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Collaborating to improve diagnosis of CF in adults
Many people with CF are diagnosed as babies through the national newborn screening programme. However, some people may not have a CF diagnosis confirmed until later in life, often due to their rare CF variations. We’re funding research to set up an innovative test to improve diagnosis, and to test whether modulator medicines may work for these people, testing each person individually.
This research is funded through a Development Award grant. It is led by Professor Nick Simmonds at the Royal Brompton Hospital and called ADVANCE-CFTR. Prof Simmonds is working with CF doctors and lab-based scientists, based in London and in Utrecht in The Netherlands. They held an in-person meeting in London last month to discuss the project and review their progress.
Two early careers researchers within the project presented their progress so far. Dr Emma Russell-Jones is a CF paediatrician working at the Royal Brompton Hospital and Imperial College London, and Mohammed Kamran Afzal Mirza, known as Kamran, is a lab-based researcher based at King’s College, London. Both are studying for their PhDs. Emma will be recruiting people to take part in the study and supporting them to give samples for research. Kamran will be using the samples to create and analyse the organoids in the lab.
Comparing tests for diagnosing CF
Before the new organoid test can be used to help confirm a CF diagnosis, it is important to know how the results of the new test compare with the current tests that are done in the clinic. People who take part in the study will be asked to take part in tests often used in the clinic, as well as agreeing to give a rectal biopsy sample. The biopsy sample will be used for the new organoid test, and also used in another test to measure the CF protein function. During Emma’s presentation, there was plenty of time to agree some of the practicalities of running these tests.
Growing organoids and how to analyse the results
Growing organoids from a rectal biopsy sample is difficult to do in the lab. In the first year of Kamran’s PhD studies, he spent some time in Prof Beekman’s lab in Utrecht, learning how to grow organoids. On his return he began preparing the organoids in the lab at King’s College, using samples from people who don’t have CF before the study began.
The next step was to ensure that the methods for analysing CF protein function in the lab were working too. Kamran is using two methods to look at how the CF protein is working in the organoid samples. In both tests measurements are made by looking at the organoids down a microscope. One test is to measure how much the organoids ‘swell’ when a chemical called forskolin is added. Forskolin acts on the CF protein, so the more the organoids swell, the higher the activity of the CF protein.
In another test, researchers can tell from the shape of the organoid how well the CF protein is working. For example, organoids with fully working CF protein are the shape of a fully inflated football. In comparison, organoids where the CF protein is not working at all, or at a very low level, are the shape of a deflated rugby ball!
The shape of the organoid is measured in computer analysis by measuring how spherical the organoids are and how much space there is inside the organoid (or the air inside the ball in our comparison). At the meeting, Kamran shared a new method of analysing the shape of the organoids which he had developed using AI, which was positively received by colleagues visiting from Utrecht.
How can the organoid measurements be used in CF clinics?
Dr Sacha Spelier from Utrecht spoke about developing a helpful and meaningful way of explaining the results of the organoid analysis to CF teams in the clinic.
“We’re asked to help with possible CF diagnoses about a handful of times every month, and we have an established protocol for doing this,” she explained.
She also gave an overview of other activities underway in the lab, from understanding more about the faulty CF protein to improving access to CFTR modulators.
The wow moment of Sacha’s presentation was the introduction of their computer robot ‘Rosie’. The robot can run experiments 24/7, saving the researchers a lot of time. It means that they can focus on more complex experiments, for example understanding rare CF variants. Sacha did add a caveat that Rosie took three years to build, and one year to set up before it could be used.
“It was fantastic to hear the progress that is being made within this Development Award and it is always great to see the enthusiasm, commitment and discussions that are sparked by the presentations. It felt very collaborative,” commented Dr Belinda Cupid, Senior Impact Adviser at the Trust.
Find out more about the ADVANCE-CFTR Development Award.