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Stem Cells in Focus

Organoids: Advancing Regenerative Medicine

A patient’s fate may lie within a single cell. Therapeutic fate, that is. Scientists can pluck a lone cell, or just a few, out of a patient’s body, grow them in a petri dish, and coax them to form so-called organoids, three-dimensional miniature versions of the original tissue or organ that can be grown indefinitely in the lab. Organoids, while not perfect replicas of organs, display many features of the organ from which they were made, including cellular anatomy and interactions, genetics, and specific tissue functions.

Organoids are unique, multi-purpose tools for advancing our understanding of biology, and aiding the fight against disease and injury. They help researchers study human development, including what can go wrong, and they can be used to test drug treatments and develop regenerative therapies in a laboratory setting.

Several applications of organoid technology were discussed in a media panel moderated by ISSCR President Hans Clevers, that included Jürgen Knoblich, Guo-li Ming, and Melissa Little, at the ISSCR 2017 Annual Meeting in Boston. (See affiliations below).

Organoids help researchers understand the Zika virus

For many reasons, both practical and ethical, the human brain is almost impossible to access in a living being. Organoid technology can model normal human brain development, and show what goes wrong during injury or disease, without having to touch the brain.

Guo-li Ming generated brain organoids from induced pluripotent stem (iPS) cells and introduced the Zika virus to see what might happen to the organoids during early pregnancy when the virus is present. Using this approach, Ming’s group has shown that organoids with the Zika infection collapse and have a reduced number of neural stem cells and neurons compared to uninfected organoids. Her findings in a petri dish mimic the biological processes that cause microcephaly (reduced brain and head size) seen in babies born to Zika-infected mothers. Using organoid technology, Ming and her group confirmed that the Zika virus can cause microcephaly. By studying this disease in a dish, researchers can explore new ways to tackle this devastating virus.

Building a better brain

Interestingly, although organoids recapitulate many cellular aspects of an organ, the various parts of the organ often randomly arrange within the organoid (scroll down to see a representative brain organoid. Image credit: Jurgen Knoblich). To be useful for biological research, organoids should closely mirror the architecture of the original organ, with the same placement of cells and tissues. 

Jürgen Knoblich’s group works with brain organoids, and aims to maintain the integrity of the brain architecture in organoids. The brain, in particular, is one large circuit board, and the positioning of neurons (nerve cells) is critical to its formation. To align the organoid architecture, Knoblich’s lab works with brain organoids derived from induced pluripotent stem cells (iPSCs), and applies bioengineering techniques to guide more natural brain tissue organization along a pre-defined growth axis, modeling the normal developmental process.

Using these technologies, Knoblich’s group has created organoids with architecture more closely aligned with that of a human brain. This is key to being able to model brain disorders that involve underlying structural defects, such as epilepsy, autism, and schizophrenia.

Organoids as precision medicine

Recognizing that drug treatments are not equally effective for all patients, researchers are using organoids made up of a patient’s own cells to test drug therapies and learn how individual patients would respond. This testing, in a laboratory setting, relieves the patient of the time and physical burdens of drug therapy trial and error.

Hans Clevers and colleagues have grown organoids from intestinal stem cells of patients with cystic fibrosis, a severe genetic disease that affects the lungs, digestive tract, and often other organs. Current FDA-approved drugs have only been tested and approved for patients with common mutations, which account for only half of all cystic fibrosis patients.

Clevers’ lab uses tiny organoids as a surrogate for the patient, and can test several drugs at a time, monitoring the therapeutic effects of each. This application has worked well on several patients in the Netherlands (where the technology was invented), and Clevers is setting up a program with Dutch insurance companies to test all Dutch cystic fibrosis patients with existing and new drugs. In this way, therapies can be personalized based on the needs of each patient.

Tipping the balance in favor of fixing a disease

In order to fully comprehend disease progression, researchers must understand the fundamental mechanisms behind normal biological development. Melissa Little studies inherited kidney diseases in children, and her group uses iPSC-derived organoids from pediatric patients to generate otherwise inaccessible human pediatric cell types and kidney structures. The organoids can model what happens during normal and abnormal kidney development.

By applying CRISPR/Cas9, a novel tool for correcting defective genes, Little’s group is working to correct genetic defects in pediatric kidney organoids, which may advance the development of potential therapeutic applications.

Reshaping the future of medicine

The journey of organoid technology is not nearly complete. The ISSCR panel points out that researchers are trying mimic in a dish what nature does naturally- and nature is complicated. Tissues and organs don’t work in isolation, they are highly interconnected and function in the dynamic environment of the human body.

Efforts are now underway to increase the complexity of the system by integrating multiple organoids or by connecting various organoids together to study multi-organ interaction. As in real-life human physiology, the response of one organoid to a drug or a shift in environment may impact the response of another. Adding new layers of complexity to organoid technology is the next step in this research endeavor.

Cerebral OrganoidAll it takes is one little cell

It’s inspiring to think that organoid technology, together with our knowledge of human development and disease, may change modern medicine. With organoids, we can model new aspects of human development; better model diseases (hereditary, infectious, cancer, immune-mediated); test and screen potential drug therapies; and eventually, create new regenerative therapies. All this from a tiny sample of a patient’s own cells. 

Hans Clevers, MD, PhD; Director, Princess Maxima Center for Pediatric Oncology, and Professor of Molecular Genetics, Utrecht University, NL

Guo-li Ming, MD, PhD; Professor of Neuroscience, Perelman School of Medicine, University of Pennsylvania, US

Jürgen Knoblich, PhD; Deputy Director, Institute of Molecular Biotechnology, and Adjunct Professor, Medical University of Vienna, AT

Melissa Little, PhD; Professor, Kidney Research Laboratory, Murdoch Childrens Research Institute, and Professor, University of Melbourne, AU

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