We often talk about the strengths and weaknesses of different kinds of medical research, a basic understanding of which is necessary for any meaningful Science-Based Medicine assessment of medical claims. For example, in vitro research allows for highly controlled environments and interventions and can use human cells, but mostly looks at cells in isolation, and therefore misses many potential factors. Meanwhile, animal research allows scientists to examine whole-organism responses to different interventions, and also allows detailed examination of tissue after the fact. The primary limitation, however, is that non-human animals are not humans, and biological differences can affect outcomes. Human research allows for a determination of results in actual people, but has significant ethical and pragmatic limitations. This is why medical researchers use a range of research options, to combine the strengths of different approaches to get the most reliable answers.
In recent years an entirely new category of medical research has been added to the list, something that combines some of the strengths of all three main approaches outlined above – use of organoids. An organoid can be studied in vitro like a cell culture, and can use human cells, but also can include some of the structure and interactions of whole organs. Organoid research therefore lies somewhere between in vitro and in vivo human research.
This type of research has been made possible by advances in stem cell research. Typically researchers will start with adult-derived stem cells, like fibroblasts from skin, and then induce them to become pluripotent, which can become every cell type in the body. The only stem cells with more potential are totipotent, derived from early embryos, which can become every cell type in the body and also the placenta and extraembryonic cell types. Adult-derived induced pluripotent stem cells are almost as good as embryonic stem cells in research, and has allowed the field to significantly advance without the ethical and political controversy surrounding embryonic cells.
Starting with induced pluripotent stem cells, researchers have figured out how to grow organoids, which are mini-organs with some of the architecture and range of cell types found in mature organs. This allows for a type of in vitro (not in a full living organism) research but better than just a culture of cells. Organoid research can look at the interactions among different cell types in an organ, and also how those cells form organ structures. Organoids are not fully functioning organs, but they are part of the way there, and allow researchers to ask questions they could not otherwise research with just cell cultures or even human research. Technically they are three-dimensional cell cultures replicating some of the structures in a mature organ.
Beyond just being able to research human cells and organ structures, researchers can make organoids from healthy or diseased cells, in order to replicate disease states and look for differences with healthy organ development. They can even take a cell sample from an individual patient to study their organoids. In addition to studying disease states, organoids can be used as models for screening drugs to see if they alter disease progression.
One recent organoid research study shows the potential of this approach – Human ALS/FTD brain organoid slice cultures display distinct early astrocyte and targetable neuronal pathology. In this study the researchers made brain organoids from stem cells the most common mutation causing a neurodegenerative disease which combines motor neuron disease (ALS) and frontotemporal dementia (FTD). ALS causes degeneration of motor neurons resulting in progressive weakness. Meanwhile cortical brain cells also degenerate, mostly in the frontal and temporal lobes, causing progressive cognitive decline and personality change. Understanding exactly how the mutation causes changes in the development, functioning, and aging of the human brain is critical to understanding the disease and designing potential treatment.
They found that differences in brain organoid development are apparent from the early stages, indicating that patients suffering from ALS/FTD may have the beginning of the disease even at birth. Both neurons and astrocytes (the two main cell types in the brain) develop DNA damage and start to accumulate abnormal proteins. Build up of protein debris is a known mechanism, or at least a strong marker, of many neurodegenerative diseases, so this is not surprising.
This study also features an advance in the basic technology of brain organoids. Rather that growing spheres of brain tissue, they grew flatter slices of brain tissue. This allowed for better nutrition of all the cells. Typically cells in the center of a brain organoid will die, limiting the total time that they can be maintained. This was a significant limitation on research, because scientists could only model short-term changes and effects. In the current study researchers were able to maintain their brain organoid slices for 240 days, and report (although not yet published) that their lab has maintained brain organoids for 340 days. This opens the door to much longer-term effects and responses to possible treatment interventions.
In fact, in this study the researchers also tested a potential drug (GSK2606414) on their organoid model. The drug reduced the accumulation of toxic proteins and some cell death. This highlights another potential feature of organoid research, that it can serve as a type of translational research – research designed to take basic science findings and test them clinically. While not fully translational, because it is not done in living humans, organoid research can take potential treatments discovered by cell-culture research and test them in disease organoid models.
Two decades ago, when stem cell hype was taking off, use of stem cells to create organoids for research was not even discussed. The first organoid was not made until 2013. But this may turn out to be an unanticipated, and yet the most impactful, use of stem cells (at least for now). Organoid research has opened up an entirely new middle ground of medical research and we are likely to hear a lot more about this type of research in the future.