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How to build a tumour – the lab technique set to revolutionise cancer research

Did you know that researchers are growing miniature versions of human organs in the lab? A scientific technique that has been in development for nearly 20 years, the ability for us to grow “organoids” is set to revolutionise how we study human diseases, including cancer.

Humble beginnings

This story begins in Utrecht, Netherlands, in 1999. Worldwide Cancer Research supporters raised just over £135,000 to give a researcher the opportunity to study genes that might contribute to bowel cancer. That researcher was Hans Clevers, an immunologist who had some bold ideas about cancer. In 1999, Hans Clevers was struggling to get the funding he needed to pursue his ideas because his background was not in cancer research. But we were there, willing and able to take a risk on an idea that could have huge reward for the future of cancer research.

With the funding from Worldwide Cancer Research, Hans Clevers and his team were able to pull together a list of genes that control how chemical signals are transmitted from the outside of the cell to the inside, which then go on to control things like cell growth and cell division. Over the next few years, Hans Clevers and his team continued to research the genes on their list in order to understand how these signalling mechanisms were controlled. One gene on the list, called LGR5, turned out to be of great importance for how new cells are made in the gut.

The inner lining of the gut is the most rapidly self-renewing tissue found in adult mammals. This means that new gut cells are produced at a high rate to replace old and dead ones. But where do these cells come from? Like all cells in our body, they are produced by stem cells - “mother” cells that are capable of becoming any type of cell in the body when given the right biological cues. In the gut, new cells emerge from the gut lining in regions called crypts. These are not tombs as the name might suggest but the birthplace of new cells. At the time that Hans Clever was studying his list of genes, it was believed that stem cells at the base of these crypts must be the “mother” cells giving rise to new gut cells, but no one had yet found a way to spot these stem cells.

The originators

Then it all changed. In 2007, Hans Clevers and his team published research that showed the gene LGR5 is only switched on in cells that live at the bottom of the intestinal crypts. Using some nifty scientific methods they tracked these cells in mice and found that new gut cells seemed to be emerging from the cells found at the bottom of the crypt. By studying the genetics of the daughter cells, they were able to determine that every cell lining the intestines of the mice could be traced back to a “mother” cell with the LGR5 gene. They had discovered gut stem cells.

A couple years later and Hans Clevers team had worked out how to nurture these stem cells in the lab. They developed a technique that involved growing the stem cells under conditions that allows them to survive in the lab for a long period of time. By doing this, they were able to coax the stem cells to produce all the different cell types that you would normally find lining the gut. Amazingly, these cells also arranged themselves spontaneously into structures that resembled what the gut looks like on a cellular level in a mammal. They called these structures “cryptovillus organoids”, and so, in 2009, a decade after Worldwide Cancer Research supporters had set things in motion, we had the first glimpse of a technique that looks to change how we treat and study human disease.

Real life in the lab

In biomedical research there are two main types of experiments, those classed as in vitro and those as in vivo. In vitro is latin for “within the glass” and refers to experiments carried out on cells in a petri dish or a test tube. In these type of experiments, the cells usually grow in a single layer on the surface of the dish and can be very revealing about the basic biology of cells. However, in vitro experiments are far removed from the complexity of how cells behave in their natural environment within a living organism. It’s like removing an animal from its habitat, sticking it in a white room and expecting to learn everything about its normal behaviour.

In vivo experiments, meaning “within the living”, involve studying biological mechanisms within the context of a whole organism. For example, in cancer research, scientists might alter genes in mice to understand how tumours develop within specific organs. These types of experiments can be much more informative and are the gateway to getting new treatments approved for use in patient trials.

It is between these two types of experiments that organoids can play an important part. Organoids are an in vitro experiment - cells grown in a dish - but the very fact that the cells organise themselves into 3-dimensional structures similar to the organ they come from means that they are a much more powerful tool for studying human disease. Hans Clevers and other researchers around the world have been able to grow organoids for the brain, liver, kidney, breast, retina, and many other organs. These organoids provide us with a better way to study how normal tissues develop and identify what goes wrong in diseases such as cancer.

Into the clinic

Organoids are also beginning to show the first signs that they could be useful in the clinic to diagnose and treat patients. One of the first examples came from Hans Clevers himself when his team took a tissue sample from the gut of a patient with cystic fibrosis and used the stem cells to grow an organoid. They used the organoid to test a drug called ivacaftor, which health insurers would not purchase unless there was proof it would work in the patient. The data collected from the organoid experiment was enough to convince the insurers to pay up.

This type of personalised medicine is of great interest to cancer researchers and patients. Growing mini-tumours rather than organs could allow us to identify the combination of drugs that will be the most effective for every patient. The techniques to grow these mini-tumours from a patient have been developed, but they need refinement. Tumours develop genetic mutations as they grow so, over time, the organoids become less representative of the original tumour. Costs need to come down to make it viable on a large scale (it currently costs a couple of thousand dollars per patient). And the time it takes to grow organoids needs to be shortened – it takes about 3 weeks to grow a mini-tumour, which means a patient would have a long wait to start treatment.

Brain tumours are deadly, killing nearly everybody that is diagnosed. In 2017, brain organoids were developed and now scientists are using them to find better ways to treat brain cancer. Researchers in the US have developed brain organoids that they can seed with tumour cells taken from a patient. The tumour cells interact with the organoid just like they do in the brain - the scientists are effectively giving the organoid cancer. They are then able to test different drugs on the organoid to see what might work for the patient.

In 2018, the first breakthrough emerged revealing that tumour organoids are an accurate way to select drugs for cancer patients. Researchers from the Institute of Cancer Research in London grew colon and oesophageal tumour organoids from 110 patients with metastatic cancer. They then screened all the cancer drugs the patient received during their course of treatment on these organoids. They found that in 100 percent of cases, if a drug didn’t work on a patient’s organoid, then it didn’t work in the patient, and that in nearly 90 percent of cases, if a drug did work on the organoids, then it worked in the patient too.

Speaking to the The Scientist about the study, childhood cancer expert Sam Behjati of the Wellcome Sanger Institute, said: “This study shows it is technically possible to use a patient’s organoids for screening candidate cancer treatments. It begins to paint a picture whereby you could envision that in the future...we can actually find a way of doing this routinely for patients.”

From humble beginnings to emerging clinical applications, organoids truly are a revolutionary tool. The technique to produce organoids was named “Method of the Year” in 2017 by the prestigious science journal, Nature Methods, and Hans Clevers is credited for playing a big part in its development. We are proud to have played a role in kick-starting this story, but we couldn’t have done it without our supporters.

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