Mini-livers, mini-guts, even mini-brains are becoming commonplace in research. These organoids, as the name suggests, resemble miniature human organs. The clusters of cells also represent (at least in terms of genetics) an individual. They are one of the latest and most exciting tools to enter the lab and they are already enhancing research and helping our understanding of some of the earliest stages of human life and disease. If a genetic disease, from cancer to cystic fibrosis, affects the cells, an organoid gives researchers a way to mimic the condition in the lab – boosting studies into new treatments and drug development.
Where do they come from?
Scientists have been interested in how organs form for hundreds of years, and work from the 1900s to grow cells in 3D structures is the basis of modern organoid techniques. With increasing understanding of stem cells and the micro-environments that surround cells, organoid technologies have rapidly advanced over the last 20 years.
Several types of organoid were discovered serendipitously when cells growing in an incubator self-organised into 3D shapes. But in most cases, researchers have deliberately harnessed the unique power of stem cells – their capacity to turn into any other type of cell. Scientists have developed techniques to coax them to form dozens of types of organoid. This includes finding the right combination of molecules that will start a stem cell on a specific journey. The right environment is also vital, as the cells need some kind of microscopic scaffold to stick to. The process can take a year or more to get right but once they’re on their way, it’s often a case of leaving them to it. They will spontaneously self-organise into structures that mimic real organs, often including several different types of cell.
Putting organoids to work
Organoids are becoming vital research tools across many life-science areas; from studying human development, to genetic disorders, to drug screening.
What makes organoids so useful is that they reflect better what is happening in a real person, when compared to cells grown flat on a petri dish. In many cases they replicate processes that are impossible to study in people – like how the brain forms. They also reduce the need for animal research, and compliment other cellular techniques.
That’s not to say that they are perfect or about to take over as the method of choice for all cell biologists. They are limited by the lack of blood vessels, which means they can only grow to a certain size – although this is something being worked on. Another limitation is that for many studies, they are never going to be as good as looking at a whole organ in a living organism.
Making organoids that represent tumours is another growing area of research. They are made directly from a patient’s tumour cells – taken from a biopsy or surgery.
The tumour tissue is first cut up, then gently fragmented with an enzyme which dissociates the cells. Individual or small groups of cells are then put into a blob of jelly-like matrix which provides scaffolding similar to that surrounding cells in our bodies. They are incubated at 37C and bathed in nutrients. The aim is to get as close to body conditions as possible. Once established, the organoid can be divided and grown again, or frozen for transport and storage.
There is a need for more cancer organoids, as current commercially available cells for research just don’t represent the genomic diversity of the disease. And cancer can be thought of as primarily a disease of the genome. The types of DNA changes in a genome that lead to a cell becoming cancerous are numerous and varied. Hundreds of genes are involved, as well as DNA outside of those genes.
Creating organoids from individual patients allows researchers to better capture the genomic changes in cancer. This is exactly the aim of Sanger Institute researchers in the translational cancer genomics team. Working together with Cancer Research UK, they have recently created 100 organoids, representing three types of cancer. These will be available for other researchers too – boosting studies into cancer biology and treatment worldwide.
Organoids from one individual may look quite different to those from another – even if the patients have the same type of cancer. Some grow into bubble-like shapes, with a hollow middle. Others form tiny, tight clumps. There are variations in how the organoids grow too – some biopsy samples produce hundreds of organoids that are easy to grow. Others don’t make any; the cells don’t survive.
Reassuringly, recent research has shown that an organoid’s micro-structure does match up to the tumour’s original structure1. Genome sequencing of the organoid, the original tumour, and the patient’s (non-cancerous) blood is helping researchers to understand how they differ, and what drives a cancer to grow.
It’s possible that a cancer patient of the future might have an organoid made from their tumour not for research, but to help with their treatment. Researchers could test different therapies to see which one works best. This may be some way off – but it is a possibility, and it’s likely that people with cancers that are hard to treat would benefit the most.
For the immediate future, organoids are used in increasing numbers of research labs around the globe. There is still a need for more, as researchers seek to understand how genome changes cause disease, and how those effects might be undone.
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