-organization that gives organoids their immense power, and their appeal.
The stem cells behind organoids
Organoids can be cultured from a number of different stem cells, each with its own advantages. Pluripotent stem cells (PSCs) are the most flexible. Embryonic stem cells (ESCs) from early embryos are able to generate any cell type but are problematic ethically4. Induced pluripotent stem cells (iPSCs) avoid these problems: they are generated through reprogramming ordinary adult cells, such as skin or blood, to a pluripotent state5. This not only bypasses ethical concerns but also enables patient-specific organoids to be developed, which promises personalized disease modeling and medicine.
Adult stem cells (ASCs), or tissue-specific stem cells, are present in organs such as the intestine or brain. Although they can’t give rise to all cell types, they’re more easily obtained and best suited to model adult organ function or disease. Intestinal crypt stem cells, for instance, can be induced to grow “miniguts” that are very similar to the actual ones6.
How organoids are made
The process starts with a few stem cells either PSCs or ASCs7. These are inserted into a gelatinous matrix, usually Matrigel, that simulates the extracellular matrix (ECM) present in actual tissues8. The matrix offers structural support as well as important biochemical cues. The organoids that form are then immersed in a precisely defined media, full of growth factors that instruct the cells to go through the phases of development, as if they were inside the body9. What’s magical is that organoids aren’t built by hand; rather, the stem cells’ intrinsic programming kicks in and enables them to self-organize into tissue-like structures. By adjusting the order and mixture of growth factors, researchers can guide the cells to develop into various types of organoids with distinct architecture and function.
A tour through the organoid varieties
The range of organoids is nothing short of incredible. Brain organoids, or so-called “minibrains,” are cultured from PSCs and have proven themselves to be exceptionally useful for replicating neurological development, diseases such as autism or epilepsy, and even viral diseases that target the brain10. Intestinal organoids, or “miniguts,” can be cultured from either PSCs or ASCs and are employed to model gut disease, nutrient uptake, and drug response6.
Liver organoids, constructed from PSCs or ASCs, are essential for modeling drug metabolism and liver disease11. Kidney organoids, generated from PSCs, contribute to deciphering kidney development and disease mechanisms12. Lung organoids, whether derived from PSCs or ASCs, are leading the field in research into respiratory disorders, including COVID-1913. Pancreatic organoids are breaking new ground in diabetes research and beta cell biology14.
What can organoids do?
The uses of organoids and stem cell-derived cultures are diverse and revolutionary. In disease modeling, organoids derived from patients’ iPSCs enable researchers to observe the progression of diseases in an individual and to examine how an individual would react to various drugs15. Cystic fibrosis, neurodegenerative diseases, and inflammatory bowel disease are all diseases that can be recreated and examined in a dish16-18. Infectious diseases can also be examined in greater detail than ever before, such as observing SARS-CoV-2 infecting lung organoids13.
Drug discovery is being turned on its head, as organoids allow drug candidates to be screened in high throughput in a far more physiologically relevant context than 2D culture19. That is, effective drugs and potential toxicities can be determined sooner, and time, money, and animal lives can be saved. Organoids also provide a window on early human development, and scientists can investigate organ formation and even congenital defects in a dish20.
Personalized medicine is now a reality: by culturing organoids from a patient’s own cells, drugs can be precisely designed to their individual biology21. In the future, regenerative medicine can use organoids to restore or replace damaged tissue22. And in toxicology, organoids are already being used to decrease reliance on animal models for the testing of environmental toxins23.
Benefits—and the challenges that lie ahead
Organoids have distinct benefits: they are more physiologically relevant than conventional cell cultures, diminish the need for animal experimentation, enable the creation of patient-specific models, and permit investigation of the distinctively human biology24. Their scalability also makes them desirable for drug screening and studies25.
But there are challenges. Organoids typically don’t mature completely, more closely resembling fetal organs than adult ones26. They can’t increase beyond a certain size or complexity without blood vessels, and they don’t develop a full immune system or neural pathways27. They also can have batch-to-batch variation, and creating them can be time-consuming and expensive26. As brain organoids become more advanced, ethical concerns regarding consciousness, while still a long way off, are now on the table28.
The way forward
The future is exciting and ambitious. Scientists are designing vascularization and innervation, moving organoids towards the intricacy of native tissues29. Multi-organ systems, or assembloids, are under construction to simulate how organs talk to each other, gut-liver or brain-retina interaction30. Microrobots and nanorobots are also being utilized to precisely manipulate cells and biomaterials, helping to build more complex and structured organoids31. Organ-on-a-chip technology is combining organoids with microfluidic devices, providing accurate control of their surroundings and mechanical pressures32.
Standardization and reproducibility are a priority, as the science makes its way to stronger, universally applicable protocols. Therapeutic potential, where organoids are used not only for modeling, but even transplantation or tissue repair, is on the horizon. And with the advancing science will come the evolving ethical frameworks that shape this promising field.
Organoids and stem cell-derived cultures aren’t exactly mini-organs in a dish, they’re a window on the future of biology and medicine, a promise of improved models, improved drugs, and eventually improved health.