An organoid is a 3D cluster of cells with structural and functional features of an organ. Scientists can start with induced pluripotent stem cells (iPSCs) or adult stem cells acquired from a specific patient and generate organ- and disease-specific organoids. Consequently, organoids make it possible to study the impact of a drug on a specific disease, even a person’s own disease.
“The whole point of an in vitro system is to model a patient as closely as possible without having the patient in the lab,” says Rob Vries, CEO at the Netherlands-based HUB (Hubrecht Organoid Technology), a nonprofit company. “With organoids, we can take cells from a patient and grow them—expanding genetically stable cells—in the lab in virtually unlimited amounts to directly study disease.” He should know, as he was one of the authors on the first report of organoid development, which was created in Hans Clevers’s lab from intestinal cells that express Lgr5—a gene that turns on division on these cells.1
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Working with organoids can be challenging, but it doesn’t have to be. Find out what the experts are doingThe real key is what scientists can discover with organoids. For example, organoids generated from patient tumors can “be exposed to varying drugs in vitro to identify the best treatment to fight a particular cancer—thus personalizing medicine to treat a disease,” says Elizabeth Abraham, senior product manager at Corning. “Taking this idea even further is the ability to repair genes in cells that can form organoids, then using those organoids to understand treatment regimens.”
Expanding opportunities
Beginning with the first organoid developed in Clevers’s lab, scientists wanted to show that an organoid developed from a patient’s cell replicates what occurs in the patient. Now, Clevers and his colleagues have done that with cystic fibrosis2 and cancer.3 Based on this research and work by other scientists, Vries says, “There’s an extremely high correlation between how an organoid and a patient behaves.” That was a fundamental requirement in moving ahead with organoids in clinical work.
To date, organoids have been made from many tissues, including brain, breast, intestine, kidney, liver, lung, pancreas, and prostate.4 Some of the next steps in using organoids will involve creating even more complex systems, and some examples already exist. One comes from Takanori Takebe, assistant professor of pediatrics at the University of Cincinnati, and his colleagues, who created the first connected tri-organoid system—the human hepato-biliary-pancreatic organoid.5
“This is a remarkable achievement since it moves the field from individual organoid research to connected organoid systems, which more physiologically mimic the interplay between human tissues,” says Roxanna Ghadessy, technical marketing manager at Corning.
Creating a cluster
Scientists generate organoids in a way that works best for a specific application. The key is finding a process that nurtures an organoid to form and grow as needed, and then allows a researcher to access the organoids.
For example, organoids can be grown in a drop of Matrigel® matrix that forms a dome. At the Medical College of Wisconsin, scientists grew patient-derived pancreatic organoids in Matrigel domes, and they reported: “These studies provide the first report of novel and disease-relevant 3D in-vitro models representing pancreatic tumor, stromal and immune components using primary organoid co-cultures representative of the tumor-microenvironment.”6 These domes can be created in various types of labware, including the Corning spheroid microplates.
At the University of Washington, assistant professor Benjamin Freedman, Ph.D., grows kidney organoids. “We start out in a very thin layer of Corning® Matrigel matrix, and we put the pluripotent stem cells on top,” he explains. “Then, we sandwich them in another thin layer of Matrigel.” He uses Corning ultra-low attachment plates in his organoid work. “These have been very helpful in growing our organoids in suspension,” he says. “What we’ve seen is that the organoids can grow in a disease state to a very large size—centimeters in size—using these plates, and they couldn’t do that when they were growing attached to the dish or even surrounded by Matrigel matrix.” The plates also prove helpful in experiments that last for weeks, when Freedman needs the cells to resist attachment to the plate.7
Organoid applications
Scientists can use organoids in many ways. For example, Freedman is looking for new kidney disease treatments from his work on organoids, but he also envisions other uses. “In the long term, we’d like to be able to generate new grafts from people’s own bodies that can recreate the function of the kidney,” he says. “Being able to do this in 3D culture could be a way of developing those kinds of transplant modalities.”
From the NCI Center for Systems Biology of Small Cell Lung Cancer at Vanderbilt University, scientific center manager Amanda Linkous, Ph.D., says, “Our main focus is to improve the preclinical models of glioblastoma.” She adds, “We want to model the human brain using cerebral organoids.” She and her colleagues create “mini-brains” from a patient’s iPSCs and, subsequently, co-culture these cerebral organoids with the patient’s glioma stem cells.8 “So, you have the patient’s tumor cells invading into the patient’s mini-brain, and then we can monitor the growth of that tumor,” she says. “Our hope is to ultimately screen those tumors growing in the mini-brains against a library of a variety of different combinations of drug therapies, and be able to predict which combination or just the reagent or drug alone that may be most beneficial to inhibiting that patient’s tumor growth.”
Moving forward
Organoid-based research is not easy. “Working with organoids requires a certain level of precision, working in a very structured manner that is more complex,” Vries says. “Plus, two to three different patients can give two to three answers to a question about one kind of disease.”
However, dealing with that complexity and heterogeneity allows scientists to learn more at earlier stages of drug development. “We move some clinical work to the preclinical phase,” Vries says, “and that reduces the time of a project and makes it cost less.” Plus, organoids can be used to study the basics of biology in many organs, the development and growth of a wide range of diseases, and much more.
To learn more about working with organoids, download our free eBook “All About Organoids” now.
References
1. Sato, T., Vries, R.G., Snippert, H.J., et al. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nat. 2009. 459(7244):262–265.
2. Berkers, G., van Mourik, P., Vonk, A.M., et al. Rectal organoids enable personalized treatment of cystic fibrosis. Cell Rep. 2019. 26(7):1701–1708.
3. Byrne, A.T., Alférez, D.G., Amant, F., et al. Interrogating open issues in cancer precision medicine with patient-derived xenografts. Nat. Rev. Cancer. 2017. 17(4):254–268.
4. Lancaster, M.A., Renner, M., Martin, C.A., et al. Cerebral organoids model human brain development and microcephaly. Nat. 2013. 501(7467):373–379.
5. Koike, H., Iwasawa, K., Ouchi, R., et al. Modelling human hepato-biliary-pancreatic organogenesis from the foregut–midgut boundary. Nat. 2019. 574(7776):112–116.
6. Tsai, S., McOlash, L., Palen, K., et al. Development of primary human pancreatic cancer organoids, matched stromal and immune cells and 3D tumor microenvironment models. BMC Cancer. 2018. 18(1):335.
7. Cruz, N.M., Song, X., Czernjecki, S.M., et al. Organoid cystogenesis reveals a critical role of microenvironment in human polycystic kidney disease. Nat. Mater. 2017. 16(11):1112–1119.
8. Linkous, A., Balamatsias, D., Snuderl, M., et al. Modeling patient-derived glioblastoma with cerebral organoids. Cell Rep. 2019. 26(12):3203–3211.